Patent Application
20240245780
The invention generally relates to the field of pharmaceutical preparations and manufacturing. It particularly relates to pharmaceutical compositions containing amorphous solid solutions or amorphous solid dispersions, processes for making the same, and methods of increasing dissolution rate and extent, and of modulating dissolution behavior, oral absorption, and/or bioavailability of poorly water-soluble drugs.
Approximately 75-90% of discovered drugs display solubility-limited absorption, which presents the pharmaceutical industry with a “poor solubility challenge”. Such drug candidates tend to display high lipophilicity, poor aqueous solubility, and consequently, low oral bioavailability.
Various pharmaceutical approaches have been proposed to improve the properties of such drugs. These approaches include salt formation, polymorphs, amorphization, complexation, particle size reduction, and drug delivery systems, e.g., liposome, microemulsion, etc.
High lattice energy, which is often reflected by a high melting temperature, is an impediment to attain adequate solubility. Any approach that reduces or eliminates lattice energy would enhance apparent solubility, such as metastable and amorphous polymorph.
In amorphization, a crystalline drug is transformed to amorphous form. Amorphous form is, by definition, a non-crystalline material which possesses no long-range order. It behaves both as a glassy solid (hard and brittle, high viscosity, low molecular mobility) and a super-cooled liquid (softer and rubbery state, low viscosity, high molecular mobility), depending on the temperature. The transition from the glassy to the rubbery state is characterized by a temperature called the glass-transition temperature (Tg). An increase in the molecular mobility of an amorphous material above its Tg is usually also accompanied by devitrification to a more stable crystalline form. As a result, a high glass-transition temperature, amorphous form of a drug is often preferred.
Amorphous drugs tend to exhibit supersaturated solubility due to their lack of crystalline order at the molecular level, and thus, tend to have a higher dissolution rate and extent followed by greater absorption. However, the amorphous form of a drug is thermodynamically unstable and may convert to the more stable crystalline form at ambient conditions, or conversion can happen at a faster rate at exaggerated temperature and humidity conditions. Due to this reason, amorphous drugs are not typically used as such in dosage forms.
To increase the thermodynamic stability of an amorphous drug, hydrophilic or hydrophobic polymers are typically added. Hydrophilic polymers are often preferred over hydrophobic ones due to their ability to increase the wettability, dispersion, and dissolution rate of the drug. Most commonly used hydrophilic polymers are hydroxypropyl methylcellulose (HPMC), hydroxy ethyl cellulose, hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), methyl cellulose, chitosan, carboxymethyl cellulose, ethyl cellulose, carboxymethyl ethyl cellulose, cyclodextrin and derivatives, lactose, poloxamers, polyvinylpyrrolidone (PVP), polymethacrylates (EUDRAGIT E, L, S, FS), polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA 64), polyvinyl acetate phthalate (PVAP), and polyethylene glycols (PEG) derivatives.
The increase in stability of an amorphous solid dispersion is a function of drug and polymer properties, concentration, processing method, storage condition, etc. The polymer can increase the stability of an amorphous drug by increasing its Tg and the distance between the drug molecules. However, forming amorphous solid dispersions generally does not increase the stability of the amorphous drug indefinitely or for all conditions. The amorphous drug may be relatively stable at ambient temperature and humidity conditions. However, excursion from ambient conditions (such as exposure to high temperature or humidity, which can happen during manufacturing, transportation, storage, or usage) can cause the amorphous drug to crystallize. That crystallization may cause the drug to fail dissolution specifications. Another reason for crystallization can be non-homogenous distribution of the amorphous drug in the solid dispersion, which could lead to formation of crystal nuclei in the region poor in polymer concentration and rich in the drug.
The stability of an amorphous drug in a polymer or excipient can be increased if it forms a homogenous solution instead of a dispersion, since solutions are thermodynamically more stable.
Sucrose acetate isobutyrate (SAIB) was introduced as a food additive in 1969 and is approved as a food additive for use in carbonated and non-carbonated beverages in over 28 countries. Although SAIB has found many uses in the coatings industry, its only use in foods at the present time is as a “weighting” or “density-adjusting” agent in citrus-based carbonated or non-carbonated beverages. That is, SAIB has the ability, when mixed with flavor oils (e.g., orange oil), to adjust the density of the oil-weighting agent blend to stabilize the emulsion of the flavor oil in water. The maximum level of SAIB permitted in soft drinks in any country is 500 ppm. Extensive safety data on SAIB are available, both in animals (mice, rats, and dogs) and in humans, including children.
SAIB is classified as “Generally Recognized as Safe” (GRAS) by the USFDA and as a food additive by the European Union as indicated by “E” in the number E444.
In 1996, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) assigned a permanent acceptable daily intake for SAIB of up to 20 mg/kg body weight including in pediatric populations.
SAIB has been disclosed in depot formulations (see, e.g., U.S. Pat. No. 10,682,340) as well as in oral dosage forms (see, e.g., U.S. Pat. No. 8,133,507).
There is a continuing need to provide alternative and/or improved methods for increasing the solubility, dissolution, and/or oral bioavailability of poorly water-soluble drugs.
The present invention addresses this need as well as others, which will become apparent from the following description and the appended claims.
The invention is as set forth in the appended claims.
Briefly, in one aspect, the invention provides a pharmaceutical composition. The composition comprises:
In another aspect, the invention provides an oral dosage form comprising the pharmaceutical composition of the invention.
