Patent Application
20250009671
This disclosure pertains to coated drug compositions and methods of preparing coated drug compositions.
It is of great interest to the pharmaceutical industry to develop improved formulations of active pharmaceutical ingredients (APIs). Formulation can influence the stability and bioavailability of the APIs as well as other characteristics. Formulation can also influence various aspects of drug product (DP) manufacture, for example, the ease and safety of the manufacturing process.
Many APIs are poorly soluble. Among approved drugs, about 40% contain an API that is poorly soluble. The percentage of poorly soluble compounds among those in development is far higher. Poor solubility contributes to poor bioavailability. Amorphous forms of APIs are generally more soluble than the crystalline form. Thus, it is often desirable to produce a drug formulation in which the API is amorphous rather than crystalline and remains amorphous during storage. An amorphous solid dispersion (ASD) of an API in, usually, a polymer can stabilize the amorphous form of the API against crystallization. ASDs have advantages in terms of supersaturation solubility, dissolution, and improved bioavailability. ASDs are thermodynamically unstable compared to the crystalline form of the API. However, the polymer matrix inhibits recrystallization, for example by exhibiting higher viscosity below the glass transition temperature (Tg) or through drug-polymer interactions. ASD are most often created by hot-melt extrusion, spray drying or anti-solvent precipitation. Ideally, ASDs would be kinetically stable for the duration of their anticipated shelf-life, but most revert to the crystalline form. Exposure to high humidity or high temperature significantly increases the mobility of the API in the ASD and reduces the ability of polymers to inhibit recrystallization. Crystallization of an API in an ASD can occur both via bulk crystallization and surface crystallization.
Described herein is a method of preparing a pharmaceutical composition comprising coated particles comprising amorphous solid dispersion of an active pharmaceutical ingredient (ASD particles) enclosed by one or more metal oxide layers, the method comprising the sequential steps of: (a) providing particles of an amorphous solid dispersion comprising an active pharmaceutical ingredient and a polymer; (b) performing atomic layer deposition to apply a metal oxide layer to particles of an amorphous solid dispersion comprising an active pharmaceutical ingredient and a polymer thereby preparing coated particles comprising an active pharmaceutical ingredient enclosed by one or more metal oxide layers; and (c) processing the coated particles to prepare a pharmaceutical composition.
In various embodiments: the particles are at least 50%, 60%, 65%, 70%, wt/wt drug; the particles have a D50 of 0.1 μm to 200 μm (e.g., 0.1 μm to 10 μm or 0.1 μm to 5 μm) on a volume average basis; the particles have a D90 of 200 μm to 2000 μm on a volume average basis; the glass transition temperature of the active pharmaceutical ingredient in the coated particles is higher than the glass transition temperature of the active pharmaceutical ingredient in the provided particles;
the polymer is selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinyl acetate (PVPVA), polyethylene glycol (PEG), polyacrylates and polymethacrylates; step (a) comprises preparing ASD particles by hot melt extrusion; step (a) comprises preparing ASD particles by spray drying;
In various embodiments: the step of performing atomic layer deposition comprises:
In various embodiments: steps (b2)-(b5) are performed two or more times to increase the total thickness of the metal oxide layer before step (c) is performed; the reactor contents are agitated prior to and/or during step (a); the reactor pressure is allowed to stabilize following step (b1), step (b2), and/or step (b4); the reactor contents are agitated prior to and/or during step (b1), step (b3), and/or step (b5); a subset of vapor or gaseous content is pumped out prior to step (b3) and/or step (b5); the metal oxide layer has a thickness in range of 0.1 nm to 100 nm (e.g., 0.1 nm to 50 nm); step (c) comprises combining the coated particles with one or more pharmaceutically acceptable excipients; the metal oxide is selected from the group consisting of: zinc oxide, aluminum oxide, silicon oxide and titanium oxide; step (b) takes place at a temperature between 25° C. and 50° C.;
step (b) takes place at a temperature between 25° C. and 100° C.
