Patent Application
20250064727
It is well-known that optimal treatment of many kinds of disease requires maintenance of a controlled drug concentration in blood over hours, days, weeks, months, or even years. At present, however, such controlled drug concentration in blood can often times not be achieved.
By way of example but not by way of limitation, numerous drugs that inhibit mutated kinases are fairly effective in treating specific types of cancer, provided the drug concentration in blood is consistently high (see, e.g., D.S. Krause, R.A. van Etten, Tyrosine kinases as targets for cancer therapy, New Engl. J. Med. 353 (2005) 172-187; J. Zhang, P.L. Yang, N.S. Gray, Targeting cancer with small molecule kinase inhibitors, Nature Reviews Cancer 9 (2009) 28-39; and others).
But the drug concentration in blood should not be too high. Such common side effects as prolongation of the Q-t interval, high blood pressure, acute liver damage, headache, and so on, result almost immediately when it exceeds a threshold value (see, e.g., J.R. Mitchell, et al., Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism, J. Pharmacol. Exp. Ther. 197 (1973) 185-194; L. Carlsson, et al., Proarrhythmic effects of the class III agent almokalant: importance of infusion rate, QT dispersion, and early afterdepolarisations, 27 (1993) 2186-2193; D.M. Roden, Drug-induced prolongation of the QT interval, N. Engl. J. Med. 350 (2004) 1013-1022; S.D. Lamore, R.A. Kohnken, M.F. Peters, K.L. Kolaja, Cardiovascular toxicity induced by kinase inhibitors: Mechanisms and preclinical approaches, Chem. Res. Toxicol. 33 (2020) 125-136; and others).
At present, most kinase inhibitors (KIs) are delivered by oral immediate-release tablets or capsules comprising lightly compacted or loose mixtures of drug and excipient particles. A common property of many kinds of KI, however, is that their solubility in gastrointestinal fluid is highly pH-dependent. While slightly soluble in the acidic gastric fluid, they may be sparingly soluble or virtually insoluble in the pH-neutral intestinal fluid (see, e.g., N.R. Budha, et al., Drug Absorption Interactions Between Oral Targeted Anticancer Agents and PPIs: Is PH-Dependent Solubility the Achilles Heel of Targeted Therapy?, Clinical Pharmacology and Therapeutics 92 (2012) 203-213; B. Herbrink et al., Variability in bioavailability of small molecular tyrosine kinase inhibitors, Cancer Treatment Reviews 41 (2015) 412-422; W. Sun et al., Impact of acid-reducing agents on the pharmacokinetics of palbociclib, a weak base with pH-dependent solubility, with different food intake conditions, Clinical Pharmacology in Drug Development 6 (2017) 614-626).
As shown schematically in the non-limiting
The drug particles, however, may not dissolve in the intestine. Thus, drug absorption may stop when the drug has been swept out of the stomach, and the drug concentration in blood may decrease, FIG. 1b. Consequently, because the gastric residence time of the drug particles and molecules may be much shorter than the convenient dosing intervals, upon repeated dosing the drug concentration in blood may rise and fall,
A steady drug concentration in blood could be achieved, however, by expandable, gastroretentive fibrous dosage forms the present inventors (Blaesi and Saka) have recently introduced (see, e.g., the International Application No. PCT/US21/53027 titled “Gastroretentive structured dosage form”). As shown schematically in
To assure that the expanded fibrous dosage form had adequate mechanical properties for prolonged gastric residence, the prior gastroretentive fibrous dosage forms consisted of drug-laden fibers that were coated with a strengthening enteric excipient,
In this specification, therefore, a new dosage form design is presented where the mechanical properties of the expanded dosage form and the drug release rate can be decoupled and independently controlled.
Generally, as shown schematically in the non-limiting
More specifically, in one aspect the pharmaceutical solid dosage form disclosed herein comprises an expandable three dimensional structural network of one or more fluid-absorptive fibers, a mechanically strengthening semi-permeable layer, and a drug-containing solid; said structural network of fibers substantially encapsulated by said mechanically strengthening semi-permeable layer; said encapsulated fiber network comprising encapsulated segments spaced apart from adjoining encapsulated segments by encapsulated-fiber-free spacings defining one or more encapsulated-fiber-free spaces within the outer volume of said encapsulated fiber network; and said drug-containing solid attached to said encapsulated fiber network and occupying at least part of said one or more encapsulated-fiber-free spaces.
In some embodiments, one or more encapsulated-fiber-free spaces further comprise one or more free spaces or one or more channels.
In some embodiments, one or more fibers or segments thereof are substantially orderly arranged in a three dimensional fiber structural network.
In some embodiments, a three dimensional structural network of one or more fluid-absorptive fibers comprises criss-crossed stacked layers of one or more fluid-absorptive fibers.
In some embodiments, at least a fiber or fiber segment is bonded to another fiber or fiber segment.
In some embodiments, one or more fibers comprise fiber segments spaced apart from adjoining fiber segments by fiber-free spacings defining one or more fiber-free spaces within the outer volume of the fiber structural network, and wherein average fiber-free spacing through or more fiber-free spaces is in the range of 10 μm-5 mm.
In some embodiments, average thickness of one or more fibers forming a three dimensional structural network is in the range of 5 μm-2.5 mm.
In some embodiments, a composition of a fluid-absorptive fiber or fiber network includes at least a fluid-absorptive first excipient.
In some embodiments, solubility of a physiological fluid (e.g., gastric fluid) in a fluid-absorptive first excipient is greater than 700 mg/ml under physiological conditions.
In some embodiments, at least a fluid-absorptive first excipient is substantially mutually soluble with a physiological fluid (e.g., gastric fluid) under physiological conditions.
In some embodiments, a fluid-absorptive first excipient comprises hydroxypropyl methylcellulose.
In some embodiments, a fluid-absorptive first excipient is selected from the group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl ether cellulose, starch, polymethacrylates (e.g., poly(methacrylic acid, ethyl acrylate) 1:1, or butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmathacrylat-copolymer), polyethylene oxide, xanthan gum, or vinylpyrrolidone-vinyl acetate copolymer.
In some embodiments, volume or weight fraction of one or more fluid-absorptive first excipients in a fluid-absorptive fiber or fiber framework is greater than 0.05.
In some embodiments, a mechanically strengthening semi-permeable layer comprises at least a strengthening second excipient.
In some embodiments, solubility of a physiological fluid (e.g., gastric fluid) in a strengthening second excipient is no greater than 800 mg/ml under physiological conditions.
In some embodiments, a strengthening second excipient comprises a tensile strength greater than 0.05 MPa after soaking with a physiological fluid (e.g., gastric fluid) under physiological conditions.
In some embodiments, a strengthening second excipient is selected from the group comprising methacrylic acid-ethyl acrylate copolymer.
In some embodiments, a strengthening second excipient is selected from the group comprising methacrylic acid-ethyl acrylate copolymer, methacrylic acic-methyl methacrylate copolymer, ethyl acrylate-methylmethacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate, polymers including methacrylic acid, polymers including ethyl acrylate, polymers including methyl methacrylate, polymers including methacrylate, Poly[Ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], and ethylcellulose.
In some embodiments, a mechanically strengthening semi-permeable layer comprises a volume or weight fraction of strengthening second excipient no less than 0.3.
In some embodiments, a mechanically strengthening semi-permeable layer forms a viscoelastic, semi-permeable membrane upon exposure to a physiological fluid (e.g., gastric fluid) under physiological conditions.
In some embodiments, a drug-containing solid is bonded to a mechanically strengthening semi-permeable layer.
In some embodiments, drug-containing solid occupies encapsulated-fiber-free space between a free space or channel and encapsulated fiber network.
In some embodiments, drug-containing solid forms at least an annulus within one or more encapsulated-fiber-free spaces.
In some embodiments, a drug containing solid comprises a thickness or an average thickness in the range 5 μm-5 mm.
In some embodiments, a drug containing solid comprises at least an active pharmaceutical ingredient or drug and one or more third excipients.
In some embodiments, drug is dispersed as drug particles and/or as drug molecules in one or more third excipients.
In some embodiments, at least one third excipient is soluble in a physiological fluid (e.g., gastric fluid) under physiological conditions.
In some embodiments, at least one third excipient that is soluble in a physiological fluid under physiological conditions (e.g., at least a soluble third excipient) comprises a solubility greater than 0.1 mg/ml in said physiological fluid under physiological conditions (e.g., gastric fluid).
In some embodiments, at least one third excipient that is soluble in a physiological fluid under physiological conditions (e.g., at least a soluble third excipient) is substantially mutually soluble with said physiological fluid under said physiological conditions.
In some embodiments, at least one third excipient that is soluble in a physiological fluid under physiological conditions (e.g., at least a soluble third excipient) comprises hydroxypropyl methylcellulose.
In some embodiments, at least one third excipient that is soluble in a physiological fluid under physiological conditions (e.g., at least a soluble third excipient) is selected from the group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl ether cellulose, starch, polymethacrylates (e.g., poly(methacrylic acid, ethyl acrylate) 1:1, or butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmathacrylat-copolymer), polyethylene oxide, or vinylpyrrolidone-vinyl acetate copolymer.
In some embodiments, at least one third excipient comprises a stabilizing third excipient.
In some embodiments, a stabilizing third excipient is selected from the group comprising methacrylic acid-ethyl acrylate copolymer, methacrylic acic-methyl methacrylate copolymer, ethyl acrylate-methylmethacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate, polymers including methacrylic acid, polymers including ethyl acrylate, polymers including methyl methacrylate, polymers including methacrylate, Poly[Ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], and ethylcellulose.
In some embodiments, one or more free spaces or one or more channels are substantially open to an exterior surface of an encapsulated, three-dimensional fiber structural network.
In some embodiments, at least one free space or channel is substantially connected within or through an exterior dimension of an encapsulated fiber structural network.
In some embodiments, at least one free space is oriented substantially orthogonally to one or more fibers or segments thereof.
In some embodiments, the free spacing through (e.g., across, along, etc.) one or more free spaces or channels is in the range 5 μm-3 mm.
In some embodiments, a free space or channel is filled with a matter selected from the group comprising gas, liquid, or solid, or combinations thereof, and wherein said matter is partially or entirely removed upon contact with a physiological/body fluid (e.g., gastric fluid) under physiological conditions.
In some embodiments, a free space is filled with a matter comprising air.
In some embodiments, upon immersing said pharmaceutical solid dosage form in a physiological fluid under physiological conditions said encapsulated fiber network expands with fluid absorption to form an expanded solid or semi-solid having at least one exterior dimension expanded to greater than than 1.2 times its length prior to immersing in said physiological fluid.
In some embodiments, eighty percent of the content of a drug in a drug-containing solid is released within 1.5-96 hours of immersing said dosage form in a physiological fluid (e.g., gastric fluid) under physiological conditions.
In some embodiments, an amount or mass of a drug released from said pharmaceutical solid dosage form into said physiological fluid increases substantially linearly with or substantially in proportion to the time of immersing said pharmaceutical solid dosage form in said physiological fluid under said physiological conditions.
In another aspect, the pharmaceutical solid dosage form disclosed herein comprises an expandable three dimensional structural network of one or more fluid-absorptive fibers, a mechanically strengthening semi-permeable layer, at least a drug-containing solid, and one or more free spaces; said structural network of fibers substantially encapsulated by said mechanically strengthening semi-permeable layer; said encapsulated fiber network comprising encapsulated segments spaced apart from adjoining encapsulated segments by encapsulated-fiber-free spacings defining one or more encapsulated-fiber-free spaces within the outer volume of said encapsulated fiber network; said drug-containing solid attached to said encapsulated fiber network; and said drug-containing solid and said one or more free spaces occupying at least part of said one or more encapsulated-fiber-free spaces.
In another aspect, the pharmaceutical solid dosage form disclosed herein comprises an expandable three dimensional structural network of one or more fluid-absorptive fibers, a mechanically strengthening semi-permeable layer, at least a drug-containing solid, and one or more free spaces; said structural network of fibers substantially encapsulated by said mechanically strengthening semi-permeable layer; said encapsulated fiber network comprising encapsulated segments spaced apart from adjoining encapsulated segments by encapsulated-fiber-free spacings defining one or more encapsulated-fiber-free spaces within the outer volume of said encapsulated fiber network; said drug-containing solid attached to said encapsulated fiber network; and said drug-containing solid and said one or more free spaces occupying at least part of said one or more encapsulated-fiber-free spaces; wherein said structural network of fibers comprises at least a fluid-absorptive first excipient; said mechanically strengthening semi-permeable layer comprises at least a strengthening second excipient; said drug-containing solid comprises at least an active pharmaceutical ingredient or drug and one or more third excipients; and said one or more free spaces comprise a matter selected from the group comprising gas, liquid, or solid, or combinations thereof, and wherein said matter is partially or entirely removed upon contact with a physiological/body fluid (e.g., gastric fluid) under physiological conditions.
It may be obvious to a person of ordinary skill in the art that more aspects and embodiments that reflect the spirit and scope of the invention could be written. All such aspects and embodiments are included herein.
The objects, embodiments, features, and advantages of the present invention may be more fully understood when considered in conjunction with the following accompanying drawings:
In order for the present disclosure to be more readily understood, definitions for certain terms are suggested below. Additional definitions for the following terms and other terms are set forth throughout the specification. It may be noted that the definitions are not meant to be limited in any way.
In this application, the use of “or” means “and/or” unless stated otherwise. As used in this application, the term “comprise” and variations of the term, such as “comprising” and “comprises,” are not intended to exclude other additives, components, integers or steps. As used in this application, the terms “about” and “approximately” are used as equivalents. Any numerals used in this application with or without about/approximately are meant to cover any normal fluctuations appreciated by one of ordinary skill in the relevant art.
Moreover, in the disclosure herein, the terms “active ingredient”, “one or more active ingredients”, “active pharmaceutical ingredient”, “one or more active pharmaceutical ingredients”, “drug”, “one or more drugs”, and so on are used interchangeably. As used herein, an “active ingredient” or “active agent” or “drug” refers to an agent whose presence or level correlates with elevated level or activity of a target, as compared with that observed absent the agent (or with the agent at a different level). In some embodiments, an active ingredient is one whose presence or level correlates with a target level or activity that is comparable to or greater than a particular reference level or activity (e.g., that observed under appropriate reference conditions, such as presence of a known active agent, e.g., a positive control).
In the invention herein, a drug-containing solid generally comprises a solid that includes or contains at least a drug. A drug-containing solid generally can have any shape, geometry, or form.
Furthermore, in the context of some embodiments herein, a three dimensional structural framework (or network) of one or more elements comprises a structure (e.g., an assembly or an assemblage or an arrangement or a skeleton or a skeletal structure or a three-dimensional lattice structure of said one or more elements) that may extend over a length, width, and thickness greater than 100 μm. This includes, but is not limited to structures that extend over a length, width, and thickness greater than 200 μm, or greater than 300 μm, or greater than 500 μm, or greater than 700 μm, or greater than 1 mm, or greater than 1.25 mm, or greater than 1.5 mm, or greater than 2 mm.
In other embodiments, a three dimensional structural framework (or network) of elements may comprise a structure (e.g., an assembly or an assemblage or a skeleton or a skeletal structure or a lattice structure of said elements) that extends over a length, width, and thickness greater than the average thickness of at least one element (or at least one segment) in the three dimensional structural framework (or network) of elements. This includes, but is not limited to structures that extend over a length, width, and thickness greater than 1.5, or greater than 2, or greater than 2.5, or greater than 3, or greater than 3.5, or greater than 4 times the average thickness of at least one element (or at least one segment) in the three dimensional structural framework (or network) of elements.
In some embodiments, a three dimensional structural framework (or network) of elements is continuous. In other words, in some embodiments a three dimensional structural framework (or network) of elements forms a continuous structure. Furthermore, in some embodiments, one or more elements or segments thereof are bonded to each other or interpenetrating.
It may be noted that the terms “three dimensional structural network”, “structural network”, “network”, “three dimensional structural framework”, “structural framework”, “framework”, and “three dimensional lattice structure” are used interchangeably herein. Also, the terms “three dimensional structural framework of elements”, “three dimensional structural framework of one or more elements”, “three dimensional structural network of one or more fibers”, “three dimensional fiber structural network”, “fiber network”, “three dimensional fibrous structural network”, “fibrous structural network”, “fiber structural network”, “three dimensional structural network of fibers”, “three dimensional network”, “structural network”, etc. are used interchangeably herein.
In the invention herein, a “structural element” or “element” generally refers to a one-dimensional element or fiber.
As used herein, therefore, the terms “fiber”, “fibers”, “one or more fibers”, “element”, and “one-dimensional element” are used interchangeably. They are understood as the solid, structural elements (or building blocks) that can make up part of a three dimensional structural framework or network or an entire three dimensional structural framework or network. A fiber may have a length much greater than its width and thickness. In the present disclosure, a fiber is referred to as having a length greater than 2 times its width and thickness (e.g., the length is greater than 2 times the fiber width and the length is greater than 2 times the fiber thickness). This includes, but is not limited to a fiber length greater than 3 times, or greater than 4 times, or greater than 5 times, or greater than 6 times, or greater than 8 times, or greater than 10 times, or greater than 12 times the fiber width and thickness. In other embodiments that are included but not limiting in the disclosure herein, the length of a fiber may be greater than 0.3 mm, or greater than 0.5 mm, or greater than 1 mm, or greater than 2.5 mm.
Moreover, as used herein, the term “fiber segment” or “segment” refers to a fraction of a fiber along the length of said fiber.
In the invention herein, fibers (or fiber segments) may be bonded, and thus they may serve as building blocks of “assembled structural elements” with a geometry different from that of the original fibers. Such assembled structural elements include two-dimensional elements, one-dimensional elements, or zero-dimensional elements. For a definition of two-dimensional elements and zero-dimensional elements, see, e.g., the International Application No. PCT/US21/53027 titled “Gastroretentive structured dosage form”.
In the invention herein, a “layer” or a “ply” of one or more fibers refers to a layer or ply formed by at least two fibers or at least two fiber segments in a plane defining said layer or ply. This includes, but is not limited to a layer or ply formed by at least three fibers or at least three fiber segments, or least four fibers or at least four fiber segments in a plane defining said layer or ply.
In the invention herein, an “expandable solid” refers to a solid or semi-solid or viscoelastic material that expands upon immersing in a relevant physiological fluid under physiological conditions. A solid or semi-solid or viscoelastic material is referred to as “expanding upon immersing in a relevant physiological fluid under physiological conditions” if it has at least one exterior dimension expanded to greater than its length prior to immersing in said physiological fluid.
In some embodiments of the invention herein, an expandable solid is also a gastroretentive solid. In such embodiments, the terms “expandable solid”, “gastroretentive solid”, “gastroretentive, expandable solid”, and “expandable, gastroretentive solid” are used interchangeably herein.
As used herein, a “gastroretentive solid” refers to a solid or semi-solid or viscoelastic material which upon ingestion by a human subject (or an animal subject that reasonably resembles a human subject) resides in the stomach longer than a small particle that is substantially insoluble in gastric fluid. This includes, but is not limited to a solid or semi-solid or viscoelastic material which upon ingestion by a human subject (or an animal subject that reasonably resembles a human subject) resides in the stomach substantially longer than a small particle that is substantially insoluble in gastric fluid. This also includes, but is not limited to a solid or semi-solid or viscoelastic material which upon ingestion by a human subject (or an animal subject that reasonably resembles a human subject) resides in the stomach at least 1.2 (e.g., at least 1.4, or at least 1.6, or at least 1.8, or at least 2, or at least 3, or at least 4, or at least 5) times as long as a small particle that is substantially insoluble in gastric fluid. By way of example but not by way of limitation, a small particle may comprise a substantially insoluble, biologically inert particle with a size of the order of 1 mm-5 mm or similar.
As used herein, the terms “physiological fluid”, “body fluid”, “dissolution medium”, “dissolution fluid”, “medium”, “fluid”, “aqueous solution”, “fluid”, “penetrant”, etc. are used interchangeably. They are understood as any fluid produced by or contained in a human body under physiological conditions, or any fluid that resembles a fluid produced by or contained in a human body under physiological conditions. Generally, a dissolution fluid contains water and thus may be aqueous. Examples include, but are not limited to: water, saliva, stomach fluid, gastrointestinal fluid, saline, simulated gastric fluid, etc. at a temperature of 37° C. and a pH value adjusted to the relevant physiological condition.
In the invention herein, moreover, a “relevant physiological fluid” is understood as the relevant physiological fluid surrounding the dosage form in the relevant physiological application. For example, if the dosage form is a gastroretentive dosage form, a relevant physiological fluid is gastric fluid or a fluid that resembles gastric fluid.
As used herein, moreover, the terms “gastric fluid”, “fluid that resembles gastric fluid”, “simulated gastric fluid”, “acidic water”, and so on are used interchangeably. They refer to gastric fluid or a fluid that resembles gastric fluid. A fluid that resembles gastric fluid is generally understood herein as acidic water at a pH in the range of about 1-2 and a temperature of about 37° C. This includes, but is not limited to acidic water at a pH of about 1.5 and a temperature of about 37° C. This also includes, but is not limited to a mixture of water and hydrochloric acid at a pH in the range of 1-2 and a temperature of about 37° C. This also includes, but is not limited to a mixture of water and hydrochloric acid at a pH of 1.5 and a temperature of about 37° C. Generally, moreover, a fluid that resembles gastric fluid may be stirred.
In the invention herein, moreover, the terms “intestinal fluid”, “fluid that resembles intestinal fluid”, “simulated intestinal fluid”, and so on are used interchangeably. They refer to intestinal fluid or a fluid that resembles intestinal fluid. A fluid that resembles intestinal fluid is generally understood herein as water at a pH in the range of about 6-7.5 and a temperature of about 37° C. This includes, but is not limited to an aqueous buffer solution at a pH in the range of 6-7.5 and a temperature of about 37° C. This also includes, but is not limited to an aqueous buffer solution at a pH of about 6.8 and a temperature of about 37° C. This also includes, but is not limited to an aqueous buffer solution at a pH of about 7.2 and a temperature of about 37° C. Generally, moreover, a fluid that resembles intestinal fluid may be stirred.
Furthermore, in the invention herein, a fluid-absorptive solid, such as a fluid-absorptive solid core, a fluid-absorptive core, a fluid-absorptive structural framework, a fluid-absorptive structural element, a fluid-absorptive element, a fluid-absorptive fiber, and so on, may generally comprise at least a fluid-absorptive excipient.