Also described is a pharmaceutical composition comprising coated particles comprising amorphous solid dispersion of an active pharmaceutical ingredient enclosed by one or more metal oxide layers, prepared by a method comprising the sequential steps of:
In various embodiments of the composition: the step of performing atomic layer deposition comprises:
In various embodiments of the composition: the particles are at least 50%, 60%, 65%, 70%, wt/wt drug; the particles have a D50 of 0.1 μm to 200 μm (e.g., 0.1 μm to 10 μm or 0.1 μm to 5 μm) on a volume average basis; the particles have a D90 of 200 μm to 2000 μm on a volume average basis; the glass transition temperature of the active pharmaceutical ingredient in the coated particles is higher than the glass transition temperature of the active pharmaceutical ingredient in the provided particles; the polymer is selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate succinate, and polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate, polyethylene glycol (PEG), polyacrylates and polymethacrylates; step (a) comprises preparing ASD particles by hot melt extrusion; step (a) comprises preparing ASD particles by spray drying;
In various embodiments: the step of performing atomic layer deposition comprises:
In various embodiments: steps (b2)-(b5) are performed two or more times to increase the total thickness of the metal oxide layer before step (c) is performed; the reactor contents are agitated prior to and/or during step (a); the reactor pressure is allowed to stabilize following step (b1), step (b2), and/or step (b4); the reactor contents are agitated prior to and/or during step (b1), step (b3), and/or step (b5); a subset of vapor or gaseous content is pumped out prior to step (b3) and/or step (b5); the metal oxide layer has a thickness in range of 0.1 nm to 100 nm; step (c) comprises combining the coated particles with one or more pharmaceutically acceptable excipients; the metal oxide is selected from the group consisting of: zinc oxide, aluminum oxide, silicon oxide and titanium oxide; step (b) takes place at a temperature between 25° C. and 50° C.; step (b) takes place at a temperature between 25° C. and 50° C.
Prior to coating, particles may have a median particle size, on a volume average basis, between 0.01 μm and 1000 μm.
The pharmaceutical composition may be removed from the reactor and admixed with one or more pharmaceutically acceptable diluent or carrier.
Prior to coating, the particles may consist essentially of an API.
The one or more oxide materials include silicon oxide and various metal oxides including: aluminum oxide, titanium oxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, and/or zirconium dioxide.
The oxidant may be selected from the group of water, ozone, and organic peroxide.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.
The present disclosure provides methods of preparing pharmaceutical compositions comprising particles of an amorphous solid dispersion (ASD) (“ASD particles”) coated with one or more layers of an oxide, e.g., a metal oxide. The coating layers are conformal and of controlled thickness. The coating process described herein can provide ASD particles in which crystallization of the API is significantly inhibited. Importantly, the coating can reduce the need for a high weight percent of polymer in the ASD. This permits the preparation of ASD particles with high drug loading. For example, the ASD particles can have 50%, 60% or 70% wt/wt drug loading. This high drug loading of the particles together with the relative thinness of the oxide coating permits the preparation of pharmaceutical compositions. Because the coating is relatively thin, drug products with high drug loading can be produced. For example, the metal oxide layer can have a thickness in range of 0.1 nm to 100 nm. In addition, the oxide coating can improve characteristic of ASD particles related to various aspects of drug product manufacturing. For example, coated ASD particles can have improved flowability and compressibility compared to otherwise identical uncoated ASD particles. In addition, coated ASD particles can have a reduced tendency to agglomerate compared to otherwise identical uncoated ASD particles. Finally, there are benefits with respect to cost and ease of manufacture because multiple coatings can be applied in the same reactor.
The term “drug,” in its broadest sense includes all small molecule (e.g., non-biologic) APIs, in particular APIs that are organic molecules. The drug could be selected from the group consisting of an analgesic, an anesthetic, an anti-inflammatory agent, an anthelmintic, an anti-arrhythmic agent, an antiasthma agent, an antibiotic, an anticancer agent, an anticoagulant, an antidepressant, an antidiabetic agent, an antiepileptic, an antihistamine, an antitussive, an antihypertensive agent, an antimuscarinic agent, an antimycobacterial agent, an antineoplastic agent, an antioxidant agent, an antipyretic, an immunosuppressant, an immunostimulant, an antithyroid agent, an antiviral agent, an anxiolytic sedative, a hypnotic, a neuroleptic, an astringent, a bacteriostatic agent, a beta-adrenoceptor blocking agent, a blood product, a blood substitute, a bronchodilator, a buffering agent, a cardiac inotropic agent, a chemotherapeutic, a contrast media, a corticosteroid, a cough suppressant, an expectorant, a mucolytic, a diuretic, a dopaminergic, an antiparkinsonian agent, a free radical scavenging agent, a growth factor, a haemostatic, an immunological agent, a lipid regulating agent, a muscle relaxant, a parasympathomimetic, a parathyroid calcitonin, a biphosphonate, a prostaglandin, a radio-pharmaceutical, a hormone, a sex hormone, an anti-allergic agent, an appetite stimulant, an anoretic, a steroid, a sympathomimetic, a thyroid agent, a vaccine, a vasodilator and a xanthine.