In the invention herein, a “fluid-absorptive excipient” is referred to as an excipient that is “absorptive” of gastric or a relevant physiological fluid under physiological conditions. Generally, said absorptive excipient is a solid, or a semi-solid, or a viscoelastic material in the dry state at room temperature. Upon contact with (e.g., immersion in) gastric or a relevant physiological fluid under physiological conditions, however, said fluid-absorptive excipient can absorb said fluid and form solutions or mixtures with said fluid having a weight fraction of gastric or relevant physiological fluid greater than 0.4. This includes, but is not limited to the formation of solutions or mixtures with a weight fraction of gastric or relevant physiological fluid greater than 0.5, or greater than 0.6, or greater than 0.7, or greater than 0.75, or greater than 0.8, or greater than 0.85, or greater than 0.9, or greater than 0.95. In other words, the solubility of gastric fluid or a relevant physiological fluid in the fluid-absorptive excipient under physiological conditions generally is greater than about 400 mg/ml. This includes, but is not limited to solubility of gastric or relevant physiological fluid in an absorptive excipient greater than 500 mg/ml, or greater than 600 mg/ml, or greater than 700 mg/ml, or greater than 750 mg/ml, or greater than 800 mg/ml, or greater than 850 mg/ml, or greater than 900 mg/ml, or greater than 950 mg/ml. It may be noted that the terms “fluid-absorptive”, “physiological fluid-absorptive”, “fluid-absorbing”, “physiological fluid-absorbing”, “water-absorptive”, “water-absorbing”, “gastric fluid-absorptive”, “gastric fluid-absorbing”, “absorptive”, “absorbing”, and so on are generally used interchangeably herein.
It may be noted, furthermore, that an absorptive excipient may also be highly soluble in a physiological fluid.
Preferably, an absorptive excipient may be mutually soluble with a relevant physiological fluid under physiological conditions, such as gastric fluid. By way of example but not by way of limitation, an absorptive excipient may be mutually soluble with a relevant physiological fluid (e.g., with a relevant physiological fluid under physiological conditions) in all proportions. Non-limiting examples of preferred absorptive excipients may include, but are not limited to water-soluble polymers of large molecular weight and with amorphous molecular structure, such as hydroxypropyl methylcellulose with a molecular weight (e.g., a number-average molecular weight) greater than 50 kg/mol or hydroxypropyl methylcellulose with a molecular weight (e.g., a number-average molecular weight) in the range between 50 kg/mol and 1000 kg/mol.
Similarly, in the invention herein, a mechanically strengthening phase may generally comprise at least a mechanically strengthening excipient.
In the invention herein, a “strengthening excipient”, too, may generally be a solid, or a semi-solid, or a viscoelastic material in the dry state at room temperature. Upon contact with (e.g., immersion in, etc.) gastric or a relevant physiological fluid under physiological conditions, however, said strengthening excipient may be far less absorptive of said fluid, and thus it may remain a solid, or semi-solid, or viscoelastic, or highly viscous material. Generally, the solubility of gastric or relevant physiological fluid in strengthening excipient under physiological conditions may be no greater than 800 mg/ml. This includes, but is not limited to a solubility of gastric or a relevant physiological fluid in strengthening excipient under physiological conditions no greater than 750 mg/ml, or no greater than 700 mg/ml, or no greater than 650 mg/ml, or no greater than 600 mg/ml, or no greater than 550 mg/ml, or no greater than 500 mg/ml, or no greater than 450 mg/ml, or no greater than 400 mg/ml. In the non-limiting extreme case, the relevant physiological fluid can be insoluble or practically insoluble in a strengthening excipient.
Typically, however, a relevant physiological fluid may be sparingly-soluble in a strengthening excipient. Thus, upon immersion of said strengthening excipient in said relevant physiological fluid, the stiffness (e.g., the clastic modulus) or the viscosity of said strengthening excipient may decrease somewhat compared with the stiffness or viscosity of the dry strengthening excipient. Similarly, upon immersing strengthening excipient in a relevant physiological fluid, the strain at fracture of said strengthening excipient may increase compared with the strain at fracture of the dry strengthening excipient. Because the strengthening excipient can be a solid, viscoelastic, semi-solid, or highly viscous material even after prolonged immersion in a relevant physiological fluid, it may also referred to herein as “stabilizing excipient”, or “viscoelastic excipient”. It may be further be noted that the terms “strengthening”, “mechanically strengthening”, “strength-enhancing”, and so on are generally used interchangeably herein.
In some embodiments of the invention herein, moreover, a mechanically strengthening phase (e.g., a “mechanically strengthening layer”, a “strength-enhancing layer”, “strengthening layer”, “strengthening phase”, and so on) may be attached to a core. In such embodiments, upon exposure to a relevant physiological fluid, the mechanical properties, such as elastic modulus, yield strength, tensile strength, viscosity, and so on, of said mechanically supported core (e.g., said core with attached strengthening phase) may generally be greater than the mechanical properties of said core without any mechanically strengthening phase. Typically, upon exposure to a relevant physiological fluid, at least a mechanical property, such as elastic modulus, yield strength, tensile strength, viscosity, and so on, of said mechanically supported core (e.g., said core with attached strengthening phase) may generally be at least two times greater than the corresponding mechanical property of said core without any strengthening phase. This includes, but is not limited to at least a mechanical property, such as elastic modulus, yield strength, tensile strength, viscosity, and so on, of said mechanically supported core (e.g., said core with attached strengthening phase) at least three, or at least four, or at least five or at least six, or at least seven, or at least eight times, or at least nine, or at least ten times greater than the corresponding mechanical property of said core without any strengthening phase.
In the invention herein, a material (e.g., a membrane, a layer, a strengthening phase, a composite mass, etc.) may generally be referred to as “viscoelastic” if it exhibits both viscous and elastic characteristics when undergoing deformation. By way of example but not by way of limitation, upon exposure of a viscoelastic material to a small stress or load for a short time, said viscoelastic material may behave similar to an elastic solid and spring back after unloading. If the viscous material is exposed to said small stress or load for a long time, however, said viscoelastic material may behave more like a highly viscous mass and deform plastically. An estimate of the “critical time” (e.g., the loading time below which a viscoelastic material may behave more like an elastic solid and above which said viscoelastic material may exhibit substantial plastic deformation) is the “relaxation time” defined as the ratio of elongational viscosity and elastic modulus of the material. Typically, as used herein the relaxation time of a viscoelastic material may be greater than about 0.1-0.5 seconds, and more preferably greater than about a second, and even more preferably greater than about 2-5 seconds. Also, upon loading and unloading a viscoelastic material the stress-strain curve of said viscoelastic material may exhibit a hysteresis loop. A non-limiting example of a viscoelastic material is rubber, such as natural rubber.
In the invention herein, moreover, a core may generally be referred to as “substantially encapsulated” by a surface layer if said surface layer covers (e.g., encloses, coats, etc.) at least 20 percent of the surface of said core. This includes, but is not limited to said surface layer covering at least 30 percent, or at least 40 percent, or at least 50 percent, or at least 60 percent, or at least 70 percent, or at least 80 percent, or at least 90 percent, or about 100 percent of the surface of said core.
In the invention herein, furthermore, the terms “semi-permeable layer”, “semi-permeable phase”, “semi-permeable membrane”, and so on may generally be understood as a membrane, layer, film, coating, coating film, etc. through which physiological fluid (e.g., water or water molecules) can fairly readily (e.g., fairly easily, fairly rapidly, etc.) pass upon exposure to said physiological fluid, but through which passage of at least an absorptive excipient is hindered or slow or slowed down. Thus, a “semi-permeable layer” is generally referred to as a membrane through which the diffusivity of physiological fluid (e.g., water) is substantially greater than the diffusivity of a fluid-absorptive excipient. Typically, upon exposure of a semi-permeable layer to a physiological fluid (e.g., water, saliva, gastric fluid, etc.) the diffusivity of said fluid through said layer is at least 5 times greater than the diffusivity of a fluid-absorptive excipient through said layer. This includes, but is not limited to diffusivity of physiological fluid through a semi-permeable layer at least 10 times, or at least 20 times, or at least 50 times, or at least 100 times greater than diffusivity of a fluid-absorptive excipient through said semi-permeable layer.
In the invention herein, drug release from a drug-containing solid (or a drug releasable solid, or a solid dosage form, or a pharmaceutical solid dosage form, etc.) refers to the conversion of drug (e.g., one or more drug particles, or drug molecules, or clusters thereof, etc.) that is/are embedded in or attached to the drug-containing solid (or or a drug releasable solid, or a solid dosage form, or a pharmaceutical solid dosage form, etc.) to drug in a dissolution medium.
In the invention herein, the term “drug delivery” or “delivery” is generally referred to as “delivery of drug molecules to a human or animal body”. In specific circumstances it can refer to “delivery of drug molecules into the blood of a human or animal subject”.
In the invention herein, an “excipient matrix” may generally be understood as the component in a drug-containing solid that holds dispersed drug particles and/or dispersed drug molecules together.
As used herein, moreover, an excipient matrix may be understood “erodible” if said excipient matrix erodes or dissolves upon exposure to a relevant physiological fluid (e.g., gastric fluid) under physiological conditions.
Similarly, in the invention herein an excipient may be considered “soluble” if a solid particle of said excipient dissolves upon exposure to a relevant physiological fluid under physiological conditions (e.g., gastric fluid).
In the invention herein, moreover, a “stabilizing excipient” in an erodible excipient matrix may be understood as an excipient that slows down the erosion rate of said excipient matrix.
Further information related to the definition, characteristics, features, composition, analysis etc. of the disclosed dosage forms, and the elements for fabricating or constructing them, is provided throughout this specification.
In some embodiments, an expandable, three dimensional structural network of one or more fluid-absorptive fibers may comprise criss-crossed stacked layers of one or more fluid-absorptive fibers.
In some embodiments, moreover, one or more fiber-free spaces (or fiber-free space) may comprise free space filled with matter that is partially or entirely removed upon contact with a physiological/body fluid (e.g., gastric fluid) under physiological conditions. In the invention herein, “matter that is partially or entirely removed upon contact with a physiological/body fluid (e.g., gastric fluid)” may usually be understood as matter in a dosage form that upon contact of said dosage form with (e.g., that upon exposure of said dosage form to) a physiological/body fluid (e.g., gastric fluid) is removed from said dosage form faster (e.g., substantially faster, much faster, etc.) than a relevant drug-containing solid in said dosage form dissolves or releases drug. Such matter includes, but is not limited to gases, such as air, nitrogen, oxygen, and so on, or highly soluble solid materials, such as polyols, water-soluble polymers of low molecular weight, and so on.
It may be noted that in some embodiments, at least a free space may form a channel (e.g., an open channel, etc.) that is substantially connected through at least one outer dimension of a fiber structural network.
In some embodiments, furthermore, at least a fiber-free space may comprise (e.g., may have, may be filled with, etc.) both drug-containing solid and free space.
In some embodiments, moreover, drug-containing solid may be attached to (e.g., bonded to, adhered to, partially or entirely surrounding, partially or entirely covering, attached to a surface of, partially or entirely covering a surface of, etc.) a three dimensional structural network of one or more fibers and occupy fiber-free space between a free space (e.g., a channel, an open channel, a channel that is substantially connected through an outer dimension of said three dimensional structural network of one or more fibers, etc.) and said three dimensional structural network of one or more fibers.
In some embodiments, moreover, the pharmaceutical solid dosage form disclosed herein may further comprise a mechanically strengthening semi-permeable layer, which may substantially encapsulate (e.g., substantially surround, substantially coat, etc.) a three dimensional structural network of one or more fibers.
As mentioned previously, in some embodiments herein a three dimensional structural network of fibers comprises criss-crossed stacked layers of fibers.
In some embodiments, an encapsulated fiber structural network (or framework) may comprise encapsulated segments spaced apart from adjoining encapsulated segments by encapsulated-fiber-free spacings, λf,ef, defining one or more encapsulated-fiber-free spaces within an outer volume of said encapsulated network.
In some embodiments, moreover, drug-containing solid may occupy encapsulated-fiber-free space. By way of example but not by way of limitation, drug-containing solid may occupy encapsulated-fiber-free space within an outer volume of an encapsulated network of one or more fibers.
It may be noted that at least a three dimensional structural network of one or more fluid-absorptive fibers, at least a mechanically strengthening semi-permeable layer, and at least a drug containing solid may form an expandable, drug releasable solid.
Upon exposure of the dosage form 400 or expandable, drug releasable solid 401 to a relevant physiological fluid (e.g., gastric fluid) 460 under physiological conditions (e.g., upon immersing the dosage form 400 in a relevant physiological fluid 460 under physiological conditions), the encapsulated structural network 405,410 may expand with fluid 460 absorption, and said drug-containing solid 420 may release drug 425 over time.
In some embodiments, moreover, one or more encapsulated-fiber-free spaces within an outer volume of an encapsulated network of one or more fibers may comprise one or more free spaces or one or more channels. Similarly, in some embodiments, a drug-containing solid may have at least a free space or channel within or through it. In some embodiments, moreover, drug-containing solid may occupy encapsulated-fiber-free space between a free space (e.g., a channel, an open free space, an open channel, etc.) and an encapsulated structural network (or framework) of fibers.
It may be noted that in preferred embodiments, drug containing solid may also be attached (e.g., immovably attached, fixed, bonded, etc.) to said encapsulated network of fibers. Moreover, it may be noted that at least a three dimensional structural network of one or more fluid-absorptive fibers, at least a mechanically strengthening semi-permeable layer, at least a drug containing solid, and one or more free spaces or channels may form an expandable, drug releasable solid.
It may be noted that the role or function of one or more free spaces 530 in an expandable, drug releasable solid 501 can be to provide faster access of physiological fluid 560 to the interior of said expandable, drug releasable solid 501 after exposure of said expandable, drug releasable solid 501 to said physiological fluid 560. In some embodiments, therefore, one or more free spaces 530 (e.g., one or more interconnected free spaces, or one or more substantially interconnected free spaces, one or more substantially open free spaces, etc.) may be filled with a matter that is removable by a physiological fluid 560 under physiological conditions. Such matter that is removable by a physiological fluid under physiological conditions can, for example, be a gas which escapes a free space upon percolation of said free space by said physiological fluid. Such matter that is removable by a physiological fluid under physiological conditions can, however, also be a solid that is soluble or highly soluble in said physiological fluid, and thus may dissolve upon exposure to said physiological fluid.
Thus, upon exposure of the dosage form 500 to a relevant physiological fluid (e.g., gastric fluid) 560 under physiological conditions (e.g., upon immersing the dosage form 500 in a relevant physiological fluid 560 under physiological conditions), the fluid 560 may percolate one or more interconnected free spaces 530, and said encapsulated structural framework 505,510 may expand with fluid 560 absorption (e.g., due to diffusion or osmosis of physiological fluid into said framework, etc.). Also, said drug-containing solid 520 may release drug 525 over time.
Upon exposure of the dosage form 500 to a relevant physiological fluid 560 under physiological conditions (e.g., upon immersing the dosage form 500 in a relevant physiological fluid 560 under physiological conditions), the fluid 560 may percolate one or more free spaces 530, and said encapsulated structural network 505,510 may expand with fluid 560 absorption. Also, said drug-containing solid 520 may release drug 525 over time.
It may be obvious to a person of ordinary skill in the art that many more non-limiting examples of dosage forms according to this invention could be given. Additional aspects and embodiments of dosage forms disclosed herein are described throughout this specification. Any more aspects and embodiments that would be obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
Generally, said expandable three dimensional fiber structural network, or one or more fibers, or one or more fiber segments, etc. 305,405,505 may comprise one or more first excipients. Said one or more first excipients may include at least a fluid-absorptive excipient. A non-limiting example of a fluid-absorptive first excipient is hydroxypropyl methylcellulose, and preferably hydroxypropyl methylcellulose with a molecular weight greater than 30 kg/mol, or even more preferably greater than 50 kg/mol.
Similarly, said mechanically strengthening semi-permeable layer 410,510 may comprise one or more second excipients. Said one or more second excipients may include at least a strengthening excipient. A non-limiting example of a strengthening excipient is methacrylic acid-ethyl acrylate copolymer, and preferably methacrylic acid-ethyl acrylate copolymer with a molecular weight of about 250 kg/mol (also referred to herein as “Eudragit L100-55”).
The drug-containing solid 320,420,520 may comprise at least one active pharmaceutical ingredient or drug. In some embodiments, the drug-containing solid also comprises one or more third excipients.
In preferred embodiments, moreover, upon exposure of the dosage form 300,400,500 to a relevant physiological fluid (e.g., gastric fluid) 360,460,560 the fiber structural network 305 or the encapsulated network 405,410,505,510 may expand primarily with fluid 360,460,560 absorption. In the invention herein. a solid is generally understood as “expanding primarily with fluid absorption” if upon exposure of said solid to a relevant physiological fluid, the greatest expansion of said solid (e.g., the greatest longitudinal expansion, such as the greatest increase in a length or normalized length; the greatest volumetric expansion, such as the greatest increase in a volume or normalized volume; etc.) is mostly or primarily due to the absorption of said physiological fluid 360,460,560. It may be noted that the fiber structural network 305 or the encapsulated network 405,410,505,510 may generally transition to a viscoelastic mass, viscoelastic solid, viscoelastic composite, semi-solid, or viscous (e.g., highly viscous) mass as it expands with fluid 360,460,560 absorption.
In preferred embodiments, upon exposure of the dosage form 400,500 to a relevant physiological fluid 460,560 under physiological conditions, a mechanically strenghtening, semi-permeable layer 410,510 may form a semi-permeable, viscoelastic membrane.
In preferred embodiments, moreover, upon exposure of the dosage form 400,500 to a relevant physiological fluid 460,560 under physiological conditions, a mechanically strengthening, semi-permeable layer 410,510 may be substantially permeable to said physiological fluid 460,560. In the invention herein, a membrane or layer may generally be referred to as “substantially permeable” to a physiological fluid 460,560 if the diffusivity of water in said membrane or layer is greater than about 0.0001 times the self-diffusivity of water. Thus, generally, in the invention herein a membrane or layer may be understood “substantially permeable” to a physiological fluid 460,560 if the diffusivity of water in said membrane or layer under physiological conditions (e.g., at a temperature of 37° C.) is greater than about 1×10−13 m2/s.
Similarly, in preferred embodiments, upon exposure of the dosage form 400,500 to a physiological fluid 460,560 said mechanically strengthening, semi-permeable layer 410,510 may be substantially impermeable to at least one fluid-absorptive first excipient. In the invention herein, a membrane or layer 410,510 may generally be understood “substantially impermeable” to a fluid-absorptive first excipient if a diffusivity of said fluid-absorptive first excipient in or through said membrane or layer 410,510 is smaller than about 0.1 times the diffusivity of water in or through said membrane or layer 410,510. This includes, but is not limited to a diffusivity of said fluid-absorptive first excipient in or through said membrane or layer 410,510 smaller than 0.05 times, or smaller than 0.02 times, or smaller than 0.01 times, or smaller than 0.005 times the diffusivity of water in or through said membrane or layer 410,510.
In preferred embodiments, moreover, upon exposure of the dosage form 400,500 to a relevant physiological fluid 460,560 under physiological conditions, the mechanically strenghtening semi-permeable layer 410,510 may expand due to an internal pressure in the network 405,505 it encapsulates. Said internal pressure may, for example, be generated by osmotic flow of fluid 460,560 into said network 405,505.
Generally, furthermore, upon exposure of the dosage form 300,400,500 to a relevant physiological fluid 360,460,560, the fiber structural network 305 or the encapsulated network 405,410,505,510 may form an expanded, viscoelastic composite mass 305,360,405,410,460,505,510,560.
In preferred embodiments, moreover an expandable network 305,405,505 may generally have at least one exterior dimension (e.g., a length, width, or thickness) greater than 3 mm.
Additional embodiments of dosage forms disclosed herein are described throughout this specification. Any more embodiments that would be obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
This section presents non-limiting ways by which the properties of disclosed gastroretentive dosage forms may be modeled. For comparison, models of the properties of an immediate-release particulate dosage form are also presented. The models and examples will enable one of skill in the art to more readily understand the conceptual details and advantages of the invention. The models and examples are for illustrative purposes only, and are not meant to be limiting in any way.
Theoretical models of dosage form properties: Microstructures and compositions of dosage forms
As shown schematically in
The microstructure of the non-limiting gastroretentive dosage form considered in the models is schematically illustrated in
Said internal structure 704 comprises at least an expandable, three dimensional structural network of criss-crossed stacked layers of one or more fluid-absorptive fibers 705, a mechanically strengthening semi-permeable layer 710, a drug-containing solid 720, and one or more free spaces or channels 730.
Said structural network 705 may be substantially encapsulated by said mechanically strengthening layer 710. Said encapsulated structural network 705,710 may comprise encapsulated segments spaced apart from adjoining encapsulated segments by encapsulated-fiber-free spacings, λf,ef, defining one or more encapsulated-fiber-free spaces within the expandable, drug releasable solid 701. At least one encapsulated-fiber-free space may have an open channel 730 through it.
Drug-containing solid 720 may be attached to the encapsulated network of fibers 705,710 and occupy encapsulated-fiber-free space (e.g., form an annulus) between an open channel 730 and the encapsulated network of fibers 705,710.
It may be noted that a “three-dimensional structural network of criss-crossed stacked layers of one or more fluid-absorptive fibers” is also referred to herein as a “three-dimensional structural network of one or more fluid-absorptive fibers stacked in a cross-ply arrangement” or as a “three-dimensional structural network of one or more fluid-absorptive fibers forming fiber layers stacked in a cross-ply arrangement”. The non-limiting dosage form modeled herein (and included in this invention) further comprises an ordered or substantially ordered structure; the one or more fibers in the criss-crossed stacked layers of one or more fibers may be orderly or substantially orderly arranged. Moreover, because the gastroretentive dosage form modeled herein is based on a network (or framework) of fibers, it is also referred to as “fibrous dosage form”. Selected microstructural parameters of the specific non-limiting fibrous dosage form modeled herein are listed in Table 1.
Any other ways of describing the structure of the non-limiting fibrous dosage forms modeled herein are all within the spirit and scope of this invention.
The composition, or formulation, of the various phases or “structural phases” or “structural components” of the non-limiting gastroretentive dosage form 700 considered in the models may be as shown schematically in the inset of
The structural network of fluid-absorptive fibers 705 may comprise a mixture of a physiological fluid-absorptive excipient 715, a mechanically strengthening excipient 716, and a gastrointestinal contrast agent. The physiological fluid-absorptive excipient 715 in the fibers 705 may comprise hydroxypropyl methylcellulose (HPMC) with large molecular weight, referred to herein as “HPMC2”. The mechanically strengthening excipient 716 in the fibers 705 may comprise methacrylic acid-ethyl acrylate copolymer (e.g., Eudragit L100-55). The gastrointestinal contrast agent in the fibers 705 may comprise barium sulfate (not shown in the schematic; it may not be needed to produce a dosage form that is functional). The weight fractions of HPMC2 715, Eudragit L100-55 716, and barium sulfate in the solid fibers 705 may be about 0.4375, 0.2625, and 0.3, respectively.
aCalculated as nα = nc = πRdf,02/λ02.
b The trade name of the non-limiting enteric methacrylic acid-ethyl acrylate excipient used is Eudragit L100-55.
c Calculated as ρα = 1/(WHPMC1,α/ρHPMC1 + Wd,α/ρα + Wee,α/ρee), where the densities of HPMC1, nilotinib, and enteric excipient, ρHPMC1 = 1300, ρα = 1360, and ρee = 800 kg/m3.
The mechanically strenghtening, semi-permeable layer 710 (e.g., a mechanically strengthening phase) may comprise a mechanically strengthening excipient 717. The mechanically strengthening excipient 717 in the strengthening phase 710 may comprise methacrylic acid-ethyl acrylate copolymer (e.g., Eudragit L100-55).
The drug-containing solid 720 may comprise a drug 721,722 (e.g., in the form of drug particles 721 and/or drug molecules 722) and one or more excipients 725,726 for releasing the drug at the desired rate after immersing the dosage form 700 in a physiological fluid under physiological conditions. The drug 721,722 may comprise nilotinib (e.g., nilotinib hydrochloride monohydrate). The one or more excipients 725,726 may include at least an excipient 725 that is soluble in a physiological fluid (e.g., water, etc.) and a mechanically strengthening excipient 726. The physiological fluid-soluble excipient 725 in the drug-containing solid 720 may comprise hydroxypropyl methylcellulose (HPMC) with low molecular weight, referred to herein as “HPMC1”. The mechanically strengthening excipient 726 in the drug-containing solid 720 may comprise methacrylic acid-ethyl acrylate copolymer (e.g., Eudragit L100-55). The weight fractions of nilotinib 721,722, HPMC1 725, and Eudragit L100-55 726 in the drug-containing solid 720 may be about 0.6, 0.36, and 0.04, respectively.
The one or more open channels 730 may be filled with air.
Any other ways of describing the composition of the non-limiting fibrous dosage forms modeled herein are all within the spirit and scope of this invention.
Upon immersing the particle-filled capsule in a dissolution fluid (e.g., acidic water, simulated gastric fluid, gastric fluid, etc.), the capsule may dissolve and drug particles may be released. An analysis of the dissolution of the gelatin capsule is beyond the scope of this disclosure. Suffice it to state, however, that a typical immediate-release gelatin capsule may dissolve in 3-6 minutes, and thereafter release the drug particles almost immediately into the dissolution fluid. The drug particles in the dissolution fluid may then dissolve and release drug molecules.
As shown in
where tdis and td,c are the times at which the particle and the capsule have dissolved after immersing the dosage form in a dissolution fluid, ρd is the density of the drug particle, cs the drug solubility in the dissolution fluid, Rp,0 the initial radius of the particle, Dd the drug diffusivity in the dissolution fluid, and v∞,p the far-field velocity of the dissolution fluid.
Substituting the non-limiting parameter values ρd=1360 kg/m3, cs=1 mg/ml, Rp,0=18.5 μm, Dd=4.22×10−10 m2/s, and v∞,p=29 μm/s in Eq. (1), tdis−td,c=16 min. Thus, the drug particle may be dissolved just about 16 minutes after dissolution of the capsule.
Similarly, from companion work (see, e.g., REF. [1]), the drug release rate by a collection of identical drug particles that do not interact with each other may be estimated as:
where Mdis the mass of drug particles in the dissolution fluid, cd(t) the drug-molecule concentration in the dissolution fluid, and Rp the radius of the drug particles.
Eq. (2) stipulates that the drug release rate may be time-dependent because both the drug mass in the dissolution fluid and the particle radius may be time-dependent. Regardless, substituting the non-limiting initial values, Md,0=200 mg and Rp,0=18.5 μm, and the non-limiting parameters cs=1 mg/ml, ρd=1360 kg/m3, Dd=4.22×10−10 m2/s, and v∞,p=29 μm/s, in Eq. (2), the “initial” drug release rate in a large volume of dissolution fluid with cd(t)˜0 is 23 mg/min. At this release rate, 200 mg of drug particles dissolve in 8.7 minutes, just 1.8 times shorter than the dissolution time calculated by Eq. (1) above. Thus, in a large volume of dissolution fluid the “initial” drug release rate may be considered a fairly reasonable approximation of the release rate by the particles.
Any other models for estimating the dissolution time and/or the drug release rate by particulate dosage forms or drug particles obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
By contrast, upon immersing the fibrous dosage forms in a dissolution fluid (e.g., acidic water, simulated gastric fluid, gastric fluid, etc.), the fluid may rapidly percolate the open channels, and diffuse into the solid walls comprising the drug-excipient annulus, the enteric fiber coating, and the high-molecular weight HPMC (HPMC2) fibers,
An exact analysis of the coupled diffusion-expansion problem is beyond the scope of this disclosure. From companion work (see, e.g., REF. [1]), the normalized radial expansion of the dosage form may be estimated as:
where ΔRdf=Rf−Rdf,0, and Rdf is the radius of the expanding dosage form, Rdf,0 the radius of the initial solid dosage form, k2 a dimensionless constant, σθ the tensile stress in the coating, η the elongational viscosity of the acidic water-soaked coating, Π0 the osmotic pressure in the fiber intially (e.g., at time, t=0 and at “zero” expansion), φf and φec, respectively, are the volume fractions of fiber and coating in the solid dosage form, R is the ideal gas constant, T the absolute temperature, φHPMC2,f the volume fraction of HPMC2 in the fibers, and ρHPMC2 the solid density of HPMC2, MHPMC2 the molecular weight of HPMC2, and C2 a dimensional constant.
It will be shown later in subsection “Example 6: In vitro expansion of gastroretentive dosage forms” of section “Experimental Examples” that a non-limiting approximation of the constant, k2˜0.108. Substituting this value and the non-limiting parameter values, R=8.314 J/molK, T=310 K, φHPMC2,f=0.46, ρHPMC2=1300 kg/m3, MHPMC2=120 kg/mol, φf=0.3, φec=0.15, and η=1.36×108 Pa·s in Eq. (3), the dosage form may expand to about 1.5 times the initial radius in about 3.5 hours. Prior work suggests that this amount of expansion may prevent the premature passage of the dosage form through the pylorus (see, e.g., A.H. Blaesi, D. Kümmerlen, H. Richter, N. Saka, Mechanical strength and gastric residence time of expandable fibrous dosage forms, Int. J. Pharm. 613 (2022) 120792).
Any other models for estimating the expansion rate of the disclosed dosage forms obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
In the stomach, the expanded dosage form may be exposed to repeated compression-decompression pulses by the stomach walls. Thus, to remain in the stomach for prolonged time, the expanded dosage form may withstand these loads.
From companion work (see, e.g., REF. [1]), a predominant component that may add strength to the expanded dosage form is the strengthening coating over the fibers. If the width of the compression-decompression pulses, τpulse˜1 s, is much smaller than relaxation time of the acidic water-soaked coating, τrel˜24 s, the coating, and the expanded dosage form, may behave essentially like an elastic solid under these loads, and may fracture.
Treating the internally pressurized coating network in the expanded dosage form as a cellular solid, the fracture strength of the expanded dosage form may be estimated as (see, e.g., REF. [1]):
where C8 is a constant, φec the volume fraction of the enteric coating in the expanded dosage form, n a constant, and σec the fracture strength of the acidic water-soaked coating.
Substituting the non-limiting values, C8=0.93, φec=0.15, n=1.19, and σec=1.8 MPa in Eq. (4), the fracture strength, σf,df=0.175 MPa. Prior work suggests that this fracture stress may be sufficient to hold the dosage form in the stomach for prolonged time (see, e.g., A.H. Blaesi, D. Kümmerlen, H. Richter, N. Saka, Mechanical strength and gastric residence time of expandable fibrous dosage forms, Int. J. Pharm. 613 (2022) 120792). Thus, with the coating volume fraction, φc=0.15, both the expansion rate and the post-expansion mechanical strength of the dosage form may be fairly adequate.
Any other models for estimating the post-expansion mechanical properties of the disclosed dosage forms obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
In the dissolution fluid (e.g., acidic water, simulated gastric fluid, gastric fluid, etc.), moreover, the gastroretentive fibrous dosage form may release drug from the drug-containing annuli into the dissolution fluid.
As shown in the non-limiting
As shown in the non-limiting
If the excipient in the annuli erodes or dissolves faster than the drug, the drug particles at the surface of the annuli may be released as the surrounding HPMC1-enteric excipient matrix dissolves. Further assuming that the excipient concentration at the channel exit is about the same as that at the interface between the annulus and the fluid-filled channel,
where wd,a and wHPMC1,a, respectively, are the weight fractions of drug and HPMC1 in the solid annuli, nc the number of channels in the dosage form, Rc the channel radius vr
the average velocity of dissolution fluid through a channel, and cHPMC1* the the concentration of HPMC1 at the channel surface (i.e., the HPMC1 concentration at which the HPMC1-enteric excipient composite may disentangle).
Eq. (5) shows that the drug release rate may be constant and controllable by the number of channels, nc, and the HPMC1 concentration at which the HPMC1-enteric excipient composite may disentangle, cHPMC1*. For the non-limiting parameters, d=0.6, wHPMC1=0.36, nc=91.4, Rc=453 μm , vz
=6.68 μm/s, and cHPMC1*=3.27 mg/ml, by Eq. (5), dmd,r/dt=7.72 mg/h. This is about 179 times slower than the release rate of drug particles estimated in subsection (a) above.
Moreover, by integrating the drug release rate over time the mass of drug released may be obtained as:
Dividing md,r(t) by the drug mass in the dosage form and rearranging may give the fraction of drug released as:
Thus, under the assumptions made, the fraction of drug released may increase fairly linearly with time until it may reach unity at the dissolution time, tdis.
By substituting md,r/Md,0=1 into Eq. (7) and rearranging, the drug dissolution time may be estimated as:
For the non-limiting parameter values listed in Table 1, and vz
=6.68 μm/s and cHPMC1*=3.27 mg/ml, by Eq. (8) tdis=26 hours.
The calculated dissolution time is of the order of the reasonable dosing interval of a day. Thus, the gastroretentive fibrous dosage forms may enable a substantially constant drug release rate for prolonged time.
Any other models for estimating the drug release rate of the disclosed dosage forms obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
Upon administering to a human or animal, however, the course of the dosage form and of the drug may generally be far more complex than that in an in vitro dissolution vessel.
In what follows, the above processes are modeled for estimating drug concentration in blood versus time after administering particulate and fibrous dosage forms. In all models the anatomical and physiological parameter values of the fasted dog may be used. The models may, however, be readily extended to humans.
Upon entering the stomach, the particle-filled capsule may disintegrate and release drug particles into the gastric fluid which may then dissolve. In the present models, the mass of drug per unit volume of the gastric fluid, Md,0/Vgf, may generally be far greater than the solubility of the drug, cs,gf. Thus, as shown schematically in the non-limiting
Assuming that (a) the volumetric inflow and outflow rates of gastric fluid, Qgf, are the same and time-invariant, (b) the particles in the stomach are perfectly mixed with the gastric fluid, and (c) no drug particle will dissolve completely, the rate at which the number of drug particles per unit volume of gastric fluid, np,gf, changes may be written as:
where Vgf is the volume of the gastric fluid.
If the drug particles are released immediately after the capsule reaches the stomach, at time, t=0 the number of drug particles in the gastric fluid may be written as:
where np,0 is the number of drug particles in the solid capsule per unit volume of gastric fluid.
Rearranging and integrating Eq. (9a) with the initial condition, Eq. (9b), may give:
From Eq. (10) the number of drug particles in the gastric fluid may decrease to 37 percent of the initial value at the characteristic residence time:
For the non-limiting parameter values roughly resembling an empty stomach of a dog, Vgf=20 ml and Qgf=14 ml/h, by Eq. (11) tr,p˜1.43 h, Table 2 later.
For further details related to the estimation of the gastric residence time of drug particles, see, e.g., A.H. Blaesi and N. Saka, Gastroretentive fibrous dosage forms for prolonged delivery of sparingly soluble tyrosine kinase inhibitors. Part 3: Theoretical models of drug concentration in blood, to be published in the International Journal of Pharmaceutics, and referred to herein as “REF. [3]”.
Any other models for estimating the gastric residence time of particulate dosage forms or drug particles obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
Generally, the drug in the gastrointestinal system should be in molecular form for absorption by blood. Indeed, as was shown schematically in
Because the particles release drug rapidly, and in the present models, the mass of drug per unit volume of the gastric fluid, Md,0/Vgf>>cs,gf, the drug solubility in gastric fluid, the drug concentration in gastric fluid may rapidly rise to solubility. Thus, up to the “gastric residence time” of drug particles, tr,p, the drug concentration in gastric fluid may roughly be approximated as:
An estimate of the solubility of nilotinib in an empty stomach of a dog, cs,gf˜1 mg/ml.
After tr,p the stomach may be assumed to be mostly depleted of drug particles, and only comprise residual drug molecules. From a companion work (see, e.g., REF. [3]), the residual drug molecules may flow out of the stomach with the gastric fluid flow. A rough estimate of the drug concentration in gastric fluid may be written as:
Thus, after the “residence time” of the particles, the concentration of drug molecules in the gastric fluid may drop exponentially at the time constant, τgf=Vgf/Qgf. For the non-limiting parameter values roughly resembling an empty stomach of a dog, Vgf=20 ml and Qgf=14 ml/h, the time constant, τgf˜1.43 h.
Any other models for estimating the drug concentration in gastric fluid after administering particulate dosage forms obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
By contrast, the gastroretentive fibrous dosage form may expand in the stomach as shown schematically in the non-limiting
where Pa,max is the maximum load intensity (load per unit thickness) applied by the stomach walls, and Rdf the radius of the expanded dosage form.
For non-limiting parameter values roughly resembling an expanded dosage form in an empty stomach of a dog, Pa,max˜1 N/mm and Rdf˜10.5 mm, by Eq. (14) σa,max˜0.03 MPa. This is smaller than the estimated tensile stress of the dosage form, σf,df=0.175 MPa, calculated in subsection (c) of “Theoretical models of dosage form properties: In vitro expansion, mechanical properties, and drug release”. Thus, the expanded dosage form may remain in the stomach initially. Eventually, however, it may fracture or disintegrate due to dynamic fatigue or similar effects.
From companion work (see, e.g., REF. [3]), a highly approximate estimate of the time to fracture an expanded dosage form in dynamic fatigue may be written as:
where tpulse is the period of the compression pulses by the stomach walls, σa,max the maximum tensile stress due to the compression pulses, σf,df the tensile stress of the dosage form, b, C8, and n are constants, φec is the volume fraction of enteric coating in the solid dosage form, and σec the fracture strength of the acidic water-soaked enteric coating.
Substituting the highly approximate, non-limiting values roughly resembling a fibrous dosage form in an empty stomach of a dog, tpuls˜10 s, σa,max˜0.03 MPa, σf,df=0.175 MPa, and b˜−0.214 in Eq. (15), the time to fracture, tf may be about 10 hours.
Fractured fragments that are smaller than the diameter of the pylorus may pass into the intestine with the gastric fluid flow. Fragments that are larger may continue to be subjected to the compressive loads by the stomach walls, and fracture eventually into smaller fragments that may flow out of the stomach.
The gastric residence time of the fibrous dosage form may be estimated as:
where tr,f is the characteristic time to decrease the amount of fragments in the stomach substantially. Substituting the non-limiting values, tf˜10 h and tr,fr˜1.43 h (the same as the estimated “gastric residence time” of drug particles in an empty stomach of a dog), by Eq. (16) tr,f˜11.43 h. This is about an order of magnitude longer than the “gastric residence time” of drug particles estimated in subsection (b) above.
Any other models for estimating the gastric residence time of the disclosed dosage forms obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
In the stomach, moreover, the fibrous dosage form may release drug as shown in the non-limiting
where Vgf is the volume of gastric fluid, Qgf the flow rate of gastric fluid into and out of the stomach, and dmd,r/dt the drug release rate by the dosage form.
From subsection (d) of section “Theoretical models of dosage form properties: In vitro expansion, mechanical properties, and drug release”, the drug release rate may be written as:
where wd,a and wHPMC1,a, respectively, are the weight fractions of drug and HPMC1 in the drug-containing annulus, nc is the number of channels, Rc the radius of the channel in the expanded annulus, vz
the average velocity of the dissolution fluid through the channel, cHPMC1* the HPMC1 concentration at the channel/annulus interface, and const a dimensional constant. For the non-limiting parameters, wd=0.6, wHPMC1=0.36, nc=91.4, Rc=453 μm,
vz
=6.68 μm/s, and cHPMC1*=32.7 mg/ml, the drug release rate, dmd,r/dt=const=7.72 mg/h.
It may be assumed here that this release rate is maintained as long as the fibrous dosage form resides in the stomach. By substituting dmd,r/dt=const in Eq. (17), and solving the equation with the initial condition, cd,gf=0 at t=0, up to the gastric residence time of the fibrous dosage form the drug concentration in gastric fluid may be obtained as (see, e.g., REF. [3]):
For t>tr,f, however, dmd,r/dt˜0. Substituting this release rate in Eq. (17), and solving the equation may give:
where
may be obtained from Eq. (19).
Thus, in comparison with the particulate form, the drug concentration in the gastric fluid may be lower but it may be maintained for a longer time.
Any other models for estimating the drug concentration in gastric fluid after administering the disclosed dosage forms obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
Drug molecules released in the stomach may pass into the duodenum (first part of the small intestine) and diffuse through the duodenal epithelial membrane into the blood capillaries, as shown in the non-limiting
From companion work (see, e.g., REF. [3]), if the diffusivity of drug through the duodenal membrane is large, the number of drug molecules that exit the duodenum and enter the lower parts of the intestines may be very small. Further assuming that the drug molecules do not precipitate in the duodenum, the drug absorption rate by the blood may roughly be given by the mass flow rate at which drug molecules exit the stomach. Thus,
By Eq. (41) the absorption rate, dmd,a/dt, may be directly proportional to the drug concentration in gastric fluid, cd,gf. Thus, the absorption rate may be constant and/or controllable if the drug concentration in gastric fluid is constant and/or controllable.
Any other models for estimating drug absorption rate obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
The absorbed drug molecules may be transported forward with the blood along the duodenal or intestinal capillaries. Concurrently, they may diffuse from the capillaries into the surrounding tissue (cellular and extracellular space without blood), as shown schematically in the non-limiting
Shown schematically in the non-limiting
The drug concentration in the tissue may then be estimated as:
where Kp,t is the tissue-blood partition coefficient and cd,b the drug concentration in blood.
Thus, the drug concentration in the tissue may rise and fall with the drug concentration in blood. A non-limiting value of Kp,t for nilotinib in a dog, Kp,t=2.08.
Any other models for determining drug distribution into tissues obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
The absorbed drug molecules in the blood capillaries of the duodenum may further be convected into the portal vein and the sinusoidal blood capillaries of the liver. In the sinusoidal capillaries, the drug may be continuously eliminated from the blood by diffusion through the hepatic plates into the biliary canaliculi, as shown in the non-limiting
From companion work (see, e.g., REF. [3]), a rough estimate of the elimination rate of drug molecules by the liver may be written as:
where Kp,hp=(cd,hp/Cd,b)r=Ri is the partition coefficient of the drug between the hepatic plates and the blood in the sinusoidal capillary, Dd,hp the drug diffusivity through the hepatic plates, Ls the length of the sinusoids, Ro the outer radius of the hepatic plates, Ri the radius of the sinusoidal capillaries, Qb,s the flow rate of blood through a sinusoidal capillary, Qb,l the flow rate of blood through the liver, and cd,b the drug concentration in blood.
Eq. (23) suggests that the drug elimination rate may be roughly proportional to the drug concentration in blood.
Any other models for estimating the drug elimination rate from the blood obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
(i) Drug Concentration in Blood Versus Time
Finally, the models of drug absorption, drug distribution, and drug elimination may be combined for expressing the drug concentration in the blood versus time. As shown schematically in
where Vb is the volume of blood and Vt the volume of tissue in the body.
Substituting Eq. (21) for dmd,a/dt and Eq. (23) for dmd,el/dt in Eq. (24) may give:
Rearranging and rewriting:
where τel may be consided an elimination time constant, given by:
For the non-limiting parameter values Vb=1.1 l, Kp,t=2.08, vt=12.8 l, Ro=15 μm, Ri=5 μm, Qb,s=3.93×10−8 ml/s, Kp,hp=2.08, Dd,hp=5.24×10−12 m2/s, Ls=275 μm, and Qb,l=9 ml/s, by Eq. (26b) τel=1.96 h.
In the following subsections, the drug concentration in gastric fluid derived in the earlier sections is substituted in Eq. (26a), and the drug concentration in blood is estimated for both the particulate and the fibrous dosage forms. The solution may be divided into two time intervals: Before and after the gastric residence time.
(i.1.a) 0≤t≤tr,p
Up to the gastric residence time of drug particles, tr,p˜Vgf/Qgf˜1.43 h, the drug concentration in gastric fluid, by Eq. (12) may be about equal to the solubility. Substituting cd,gf=cs,gf in Eq. (63a) and solving the equation with the initial condition, dd,b=0 at t=0, may give (see, e.g., REF. [3]):
Because the “gastric residence time” of the drug particles, tr,p=1.43 h, is shorter than the time constant, τel=1.96 h, up to tr,p the exponential term in Eq. (27a) may be expanded as 1−t/τel. Substituting this term for the exponential term gives:
(i.1.b) t>tr,p
After the gastric residence time of drug particles, by substituting Eq. (13) in Eq. (26a), and solving the equation with cd,b at t=tr,p obtained from Eq. (27a), the drug concentration in blood may be obtained as (see, e.g., REF. [3]):
Therefore, because tr,p is short, after administering the particulate dosage form the drug concentration in blood may rise and fall. As listed in Table 2, the maximum drug concentration, cmax˜0.59 μg/ml at tmax˜2.2 h. The width of the peak at half-height, w1/2˜4.3 hours. This is much shorter than the reasonable dosing intervals, 12 or 24 hours.
Any other models for estimating the drug concentration in blood after administering particulate dosage forms obvious to a person of ordinary skill in the art are all within the spirit and scope of this disclosure.