Exemplary types of small molecule drugs include, but are not limited to, acetaminophen, clarithromycin, azithromycin, ibuprofen, fluticasone propionate, salmeterol, pazopanib HCl, palbociclib, and amoxicillin potassium clavulanate.
The term “metal oxide material,” in its broadest sense includes all materials formed from the reaction of elements considered metals or metalloid with oxygen-based oxidants. Exemplary metal oxide materials include, but are not limited to, aluminum oxide, titanium dioxide, iron oxide, gallium oxide, magnesium oxide, zinc oxide, niobium oxide, hafnium oxide, tantalum oxide, lanthanum oxide, and zirconium dioxide. Silicon oxide is an example of a metal oxide created by reaction between a metalloid and an oxygen-based oxidants. Exemplary oxidants include, but are not limited to, water, ozone, and inorganic peroxide.
Atomic layer deposition is a thin film deposition technique in which the sequential addition of self-limiting monolayers of an element or compound allows deposition of a film with thickness and uniformity controlled to the level of an atomic or molecular monolayer. Self-limited means that only a single atomic layer is formed at a time, and a subsequent process step is required to regenerate the surface and allow further deposition.
The term “reactor system” in its broadest sense includes all systems that could be used to perform ALD. An exemplary reactor system is illustrated in
Again, illustrating an ALD process, the reactor system 10 includes a stationary vacuum chamber 20 which is coupled to a vacuum pump 24 by vacuum tubing 22. The vacuum pump 24 can be an industrial vacuum pump sufficient to establish pressures less than 1 Torr, e.g., 1 to 100 mTorr, e.g., 50 mTorr. The vacuum pump 24 permits the chamber 20 to be maintained at a desired pressure and permits removal of reaction byproducts and unreacted process gases.
In operation, the reactor 10 performs the ALD thin-film coating process by introducing gaseous precursors of the coating into the chamber 20. The gaseous precursors are spiked alternatively into the reactor. This permits the ALD process to be a solvent-free process. The half-reactions of the ALD process are self-limiting, which can provide Angstrom level control of deposition. In addition, the ALD reaction can be performed at low temperature conditions, such as below 50° C., e.g., below 35° C.
The chamber 20 is also coupled to a chemical delivery system 30. The chemical delivery system 30 includes three or more gas sources 32a, 32b, 32c coupled by respective delivery tubes 34a, 34b, 34c and controllable valves 36a, 36b, 36c to the vacuum chamber 20. The chemical delivery system 30 can include a combination of restrictors, gas flow controllers, pressure transducers, and ultrasonic flow meters to provide controllable flow rate of the various gasses into the chamber 20. The chemical delivery system 30 can also include one or more temperature control components, e.g., a heat exchanger, resistive heater, heat lamp, etc., to heat or cool the various gasses before they flow into the chamber 20. Although
Two of the gas sources provide two chemically different gaseous reactants for the coating process to the chamber 20. Suitable reactants for ALD methods include any of or a combination of the following: monomer vapor, metal-organics, metal halides, oxidants, such as ozone or water vapor, and polymer or nanoparticle aerosol (dry or wet). For example, the first gas source 32a can provide gaseous trimethylaluminum (TMA) or titanium tetrachloride (TiCl4), whereas the second gas source 32b can provide water vapor.
One of the gas sources can provide a purge gas. In particular, the third gas source can provide a gas that is chemically inert to the reactants, the coating, and the particles being processed. For example, the purge gas can be N2, or a noble gas, such as argon.
A rotatable coating drum 40 is held inside the chamber 20. The drum 40 can be connected by a drive shaft 42 that extends through a sealed port in a side wall of the chamber 20 to a motor 44. The motor 44 can rotate the drum at speeds of 1 to 100 rpm. Alternatively, the drum can be directly connected to a vacuum source through a rotary union.
The particles to be coated, shown as a particle bed 50, are placed in an interior volume 46 of the drum 40. The drum 40 and chamber 20 can include sealable ports (not illustrated) to permit the particles to be placed into and removed from the drum 40.
The body of the drum 40 is provided by one or more of a porous material, a solid metal, and a perforated metal. The pores through the cylindrical side walls of the drum 40 can have a dimension of 10 μm.