(1.2.a) 0≤t≤tr,f
Up to the gastric residence time of the fibrous dosage form, tr,f˜11.43 h, by substituting Eq. (19) in Eq. (26a) and solving the equation with the initial condition, cd,b=0 at t=0, the drug concentration in blood may be obtained as (see, e.g., REF. [3]):
(i.2.b) t>tr,f
After the gastric residence time of the fibrous dosage form, substituting Eq. (20) in Eq. (26a), and solving the equation with cd,b at t=tr,f obtained from Eq. (29), the drug concentration in blood may be obtained as (see, e.g., REF. [3]):
Thus, upon repeated dosing the fibrous dosage form may be able to maintain a fairly steady drug concentration in blood—enhancing efficacy and mitigating side effects of the drug therapy.
Any more models and concepts of demonstrating superiority of the disclosed dosage forms to state-of-the-art or other dosage forms obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
In view of the theoretical models and non-limiting examples above, which are suggestive and approximate rather than exact, and other considerations, the dosage forms disclosed herein may further comprise the following embodiments.
Generally, the dosage forms disclosed herein may be used for delivery of drugs by oral ingestion. Thus, to assure that the dosage form is swallowable by a human or animal subject, the exterior dimensions of the dosage form (or of a fluid-absorptive fiber network or of an expandable, drug releasable solid) disclosed herein may not be too large. In some embodiments, therefore, at least one exterior dimension of the dosage form or of a fluid-absorptive fiber network or of an expandable, drug releasable solid herein may be no greater than 16 mm. This includes, but is not limited to at least one exterior dimension of the dosage form or of a fluid-absorptive fiber network or of an expandable, drug releasable solid no greater than 15 mm, or no greater than 14 mm, or no greater than 13 mm, or no greater than 12 mm or no greater than 11 mm, or no greater than 10 mm.
After ingestion, however, the dosage form (or fluid-absorptive fiber network or expandable, drug releasable solid) should remain in the stomach for prolonged time. Thus, to prevent premature passage into the small intestine, the dosage form (or fluid-absorptive fiber network or expandable, drug releasable solid) disclosed herein may expand in the stomach to a size of the order of or greater than the diameter of the pylorus (e.g., the diameter of the pyloric sphincter, etc.). Because the maximum expansion and the expansion rate may be limited, dosage forms (or fluid-absorptive fiber networks or expandable, drug releasable solids) with greater exterior dimensions may be preferred. In some embodiments, therefore, at least one exterior dimension of the dosage form or of a fluid-absorptive fiber network or of an expandable, drug releasable solid herein may be greater than 3 mm. This includes, but is not limited to at least one exterior dimension of the dosage form or of a fluid-absorptive fiber network or of an expandable, drug releasable solid greater than 4 mm, or greater than 5 mm, or greater than 6 mm, or greater than 7 mm, or greater than 8 mm, or greater than 9 mm.
In some embodiments, therefore, at least one exterior dimension of the dosage form or of a fluid-absorptive fiber network or of an expandable, drug releasable solid herein may be in the range of 3 mm-16 mm. This includes, but is not limited to at least one exterior dimension of the dosage form or of a fluid-absorptive fiber network or of an expandable, drug releasable solid in the ranges 4 mm-16 mm, 5 mm-16 mm, 6 mm-16 mm, 5 mm-16 mm, or 6 mm-15 mm.
The dosage form (or fluid-absorptive fiber network or expandable, drug releasable solid) disclosed herein can have any common or uncommon outer shape of oral solid dosage forms (e.g., tablets, capsules, etc.). For non-limiting examples of common tablet shapes, see, e.g., K. Alexander, Dosage forms and their routes of Administration, in M. Hacker, W. Messer, and K. Bachmann, Pharmacology: Principles and Practice, Academic Press, 2009. Any other outer geometries, outer shapes, outer surfaces, or dimensions of dosage forms or fluid-absorptive fiber networks or expandable, drug releasable solids obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
For assuring that the dosage form (or an expandable, drug releasable solid) herein comprises the desired properties, such as the desired expansion rate, adequate mechanical properties after expansion, the desired drug release rate, and so on, in some embodiments a three dimensional structural network of one or more fluid-absorptive fibers may comprise segments separated and spaced from adjoining segments by fiber-free spacings. Such fiber-free spacings may define one or more fiber-free spaces within the exterior (or outer) volume of the three dimensional structural network of fibers.
If such fiber-free spaces are reasonably well connected within or through an exterior volume of a three dimensional structural network of fibers, they may enable percolation of a fluid into one or more of said fiber-free spaces upon immersing said network into said fluid.
Percolation of fluid into one or more fiber-free spaces can be desirable for various reasons. By way of example but not by way of limitation, a non-limiting method or way of manufacturing dosage forms as disclosed herein includes dip-coating a structural network of fluid-absorptive fibers with an encapsulating mechanically strengthening coating. If a dip-coating solution (e.g., a solution comprising at least a coating substance and a solvent) percolates the fiber-free spaces surrounding said network, the coating may encapsulate said network. The more connected the fiber-free spaces, the more uniformly may the dip-coating solution percolate the fiber-free spaces, and the more uniformly may the mechanically strengthening coating be applied around said network. A more uniform coating may result in improved properties of the dosage form or expandable, drug releasable solid, such as greater mechanical strength after expansion, etc.
In some embodiments, therefore, one or more fiber-free spaces within an exterior volume of a three-dimensional structural network of fibers may be substantially connected through an exterior dimension of said structural network. Similarly, in some embodiments, one or more fiber-free spaces within an exterior volume of a three-dimensional structural network of criss-crossed stacked layers of one or more fibers may be substantially connected through an exterior dimension of said structural network.
In some embodiments of the invention herein, one or more fiber-free spaces within an exterior volume of a three dimensional structural network of fibers may be considered “substantially connected” if a fluid can substantially percolate said one or more fiber-free spaces upon immersing said network in said fluid.
In some embodiments of the invention herein, moreover, one or more fiber-free spaces within an exterior volume of a three dimensional structural network of fibers may be considered “substantially connected” if they extend over a length at least about a third of an exterior dimension of said structural network. This includes, but is not limited to one or more fiber-free spaces within an exterior volume of a three-dimensional structural network of fibers extending over a length at least two thirds of an exterior dimension of said structural network, or over a length at least equal to an exterior dimension of said structural network, or over a length and width at least equal to an exterior dimension of said structural network, or over the entire length, width, and thickness of the exterior volume of said three-dimensional structural network.
In the invention herein, one or more fiber-free spaces that are “connected” may also be referred to as one or more fiber-free spaces that are “interconnected”, “contiguous”, “in direct contact”, “merged”, “without any wall in between”, and so on. Similarly, an “exterior dimension of a structural network” may be considered a “length of an exterior volume of said structural network”, and so on.
As shown in the non-limiting schematic of section A-A, at least one interconnected fiber-free space 2530 extends over the entire length and thickness of the outer or exterior volume of the three dimensional structural network 2504. In other words, the length, Lef, over which the interconnected fiber-free space 2530 extends is the same or about the same as the length of the outer or exterior volume of the three dimensional structural network 2504; the thickness, Hef, over which the interconnected fiber-free space 2530 extends is the same or about the same as the thickness, H, of the outer or exterior volume of the three dimensional structural network 2504. It may be noted that the term “section” is understood herein as “plane” or “surface”. Thus a “section” is not a “projection” or “projected view”.
Moreover, in the non-limiting example of
Furthermore, in the non-limiting microstructure of
Several microstructural features can be defined to further characterize such structures. By way of example but not by way of limitation, as shown in
In some embodiments, therefore, one or more fibers or segments thereof may be repeatably or substantially repeatably arranged. More specifically, in some embodiments, one or more fibers or segments thereof may be repeatably or substantially repeatably arranged within a three dimensional structural network formed by said one or more fibers or segments. Similarly, in some embodiments one or more fibers or segments thereof may be orderly or substantially orderly arranged. More specifically, in some embodiments. one or more fibers or segments thereof may be orderly or substantially orderly arranged within a three dimensional structural network formed by said one or more fibers or segments thereof.
Also, in some embodiments one or more fibers or segments thereof may be orderly or substantially orderly arranged in a three dimensional structural network of criss crossed stacked layers of one or more fibers. Similarly, in some embodiments one or more fibers or segments thereof forming a three dimensional structural network of criss-crossed stacked fiber layers may be substantially orderly arranged.
It may be noted, furthermore, that in embodiments where a three dimensional structural network of fibers comprises criss-crossed stacked layers of fibers, the inter-fiber spacing in a layer may be uniform or substantially uniform. In some embodiments, furthermore, the inter-fiber spacing in the fiber layers (e.g., in all fiber layers, etc.) of a structural network of criss-crossed stacked fiber layers may be substantially the same and/or substantially uniform within the exterior volume of said network.
In some embodiments, moreover, one or more fibers or fiber segments in a layer of a three dimensional structural network of criss-crossed stacked fiber layers may be substantially parallel.
In some embodiments moreover, at least four (e.g., at least five, at least six, at least seven, etc.) substantially flat layers of one or more fibers or fiber segments may be stacked in a cross-ply arrangement to form a three dimensional structural network.
In some embodiments, moreover a three dimensional structural network may comprise a single continuous structure.
Moreover as the theoretical models and the experimental examples suggests, a relevant parameter for determining the expansion rate and other properties of a dosage form (or of a fluid-absorptive fiber network or of an expandable, drug releasable solid) herein may be the volume fraction of one or more fluid-absorptive fibers in an outer volume of a three dimensional structural network formed by said one or more fibers. In some embodiments, a larger volume fraction of fluid-absorptive fibers may increase the expansion rate of a dosage form (or of a fluid-absorptive fiber network or of an expandable, drug releasable solid) and enhance some mechanical properties, such as an elastic modulus, of an expanded dosage form or of an expanded drug releasable solid.
In some embodiments, therefore, a three dimensional structural network of one or more fibers comprises an outer surface and an outer volume, said outer volume defined by the volume enclosed (e.g., enveloped, etc.) by said outer surface. In some embodiments, the volume fraction of one or more fluid-absorptive fibers within an outer volume of a three dimensional structural network formed by said one or more fibers may be greater than 0.01. This includes, but is not limited to a volume fraction of one or more fluid-absorptive fibers within an outer volume of a three dimensional structural network formed by said one or more fibers greater than 0.03, or greater than 0.05, or greater than 0.07, or greater than 0.08, or greater than 0.1, or greater than 0.12. or greater than 0.14, or greater than 0.15, or greater than 0.17, or greater than 0.18, or greater than 0.2.
The volume fraction of one or more fluid-absorptive fibers within an outer volume of a three dimensional structural network formed by said one or more fibers may, however, also not be too large to assure that the dosage form or drug releasable solid possesses the desired properties. In some embodiments, therefore, the volume fraction of one or more fluid-absorptive fibers within an outer volume of a three dimensional structural network formed by said one or more fibers is in the range between 0.005 and 0.75. This includes, but is not limited to a volume fraction of one or more fluid-absorptive fibers within an outer volume of a three dimensional structural network formed by said one or more fibers in the ranges 0.01-0.75. or 0.02-0.075, or 0.005-0.7, or 0.01-0.7, or 0.02-0.7.
Any more structures of three dimensional fiber structural networks would be obvious to a person of ordinary skill in the art. All of them are included in this invention.
To assure that fluid can percolate fiber-free space and/or to assure that fiber-free space can be adequately occupied by encapsulating coating, drug-containing solid, and/or free space into which a physiological fluid can percolate, the fiber-free spacing (e.g., the channel size or diameter, channel width, pore size, etc.) between fibers or segments thereof may be on the micro-or macro-scale. Thus, in some embodiments, the fiber-free spacing, Δff, between fibers or fiber segments through (e.g., across, along, etc.) one or more fiber-free spaces or through (e.g., across, along, etc.) one or more connected fiber-free spaces (e.g., the channel size or channel diameter) is greater than 10 μm. This includes, but is not limited to Δff greater than 15 μm, or greater than 20 μm, or greater than 25 μm, or greater than 30 μm, or greater than 35 μm, or greater than 40 μm, or greater than 45 μm, or greater than 50 μm, or greater than 60 μm, or greater than 70 μm, or greater than 80 μm, or greater than 90 μm, or greater than 100 μm, or greater than 125 μm, or greater than 150 μm, or greater than 175 μm, or greater than 200 μm.
For assuring that the dosage form has the required properties (e.g., the required mechanical properties), however, the fiber-free spacing may also not be too large. Thus, in some embodiments, the fiber-free spacing through (e.g., across, along, etc.) one or more fiber-free spaces or through (e.g, across, along, etc.) a connected fiber-free space may be in the ranges 10 μm-5 mm, 10 μm-3 mm, 15 μm-5 mm, 25 μm-5 mm, 25 μm-3 mm, 50 μm-4.5 mm, 50 μm-4 mm, 100 μm-5 mm, 100 μm-4 mm, 200 μm-5 mm, 150 μm-4 mm, 200 μm-4 mm, 50 μm-4 mm, 40 μm-4 mm, or 100 μm-5 mm.
Moreover, in some embodiments herein one or more fiber-free spacings between one or more fibers or fiber segments within the outer volume of a three dimensional structural network may be precisely controlled. Similarly, in some embodiments herein one or more fiber-free spacings between one or more fibers or fiber segments through (e.g., across, along, etc.) one or more interconnected fiber-free spaces may be precisely controlled.
The fiber-free spacing may be determined experimentally from microstructural images (e.g., scanning electron micrographs, micro computed tomography scans, and so on) of a three dimensional structural fiber network or of an expandable, drug releasable solid or dosage form. Non-limiting examples describing and illustrating how a fiber-free spacing may be determined from microstructural images are given in the U.S. application Ser. No. 15/482,776 titled “Fibrous dosage form”.
Any more details of fiber-free spacings would be obvious to a person of ordinary skill in the art. All of them are included in this invention.
To assure that the dosage form or expandable, drug releasable solid disclosed herein may achieve several properties, such as fast expansion after immersing in a physiological fluid under physiological conditions, adequate drug release rate, and so on, a large specific surface area (i.e., a large surface area-to-volume ratio) of the fiber network can be desirable. In some embodiments, therefore, one or more fibers forming a three-dimensional structural network may have an average thickness, h0, no greater than 2.5 mm. This includes, but is not limited to h0 no greater than 2 mm, or no greater than 1.75 mm, or no greater than 1.5 mm, or no greater than 1.25 mm, or no greater than 1 mm, or no greater than 750 μm.
It may be noted, however, that if the fibers or fiber segments are very thin and tightly packed, the spacing and free spacing between the fibers or fiber segments may be too small. Thus, in some embodiments one or more fibers forming a three dimensional structural network may have an average thickness, h0, in the range of 5 μm-2.5 mm. This includes, but is not limited to average thickness, h0, of one or more fibers forming a three dimensional structural network in the ranges 10 μm-2 mm, 20 μm-2 mm, 25 μm-2 mm, 30 μm-2 mm, 20 μm-1.5 mm, 25 μm-1.5 mm, 25 μm-1.25 mm, 25 μm-1 mm, 30 μm-1.5 mm. 30μm-1.25 mm, 30 μm-1 μm, 40 μm-1.5 mm, or 50 μm-1.25 mm.
In some embodiments, moreover, the average thickness of the one or more fibers comprising or composing (e.g., producing, making up, etc.) a three dimensional structural network (e.g., the average thickness of the fibers or fiber segments in a three dimensional structural network) may be precisely controlled.
The fiber thickness, h, may be considered the smallest dimension of a fiber (i.e., h≤w and h≤l, where h, w and/are the thickness, width and length of the fiber, respectively). The average fiber thickness, ho, is the average of the fiber thickness along the length of the one or more fibers. A non-limiting example illustrating how an average fiber thickness may be derived is presented in U.S. application Ser. No. 15/482,776 titled “Fibrous dosage form”.
In some embodiments, at least one outer surface of one or more fibers or fiber segments comprises a coating. Said coating may cover part of or the entire outer surface of one or more fibers or segments thereof. Said coating may further have a composition that is different from the composition of one or more fibers or segments thereof. The coating may be a solid, and may or may not comprise or contain a drug.
Any more fiber geometries would be obvious to a person of ordinary skill in the art. All of them are included in this invention.
Generally, in the invention herein a fluid-absorptive fiber or fiber network may comprise at least a physiological fluid-absorptive first excipient, also referred to herein as “fluid-absorptive first excipient”, “absorptive first excipient”, or “first excipient”. Generally, a fiber or a fiber network comprising an absorptive first excipient may expand with fluid absorption upon immersing said fiber or fiber network in a physiological fluid under physiological conditions.
In some embodiments, therefore, upon exposure to or immersion in a physiological fluid under physiological conditions, an absorptive first excipient (or the excipient in the fiber or fiber network in its totality) can absorb said physiological fluid and form solutions or mixtures with said fluid having a weight fraction of said physiological fluid greater than 0.2. This includes, but is not limited to an absorptive first excipient forming solutions or mixtures with a physiological fluid under physiological conditions having a weight fraction of said physiological fluid greater than 0.3, or greater than 0.4, or greater than 0.5, or greater than 0.6, or greater than 0.7, or greater than 0.8, or greater than 0.9, or greater than 0.95.
In some embodiments, moreover, the solubility of gastric fluid or a relevant physiological fluid in an absorptive first excipient under physiological conditions can be greater than about 200 mg/ml. This includes, but is not limited to solubility of gastric or relevant physiological fluid in an absorptive first excipient greater than 300 mg/ml, or greater than 400 mg/ml, or greater than 500 mg/ml, or greater than 600 mg/ml, or greater than 700 mg/ml, or greater than 750 mg/ml, or greater than 800 mg/ml, or greater than 850 mg/ml. Generally, a greater solubility of gastric or a relevant physiological fluid in an absorptive first excipient under physiological conditions may be preferable.
In some embodiments, moreover an effective diffusivity of physiological/body fluid in an absorptive first excipient (and/or an element or a segment comprising an absorptive first excipient) may be greater than 0.05×10−11 m2/s under physiological conditions. This includes, but is not limited to an effective diffusivity of physiological/body fluid in an absorptive first excipient (and/or an element or a segment comprising an absorptive first excipient) greater than 0.1×10−11 m2/s, or greater than 0.2×10−11 m2/s, or greater than 0.5×10−11 m2/s, or greater than 0.75×10−11 m2/s, or greater than 1×10−11 m2/s, or greater than 2×10−11 m2/s, or greater than 3×10−11 m2/s, or greater than 4×10−11 m2/s under physiological conditions. Generally, a greater diffusivity of gastric or a relevant physiological fluid in an absorptive first excipient under physiological conditions may be preferable.
Alternatively, for absorptive first excipients where diffusion of physiological/body fluid to the interior may or may not be Fickian, a rate of penetration may be specified. In some embodiments, the rate of penetration of a physiological/body fluid into an element or a segment comprising an absorptive first excipient may be greater than an average thickness of said element divided by 3600 seconds (i.e., h0/3600 μm/s). In other examples without limitation, rate of penetration may be greater than h0/1800 μm/s, greater than h0/1200 μm/s, greater than h0/800 μm/s, greater than h0/600 μm/s, or greater than h0/500 μm/s, or greater than h0/400 μm/s, or greater than h0/300 μm/s. Generally, a greater rate of penetration of gastric or a relevant physiological fluid into an element comprising an absorptive first excipient under physiological conditions may be preferable.
For determining the effective diffusivity (and/or the rate of penetration) of dissolution medium in a solid, absorptive first excipient (and/or an element or a segment comprising said absorptive first excipient) the following procedure may be applied. An element (e.g an element or segment of the dosage form structure, or preferably an element or segment that just consists of the absorptive first excipient) may be placed in a still dissolution medium at 37° C. The time ti for the element to break apart or deform substantially may be recorded. (By way of example but not by way of limitation, a deformation of an element may generally be considered substantial if either the length, width, or thickness of the element differs by at least 20 to 80 percent (e.g., at least 20 percent, or at least 30 percent, or at least 40 percent, or at least 50 percent, or at least 60 percent, or at least 70 percent, or at least 80 percent, etc.) from its initial value.) The effective diffusivity, Deff, may then be determined according to Deff=hinit2/4t1 where hinit is the initial element or segment thickness (e.g., the thickness of the dry element or segment). Similarly, the rate of penetration of a physiological/body fluid into the element or segment may be equal to hinit/2t1. Further non-limiting examples for deriving the effective diffusivity or rate of penetration are presented in U.S. application Ser. No. 15/482,776 titled “Fibrous dosage form”.
In some embodiments, at least one fluid-absorptive first excipient may comprise hydroxypropyl methylcellulose.
In some embodiments, at least one fluid-absorptive first excipient comprises hydroxypropyl methylcellulose with an average molecular weight greater than 30 kg/mol. In some embodiments, moreover, at least one fluid-absorptive first excipient comprises hydroxypropyl methylcellulose with a number-average molecular weight greater than 30 kg/mol.
In some embodiments, at least one fluid-absorptive first excipient may comprise hydroxypropyl methylcellulose with an average molecular weight greater than 30 kg/mol, and wherein the volume or weight fraction of hydroxypropyl methylcellulose with average molecular weight greater than 30 kg/mol in the fluid-absorptive solid core may be greater than 0.05.
In some embodiments, moreover, at least one fluid-absorptive first excipient may be selected from the group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl ether cellulose, starch, chitosan, pectin, polymethacrylates (e.g., poly(methacrylic acid, ethyl acrylate) 1:1, or butylmethacrylat-(2-dimethylaminoethyl) methacrylat-methylmathacrylat-copolymer), polyacrylic acid, polyethylene oxide, vinylpyrrolidone-vinyl acetate copolymer, and/or others.
To ensure that a dosage form or drug releasable solid may expand substantially, and that the integrity of an expanded dosage form or an expanded expandable, drug releasable solid (e.g., a semi-solid or viscoelastic mass, etc.) may be preserved for prolonged time within a physiological fluid under physiological conditions, the molecular weight of the one or more physiological fluid-absorptive first excipients may be quite large. In some embodiments, therefore, the molecular weight (e.g., the number-average molecular weight) of at least one absorptive first excipient may be greater than 30 kg/mol. This includes, but is not limited to at least one fluid-absorptive first excipient having a molecular weight (e.g., a number-average molecular weight) greater than 40 kg/mol, or greater than 50 kg/mol, or greater than 60 kg/mol, or greater than 70 kg/mol, or greater than 80 kg/mol.
To ensure that the dosage form can be processed by patterning a viscous paste comprising absorptive first excipient, and for other reasons, the molecular weight of at least one absorptive first excipient (or the absorptive first excipient in its totality) may, however, also be limited.
By way of example but not by way of limitation, the number-average molecular weight of at least one absorptive first excipient (or the number-average molecular weight of the absorptive first excipient in its totality) may be in the ranges 30 kg/mol-10,000.000 kg/mol. 50 kg/mol-10,000,000 kg/mol, 70 kg/mol-10,000,000 kg/mol, 80 kg/mol-10,000,000 kg/mol, 70 kg/mol-5,000,000 kg/mol, 70 kg/mol-2,000,000 kg/mol. In preferable embodiments, a physiological fluid-absorptive first excipient comprises hydroxypropyl methylcellulose with a molecular weight (e.g., a number-average molecular weight) in the range between about 50 kg/mol and 1000 kg/mol (e.g., 70 kg/mol-500,000 kg/mol).
Thus, in some embodiments, at least one absorptive first excipient (or the absorptive excipient in its totality) may comprise a plurality of individual chains or molecules that dissolve or disentangle upon immersion in a physiological fluid.
In some embodiments, moreover, at least one absorptive first excipient may have a solubility greater than 20 g/l in a relevant physiological/body fluid under physiological conditions. This includes, but is not limited to at least one absorptive first excipient (or the absorptive first excipient in its totality) having a solubility in a relevant physiological/body fluid under physiological conditions greater than 50 g/l, or greater than 75 g/l, or greater than 100 g/l, or greater than 150 g/l, or greater than 175 g/l, or greater than 200 g/l, or greater than 250 g/l, or greater than 300 g/l, or greater than 350 g/l. In the extreme case, absorptive first excipient (e.g., at least one absorptive first excipient or the absorptive first excipient in its totality) may be mutually soluble with a relevant physiological fluid under physiological conditions. The solubility of a material is referred to herein as the maximum amount or mass of said material that can be dissolved at equilibrium in a given volume of physiological fluid under physiological conditions divided by the volume of said fluid or of the solution formed. By way of example but not by way of limitation, the solubility of a solute in a solvent may be determined by optical methods.
Preferably, moreover, at least one absorptive first excipient (or the absorptive first excipient in its totality) may comprise an amorphous molecular structure (e.g., an amorphous arrangement of molecules, or an arrangement of molecules without long-range order) in the solid state. A non-limiting method for determining the molecular structure of a solid (e.g., distinguishing amorphous molecular structure from crystalline molecular structure, etc.) is Differential Scanning calorimetry.
In some embodiments, volume or weight fraction of one or more fluid-absorptive first excipients in a fluid-absorptive fiber or fiber structural network may be greater than 0.05. This includes, but is not limited to volume of weight fraction of one or more fluid-absorptive first excipients in a fiber or fiber structural network greater than 0.15 or greater than 0.2.
In some embodiments the weight fraction of absorptive first excipient in at least a fiber or fiber structural network with respect to the total weight of said fiber or fiber structural network may be greater than 0.1. This includes, but is not limited to a weight fraction of absorptive first excipient in a fiber or fiber structural network with respect to the total weight of said fiber or fiber structural network greater than 0.15, or greater than 0.2, or greater than 0.25, or greater than 0.3, or greater than 0.35, or greater than 0.4. Generally, a greater weight fraction of fluid-absorptive first excipient in a fiber or fiber structural network may be preferable for achieving greater expansion of said fiber or fiber structural network.
In some embodiments, the concentration of at least an absorptive first excipient may be substantially uniform within or through or across a fiber or fiber structural network.
In some embodiments, moreover, a fiber or fiber structural network may comprise a plurality of (e.g., two or more) segments having substantially the same weight fraction of physiological fluid-absorptive first excipient distributed within the segments (e.g., the standard deviation of the weight fraction of absorptive first excipient within the segments is no greater than the average value, etc.).
To stabilize a fiber, fiber structural network, drug releasable solid, or dosage form after soaking with a physiological fluid under physiological conditions, in some embodiments, a fluid-absorptive fiber or fiber structural network may further comprise a mechanically strengthening first excipient. A non-limiting example of a mechanically strengthening first excipient is methacrylic acid-ethyl acrylate copolymer.
Moreover, it may be obvious to a person of ordinary skill in the art that additional excipients, such as gastrointestinal contrast agents, fillers, process agents, and so on can be added to a fluid absorptive fiber or fiber structural network.
Any further compositions of fibers, fiber structural networks, or physiological fluid-absorptive fibers or fiber structural networks may be obvious to a person of ordinary skill in the art. All of them are within the spirit and scope of this invention.
Generally, for assuring that the dosage form possesses the desired expansion rate, mechanical properties, drug release rate, and so on, a mechanically strengthening semi-permeable layer as disclosed herein may substantially encapsulate a fluid-absorptive fiber structural network. Generally a network may be referred to as “substantially encapsulated” by a mechanically strengthening semi-permeable layer if after expansion with fluid absorption the mechanical properties (e.g., the tensile strength, elastic modulus, etc.) of said expanded encapsulated network are substantially greater than the mechanical properties of the expanded network without encapsulation.
In some embodiments, moreover, a network may be referred to as “substantially encapsulated” by a mechanically strengthening semi-permeable layer if said mechanically strengthening semi-permeable layer covers (e.g., encloses, coats, etc.) at least 20 percent of the surface of said network. This includes, but is not limited to said mechanically strengthening semi-permeable layer covering at least 30 percent, or at least 40 percent, or at least 50 percent, or at least 60 percent, or at least 70 percent, or at least 80 percent, or at least 90 percent, or about 100 percent of the surface of said network. Generally, a greater area of a network covered by mechanically strengthening semi-permeable layer may be preferable for achieving a pharmaceutical solid dosage form with the desired properties.
It may generally be desirable that mechanically strengthening semi-permeable layer may substantially stabilize a large part or the entire body of an expanded solid or semi-solid. In preferred embodiments, therefore, mechanically strengthening phase may be substantially connected (e.g., substantially continuous, etc.) through a length, and/or through a width, and/or through a thickness, and/or through a volume of an encapsulated fiber structural network (e.g., a fiber structural network encapsulated by said mechanically strengthening semi-permeable layer). In some embodiments, therefore, a mechanically strengthening, semi-permeable layer may form a substantially connected structure through or across an exterior volume of an encapsulated three dimensional structural network of one or more fibers.
In some embodiments, moreover, a mechanically strengthening semi-permeable layer comprising a thickness or an average thickness greater than 1 μm (e.g., greater than 2 μm, no less than 5 μm, no less than 10 μm) may be substantially connected through a length of an encapsulated fiber network (e.g., a fiber network encapsulated by said mechanically strengthening semi-permeable layer). This includes, but is not limited to a mechanically strengthening semi-permeable layer comprising a thickness or an average thickness greater than 1 μm (e.g., greater than 2 μm, no less than 5 μm, no less than 10 μm) substantially connected through a volume of an encapsulated fiber network (e.g., a fiber network encapsulated by said mechanically strengthening semi-permeable layer).
Moreover as the theoretical models and the experimental examples suggest, a relevant parameter for determining the expansion rate and other properties of a dosage form (or of an encapsulated fluid-absorptive fiber network, or of an expandable, drug releasable solid) herein may be the volume fraction of mechanically strengthening, semi-permeable layer in an outer volume of an encapsulated fiber network. In some embodiments, a larger volume fraction of mechanically strengthening semi-permeable layer may decrease the expansion rate of a dosage form (or of an encapsulated fluid-absorptive fiber network or of an expandable, drug releasable solid) but enhance several mechanical properties, such as a tensile strength, an clastic modulus, etc., of an expanded dosage form or an expanded drug releasable solid.
In some embodiments, the volume fraction of mechanically strengthening semi-permeable layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening semi-permeable layer may be no less than 0.005. This includes, but is not limited to a volume fraction of mechanically strengthening layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening layer no less than 0.01, or no less than 0.02, or no less than 0.03, or greater than 0.03, or greater than 0.04, or greater than 0.05, or greater than 0.06, or greater than 0.07, or greater than 0.08, or greater than 0.09, or greater than 0.1.
The volume fraction of mechanically strengthening semi-permeable layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening semi-permeable layer may, however, also not be too large to assure that the dosage form or drug releasable solid possesses the desired properties. In some embodiments, therefore, the volume fraction of mechanically strengthening semi-permeable layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening semi-permeable layer may be in the range between 0.005 and 0.7. This includes, but is not limited to a volume fraction of mechanically strengthening layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening layer in the ranges 0.01-0.7, or 0.02-0.7, or 0.005-0.65, or 0.01-0.65, or 0.02-0.65.
In some embodiments, moreover, the weight fraction of mechanically strengthening semi-permeable layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening semi-permeable layer may be no less than 0.005. This includes, but is not limited to a weight fraction of mechanically strengthening layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening layer no less than 0.01, or no less than 0.02, or no less than 0.03, or greater than 0.03, or greater than 0.04, or greater than 0.05, or greater than 0.06, or greater than 0.07, or greater than 0.08, or greater than 0.09, or greater than 0.1.
In some embodiments, moreover, the weight fraction of mechanically strengthening semi-permeable layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening semi-permeable layer may be in the range between 0.005 and 0.7. This includes, but is not limited to a weight fraction of mechanically strengthening layer within an outer volume of a three dimensional fiber structural network encapsulated by said mechanically strengthening layer in the ranges 0.01-0.7, or 0.02-0.7, or 0.005-0.65, or 0.01-0.65, or 0.02-0.65, or 0.01-0.55, or 0.01-0.5, or 0.01-0.45, or 0.01-0.4.
In some embodiments, moreover the volume of mechanically strengthening semi-permeable surface layer per unit volume of an exterior volume of an encapsulated fiber structural network (e.g., a fiber structural network encapsulated by said mechanically strengthening semi-permeable surface layer) may be greater than 0.005. This includes, but is not limited to volume of mechanically strengthening semi-permeable surface layer per unit volume of an exterior volume of an encapsulated fiber structural network greater than 0.01, or greater than 0.015, or greater than 0.02, or greater than 0.025.
In some embodiments, the weight of mechanically strengthening semi-permeable surface layer per unit volume of an exterior volume of an encapsulated fiber structural network (e.g., the density of said mechanically strengthening semi-permeable surface layer in an outer volume of said encapsulated fiber structural network) is greater than 5 kg/m3. This includes, but is not limited to a weight of mechanically strengthening semi-permeable surface layer per unit volume of an exterior volume of an encapsulated fiber structural network greater than 10 kg/m3, or greater than 15 kg/m3, or greater than 20 kg/m3.
In some embodiments, moreover, the ratio of the volume fraction of a fluid-absorptive three dimensional fiber structural network and the volume fraction of mechanically strengthening, semi-permeable layer within an outer volume of an encapsulated three dimensional fiber structural network may be in the range between 0.1 and 50. This includes, but is not limited to a ratio of the volume fraction of a fluid-absorptive three dimensional fiber structural network and the volume fraction of mechanically strengthening, semi-permeable layer within an outer volume of an encapsulated three dimensional fiber structural network in the ranges 0.1-40, or 0.2-0.50, or 0.2-40, or 0.1-30, or 0.2-30.
As for the three dimensional structural network of one or more fibers, in some embodiments the encapsulated three dimensional fiber structural network may comprise one or more substantially connected encapsulated-fiber-free spaces within its exterior volume.
In some embodiments of the invention herein, one or more encapsulated-fiber-free spaces within an exterior volume of an encapsulated three dimensional fiber structural network may be considered “substantially connected” if a fluid can substantially percolate said one or more encapsulated-fiber-free spaces upon immersing said encapsulated network in said fluid.
In some embodiments of the invention herein, moreover, one or more encapsulated-fiber-free spaces within an exterior volume of an encapsulated three dimensional fiber structural network may be considered “substantially connected” if they extend over a length at least about a third of an exterior dimension of said encapsulated structural network. This includes, but is not limited to one or more encapsulated-fiber-free spaces within an exterior volume of an encapsulated three-dimensional structural network of fibers extending over a length at least two thirds of an exterior dimension of said encapsulated fiber structural network, or over a length at least equal to an exterior dimension of said encapsulated fiber structural network, or over a length and width at least equal to an exterior dimension of said encapsulated fiber structural network, or over the entire length, width, and thickness of the exterior volume of said encapsulated three-dimensional fiber structural network.
In the invention herein, one or more encapsulated-fiber-free spaces that are “connected” may also be referred to as one or more encapsulated-fiber-free spaces that are “interconnected”, “contiguous”, “in direct contact”, “merged”, “without any wall in between”, and so on. Similarly, an “exterior dimension of a encapsulated fiber structural network” may be considered a “length of an exterior volume of said encapsulated fiber structural network”, and so on.
Any more microstructures of surface layer-encapsulated three dimensional structural networks of one or more fibers would be obvious to a person of ordinary skill in the art. All of them are included in this invention.
As for the fiber-free spacing, to assure that fluid can percolate encapsulated-fiber-free space and/or to assure that encapsulated-fiber-free space can be adequately occupied by drug-containing solid and/or free space into which a physiological fluid can percolate, the encapsulated-fiber-free spacing (e.g., the channel size or diameter, channel width, pore size, etc.) between encapsulated fibers or fiber segments may be on the micro-or macro-scale.
Thus, in some embodiments, an encapsulated-fiber-free spacing, λf,ef, between encapsulated fibers or encapsulated fiber segments through (e.g., across, along, etc.) one or more encapsulated fiber-free spaces or one or more connected encapsulated-fiber-free spaces may be greater than 10 μm. This includes, but is not limited to λf,ef greater than 15 μm, or greater than 20 μm, or greater than 25 μm, or greater than 30 μm, or greater than 35 μm, or greater than 40 μm, or greater than 45 μm, or greater than 50 μm, or greater than 60 μm, or greater than 70 μm, or greater than 80 μm, or greater than 90 μm, or greater than 100 μm, or greater than 125 μm, or greater than 150 μm, or greater than 175 μm, or greater than 200 μm.
The encapsulated-fiber-free spacing may, however, also not be too large. Thus, in some embodiments, the encapsulated-fiber-free spacing through (e.g., along, across, etc.) one or more encapsulated-fiber-free spaces or through (e.g., along, across, etc.) a connected encapsulated-fiber-free space may be in the ranges 10 μm-5 mm, 10 μm-3 mm, 15 μm-5 mm, 25 μm-5 mm, 25 μm-3 mm, 50 μm-4.5 mm, 50 μm-4 mm, 100 μm-5 mm, 100 μm-4 mm, 200 μm-5 mm, 150 μm-4 mm, 200 μm-4 mm, 50 μm-4 mm, 40 μm-4 mm, or 100 μm-5 mm.
The encapsulated-fiber-free spacing may be determined experimentally from microstructural images (e.g., scanning electron micrographs, micro computed tomography scans, and so on) of an encapsulated fiber structural network or of an expandable, drug releasable solid. Non-limiting examples describing and illustrating how an encapsulated-fiber-free spacing may be determined from microstructural images are given in the U.S. application Ser. No. 15/482,776 titled “Fibrous dosage form”.
It may be noted, that in some embodiments herein the encapsulated-fiber-free spacing between encapsulated fibers or encapsulated fiber segments within an exterior volume of an encapsulated three dimensional fiber structural network or through (e.g., along, across, etc.) one or more encapsulated-fiber-free spaces may be precisely controlled.
Any more details of encapsulated-fiber-free spacings would be obvious to a person of ordinary skill in the art. All of them are included in this invention.
Generally, a mechanically strengthening semi-permeable layer comprises at least a mechanically strengthening second excipient. A mechanically strengthening second excipient is also referred to herein as “strength-enhancing second excipient”, “strengthening second excipient” or “second excipient”.
For assuring that a pharmaceutical dosage form or drug releasable solid possesses desirable properties, a mechanically strengthening semi-permeable layer (or a strength-enhancing second excipient, or strength-enhancing second excipient in its totality, etc.) may have several characteristics, features, or properties.
By way of example but not by way of limitation, for assuring that a mechanically strengthening semi-permeable layer-encapsulated solid core can expand with fluid absorption, a mechanically strengthening semi-permeable layer (or a strengthening second excipient, or strengthening second excipient in its totality, etc.) may form a viscoelastic, semi-permeable membrane or material upon exposure to a physiological fluid (e.g., gastric fluid) under physiological conditions.
Similarly, for assuring that a mechanically strengthening semi-permeable layer-encapsulated fiber structural network can expand with fluid absorption, a mechanically strengthening semi-permeable layer (or a strengthening second excipient, or strengthening second excipient in its totality, etc.) that encapsulates a fluid-absorptive fiber structural network may be permeable or substantially permeable to a physiological fluid upon immersing (e.g. upon soaking, etc.) said mechanically strengthening semi-permeable layer-encapsulated fiber structural network in a physiological fluid under physiological conditions.
In some embodiments, therefore, the diffusivity of a relevant physiological fluid under physiological conditions in at least a mechanically strengthening layer (or a strengthening second excipient, or strengthening second excipient in its totality, etc.) may be greater than 0.5×10−13 m2/s. This includes, but is not limited to a diffusivity of a relevant physiological fluid under physiological conditions in at least a mechanically strengthening layer (or in at least one strengthening second excipient, or in the strengthening second excipient in its totality) greater than 1×10−13 m2/s, or greater than 2×10−13 m2/s, or greater than 5×10−12 m2/s, or greater than 1×10−12 m2/s, or greater than 2×10−12 m2/s, or greater than 3×10−12 m2/s, or greater than 4×10−12 m2/s, or greater than 5×10−12 m2/s, or greater than 6×10−12 m2/s, or greater than 1×10−11 m2/s. A larger fluid diffusivity is generally preferable for promoting rapid expansion of the fiber structural network.
Similarly, for preventing or reducing outflow of a fluid-absorptive excipient (e.g., a fluid-absorptive first excipient) from a mechanically strengthening semi-permeable layer-encapsulated fiber structural network, a mechanically strengthening semi-permeable layer that encapsulates a fluid-absorptive fiber structural network may be substantially impermeable to a fluid-absorptive first excipient upon immersing (e.g., soaking, etc.) said mechanically strengthening semi-permeable layer-encapsulated fiber structural network in a physiological fluid under physiological conditions.
In some embodiments, accordingly, upon immersing a mechanically strenghtening semi-permeable layer-encapsulated fiber structural network (e.g., enclosing or encapsulating layer and fiber structural network combined) in a relevant physiological fluid under physiological conditions, the diffusivity of at least one physiological fluid-absorptive first excipient in or through said mechanically strengthening, semi-permeable layer (or through a strengthening second excipient, or through a strengthening second excipient in its totality, etc.) may be no greater than 1×10−11 m2/s. This includes, but is not limited to a diffusivity of at least one physiological fluid-absorptive first excipient in or through a mechanically strengthening, semi-permeable layer (or through a strengthening second excipient or through a strengthening second excipient in its totality) after soaking with a physiological fluid under physiological conditions no greater than 5×10−12 m2/s, or no greater than 2×10−12 m2/s, or no greater than 1×10−12 m2/s, or no greater than 5×10−13 m2/s, or no greater than 2×10−13 m2/s, or no greater than 1×10−13 m2/s, or no greater than 5×10−14 m2/s, or no greater than 2×10−14 m2/s. Generally, a smaller diffusivity of absorptive first excipient through a mechanically strengthening layer after soaking with a physiological fluid under physiological conditions may be preferable for preserving the integrity of an expanded dosage form (or of an expanded mechanically strenghtening semi-permeable layer-encapsulated fiber structural network, or of an expanded expandable, drug releasable solid) in a physiological fluid.
In some embodiments, furthermore, upon immersing a mechanically strenghtening semi-permeable layer-encapsulated fiber structural network (e.g., enclosing or encapsulating layer and fiber structural network combined) in a relevant physiological fluid under physiological conditions, the diffusivity of at least one physiological fluid-absorptive first excipient in or through said mechanically strengthening, semi-permeable layer (or through a strength-enhancing second excipient, or through strength-enhancing second excipient in its totality, etc.) is no greater than 0.3 times the self-diffusivity of said at least one absorptive first excipient in a relevant physiological fluid under physiological conditions. This includes, but is not limited to the diffusivity of at least one absorptive first excipient in or through mechanically strengthening, semi-permeable surface layer (or through a strength-enhancing second excipient, or through strength-enhancing second excipient in its totality, etc.) after soaking with a physiological fluid under physiological conditions no greater than 0.2 times, or no greater than 0.1 times, or no greater than 0.05 times, or no greater than 0.02 times, or no greater than 0.01 times, or no greater than 0.005 times, or no greater than 0.002 times, or no greater than 0.001 times the self-diffusivity of said at least one absorptive first excipient in a relevant physiological fluid under physiological conditions.
Generally, to assure that a mechanically strengthening, semi-permeable layer (e.g., mechanically strengthening second excipient) remains a semi-solid or viscoelastic material and stabilizes, or mechanically supports or enforces a one or more fibers or a fiber structural network after exposure to a physiological fluid (e.g., gastric fluid, etc.), the solubility of said mechanically strengthening, semi-permeable layer (e.g., said strengthening second excipient) in said physiological fluid may be limited. In some embodiments, therefore, at least one mechanically strengthening second excipient may have a solubility no greater than 1 g/l in a relevant physiological/body fluid under physiological conditions. This includes, but is not limited to at least one mechanically strenghtening second excipient (or one or more strengthening second excipients, or the strengthening second excipient in its totality) having a solubility in a relevant physiological/body fluid under physiological conditions no greater than 0.5 g/l, or no greater than 0.4 g/l, or no greater than 0.2 g/l, or no greater than 0.1 g/l, or no greater than 0.05 g/l, or no greater than 0.02 g/l, or no greater than 0.01 g/l, or no greater than 0.005 g/l, or no greater than 0.002 g/l, or no greater than 0.001 g/l. In the extreme case, strengthening second excipient (e.g., at least one strengthening second excipient or the strengthening second excipient in its totality) may be insoluble or at least practically insoluble in a relevant physiological fluid under physiological conditions. A smaller solubility of mechanically strengthening, semi-permeable layer (or a strengthening second excipient) in physiological fluid may generally be preferable for preserving the integrity of an expanded dosage form (or of an expanded mechanically strenghtening semi-permeable layer-encapsulated fiber structural network, or of an expanded expandable, drug releasable solid) in a physiological fluid.