In operation, one of the gasses flows into chamber 20 from the chemical delivery system 30 as the drum 40 rotates. A combination of pores (1-100 μm), holes (0.1-10 mm), or large openings in the coating drum 40 serve to confine the particles in the coating drum 40 while allowing rapid delivery of precursor chemistry and pumping of byproducts or unreacted species. Due to the pores in the drum 40, the gas can flow between the exterior of the drum 40, i.e., the reactor chamber 20, and the interior of the drum 40. In addition, rotation of the drum 40 agitates the particles to keep them separate, ensuring a large surface area of the particles remains exposed. This permits fast, uniform interaction of the particle surface with the process gas.
In some implementations, one or more temperature control components are integrated into the drum 40 to permit control of the temperature of the drum 40. For example, resistive heater, a thermoelectric cooler, or other component can in or on the side walls of the drum 40.
The reactor system 10 also includes a controller 60 coupled to the various controllable components, e.g., vacuum pump 24, gas distribution system 30, motor 44, a temperature control system, etc., to control operation of the reactor system 10. The controller 60 can also be coupled to various sensors, e.g., pressure sensors, flow meters, etc., to provide closed loop control of the pressure of the gasses in the chamber 20.
In general, the controller 60 can operate the reactor system 10 in accord with a “recipe.” The recipe specifies an operating value for each controllable element as a function of time. For example, the recipe can specify the times during which the vacuum pump 24 is to operate, the times of and flow rate for each gas source 32a, 32b, 32c, the rotation rate of the motor 44, etc. The controller 60 can receive the recipe as computer-readable data (e.g., that is stored on a non-transitory computer readable medium).
The controller 60 and other computing devices part of systems described herein can be implemented in digital electronic circuitry, or in computer software, firmware, or hardware. For example, the controller can include a processor to execute a computer program as stored in a computer program product, e.g., in a non-transitory machine-readable storage medium. Such a computer program (also known as a program, software, software application, or code) can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a standalone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. In some implementations, the controller 60 is a general-purpose programmable computer. In some implementations, the controller can be implemented using special purpose logic circuitry, e.g., an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit).
Initially, particles are loaded into the drum 40 in the reactor system 10. The particles can have a solid core comprising a drug, e.g., one of the drugs discussed above. Once any access ports are sealed, the controller 60 operates the reactor system 10 according to the recipe in order to form the thin-film metal oxide layers on the particles.
In particular, the two reactant gases are alternately supplied to the chamber 20, with each step of supplying a reactant gas followed by a purge cycle in which the inert gas is supplied to the chamber 20 to force out the reactant gas and by-products used in the prior step. Moreover, one or more of the gases (e.g., the reactant gases and/or the inert gas) can be supplied in pulses in which the chamber 20 is filled with the gas to a specified pressure, a delay time is permitted to pass, and the chamber is evacuated by the vacuum pump 24 before the next pulse commences.
In particular, the controller 60 can operate the reactor system 10 as follows.
In a first reactant half-cycle, while the motor 44 rotates the drum 40 to agitate the particles 50:
These steps (i)-(iii) can be repeated a number of times set by the recipe, e.g., two to ten times, e.g., six times.
Next, in a first purge cycle, while the motor 44 rotates the drum to agitate the particles 50:
These steps (iv)-(vi) can be repeated a number of times set by the recipe, e.g., six to twenty times, e.g., sixteen times.
In a second reactant half-cycle, while the motor 44 rotates the drum 40 to agitate the particles 50:
These steps (vii)-(ix) can be repeated a number of times set by the recipe, e.g., two to ten times, e.g., six times.
Next, a second purge cycle is performed. This second purge cycle can be identical to the first purge cycle, or can have a different number of repetitions of the steps (iv)-(vi) and/or different delay time and/or different pressure. The cycle of the first reactant half-cycle, first purge cycle, second reactant half cycle and second purge cycle can be repeated a number of times set by the recipe, e.g., one to ten times. As noted above, the coating process can be performed at low processing temperature, e.g., below 50° C., e.g., at or below 35° C. In particular, the particles can remain or be maintained at such temperatures during all of steps (i)-(ix) noted above. In general, the temperature of the interior of the reactor chamber does not exceed 35° C. during of steps (i)-(ix). This can be achieved by having the first reactant gas, second reactant gas and inert gas be injected into the chamber at such temperatures during the respective cycles. In addition, physical components of the chamber can remain or be maintained at such temperatures, e.g., using a cooling system, e.g., a thermoelectric cooler, if necessary.