It may be noted that even if the solubility of a relevant physiological fluid is low in a mechanically strengthening, semi-permeable layer (or in a strengthening second excipient, or in strengthening second excipient in its totality, etc.), said mechanically strengthening, semi-permeable layer (e.g., said strengthening second excipient, or said strengthening second excipient in its totality, etc.) may soften or plasticize somewhat upon contact with or immersion in said physiological fluid under physiological conditions. As a result, a mechanically strengthening, semi-permeable layer (e.g., at least a strengthening second excipient) can be a solid in the dry state, but upon immersion in or exposure to a relevant physiological fluid (e.g., gastric fluid, etc.) under physiological conditions, it may transition to a semi-solid or viscoelastic material.
Generally, the mechanical properties (such as stiffness, yield strength, tensile strength, elongational viscosity, etc.) of physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g. physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.), should be large enough to stabilize or mechanically support the dosage form, or an expandable, drug releasable solid, or an encapsulated fiber structural network after soaking with a physiological fluid under physiological conditions. In the invention herein, the term “physiological fluid-soaked mechanically strengthening, semi-permeable layer” is generally referred to as a film of mechanically strengthening, semi-permeable layer that is/has been immersed in a relevant physiological fluid (e.g., acidic water) for so long that the water concentration in the film may be roughly at equilibrium.
However, the stiffness, yield strength, tensile strength, elongational viscosity, etc. of physiological fluid-soaked mechanically strengthening, semi-permeable layer should not be too large, so that the expansion of the dosage form or drug releasable solid or fiber structural network after exposure to said physiological fluid may not be excessively impaired or constrained. Thus, mechanically strengthening, semi-permeable layers (e.g., strengthening second excipients) that comprise or form a viscoelastic or semi-solid material upon exposure to a relevant physiological fluid are typically preferred herein.
In some embodiments, physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may comprise an clastic modulus, or an elastic-plastic modulus, or a plastic modulus greater than 0.02 MPa. This includes, but is not limited to physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) comprising an elastic modulus, or an elastic-plastic modulus, or a plastic modulus greater than 0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.3 MPa, or greater than 0.4 MPa, or greater than 0.5 MPa, or greater than 0.6 MPa, or greater than 0.7 MPa, or greater than 0.8 MPa, or greater than 0.9 MPa, or greater than 1 MPa.
In some embodiments, moreover, physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may comprise an elastic modulus, or an elastic-plastic modulus, or a plastic modulus no greater than about 1000 MPa (e.g., no greater than 500 MPa, or no greater than 200 MPa, or no greater than 100 MPa, or no greater than 50 MPa, or no greater than 20 MPa, or no greater than 10 MPa). Preferably, an elastic modulus of a physiological fluid-soaked strengthening second excipient may be no less than about 0.1 MPa and no greater than about 100 MPa.
In some embodiments, moreover, physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may comprise a yield strength greater than 0.005 MPa. This includes, but is not limited to physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) comprising a yield strength greater than 0.0075 MPa, or greater than 0.01 MPa, or greater than 0.02 MPa, or greater than 0.05 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa. In some embodiments, moreover, physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) comprises a yield strength no greater than 500 MPa (e.g., no greater than 200 MPa, or no greater than 100 MPa, or no greater than 75 MPa, or no greater than 50 MPa, or no greater than 20 MPa, or no greater than 10 MPa, or no greater than 5 MPa).
In some embodiments, moreover, physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may comprise a tensile strength (or a fracture strength) greater than 0.02 MPa. This includes, but is not limited to physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) comprising a tensile strength (or a fracture strength) greater than 0.05 MPa, or greater than 0.08 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.3 MPa, or greater than 0.4 MPa, or greater than 0.5 MPa, or greater than 0.6 MPa.
In some embodiments, moreover, physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may comprise a tensile strength (or a fracture strength) no greater than 500 MPa (e.g., no greater than 200 MPa, or no greater than 100 MPa, or no greater than 75 MPa, or no greater than 50 MPa, or no greater than 20 MPa, or no greater than 10 MPa).
In some embodiments, moreover, physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) comprises a strain at fracture greater than 0.2. This includes, but is not limited to physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strength-enhancing second excipient, physiological fluid-soaked strength-enhancing second excipient in its totality, etc.) comprising a strain at fracture greater than 0.5, or greater than 0.75, or greater than 1, or greater than 1.25, or greater than 1.5, or greater than 1.75, or greater than 2, or greater than 2.25, or greater than 2.5. Preferably, the strain at fracture of a physiological fluid-soaked mechanically strengthening semi-permeable layer may be greater than about 1.
In some preferred embodiments, physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may be a viscoelastic material. If exposed to a (small) stress for a short time (e.g., for a time smaller than about the relaxation time), it may deform elastically and spring back. If exposed to a (small) stress for a long time (e.g., for a time longer or much longer than about the relaxation time), it may deform plastically.
In some embodiments, upon exposure to a stress for a long time (e.g., for a time longer or much longer than the relaxation time), physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may deform plastically and essentially behave like a viscous material having an elongational viscosity. In some embodiments, elongational viscosity of physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may be no greater than 1×1011 Pa·s. This includes, but is not limited to elongational viscosity of physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) no greater than 5×1010 Pa·s, or no greater than 2×1010 Pa·s, or no greater than 1×1010 Pa·s, or no greater than 5×109 Pa·s, or no greater than 2×109 Pa·s, or no greater than 1×109 Pa·s.
In some embodiments, moreover, elongational viscosity of physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may be greater or no less than 1×105 Pa·s. This includes, but is not limited to elongational viscosity of physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) greater than 2×105 Pa·s, or greater than 5×105 Pa·s, or greater than 1×106 Pa·s, or greater than 2×106 Pa·s, or greater than 5×106 Pa·s, or greater than 1×107 Pa·s.
In some embodiments, moreover, elongational viscosity of physiological fluid-soaked mechanically strengthening, semi-permeable layer (e.g., physiological fluid-soaked strengthening second excipient, physiological fluid-soaked strengthening second excipient in its totality, etc.) may be in the range 1×105 Pa·s-1×1011 Pa·s, and more preferably in the range 5×105 Pa·s-5×1010 Pa·s, and even more preferably in the range 1×106 Pa·s-2×1010 Pa·s, and even more preferably in the range 2×106 Pa·s-1×1010 Pa·s, which includes, but is not limited to elongational viscosity of physiological fluid-soaked mechanically strengthening, semi-permeable layer in the range 5×106 Pa·s-5×109 Pa·s.
Furthermore, in some embodiments, the solubility of at least a mechanically strengthening second excipient (or the solubility of mechanically strengthening second excipient in its totality) can differ in different physiological fluids under physiological conditions. By way of example but not by way of limitation, in some embodiments the solubility of at least one mechanically strengthening second excipient in aqueous physiological fluid may depend on the pH value of said physiological fluid. More specifically, in some embodiments at least one mechanically strengthening second excipient can be sparingly-soluble or insoluble or practically insoluble in an aqueous physiological fluid that is acidic (e.g., in gastric fluid, or in fluid with a pH value smaller than about 4, or in fluid with a pH value smaller than about 5, etc.), but it can be soluble in an aqueous physiological fluid having a greater pH value (e.g., in a fluid with a pH value greater than about 6, or greater than about 6.5, or greater than about 7, or greater than about 7.5, etc.), such as intestinal fluid. A mechanically strengthening second excipient comprising a solubility that is smaller in acidic solutions than in PH neutral or basic solutions is also referred to herein as “enteric excipient”.
In some embodiments, therefore, at least one strengthening second excipient comprises a solubility in aqueous fluid with a pH value no greater than 4 at least 10 (e.g., at least 20, or at least 50, or at least 100, or at least 200, or at least 500) times smaller than the solubility of said strenghtening second excipient in an aqueous fluid with a pH value greater than 7 (e.g., the latter includes, but is not limited to an aqueous fluid with a pH value greater than 8).
A non-limiting example of such a mechanically strengthening second excipient that is sparingly-soluble in gastric or acidic fluid, but dissolves in intestinal fluid (e.g., aqueous fluid with a pH value greater than about 5.5), is methacrylic acid-ethyl acrylate copolymer. In some embodiments, therefore, a strengthening second excipient comprises is methacrylic acid-ethyl acrylate copolymer.
Another non-limiting example of a mechanically strengthening second excipient is polyvinyl acetate.
Other non-limiting examples of strength-enhancing second excipients herein may include methacrylic acid-ethyl acrylate copolymer, methacrylic acic-methyl methacrylate copolymer, ethyl acrylate-methylmethacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate, polymers including methacrylic acid, polymers including ethyl acrylate, polymers including methyl methacrylate, polymers including methacrylate, Poly[Ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], and ethylcellulose, and so on.
Moreover, to assure that one or more strengthening second excipients (or strengthening second excipient in its totality) may mechanically strengthen an expanded encapsulated core adequately or sufficiently, in some embodiments a volume or weight fraction of one or more strengthening second excipients (or the strengthening second excipient in its totality) in a mechanically strengthening semi-permeable layer may be greater than 0.35. This includes, but is not limited to a volume or weight fraction of one or more strengthening second excipients (or the strengthening second excipient in its totality) in a mechanically strengthening semi-permeable layer greater than 0.4, or greater than 0.45, or greater than 0.5, or greater than 0.55, or greater than 0.6.
Any more examples, details, or features of a mechanically strengthening semi-permeable layer or of a strengthening second excipient obvious to a person of ordinary skill in the art are all included in the spirit and scope of this invention.
In addition to the fiber structural network and the mechanically strengthening semi-permeable layer, the pharmaceutical solid dosage form disclosed herein may comprise a drug-containing solid. Generally, at least a fraction (e.g., at least part) of said drug-containing solid may be attached to, cover, encapsulate, surround, coat, etc. a mechanically strengthening semi-permeable layer or a layer-encapsulated fiber structural network. Such placement of the drug-containing solid may prevent that mechanically strengthening semi-permeable layer blocks or slows down drug release by the drug-containing solid upon immersing said pharmaceutical solid dosage form in a physiological fluid. Thus, such placement of the drug-containing solid may enable a greater range and improved control of the drug release rate by said drug-containing solid into said physiological fluid. It may be noted that a drug-containing solid that is attached to, bonded to, covers, encapsulates, surrounds, coats, etc. a mechanically strengthening semi-permeable layer may generally be understood as a drug-containing solid that may be attached to, bonded to, cover, encapsulate, surround, coat, etc. a surface of said mechanically strengthening semi-permeable layer.
In some embodiments, at least a fraction (e.g., at least part) of a drug-containing solid may be attached to, joined to, connected to, bonded to, immovably attached to, etc. a mechanically strengthening semi-permeable layer or a layer-encapsulated fiber structural network.
In some embodiments, moreover, a drug-containing solid that is attached to, joined to, connected to, bonded to, etc. a mechanically strengthening semi-permeable layer or a layer-encapsulated fiber structural network may remain connected, attached, immovably attached, bonded, etc. to said mechanically strengthening semi-permeable layer or layer-encapsulated fiber structural network upon immersing in a physiological fluid under physiological conditions. In such embodiments, if a layer-encapsulated fiber structural network remains in the stomach for prolonged time, a drug-containing solid attached to, immovably attached to, connected to, bonded to, joined to, etc. said layer-encapsulated fiber structural network may remain in the stomach for prolonged time, too, for releasing drug into gastric fluid over time.
In preferred embodiments, therefore, a drug-containing solid may be bonded to (e.g., bonded or attached to a surface of) a mechanically strengthening semi-permeable layer.
In preferred embodiments, moreover, a drug-containing solid may be bonded to (e.g., bonded or attached to a surface of) a mechanically strengthening semi-permeable layer by interdiffusion of molecules between drug-containing solid and mechanically strenghtening semi-permeable layer or by welding drug-containing solid and mechanically strenghtening semi-permeable layer together.
In some embodiments, moreover, a drug-containing solid may occupy one or more encapsulated fiber-free spaces within a pharmaceutical solid dosage form (or within an outer volume of an encapsulated three dimensional structural network of one or more fibers or within an expandable, drug releasable solid). In some embodiments, moreover, one or more encapsulated fiber-free spaces within a pharmaceutical solid dosage form (or within an outer volume of an encapsulated three dimensional fiber structural network or within an expandable, drug releasable solid) may be occupied by free space that is not occupied by said drug-containing solid. Said free space may enable fluid percolation into the pharmaceutical solid dosage form or drug releasable solid upon immersing said pharmaceutical solid dosage form or drug releasable solid in a physiological fluid under physiological conditions.
In some embodiments, therefore said drug-containing solid may form at least an annulus within one or more encapsulated fiber-free spaces. The annulus may comprise a solid wall comprising the drug-containing solid.
For various reasons, including achieving faster expansion rate, improved control of the drug release rate, and so on, a thickness of a drug-containing solid may be controlled. In some embodiments, moreover, the thickness or average thickness of a drug-containing solid may be no greater than about 5 mm. This includes, but is not limited to a thickness or average thickness of a drug-containing solid no greater than 4.5 mm, or no greater than 4 mm, or no greater than 3.5 mm, or no greater than 3 mm, or no greater than 2.5 mm, or no greater than 2 mm, or no greater than 1.5 mm.
It may be noted, however, that if the drug-containing solid is too thin, it may be difficult to manufacture and hence the properties may again be difficult to control. Thus, in some embodiments, a drug-containing solid has a thickness or average thickness in the range of 5 μm-5 mm. This includes, but is not limited to thickness or average thickness of a drug-containing solid in the ranges 10 μm-5 mm, 20 μm-5 mm, 25 μm-4 mm, 30 μm-3 mm, 20 μm-3.5 mm, 25 μm-5 mm, 25 μm-2.5 mm, 25 μm-1.5 mm, 30 μm-2 mm, 30 μm-1.5 mm, 40 μm-3 mm, 10 μm-1.5 mm, or 50 μm-2.5 mm.
It may be noted, furthermore that the surface area of drug-containing solid may be altered for controlling the rate at which drug is released into a physiological fluid under physiological conditions. A large surface area may be desirable for achieving a large drug release rate, whereas a smaller surface area may be desirable for achieving a smaller drug release rate.
Thus, generally, a thickness (e.g., an average thickness) and surface area of a drug-containing solid may be so determined that the pharmaceutical solid dosage form or expandable, drug releasable solid comprises a desired amount or mass of active ingredient and releases said active ingredient at the desired rate over the desired time.
Any more embodiments and/or examples of the structure of a drug-containing solid obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
Generally, a drug-containing solid as disclosed herein includes at least an active ingredient or drug. In preferred embodiments, moreover, to control the rate by which a drug-containing solid releases drug and/or to control the time over which a drug-containing solid releases drug, a drug-containing solid may further comprise one or more third excipients.
Thus, in preferred embodiments a drug-containing solid may comprise at least a drug and one or more third excipients. In such embodiments one or more drug(s) may be dispersed as particles and/or as molecules in one or more third excipient(s). Thus, the one or more third excipient(s) may form an excipient matrix. The drug may be dispersed as particles and/or as molecules in said excipient matrix.
In the invention herein, an “excipient matrix” may generally be understood as the component in a composite material (e.g., a drug-containing solid) that holds a filler (e.g., a functional filler such as dispersed drug particles and/or drug molecules) together. Thus, drug particles and/or drug molecules may generally be embedded in an excipient matrix.
In some embodiments, an excipient matrix may be erodible. In the invention herein, an excipient matrix may generally be understood “erodible” if said excipient matrix erodes or dissolves upon exposure to a relevant physiological fluid (e.g., gastric fluid) under physiological conditions.
To ensure that an excipient matrix erodes or dissolves upon immersing in a relevant physiological fluid under physiological conditions, in some embodiments an excipient matrix may be formed by one or more third excipients that are soluble in a relevant physiological fluid under physiological conditions (e.g., gastric fluid, simulated gastric fluid, and so on.).
In the invention herein, a third excipient may generally be considered “soluble” if a solid particle of said third excipient dissolves upon exposure to a relevant physiological fluid under physiological conditions (e.g., gastric fluid). In preferred embodiments, moreover, the drug release rate by a drug-containing solid formed by a soluble third excipient (e.g., one or more soluble third excipients) and active ingredient particles or molecules dispersed in said soluble third excipient (e.g. said one or more soluble third excipients) is limited (e.g., substantially limited, substantially determined, etc.) by the rate at which said third excipient erodes. In some embodiments, therefore, a soluble third excipient used herein may comprise a solubility in a relevant physiological fluid (e.g., gastric fluid) under physiological conditions greater than the solubility in said physiological fluid of an active ingredient used herein. This includes, but is not limited to each of the one or more soluble third excipients forming an excipient matrix comprising a solubility in gastric fluid greater or substantially greater than a solubility in gastric fluid of an active ingredient dispersed in said excipient matrix.
More specifically, because one or more third excipients 2820 in the drug-containing solid 2810 comprise at least a third excipient 2820 that is soluble in a physiological fluid 2860 under physiological conditions (e.g., a third excipient that dissolves in said physiological fluid, or a third excipient that diffuses from drug-containing solid into said physiological fluid), said soluble third excipient 2820 may diffuse into (e.g., dissolve or erode into) said physiological fluid 2860 upon contact of said drug-containing solid 2810 with said physiological fluid 2860. As a result, due to third excipient 2820 dissolution or erosion, drug molecules 2815 (and/or drug particles 2813) that are embedded in said dissolving third excipient 2820 may be released (e.g., set free, loosened up and transferred, disattached from the drug containing solid and transferred, eroded around to lose attachment from the drug-containing solid and transferred, etc.) into the dissolution fluid 2860. In such embodiments, the drug release rate may be substantially determined by the rate at which the third excipient 2820 erodes.
Such embodiments where the drug release rate is substantially determined by the rate at which an excipient matrix erodes may be preferred herein because the drug release rate by a drug-containing solid may be controlled by the properties of said excipient matrix.
In some embodiments, therefore, one or more soluble third excipients may be the predominant third excipients an excipient matrix. In the invention herein, “one or more predominant third excipients” may generally be understood as the one or more third excipients in a drug-containing solid that determine the major properties of said drug-containing solid. By way of example but not by way of limitation, one or more soluble third excipients may be the predominant third excipients an excipient matrix of a drug-containing solid if the drug release rate by said drug-containing solid is substantially determined by the rate at which said excipient matrix erodes.
In some embodiments, furthermore, one or more soluble third excipients may be substantially connected through an excipient matrix (e.g., through an erodible excipient matrix).
In some embodiments, moreover, an erodible excipient matrix may be substantially connected through a drug-containing solid.
In some embodiments, furthermore, an erodible excipient matrix may substantially surround dispersed active ingredient particles or molecules.
In some embodiments, moreover, one or more soluble third excipients may substantially surround active ingredient particles or molecules.
Similarly, in preferable embodiments, active ingredient particles or molecules may be substantially embedded in an excipient matrix that erodes upon exposure to a physiological fluid (e.g., gastric fluid) under physiological conditions.
In some embodiments, moreover, active ingredient particles or molecules may be substantially embedded in one or more soluble third excipients.
In some embodiments, moreover, weight or volume fraction of one or more soluble third excipients in an excipient matrix (e.g., an erodible excipient matrix) may be greater than 0.3. This includes, but is not limited to weight or volume fraction of one or more soluble third excipients in an excipient matrix (e.g., an erodible excipient matrix) greater than 0.35, or greater than 0.4, or greater than 0.45, or greater than 0.5, or greater than 0.55, or greater than 0.6.
In some embodiments, moreover, at least one third excipient within a drug-containing solid comprises a solubility greater than 0.1 g/l in a relevant physiological/body fluid (e.g., gastric fluid) under physiological conditions. More preferably, at least one third excipient of a drug-containing solid material or a drug-containing phase or part of a drug-containing solid may have a solubility in a relevant physiological/body fluid (e.g., gastric fluid) under physiological conditions greater than 0.2 g/l, or more preferably greater than 0.5 g/l, or more preferably greater than 1 g/l, or more preferably greater than 2 g/l. This includes, but is not limited to at least one third excipient having a solubility in a relevant physiological/body fluid (e.g., gastric fluid) under physiological conditions greater than 5 g/l, or greater than 10 g/l, or greater than 20 g/l, or greater than 50 g/l. The solubility of a material is referred to herein as the maximum amount or mass of said material that can be dissolved at equilibrium in a given volume of physiological fluid under physiological conditions divided by the volume of said fluid or of the solution formed. By way of example but not by way of limitation, the solubility of a solute in a solvent may be determined by optical methods.
In some embodiments, moreover, at least one soluble third excipient in drug-containing solid comprises a polymer (e.g., a polymeric excipient, a polymeric material, etc.).
A non-limiting example of a soluble third excipient includes hydroxypropyl methylcellulose.
Additional non-limiting examples of soluble third excipients include excipients selected from the group comprising hydroxypropyl methylcellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl ether cellulose, starch, polymethacrylates (e.g., poly(methacrylic acid, ethyl acrylate) 1:1, or butylmethacrylat-(2-dimethylaminoethyl)methacrylat-methylmathacrylat-copolymer), polyethylene oxide, or vinylpyrrolidone-vinyl acetate copolymer.
In some embodiments, furthermore, at least one third excipient in drug-containing solid can be absorptive of a physiological fluid under physiological conditions. By way of example but not by way of limitation, in such embodiments drug may be released from a drug-containing solid by diffusion through an excipient matrix formed by one or more absorptive third excipients.
Moreover, in some embodiments at least one third excipient in drug-containing solid can be both absorptive of a physiological fluid under physiological conditions and soluble in said physiological fluid under said physiological conditions. Additionally, at least one third excipient in drug-containing solid may be mutually soluble with a relevant physiological fluid under physiological conditions.
A drug-containing solid comprising an excipient matrix that only consists of one or more soluble third excipients may be preferable in some embodiments herein, but not in all. By way of example but not by way of limitation, in some embodiments a drug-containing solid comprising an erodible excipient matrix that only comprises one or more soluble third excipients (e.g., one or more polymeric soluble third excipients, etc.) may erode and release drug too fast after immersing said drug-containing solid in a physiological fluid under physiological conditions.
In some embodiments, therefore, a drug-containing solid may comprise one or more stabilizing third excipients.
Generally, the properties of stabilizing third excipient in drug-containing solid herein may be similar to the properties of mechanically strenghtening second excipient in mechanically strengthening semi-permeable layer herein. By way of example but not by way of limitation, the solubility of stabilizing third excipient may be limited or low in a relevant physiological fluid (e.g., gastric fluid) under physiological conditions. More specifically, in some embodiments a stabilizing third excipient has a solubility no greater than 0.5 g/l in a relevant physiological/body fluid under physiological conditions. This includes, but is not limited to at least one stabilizing third excipient having a solubility in a relevant physiological/body fluid under physiological conditions no greater than 0.4 g/l, or no greater than 0.2 g/l, or no greater than 0.1 g/l. or no greater than 0.05 g/l, or no greater than 0.02 g/l, or no greater than 0.01 g/l, or no greater than 0.005 g/l, or no greater than 0.002 g/l, or no greater than 0.001 g/l. In the extreme case, a stabilizing third excipient may be insoluble or at least practically insoluble in a relevant physiological fluid under physiological conditions. A smaller solubility of stabilizing third excipient in physiological fluid can be preferable for stabilizing or mechanically supporting a drug-containing solid immersed in a physiological fluid under physiological conditions.