Provided are two exemplary methods for a pharmaceutical composition comprising a drug-containing core (an ASD particle) enclosed by one or more metal oxide materials. The first exemplary method includes the sequential steps of: (a) loading the particles comprising the drug into a reactor, (b) applying a vaporous or gaseous metal precursor to the substrate in the reactor, (c) performing one or more pump-purge cycles of the reactor using inert gas, (d) applying a vaporous or gaseous oxidant to the substrate in the reactor, and (e) performing one or more pump-purge cycles of the reactor using inert gas. In some embodiments of the first exemplary method, the sequential steps (b)-(e) are optionally repeated one or more times to increase the total thickness of the one or more metal oxide materials that enclose the solid core of the coated particles. In some embodiments, the reactor pressure is allowed to stabilize following step (a), step (b), and/or step (d). In some embodiments, the reactor contents are agitated prior to and/or during step (b), step (c), and/or step (e). In some embodiments, a subset of vapor or gaseous content is pumped out prior to step (c) and/or step (e).
The second exemplary method includes (e.g., consists of) the sequential steps of (a) loading the particles comprising the drug into a reactor, (b) reducing the reactor pressure to less than 1 Torr, (c) agitating the reactor contents until the reactor contents have a desired moisture content, (d) pressurizing the reactor to at least 10 Torr by adding a vaporous or gaseous metal precursor, (e) allowing the reactor pressure to stabilize, (f) agitating the reactor contents, (g) pumping out a subset of vapor or gaseous content and determining when to stop pumping based on analysis of content in reactor including metal precursor and byproduct of metal precursor reacting with exposed hydroxyl residues on substrate or on particle surface, (h) performing a sequence of pump-purge cycles of the reactor using insert gas, (i) pressuring the reactor to at least 10 Torr by adding a vaporous or gaseous oxidant, (j) allowing the reactor pressure to stabilize, (k) agitating the reactor contents, (l) pumping out a subset of vapor or gaseous content and determining when to stop pumping based on analysis of content in reactor including metal precursor, byproduct of metal precursor reacting with exposed hydroxyl residues on substrate or on particle surface, and unreacted oxidant, and (m) performing a sequence of pump-purge cycles of the reactor using insert gas. In some embodiments of the second exemplary method, the sequential steps (b)-(m) are optionally repeated one or more times to increase the total thickness of the one or more metal oxide materials that enclose the solid core of the coated particles.
Some embodiments provide a method of preparing a pharmaceutical composition comprising coated particles comprising amorphous solid dispersion of an active pharmaceutical ingredient enclosed by one or more metal oxide layers, the method comprising the sequential steps of: (a) providing uncoated particles of an amorphous solid dispersion comprising an active pharmaceutical ingredient (API) and a polymer; (b) performing atomic layer deposition to apply a metal oxide layer to uncoated particles of an amorphous solid dispersion comprising an active pharmaceutical ingredient and a polymer thereby preparing coated particles comprising an active pharmaceutical ingredient enclosed by one or more metal oxide layers; and (c) processing the coated particles to prepare a pharmaceutical composition.
In some embodiments, the uncoated particles are at least 50% wt/wt API. In some embodiments, the uncoated particles are at least 70% wt/wt API. In some embodiments, the coated particles have a D50 of 0.5 um to 200 um on a volume average basis. In some embodiments, the coated particles have a D90 of 200 um to 2000 um on a volume average basis.
In some embodiments, the glass transition temperature of the active pharmaceutical ingredient in the coated particles is higher than the glass transition temperature of the active pharmaceutical ingredient in the provided particles.
In some embodiments, the polymer is selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinyl acetate, polyethylene glycol (PEG),polyacrylates and polymethacrylates.
In some embodiments, step (a) comprises hot melt extrusion. In some embodiments, step (a) comprises spray drying a composition comprising the polymer and the active pharmaceutical ingredient. In some embodiments, the polymer and the active pharmaceutical ingredient are agitated prior to and/or during step (a).
In some embodiments, the step of performing atomic layer deposition comprises: (b1) loading the particles comprising the drug into a reactor; (b2) applying a vaporous or gaseous metal precursor to the particles in the reactor; (b3) performing one or more pump-purge cycles of the reactor using inert gas; (b4) applying a vaporous or gaseous oxidant to the particles in the reactor; and (b5) performing one or more pump-purge cycles of the reactor using inert gas. In some embodiments, steps (b2)-(b5) are performed two or more times to increase the total thickness of the metal oxide layer before step (c) is performed.
In some embodiments, the reactor pressure is allowed to stabilize following step (b1), step (b2), and/or step (b4). In some embodiments, the reactor contents are agitated prior to and/or during step (b1), step (b3), and/or step (b5). In some embodiments, a subset of vapor or gaseous content is pumped out prior to step (b3) and/or step (b5). In some embodiments, step (b) takes place at a temperature between 35° C. and 50° C. In some embodiments, step (c) comprises combining the coated particles with one or more pharmaceutically acceptable excipients.
In some embodiments, the metal oxide layer has a thickness in range of 0.1 nm to 100 nm. In some embodiments, the metal oxide is selected from the group consisting of: zinc oxide, aluminum oxide, silicon oxide and titanium oxide. In some embodiments, the metal oxide is aluminum oxide. In some embodiments, the metal oxide is selected from the group consisting of aluminum oxide and titanium oxide. In some embodiments, the API is selected from the group consisting of ezetimibe, erlotinib and nifedipine. In some embodiments, the polymer is selected from the group consisting of HPMCAS, PVPVA and PVP.
In some embodiments, the coated particles in step (b) are less prone to agglomeration than the uncoated particles in step (a) during storage. In some embodiments, the coated particles in step (b) remain amorphous for a longer time than the uncoated particles in step (a) during storage. In some embodiments, the coated particles in step (b) are less hygroscopic than the uncoated particles in step (a). In some embodiments, the coated particles in step (b) show slower crystallization than the uncoated particles in step (a) during storage.
Some embodiments provide a pharmaceutical composition comprising coated particles comprising amorphous solid dispersion of an active pharmaceutical ingredient enclosed by one or more metal oxide layers, prepared by a method comprising the sequential steps of: (a) providing uncoated particle of an amorphous solid dispersion comprising an active pharmaceutical ingredient and a polymer; (b) performing atomic layer deposition to apply a metal oxide layer to uncoated particles of an amorphous solid dispersion comprising an active pharmaceutical ingredient and a polymer thereby preparing coated particles comprising an active pharmaceutical ingredient enclosed by one or more metal oxide layers; and (c) processing the coated particles to prepare a pharmaceutical composition.
In some embodiments, the step of performing atomic layer deposition comprises: (b1) loading the particles comprising the drug into a reactor; (b2) applying a vaporous or gaseous metal precursor to the particles in the reactor; (b3) performing one or more pump-purge cycles of the reactor using inert gas; (b4) applying a vaporous or gaseous oxidant to the particles in the reactor; and (b5) performing one or more pump-purge cycles of the reactor using inert gas.
In some embodiments, steps (b2)-(b5) are performed two or more times to increase the total thickness of the metal oxide layer before step (c) is performed. In some embodiments, the polymer and the active pharmaceutical ingredient are agitated prior to and/or during step (a). In some embodiments, the reactor pressure is allowed to stabilize following step (b1), step (b2), and/or step (b4). In some embodiments, the reactor contents are agitated prior to and/or during step (b1), step (b3), and/or step (b5). In some embodiments, a subset of vapor or gaseous content is pumped out prior to step (b3) and/or step (b5). In some embodiments, step (b) takes place at a temperature between 35° C. and 50° C.
In some embodiments, the metal oxide layer has a thickness in range of 0.1 nm to 100 nm. In some embodiments, the uncoated particles have a median particle size, on a volume average basis between 0.1 μm and 1000 μm.
In some embodiments, the coated particles comprising an active pharmaceutical ingredient further comprise one or more pharmaceutically acceptable excipients. In some embodiments, the uncoated particles consist of the active pharmaceutical ingredient.
In some embodiments, the metal oxide is selected from the group consisting of aluminum oxide and titanium oxide. In some embodiments, the API is selected from the group consisting of ezetimibe, erlotinib and nifedipine. In some embodiments, the polymer is selected from the group consisting of HPMCAS, PVPVA and PVP.
In some embodiments, the coated particles in step (b) are less prone to agglomeration than the uncoated particles in step (a) during storage. In some embodiments, the coated particles in step (b) remain amorphous for a longer time than the uncoated particles in step (a) during storage. In some embodiments, the coated particles in step (b) are less hygroscopic than the uncoated particles in step (a). In some embodiments, the coated particles in step (b) show slower crystallization than the uncoated particles in step (a) during storage.