In some embodiments, furthermore, a stabilizing third excipient (e.g., a film of stabilizing third excipient) comprises a tensile strength greater than 0.02 MPa after soaking with a physiological fluid (e.g., gastric fluid, etc.) under physiological conditions. This includes, but is not limited to a stabilizing third excipient comprising a tensile strength greater than 0.05 MPa, or greater than 0.08 MPa, or greater than 0.1 MPa, or greater than 0.2 MPa, or greater than 0.3 MPa, or greater than 0.4 MPa, or greater than 0.5 MPa, or greater than 0.6 MPa after soaking with a physiological fluid under physiological conditions.
In some embodiments, moreover, a stabilizing third excipient (e.g., a film of stabilizing third excipient) comprises a strain at fracture greater than 0.5 after soaking with a physiological fluid (e.g., gastric fluid, etc.) under physiological conditions. This includes, but is not limited to a stabilizing third excipient comprising a strain at fracture greater than 0.75, or greater than 1, or greater than 1.25, or greater than 1.5 after soaking with a physiological fluid under physiological conditions.
It may be noted, however, that a stabilizing third excipient may soften or plasticize somewhat upon contact with or immersion in a physiological fluid under physiological conditions. As a result, a stabilizing third excipient can be a solid in the dry state, but upon immersion in or exposure to a relevant physiological fluid (e.g., gastric fluid, etc.) under physiological conditions, it may transition to a semi-solid or viscoelastic material. Because the stiffness, yield strength, tensile strength, elongational viscosity, etc. of stabilizing third excipient should not be too large to avoid injury of the gastrointestinal mucosa, such stabilizing excipients that soften somewhat upon immersing in a physiological fluid may be preferable in some embodiments of the invention herein.
In some embodiments, at least one stabilizing third excipient comprises a polymer (e.g., a polymeric excipient, a polymeric material, etc.).
In some embodiments, a stabilizing third excipient may be selected from the group comprising methacrylic acid-ethyl acrylate copolymer.
In some embodiments, moreover, a stabilizing third excipient may be selected from the group comprising polyvinyl acetate.
In some embodiments, furthermore, a stabilizing third excipient is selected from the group comprising methacrylic acid-ethyl acrylate copolymer, methacrylic acic-methyl methacrylate copolymer, ethyl acrylate-methylmethacrylate copolymer, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate, polymers including methacrylic acid, polymers including ethyl acrylate, polymers including methyl methacrylate, polymers including methacrylate, Poly [Ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride], and ethylcellulose.
To control the rate at which drug is released, moreover, in some embodiments drug-containing solid comprises a mixture of one or more soluble third excipients and one or more stabilizing third excipients.
In some embodiments, moreover, one or more soluble third excipients and one or more stabilizing third excipients may form a solid solution. Thus, in the invention herein an excipient matrix (e.g., an erodible excipient matrix) may comprise a solid solution of one or more soluble third excipients and one or more stabilizing third excipients.
In some embodiments, moreover, an excipient matrix may comprise a single-phase material. In the invention herein, a single-phase material may generally be understood as a material with uniform or substantially uniform properties and/or with uniform or substantially uniform structure throughout its volume.
Without wishing to be bound to a particular theory, it may be noted that generally, the greater a volume or weight fraction of stabilizing third excipient in a mixture of soluble and stabilizing third excipient in a drug-containing solid is, the slower may the erosion rate or the drug release rate of said drug containing solid be upon immersing it in a physiological fluid under physiological conditions. Thus, to achieve desirable drug release rates herein, the volume or weight fraction of stabilizing third excipient in a drug-containing solid (or in a mixture of soluble and stabilizing third excipient) may be limited.
In some embodiments, therefore, the volume fraction and/or the weight fraction of one or more stabilizing third excipients in a mixture of one or more soluble third excipients and one or more stabilizing third excipients in a drug-containing solid may be no greater than 0.7 (e.g., no greater than 0.65, or no greater than 0.6, or no greater than 0.55, or no greater than 0.5, or no greater than 0.45, or no greater than 0.4, or no greater than 0.35).
In some embodiments, moreover, the volume fraction and/or the weight fraction of one or more soluble third excipients in a mixture of one or more soluble third excipients and one or more stabilizing third excipients in a drug-containing solid may greater than 0.3 (e.g., greater than 0.35, or greater than 0.4, or greater than 0.45, or greater than 0.5, or greater than 0.55, or greater than 0.6, or greater than 0.65).
However, to assure that stabilizing third excipient adequately stabilizes a drug-containing solid after immersing in a physiological fluid, the volume fraction and/or the weight fraction of stabilizing third excipient in said drug-containing solid may not be too small. In some embodiments, therefore, the volume fraction and/or the weight fraction of one or more stabilizing third excipients (e.g., one or more stabilizing third excipients in their totality) in a mixture of one or more soluble third excipients and one or more stabilizing third excipients in a drug-containing solid may be no less than 0.002 (e.g., no less than 0.005, or no less than 0.007, or no less than 0.01, or no less than 0.02). It may be noted that the limitations of volume and weight fractions given above may refer to the volume or weight of a mixture of one or more soluble third excipients and one or more stabilizing third excipients in a drug-containing solid. They may not refer to the volume or weight of the entire drug-containing solid.
In some embodiments, moreover, upon immersing drug-containing solid comprising a mixture of one or more soluble third excipients and one or more stabilizing third excipients in a physiological fluid under physiological conditions, said one or more stabilizing third excipients may form a solid or semi-solid network mechanically supporting the drug-containing solid and said one or more soluble polymeric third excipients may transition to a viscous mass or a viscous solution or a solution that dissolves over time.
In some embodiments, drug is dispersed as particles and/or molecules in a mixture of one or more stabilizing third excipients and one or more soluble third excipients.
Any more compositions and microstructures of drug-containing solid obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
Generally, in the invention herein an expandable, drug releasable solid may comprise at least a three dimensional structural network of one or more fluid-absorptive fibers, at least a mechanically strengthening semi-permeable layer, and at least a drug containing solid. Said mechanically strenghthening semi-permeable layer may substantially encapsulate said fiber structural network. Also, at least part of said mechanically strengthening semi-permeable layer may be disposed between said fiber structural network and said drug-containing solid. In some embodiments, moreover, an expandable, drug releasable solid may further comprise one or more free spaces or channels within its exterior volume.
In preferred embodiments, one or more free spaces or one or more channels may be substantially open to an exterior surface of an expandable, drug releasable solid. In some embodiments, moreover, one or more free spaces or one or more channels may have at least one open end contiguous with and terminating at an exterior or outer surface of an expandable, drug releasable solid (or of an encapsulated, three-dimensional fiber structural network). In some embodiments, moreover, one or more channels may have at least two open ends contiguous with and terminating at an exterior or outer surface of an expandable, drug releasable solid (or of an encapsulated, three-dimensional fiber structural network). If one or more free spaces or one or more channels are open to an exterior surface of an expandable, drug releasable solid, physiological fluid may percolate into the interior of the internal structure of said expandable, drug releasable solid upon contact with said physiological fluid.
In some embodiments, moreover, one or more free spaces or one or more channels may be substantially connected through an exterior dimension of an expandable, drug releasable solid or through an exterior dimension of an encapsulated fiber structural network.
In some embodiments of the invention herein, one or more free spaces within an exterior volume of an expandable, drug releasable solid or within an exterior volume of an encapsulated three dimensional fiber structural network may be considered “substantially connected” if a fluid can substantially percolate said one or more free spaces upon immersing said drug releasable solid or said encapsulated fiber network (or parts or sections of said drug releasable solid or said encapsulated network) in said fluid.
In some embodiments of the invention herein, moreover, one or more free spaces within an exterior volume of an expandable, drug releasable solid or within an exterior volume of an encapsulated three dimensional fiber structural network may be considered “substantially connected” if they extend over a length at least about a third of an exterior dimension of said an expandable, drug releasable solid or of said encapsulated fiber structural network. This includes, but is not limited to one or more free spaces within an exterior volume of an expandable, drug releasable solid or of an encapsulated three-dimensional fiber structural network extending over a length at least two thirds of an exterior dimension of said expandable, drug releasable solid or encapsulated fiber structural network, or over a length at least equal to an exterior dimension of said expandable, drug releasable solid. In preferred embodiments, a free space may extend through an exterior dimension (e.g., a thickness, etc.) of an expandable, drug releasable solid or of an encapsulated three-dimensional fiber structural network.
Thus, in some embodiments, at least one encapsulated-fiber-free space may have an open channel through it.
In some embodiments, moreover, drug-containing solid may occupy encapsulated-fiber-free space between a free space or channel (e.g., an open free space or an open channel) and an encapsulated three dimensional structural network of one or more fibers. Thus, in some embodiments, a free space (e.g., a channel) may be substantially surrounded by a drug-containing annulus (e.g., an annulus formed by a drug-containing solid). Similarly, in some embodiments, a drug-containing annulus may substantially surround a free space or channel.
In some embodiments, furthermore, one or more channels may be substantially straight. Also, in some embodiments, one or more channels may comprise a substantially uniform cross section along their length. In some embodiments, furthermore, one or more channels may comprise a substantially uniform cross section along their length.
In some embodiments, moreover, a plurality of channels may be substantially parallel to each other. By way of example but not by way of limitation, in some embodiments, at least two channels may be substantially parallel to each other. This includes, but is not limited to a plurality of at least three channels, or at least four channels, or at least five channels, or at least six channels, etc. being substantially parallel to each other.
In some embodiments, furthermore, a plurality of channels may be substantially orderly arranged within an expandable, drug releasable solid. Similarly, in some embodiments, a plurality of channels may be arranged in a substantially ordered pattern within an expandable, drug releasable solid. By way of example but not by way of limitation, in some embodiments a plurality of channels may be arranged in a substantially square lattice (as shown, for example, in the non-limiting top views of
Any more details of the structure of an expandable, drug releasable solid would be obvious to a person of ordinary skill in the art. All of them are included in this invention.
Typically, moreover, for physiological or dissolution fluid to percolate into the interior of the internal structure of an expandable, drug releasable solid the channel size or diameter (e.g., channel width, or pore size, or free spacing, or effective free spacing) within free space of an expandable, drug releasable solid may be on the micro-or macro-scale. Thus, in some embodiments, the free spacing, λf, (e.g., the channel size or channel diameter) through (e.g., along, across, etc.) a free space of an expandable, drug releasable solid may be greater than 1 μm. This includes, but is not limited to As greater than 1.25 μm, or greater than 1.5 μm, or greater than 1.75 μm, or greater than 2 μm, or greater than 5 μm, or greater than 7 μm, or greater than 10 μm, or greater than 15 μm, or greater than 20 μm, or greater than 25 μm, or greater than 30 μm, or greater than 40 μm, or greater than 50 μm.
Because the dosage form volume is generally limited and for other reasons, however, the effective free spacing may not be too large. Thus, in some embodiments, the free spacing (e.g., average free spacing) through (e.g., along, across, etc.) free space of an expandable, drug releasable solid may be in the ranges 1μm-5 mm, 1 μm-3 mm, 1.25 μm-5 mm, 1.5 μm-5 mm, 1.5 μm-3 mm, 5 μm-2.5 mm, 10 μm-2mm, 10 μm-4 mm, 5 μm-4 mm, 10 μm-3 mm, 15 μm-3 mm, 20 μm-3 mm, 30 μm-4 mm, 40 μm-4 mm, or 50 μm-4 mm.
The free spacing may be determined experimentally from microstructural images (e.g., scanning electron micrographs, micro computed tomography scans, and so on) of the pharmaceutical solid dosage form or of an expandable, drug releasable solid. Non-limiting examples describing and illustrating how a free spacing may be determined from microstructural images are presented in the experimental examples or described and illustrated in the U.S. application Ser. No. 15/482,776 titled “Fibrous dosage form”.
It may be noted, that in some embodiments herein the free spacing within one or more free spaces of an expandable, drug releasable solid may be precisely controlled.
Any more details of free spacings in free space of an expandable, drug releasable solid would be obvious to a person of ordinary skill in the art. All of them are included in this invention.
Generally, one or more free spaces (e.g., one or more interconnected free spaces) may be filled with a matter that is removable by a physiological fluid under physiological conditions. Such matter that is removable by a physiological fluid under physiological conditions can, for example, be a gas which escapes a free space upon percolation of said free space by said physiological fluid. Such matter that is removable by a physiological fluid under physiological conditions can, however, also be a solid that is highly soluble in said physiological fluid, and thus dissolves rapidly upon contact with or immersion in said physiological fluid. In some embodiments, such matter that is removable by a physiological fluid under physiological conditions can even comprise a liquid.
In preferred embodiments, a biocompatible gas that may fill free space includes air. Other non-limiting examples of biocompatible gases that may fill free space include nitrogen, CO2, argon, oxygen, and nitric oxide, among others.
Non-limiting examples of solids that are removed or dissolved after contact with physiological/body fluid include sugars or polyols, such as Sucrose, Fructose, Galactose, Lactose, Maltose, Glucose, Maltodextrin, Mannitol, Maltitol, Isomalt, Lactitol, Xylitol, Sorbitol, among others. Other examples of solids include polymers, such as polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, among others. Typically, a solid material should have a solubility in physiological/body fluid (e.g., an aqueous physiological or body fluid) under physiological conditions greater than about 5 g/l to be removed or dissolved rapidly after contact with dissolution medium. This includes, but is not limited to a solubility greater than 10 g/l, or greater than 15 g/l, or greater than 20 g/l, or greater than 50 g/l. The diffusivity of the solid material (as dissolved molecule in physiological/body fluid under physiological conditions) should typically be greater than about 2×10−12 m2/s if the solid material must be dissolved rapidly after contact with dissolution medium. This includes, but is not limited to a diffusivity in physiological fluid under physiological conditions greater than 4×10−12 m2/s, or greater than 6×10−12 m2/s, or greater than 8×10−11 m2/s, or greater than 1×10−11 m2/s, or greater than 2×10−11 m2/s.
In some embodiments, moreover, a solid that may fill free space has a molecular weight (e.g., average molecular weight, such as number average molecular weight or weight average molecular weight) no greater than about 80 kg/mol. This includes, but is not limited to a molecular weight (e.g., average molecular weight, such as number average molecular weight or weight average molecular weight) no greater than 70 kg/mol, or no greater than 60 kg/mol, or no greater than 50 kg/mol, or no greater than 45 kg/mol, or no greater than 40 kg/mol, or no greater than 35 kg/mol.
Further compositions of free space obvious to a person of ordinary skill in the art who is given all information of this specification are all included in this invention.
Generally, upon immersing a pharmaceutical solid dosage form, expandable, drug releasable solid, encapsulated fiber structural network, etc. as disclosed herein in a physiological fluid under physiological conditions, said pharmaceutical solid dosage form, expandable, drug releasable solid, encapsulated fiber structural network, etc. may expand. By way of example but not by way of limitation, expansion of said pharmaceutical solid dosage form, expandable, drug releasable solid, encapsulated fiber structural network, etc. may prevent its premature passage through the pylorus after ingestion. This may enable said pharmaceutical solid dosage form, expandable, drug releasable solid, encapsulated fiber structural network, etc. to release drug into the stomach over time.
Generally, moreover, a pharmaceutical solid dosage form, expandable, drug releasable solid, encapsulated fiber structural network, etc. as disclosed herein may expand with fluid absorption upon immersing said pharmaceutical solid dosage form, expandable, drug releasable solid, encapsulated fiber structural network, etc. in a physiological fluid under physiological conditions. In preferred embodiments, moreover, upon exposure of the pharmaceutical solid dosage form, expandable, drug releasable solid, encapsulated fiber structural network, etc. to a physiological fluid, the pharmaceutical solid dosage form, expandable, drug releasable solid, encapsulated fiber structural network, etc. may expand primarily with fluid absorption. In the invention herein, a solid is generally understood as “expanding primarily with fluid absorption” if upon exposure of said solid to a physiological fluid, the greatest expansion of said solid (e.g., the greatest longitudinal expansion, such as the greatest increase in length or normalized length; the greatest volumetric expansion, such as the greatest increase in volume or normalized volume; etc.) is mostly or primarily due to the absorption of said physiological fluid. It may be noted that a surface layer-encapsulated fiber structural network may generally transition to a viscous (e.g., a highly viscous) or semi-solid mass as it expands with fluid absorption.
In some embodiments, moreover, upon exposure of a dosage form or an expandable, drug releasable solid herein to a physiological fluid under physiological conditions, a mechanically strenghtening, semi-permeable layer may expand due to an internal pressure in the fibers or fiber network it may substantially encapsulate. In some embodiments, moreover, said internal pressure may be generated by osmotic flow of fluid into said fibers or fiber network.
In some embodiments, an expanded expandable, drug releasable solid may form a substantially continuous or connected structure with an exterior dimension of the order of or greater than the diameter of the pylorus (or of the pyloric sphincter) of the human subject (or of the animal) by which the dosage form was ingested.
More specifically, in some embodiments, at least one exterior dimension of an expanded expandable, drug releasable solid may be greater than 16 mm. This includes, but is not limited to such preferred embodiments where at least one exterior dimension of an expanded solid or semi-solid may be greater than 17 mm, or greater than 18 mm, or greater than 19 mm, or even greater than 20 mm.
In some embodiments of the invention herein, moreover, at least one exterior dimension (e.g., a length, width, thickness, side length, etc.) of a dosage form or expanded, expandable, drug releasable solid herein expands to at least 1.2 times the initial value (e.g., the initial length prior to exposure to said physiological fluid) after immersing in a physiological or body fluid under physiological conditions. This includes, but is not limited to at least one exterior dimension of a dosage form or expanded expandable, drug releasable solid expanding to at least 1.25 times the initial value, or at least 1.3 times the initial value, or at least 1.35 times the initial value, or at least 1.4 times the initial value, or at least 1.45 times the initial value, or at least 1.5 times the initial value after immersing in or exposing to a physiological or body fluid under physiological conditions.
In some embodiments of the invention herein, moreover, at least one dimension (e.g., a side length or the thickness) of a pharmaceutical solid dosage form or expandable, drug releasable solid (e.g., an encapsulated fiber structural network, etc.) may expand to at least 1.2 times the initial value (e.g., the initial length prior to exposure to said physiological fluid) within no more than 500 minutes of immersing in a physiological or body fluid under physiological conditions. This includes, but is not limited to at least one dimension of a pharmaceutical solid dosage form or expandable, drug releasable solid (e.g., an encapsulated fiber structural network, etc.) reaching a length at least 1.2 times the initial length within no more than 300 minutes, or within no more than 200 minutes, or within no more than 150 minutes, or within no more than 100 minutes, or within no more than 50 minutes, or within no more than 40 minutes, or within no more than 30 minutes of immersing in said physiological or body fluid under physiological conditions. This may also include, but not be limited to at least one dimension of a pharmaceutical solid dosage form or expandable, drug releasable solid (e.g., an encapsulated fiber structural network, etc.) expanding to a length at least 1.3 times the initial length, or at least 1.4 times the initial length, or at least 1.45 times the initial length, or at least 1.5 times the initial length, or at least 1.55 times the initial length, or at least 1.6 times the initial length within no more than 300 minutes of immersing in or exposing to a physiological or body fluid under physiological conditions.
Furthermore, in some embodiments a pharmaceutical solid dosage form or expandable, drug releasable solid (e.g., an encapsulated fiber structural network, etc.) may expand to at least 2 times its initial volume within no more than about 500 minutes of immersing in a physiological or body fluid under physiological conditions. This includes, but is not limited to a pharmaceutical solid dosage form or expandable, drug releasable solid (e.g., an expandable fiber structural network, etc.) expanding to at least 2times, or at least 3 times, or at least 4 times, or at least 4.5 times, or at least 5 times, or at least 6 times, or at least 6.5 times its initial volume within no more than about 300 minutes of immersing in a physiological or body fluid under physiological conditions.
In some embodiments, upon exposure of the dosage form to a physiological fluid, an expandable, drug releasable solid may form an expanded, viscoelastic composite mass.
In some embodiments, moreover, upon prolonged exposure to a physiological fluid (e.g., longer than 2, 4, 6, 8, or 10 hours in a lightly stirred dissolution fluid such as acidic water), an expanded expandable, drug releasable solid, or an expanded network or semi-solid or viscoelastic mass may maintain its length between 1.3 and 4 times the initial length (e.g., the initial length prior to exposure to said physiological fluid) for prolonged time.
In some embodiments, an expanded expandable, drug releasable solid or a viscoelastic or semi-solid mass may comprise a substantially continuous or connected network of one or more strength-enhancing excipients.
More embodiments related to the expansion of the disclosed dosage forms or expandable solids obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
For maintaining an expanded solid or semi-solid in the stomach of a human or animal subject for prolonged time, it may have adequate mechanical properties.
In some embodiments, therefore, an expanded solid or semi-solid (e.g., an expanded expandable, drug releasable solid) comprises a tensile strength (or a fracture strength) greater than 0.006 MPa for maintaining said expanded solid or semi-solid in the stomach of a human or animal subject for prolonged time. This includes, but is not limited to an expanded solid or semi-solid having a tensile strength (or a fracture strength) greater than 0.008 MPa, or greater than 0.01 MPa, or greater than 0.02 MPa, or greater than 0.03 MPa, or greater than or greater than 0.04 MPa, or greater than 0.05 MPa.
In some embodiments, moreover, an expanded solid or semi-solid (e.g., a viscoelastic composite mass, an expanded expandable, drug releasable solid or dosage form, etc.) formed after immersing an expandable, drug releasable solid in a physiological fluid under physiological conditions comprises an elastic modulus greater than 0.0005 MPa. This includes, but is not limited to an expanded solid or semi-solid formed after immersing an expandable, drug releasable solid in a physiological or body fluid under physiological conditions comprising an elastic modulus greater than 0.002 MPa, or greater than 0.003 MPa, or greater than 0.005 MPa, or greater than 0.007 MPa, or greater than 0.01 MPa, or greater than 0.02 MPa, or greater than 0.03 MPa, or greater than 0.04 MPa, or greater than 0.045 MPa, or greater than 0.05 MPa, or greater than 0.055 MPa, or greater than 0.06 MPa, or greater than 0.065 MPa, or greater than 0.07 MPa, or greater than 0.075 MPa.