Pharmaceutically acceptable excipients include, but are not limited to:
The following materials and methods were used in the Examples. To apply an aluminum oxide coating, the vaporous or gaseous metal precursor was tri-methyl aluminum (TMA), the byproduct gaseous methane forms after TMA reacts with exposed hydroxyl groups on the particles or on surface of the coated particles, and the oxidant is water vapor.
In brief, the method for creating an Al2O3 coating comprised the sequential steps of:
In some cases, the steps of (b)-(m) were repeated more than once to increase the total thickness of the metal oxide that enclose the drug particle core. A TiO2 coating can be applied by a similar process using TiCl4.
Particles of an ASD of ezetimibe in hydroxypropyl methyl cellulose acetate succinate (HPMCAS) with 50% or 70% drug loading, were prepared by spray drying. The particles with 50% (B3-140 and B3-141) or 70% (B3-139A, B3-138B and B3-139B) drug loading were coated with aluminum oxide by ALD at 35° C., essentially as described above. The ASD particles received an approximately 5 nm thick (B3-140 and B3-139A), an approximately 15-20 nm thick (B3-138B) or an approximately 20-30 nm think coating (B3-141 and B3-139B). The size distribution of the various ASD particles is shown in Table 1.
X-ray diffraction was used to assess the coated and uncoated ASD particles. As shown in
Scanning electron microscopy was used to assess the morphology of the coated and uncoated ASD particles. As can be seen in
The compressibility and the flowability of the coated and uncoated ASD particles were measured. As can be seen in
Isothermal moisture sorption was used to assess the moisture absorption tendency of the coated and uncoated ASD particles. As can be seen in
Example 2: Metal Oxide Coated ASD Particles are Resistant to Crystallization in Accelerated Stability Study Conditions
The coated and uncoated ASD particles of Example 1 were subjected to an accelerated stability study. The coated and uncoated ASD particles were stored at 40° C./75% relative humidity. Samples of the coated and uncoated ASD particles were analyzed by x-ray diffraction at Days 12, 19, 26, 33, 40, 47, 54 and 61. As can be seen in
Thermal analysis was used to assess the thermal-induced crystallization of the coated and uncoated ASD particles subjected to the accelerated stability study. As can be seen in
Scanning electron microscopy was used to assess the morphology of the coated and uncoated ASD particles. As can be seen in
The coated and uncoated ASD particles of Example 1 (aluminum oxide/ezetimibe/HPMCAS) were subjected to an accelerated stability study under open condition (8 month storage at 40° C. and 75% relative humidity). As can be seen in
The samples were also assessed by scanning electron microscopy (SEM) to assess the particle morphology of uncoated and metal oxide coated 50% DL (drug loaded) ASD particles (aluminum oxide/ezetimibe/HPMCAS) after storage at 40° C. and 75% relative humidity for different periods (day 12, day 47, day 210, day 240 and day 270). As shown in
The samples were also assessed by scanning electron microscopy (SEM) to assess the particle morphology of uncoated and metal oxide coated 70% DL ASD particles (aluminum oxide/ezetimibe/HPMCAS) after storage at 40° C. and 75% relative humidity for different periods (day 12, day 61, day 180, day 210, day 240 and day 270). As shown in
Samples of the coated and uncoated ASD particles (aluminum oxide/ezetimibe/HPMCAS) were analyzed by x-ray diffraction after 9 month storage at 40° C. and 75% relative humidity. As shown in
The samples were also assessed by scanning electron microscopy (SEM) to assess the particle morphology of uncoated and metal oxide coated ASD particles (aluminum oxide/ezetimibe/HPMCAS) after one year storage at 40° C. and 75% relative humidity. As shown in
Samples of the coated and uncoated ASD particles (aluminum oxide/ezetimibe/HPMCAS) were analyzed by x-ray diffraction after one year storage at 40° C. and 75% relative humidity. As shown in
Crystallization decreases the solubility of ezetimibe. The release of ezetimibe from coated and uncoated ASD particles prepared as described in Example 1 was studied. In each case, the dissolution conditions were 37° C., 200 rpm stirring in 50 ml phosphate buffer of FaSSSIF (pH 6.5) solution and the amount of ASD particles used was equivalent to 10 mg of ezetimibe. Thus, in this release study, the maximum possible concentration of ezetimibe is 200 μg/ml. After adding the ASD particles equivalent to 10 mg ezetimibe, release profile data is collected by real time in situ UV dissolution measurements. As can be seen in
Particles of an ASD of erlotinib in hydroxypropyl methyl cellulose acetate succinate (HPMCAS) with 60% drug loading, were prepared by spray drying. The particles EH60-5 were coated with aluminum oxide by ALD at 35° C., essentially as described above. EH60-5 is the uncoated ASD particles (erlotinib/HPMCAS) with 60% drug loading. B3-281B is the coated ASD particles (aluminum oxide/erlotinib/HPMCAS) with 60% drug loading.