The elastic modulus of an expanded solid or semi-solid (e.g., a viscoelastic composite mass, an expanded expandable, drug releasable solid or dosage form, etc.) may, however, also be limited to prevent injury of the gastrointestinal mucosa. In some embodiments, therefore, an expanded solid or semi-solid (e.g., a viscoelastic composite mass, an expanded expandable, drug releasable solid or dosage form, etc.) formed after immersing an expandable, drug releasable solid in a physiological fluid under physiological conditions comprises an elastic modulus no greater than 100 MPa. This includes, but is not limited to an expanded solid or semi-solid (e.g., a viscoelastic composite mass, an expanded expandable, drug releasable solid or dosage form, etc.) formed after immersing an expandable, drug releasable solid in a physiological fluid under physiological conditions comprising an elastic modulus no greater than 80 MPa, or no greater than 70 MPa, or no greater than 60 MPa, or no greater than 50 MPa, or no greater than 40 MPa, or no greater than 30 MPa, or no greater than 20 MPa, or no greater than 10 MPa.
In some embodiments, therefore, an expanded solid or semi-solid (e.g., a viscoelastic composite mass, an expanded expandable, drug releasable solid or dosage form, etc.) formed after immersing an expandable, drug releasable solid in a physiological fluid under physiological conditions comprises a highly elastic or viscoelastic mass that temporarily may not break or permanently deform in a stomach (e.g., under the compressive forces of stomach walls, etc.). Eventually, however, the expanded solid or semi-solid may disentegrate or break, and be excreted from the gastrointestinal tract and from the body.
More embodiments related to the mechanical properties of disclosed expanded solids or semi-solids obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
Generally, the disclosed dosage form may be particularly useful for releasing drug into a physiological fluid over prolonged time. In some embodiments, therefore, upon immersing a pharmaceutical solid dosage form or expandable, drug releasable solid as disclosed herein in a physiological fluid under physiological conditions, eighty percent of the content of an active ingredient or drug in said expandable, drug releasable solid may be released into said physiological fluid within a time no less than about 1.5 hours of immersing said expandable, drug releasable solid in said physiological fluid under physiological conditions. This includes, but is not limited to eighty percent of the content of an active ingredient or drug in an expandable, drug releasable solid released into a physiological fluid within a time no less than 2 hours, or no less than 3 hours, or no less than 5 hours, or no less than 7 hours, or greater than 8 hours, or greater than 10 hours, or greater than 12 hours, or greater than 14 hours of immersing said expandable, drug releasable solid in said physiological fluid under physiological conditions.
The drug release time may, however, also not be too long. In some embodiments, therefore, upon immersing a pharmaceutical solid dosage form or expandable, drug releasable solid as disclosed herein in a physiological fluid under physiological conditions, eighty percent of the content of an active ingredient or drug in said expandable, drug releasable solid may be released into said physiological fluid within a time no greater than about 150 hours of immersing said expandable, drug releasable solid in said physiological fluid under physiological conditions. This includes, but is not limited to eighty percent of the content of an active ingredient in an expandable, drug releasable solid released into a physiological fluid within a time no greater than 120 hours, or no greater than 100 hours, or no greater than 90 hours, or no greater than 80 hours, or no greater than 70 hours, or no greater than 60 hours, or no greater than 50 hours, or no greater than 40 hours, or no greater than 35 hours, or no greater than 30 hours of immersing said expandable, drug releasable solid in said physiological fluid under physiological conditions.
Also, for maintaining a constant drug concentration in blood, it may be desirable to have an amount of an active ingredient released from a pharmaceutical solid dosage form or drug releasable solid into a physiological fluid under physiological conditions that increases substantially linearly with or substantially in proportion to the time of immersing said pharmaceutical solid dosage form or drug releasable solid in said physiological fluid under said physiological conditions.
In some embodiments, therefore, upon immersing a pharmaceutical solid dosage form or drug releasable solid as disclosed herein in a physiological fluid under physiological conditions, an amount or mass of an active ingredient released from said pharmaceutical solid dosage form or drug releasable solid into said physiological fluid may increase substantially linearly with or substantially in proportion to the time of immersing said pharmaceutical solid dosage form or drug releasable solid in said physiological fluid under said physiological conditions.
In some embodiments, moreover, an amount or mass of a drug released from said pharmaceutical solid dosage form into said physiological fluid increases substantially linearly with or substantially in proportion to the time of immersing said pharmaceutical solid dosage form in said physiological fluid under said physiological conditions.
More embodiments related to the drug release properties of disclosed dosage forms or expandable, drug releasable solids obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
Generally, the disclosed dosage form may be used for delivering drug to a human or animal body to treat a myriad of diseases or medical conditions. Generally, moreover, the dosage form can be used for delivering any (or almost any) drug or active ingredient. The disclosed dosage form can, however, be particularly useful for delivery of some specific drugs.
By way of example but not by way of limitation, the disclosed dosage form can be particularly useful for controlled or prolonged delivery of drugs that are sparingly or very sparingly soluble in intestinal fluid.
In some embodiments, therefore the pharmaceutical solid dosage form disclosed herein comprises at least an active ingredient or drug having a solubility in an aqueous physiological fluid at a pH in the range 5.5 to 7.5 (e.g., at a pH in the range 6-7.5) under physiological conditions (e.g., intestinal fluid) no greater than 0.5 mg/ml. This includes, but is not limited to at least an active ingredient or drug having a solubility in an aqueous physiological fluid at a pH in the range 5.5 to 7.5 (e.g., at a pH in the range 6-7.5) under physiological conditions (e.g., intestinal fluid) no greater than 0.3 mg/ml, or no greater than 0.2 mg/ml, or no greater than 0.1 mg/ml, or no greater than 0.075 mg/ml, or no greater than 0.05 mg/ml, or no greater than 0.03 mg/ml, or no greater than 0.02 mg/ml, or no greater than 0.01 mg/ml, or no greater than 0.0075 mg/ml. or no greater than 0.005 mg/ml.
Similarly, the disclosed dosage form can be particularly useful for controlled or prolonged delivery of drugs that comprise a pH-dependent solubility.
In some embodiments, therefore, at least an active pharmaceutical ingredient or drug comprises a solubility in an aqueous physiological fluid at pH in the range 1 to 2 under physiological conditions (e.g., gastric fluid) greater than a solubility in an aqueous physiological fluid at pH in the range 5.5 to 7.5 (e.g., at a pH in the range 6-7.5) under physiological conditions (e.g., intestinal fluid). This includes, but is not limited to a solubility of a drug in an aqueous physiological fluid at pH in the range 1 to 2 under physiological conditions (e.g., gastric fluid) greater than 2 times (or greater than 3 times, or greater than 4 times, or greater than 5 times, or greater than 6 times, or greater than 8 times, or greater than 10 times, or greater than 15 times, or greater than 20 times, or greater than 30 times, or greater than 50 times, or greater than 100 times) a solubility in an aqueous physiological fluid at pH in the range 5.5 to 7.5 (e.g., at a pH in the range 6-7.5) under physiological conditions (e.g., intestinal fluid).
Moreover, the invention herein can be highly useful for prolonged delivery of drugs with short elimination half-life or elimination time constant. In some embodiments, therefore, at least one active pharmaceutical ingredient or drug comprises an elimination half life or elimination time constant no greater than 50 hours. This includes, but is not limited to at least one active ingredient or drug comprising an elimination half life or elimination time constant no greater than 45 hours, or no greater than 40 hours, or no greater than 35 hours, or no greater than 30 hours, or no greater than 25 hours, or no greater than 20 hours, or no greater than 15 hours, or no greater than 14 hours, or no greater than 13 hours, or no greater than 12 hours, or no greater than 11 hours, or no greater than 10 hours.
The invention herein can be further highly useful for delivering drugs that inhibit a kinase or a mutated kinase (e.g., a tyrosine kinase or a mutated tyrosine kinase, etc.) in a human or animal body. In some embodiments, therefore, the active pharmaceutical ingredient herein comprises an inhibitor of a kinase and/or a mutated kinase (e.g., a tyrosine kinase and/or a mutated tyrosine kinase, etc.). In the invention herein, the term “kinase” includes all kinases including tyrosine kinases, janus kinases, mutated tyrosine kinases, mutated janus kinases, and so on. The term “tyrosine kinase” includes all tyrosine kinases, including mutated tyrosine kinases, and so on. A non-limiting example of a tyrosine kinase inhibitor is nilotinib (including all salts (e.g., nilotinib hydrochloride monohydrate, etc.), crystalline forms, etc. thereof) and any other combinations or forms thereof. In some embodiments, therefore, at least one active ingredient in a drug-containing solid herein comprises nilotinib.
The disclosed dosage form may further be particularly useful for treating cancer or a neoplastic disease. By way of example but not by way of limitation, a neoplastic disease or cancer may be treated with an active ingredient from the group comprising kinase inhibitors, kinase inhibiting drugs, janus kinase inhibitors, janus kinase inhibiting drugs, tyrosine kinase inhibitors, tyrosine kinase inhibiting drugs and so on.
The dosage forms herein may also be useful for achieving or maintaining a substantially constant drug concentration in the blood or at a biological target site of a human or or animal subject. In some embodiments, therefore, upon immersing a pharmaceutical solid dosage form or a drug releasable solid as disclosed herein in a physiological fluid under physiological conditions, an amount or mass of an active ingredient released from said pharmaceutical solid dosage form or drug releasable solid into said physiological fluid may increase substantially linearly with or substantially in proportion to the time of immersing said pharmaceutical solid dosage form or drug releasable solid in said physiological fluid under said physiological conditions.
It may be obvious to a person of ordinary skill in the art that the dosage form disclosed herein may comprise additional embodiments, features, materials, excipients, active ingredients, and so on. Any such embodiments, features, materials, excipients, active ingredients, and so on obvious to a person of ordinary skill in the art are all within the spirit and scope of this invention.
The following examples present non-limiting ways by which disclosed dosage forms may be prepared and analyzed, and may enable one of skill in the art to more readily understand the principle of the invention. The examples also include ways for preparing and analyzing particulate dosage forms. The examples are presented by way of illustration and are not meant to be limiting in any way.
The materials used for preparing the particulate dosage forms were as follows.
Drug powder formulation: A particulate mixture of nilotinib hydrochloride monohydrate and various excipients, extracted from marketed immediate-release nilotinib capsules (trade name: Tasigna). The immediate-release nilotinib capsules were purchased from Novartis, Basel, Switzerland, through the pharmacy of the Vetsuisse Faculty at the University of Zurich.
Contrast agent: Barium sulfate (BaSO4), purchased as solid particles of size ˜1 μm, from Humco, Austin, TX.
Empty capsules: Gelatin capsules of size 00 (trade name: Interdelta), purchased from Capsugel, La Seyne sur Mer, France.
First, the contents of a marketed immediate-release capsule containing a particulate mixture of 200 mg nilotinib and 200 mg of various excipients were removed. Then 170 mg of the contrast agent (BaSO4 particles) were added and mixed with the contents. The mixture was filled into an empty capsule that was subsequently closed. Thus, as listed in Table 3, the final particulate dosage form contained 200 mg nilotinib, 200 mg excipients, and 170 mg BaSO4.
The materials for preparing the gastroretentive dosage forms were as follows.
Excipients in the fluid-absorptive core (e.g., fluid-absorptive fibers): Hydroxypropyl methylcellulose with a number-average molecular weight of about 120 kg/mol (HPMC2), purchased from Merck KGAA, Darmstadt, Germany; methacrylic acid-ethyl acrylate copolymer (1:1), with a molecular weight of about 250 kg/mol (trade name: Eudragit L100-55), received from Evonik, Essen, Germany.
Contrast agent in the core: Barium sulfate (BaSO4), purchased as solid particles of size ˜1 μm, from Humco, Austin, TX.
Strengthening coating: Methacrylic acid-ethyl acrylate copolymer as in the core.
Excipients in the drug-containing solid: Hydroxypropyl methylcellulose with a molecular weight of 10 kg/mol (HPMC1), purchased from Merck KGaA, Darmstadt, Germany; and methacrylic acid-ethyl acrylate copolymer as in the core.
Drug: Nilotinib hydrochloride monohydrate, purchased as solid particles from the European Directorate for the Quality of Medicine (EDQM), Strasbourg, France.
Solvents: Dimethylsulfoxide (DMSO) and acetone.
First, solid particles of HPMC2, Eudragit L100-55, and barium sulfate were mixed with liquid DMSO to form a uniform suspension. The concentrations of HPMC2, Eudragit L100-55, and barium sulfate were 500, 300, and 343 mg/ml of DMSO.
The suspension was extruded through a laboratory extruder to form a uniform viscous paste. The viscous paste was put in a syringe equipped with a hypodermic needle of inner radius, Rn=205 μm. The paste was extruded through the needle to form a wet fiber that was patterned layer-by-layer in a cross-ply structure. The nominal inter-fiber spacing was 1500 μm and the number of layers was 32.
After patterning, the solvent was evaporated by blowing warm air at about 50° C. and a velocity of about 1 m/s over the structure for a day. Finally, a cylindrical disk with nominal diameter 14 mm and thickness 8 mm was punched out.
The solid fibrous cylindrical disk consisted 43.75 wt % HPMC2, 26.25 wt % Eudragit L100-55, and 30 wt % barium sulfate, Table 3 later.
It may be noted that the solid fibrous cylindrical disks may generally be understood herein as a “solid core”, an “expandable solid core”, a “fluid-absorptive core”, an “expandable framework”, and so on.
The cylindrical disks so produced were dip-coated with a fiber-strengthening, enteric coating solution. The coating solution consisted of Eudragit L100-55 and acetone at a polymer concentration of 100 mg/ml. The coating was applied by dipping the disks into the coating solution for about 5-10 seconds. The coated disks were then put in a vacuum chamber held at about 35° C. To evaporate the solvent the pressure was slowly reduced from atmospheric to 200 Pa, and maintained at this value for about two hours. After solvent evaporation, the inter-fiber spaces were opened by pushing a 0.8 mm diameter needle through them. The dipping-evaporation process was executed three times.
It may be noted that a coated cylindrical disk may generally be understood as an “expandable solid” or an “expandable, gastroretentive solid” herein.
First, solid particles of nilotinib, HPMC1, and Eudragit L100-55 were mixed with liquid DMSO to form a uniform dispersion. The weight fractions of nilotinib, HPMC1, Eudragit L100-55, and DMSO in the dispersion were 0.372, 0.223, 0.025, and 0.38, respectively.
The coated cylindrical disk was then introduced in a cylindrical mold with a diameter of 14 mm. Subsequently, about 540 mg of the dispersion was dispensed on the disk and pressed into the inter-fiber spaces with a piston. After filling, circular channels were formed in the inter-fiber spaces by pushing a 0.72mm diameter needle through them. To evaporate the solvent and solidify the dispersion the sample was put in a vacuum chamber maintained at a pressure of 200 Pa and a temperature of 20° C. for about a day.
After solvent evaporation, the composition of the inter-fiber space was 60 wt % nilotinib, 36 wt % HPMC1, and 4 wt % Eudragit L100-55, Table 3.
It may be noted, moreover, that after solvent evaporation drug-containing solid in the inter-fiber spaces was attached to the coated cylindrical disk. It may be noted, furthermore, that a method of manufacturing pharmaceutical solid dosage forms as disclosed herein or similar may comprise forming one or more channels in drug-containing matter (e.g., drug-containing plasticized matrix, drug-containing solid, etc.).
After solvent evaporation, preparation of the non-limiting experimental gastroretentive dosage forms herein was final. It may be noted, however, that the dosage forms could have been post-processed further. Any such post-processing obvious to a person of ordinary skill in the art is included in this invention.
The microstructure of drug-excipient particles of the particulate dosage forms was imaged by a Zeiss Merlin High Resolution SEM with a GEMINI column. Prior to imaging the particles were dispensed on carbon conductive tape and coated with a 10-nm thick layer of gold. The sample was imaged with an in-lens secondary electron detector. The accelerating voltage was 5 kV, and the probe current 95 pA.
The microstructures of uncoated fibrous cylindrical disks (e.g., uncoated fluid-absorptive cores), coated fibrous cylindrical disks (e.g., coated or encapsulated cores), and “final” dosage forms were imaged by a Zeiss Merlin High Resolution SEM with a GEMINI column. The top surfaces of the fibrous structures and gastroretentive dosage forms were imaged after coating the sample with a 10-nm thick layer of gold. The longitudinal sections of the disks and dosage forms were imaged after the sample was cut with a thin blade (MX35 Ultra, Thermo Scientific, Waltham, MA) and coated with gold as above. All specimens were imaged with an in-lens secondary electron detector. The accelerating voltage was 5 kV, and the probe current 95 pA.
The weights of the uncoated fibrous cylindrical disks, the coated fibrous cylindrical disks, and the final dosage forms were measured by an analytical balance with a resolution of 0.1 mg (Mettler Toledo, Greifensee, Switzerland).
The microstructure of a coated fibrous cylindrical disk is shown in
a From the scanning electron micrographs shown in FIGS. 30 and 31.
b From Eq. (33).
c From weight measurements.
d Calculated as nα = nc = πRdf,02/λ02.
e From Eq. (32) using a density of the enteric coating, ρec = 800 kg/m3.
f From Eq. (31) using a density of the solid fibers, ρf = 1367 kg/m3.
microstructure of the coated fibrous cylindrical disk may be approximated as having vertical walls of thickness, 2Rf,0, and vertical square channels of width, λ0−2Rf,0. The weight of the coated fibrous cylindrical disk was 650 mg, Table 3.
Several additional parameters may be obtained as follows. The volume fraction of fibers in the dosage form may be written as:
where Vf is the volume of fibers in the dosage form, Vdf the volume of the dosage form, Mf the mass of the uncoated fibrous cylindrical disk, ρf the density of the solid fibers, Rdf,0 the radius of the solid fibrous dosage form, and H0 its thickness. Substituting the relevant parameters listed in Table 3 in Eq. (31), φf=0.3. Similarly, the volume fraction of enteric coating in the dosage form may be written as:
where Vec is the volume of enteric coating in the dosage form, Mec the mass of the coated fibrous cylindrical disk, and ρec the density of the solid coating. For the relevant parameters listed in Table 3, by Eq. (32) φec=0.15.
The drug mass in the dosage form may be obtained as:
where wd,a is the weight fraction of drug in the annuli and Mdf the mass of the final dosage form. For the relevant parameters (wd,a=0.6, Mdf=984 mg, and Mec=650 mg), by Eq. (33) Md,0=200 mg, Table 3.
The particulate dosage form was immersed in a beaker filled with 400 ml dissolution fluid (0.03 M hydrochloric acid (HCl) in deionized (DI) water, pH=1.5, at 37° C.). The fluid was stirred with a paddle rotating at 70 rpm. The immersed sample was then imaged periodically by a Nikon DX camera.
For an analysis of in vitro expansion, the gastroretentive dosage form was immersed in a beaker filled with 400 ml dissolution fluid (0.03 M HCl in DI water, pH=1.5, at 37° C.). The fluid was stirred with a paddle rotating at 70 rpm. The immersed sample was then imaged periodically by a Nikon DX camera.
For determining the mechanical strength of the expanded dosage forms, the dosage forms were first soaked in a dissolution fluid (0.03 M HCl in DI water, pH=1.5, at 37° C.) for 10 hours. Diametral compression tests were then conducted using a Zwick Roell mechanical testing machine equipped with a 10 kN load cell and compression platens. The relative velocity of the platens was 2 mm/s. The test was stopped when the specimen fractured visibly.
Drug release by the dosage forms was determined using a USP dissolution apparatus II (Sotax AG, Aesch, Switzerland). The dissolution bath of the apparatus was filled with 1200 ml dissolution fluid (0.03 M HCl in DI water, pH=1.5, at 37° C.). The fluid was stirred with a paddle rotating at 50 rpm. The dosage forms were immersed in the fluid, and the concentration of dissolved drug versus time was measured by UV absorption using a fiber optic probe connected to a Cary 60 UV-vis spectrophotometer (Agilent Technologies, Santa Clara, CA). Drug concentrations were determined by subtracting the UV absorbance at the wavelength 310 nm from the absorbance at 300 nm.
By contrast, the gastroretentive fibrous dosage forms released drug much slower than the particulate forms,
Six experiments comprising four particulate and two fibrous dosage forms were conducted. The experiments were done with four healthy beagle dogs (12.6-16.1 kg). All four dogs received a particulate dosage form each. Additionally, two of them received a fibrous dosage form each.
The dogs fasted for 18 hours prior to the experiment. The dosage form was administered to an awake dog with 20 ml water. After administration, the dogs were periodically placed in an x-ray permeable box to monitor the position of the dosage form in the gastrointestinal tract by biplanar fluoroscopy (using a Philips Allura Clarity fluoroscopy system). Between imaging, the dogs were allowed to roam about freely with access to water.
At 3 hours after administering the dosage form, 180 grams of basic dry food was given (Grainfree 25/17. Petzeba AG, Alberswil, Switzerland). No sedatives, anesthesia, or other supplements were administered immediately before, during, or after the experiment.
The study was conducted in compliance with the Swiss Animal Welfare Act (TSchG, 2005) and the Swiss Animal Welfare Ordinance (TSchV, 2008). It was approved by the Swiss Federal Veterinary Office Zurich; the animal license number was ZH072/2021.
The compression-decompression cycles were not observed in the first few hours after administering the dosage form. But after 3-4 hours, when the dosage form had expanded and transitioned to a viscoelastic composite mass, they were observed about every 10 seconds.
Not surprisingly, therefore, as shown in
Blood samples were collected using a central venous catheter that was surgically inserted into the dog at least 48 hours before administering the dosage form. After administering, blood samples were taken at various times and blood plasma was extracted as detailed in companion work (see, e.g., A.H. Blaesi, H. Richter, and N. Saka, Gastroretentive fibrous dosage forms for prolonged delivery of sparingly soluble tyrosine kinase inhibitors. Part 4: Experimental validation of the models of drug concentration in blood,
to be published in the International Journal of Pharmaceutics, and referred to herein as “REF. [4]”). The nilotinib concentration in the plasma was then measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) as described in companion work (see, e.g., REF. [4]).
Thus, the fibrous dosage forms enable prolonged drug delivery into the blood at a controlled and/or constant rate, even for drugs that are substantially insoluble in intestinal fluids.
The below claims are suggestive and are not meant to be limiting the spirit and scope of the invention in any way.
| Number | Date | Country | |
|---|---|---|---|
| 63533792 | Aug 2023 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2024/043308 | Aug 2024 | WO |
| Child | 18908569 | US |