The freshly prepared uncoated and metal oxide coated ASD particles (aluminum oxide/erlotinib/HPMCAS) with 60% drug loading were tested for powder flowability. As shown in
The freshly prepared uncoated and coated ASD particles (aluminum oxide/erlotinib/HPMCAS) with 60% drug loading were analyzed by x-ray diffraction. As shown in
The freshly prepared uncoated and coated ASD particles (aluminum oxide/erlotinib/HPMCAS) with 60% drug loading were also analyzed by Fourier-transform infrared spectroscopy. As shown in
Particles of an ASD of erlotinib in polyvinylpyrrolidone-polyvinylacrylate copolymer (PVPVA) with 50% drug loading, were prepared by spray drying with the below parameters: 1) Inlet/Outlet Temp: 105° C./68° C.; 2) Spray Flow Rate (setting): 20%; 3) Aspirator: 100%; and 4) Gas Flow: 55. EP50-15 is the uncoated ASD particles (erlotinib/PVPVA) with 50% drug loading. B3-284A is the thin coated ASD particles (aluminum oxide/erlotinib/PVPVA) with 50% drug loading. B3-284B is the thick coated ASD particles (aluminum oxide/erlotinib/PVPVA) with 50% drug loading.
The fresh prepared thin coated ASD (B3-284A) and thick coated ASD (B3-284B) were analyzed to assess the coating thickness and oxide content. As shown in
Samples of the uncoated and coated ASD particles (aluminum oxide/erlotinib/PVPVA) with 50% drug loading that were stored in open bottles for 4 weeks at 40° C. and 43% relative humidity were also analyzed by SEM. As shown in
Particles of an ASD of nifedipine in polyvinylpyrrolidone (PVP) with 50% (SF20000521) or 70% (SF20000611) drug loading, were prepared by spray drying according to Table 2. The particles were coated with aluminum oxide by ALD at 35° C., essentially as described above.
The size distribution, bulk density and tap density of the various uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading are shown in Table 3.
The freshly prepared uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading were analyzed for nifedipine content and water content. As shown in
As shown in
PVP, nifedipine, freshly prepared uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading were analyzed by x-ray diffraction. As shown in
The uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% and 70% drug loading were subjected to moisture sorption analysis after storage in capped amber glass bottles, capped with induction sealed HDPE bottles, and open HDPE bottles with no cap for various durations. As shown in
Samples of uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading that were stored in open HDPE bottles with no cap for various durations at 40° C. and 75% relative humidity were subjected to visual inspection. As shown in
Samples of uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading that were stored in capped with induction sealed HDPE bottles for various durations were subjected to visual inspection. As shown in
Samples of uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading that were stored in capped amber bottles for various durations were subjected to visual inspection. As shown in
Samples of uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading that were stored in capped amber bottles for 3 months at 25° C. and 60% relative humidity were subjected to X-ray diffraction analysis. As shown in
Samples of uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading that were stored in capped with induction sealed HDPE bottles for 3 months at 40° C. and 75% relative humidity were subjected to X-ray diffraction analysis. As shown in
Samples of uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/PVP) with 50% (SF20000521) and 70% (SF20000611) drug loading that were stored in open HDPE bottles with no cap for 3 months at 40° C. and 75% relative humidity were subjected to X-ray diffraction analysis. As shown in
The samples were also assessed by scanning electron microscopy (SEM) to assess the particle morphology of uncoated and metal oxide coated ASD particles (aluminum oxide/nifedipine/HPMCAS) with 50% (SF20000521) and 70% (SF20000611) drug loading after 3 month storage in open HDPE bottles with no cap at 40° C. and 75% relative humidity. As shown in
This application claims priority to U.S. application Ser. No. 17/341,213, filed on Jun. 7, 2021, which claims priority to U.S. Provisional Application Ser. No. 63/035,639, filed on Jun. 5, 2020, the disclosure of which is incorporated by reference.
| Number | Date | Country | |
|---|---|---|---|
| 63035639 | Jun 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17341213 | Jun 2021 | US |
| Child | 18737814 | US |