In yet another aspect, the invention provides processes for preparing the pharmaceutical compositions of the invention. In one iteration, the process comprises:
In another iteration, the process comprises:
It has been surprisingly discovered that poorly water-soluble drugs (PSDs) can be formulated with sucrose acetate isobutyrate (SAIB) to form stable amorphous solid solutions or amorphous solid dispersions. The PSDs are present in the molecular or the amorphous state in the SAIB. The PSDs in amorphous form in the amorphous solid solutions can be stable against crystallization on exposure to elevated temperature and humidity conditions. Oral dosage forms containing the amorphous solid solutions or amorphous solid dispersions can have higher water dissolution rates, higher serum maximum concentrations (Cmax), and/or greater areas under the curve (AUC) than equivalent oral dosage forms without the SAIB.
To facilitate understanding the invention, several terms are defined below. Those left undefined have meanings as commonly understood by a person of ordinary skill in the technical areas relevant to the present invention.
The abbreviation “SAIB” refers to sucrose acetate isobutyrate. SAIB has CAS Registry No. 27216-37-1. SAIB may be obtained commercially from Eastman Chemical Company, Kingsport, Tennessee.
The terms “poorly water-soluble drugs,” “poorly soluble drugs,” and “PSDs” refer to drugs having a solubility such that the dose to be administered cannot be dissolved in 250 ml of aqueous media within the pH range of 1 to 6.8 at 37° C. and atmospheric pressure. Examples of such drugs include tacrolimus and aprepitant.
The term “crystalline” describes a solid having a highly regular chemical structure in the crystalline lattice. Crystalline solids have a sharp melting point and characteristic sharp peaks in X-ray powder diffractogram.
The term “amorphous” describes a solid material having no long-range order in the position of its atoms. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well-defined arrangement and no long-range order. Amorphous solids are generally isotropic, i.e., they exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray powder diffraction (XRPD) pattern. Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid.
In both amorphous solid solutions (AmSSols) and amorphous solid dispersions (AmSDs), the term “amorphous” characterizes the state of the PSD molecules. The PSD molecules exist in the high-energy, amorphous state. The amorphous PSD molecules are stabilized within the solid SAIB matrix to prevent recrystallization.
By “molecular state”, it is meant the PSD exists as a molecular dispersion in the SAIB, or stated another way, the PSD is molecularly dispersed in the SAIB.
By “amorphous state”, it is meant the PSD exists in an amorphous form dispersed in the SAIB.
A “solid solution”, like its liquid counterpart, has only one phase, regardless of the number of components, and that phase is solid at room temperature and pressure. In true solid solutions, one of the solid components is completely dissolved in the other solid component.
A “physical mixture” describes a mixture where the components are simply mixed. At most, there is incomplete phase transformation of the drug into solution or amorphous form. The phase transformation may be confirmed by various analytical tools, such as powder X-ray diffraction, DSC, and spectroscopic method. Typically, at least some of the drug in a physical mixture is in crystalline form.
The terms “organic solvent” and “solvent” refer to a pharmaceutically acceptable solvent which can aid the drug to solubilize in the SAIB. The pharmaceutically acceptable solvent may be selected from Class 2 or Class 3 solvents per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q3C Impurities: Guideline for Residual Solvents. Examples of pharmaceutically acceptable solvents include ethanol, isopropanol, 1-butanol, acetic acid, etc.
The terms “stable” and “stability” mean that an amorphous drug in an amorphous solid solution or an amorphous solid dispersion does not change into one or more crystalline physical forms (e.g., different solid forms as measured by XRPD, DSC, etc.) or does not produce a significant fraction (e.g., ≤25 wt %) of the crystalline drug when subjected to specified conditions, e.g., room temperature and ambient humidity or 40° C. at 75% relative humidity, for a specified period of time, e.g., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, or longer.
The terms “pharmaceutically acceptable excipient,” “excipient,” and “pharmaceutically acceptable carrier” are used interchangeably. They refer a substance, other than the PSD and the SAIB, with which the drug is formulated. The excipient generally does not provide any pharmacological activity to the formulation, though it may provide chemical and/or biological stability, and/or release characteristics. The pharmaceutically acceptable excipient can be selected from the USFDA's “Inactive Ingredient Database” or those falling within the “Generally Recognized As Safe” (GRAS) category.
Categories of excipients include diluents, disintegrants, super-disintegrants, lubricants, glidants, binders, hydrophilic polymers, surfactants, coatings, etc. Examples of diluents include lactose, mannitol, dibasic calcium phosphate, tribasic calcium phosphate, isomalt, etc. Examples of disintegrants and super-disintegrants include sodium starch glycolate, sodium croscarmellose, microcrystalline cellulose, gelatinized starch, mannitol, etc. Examples of lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, etc. Examples of binders include HPMC, HPC, chitosan, poloxamers, PVP, etc. Examples of surfactants include sodium lauryl sulfate, poloxamers, etc.
The term “insoluble” means that the substance's solubility is less than 1 g per 10,000 mL of solvent at room temperature and pressure.
The term “immediate release” or “immediate-release” means a release of the drug to an environment over a period of seconds to no more than about 120 minutes.
The term “extended release” or “extended-release” assumes the definition as widely recognized in the art of pharmaceutical sciences. An extended-release dosage form will release the drug at a substantially constant rate over an extended period (e.g., 4, 6, 8, 10, 12, or 24 hours) or a substantially constant amount of the drug will be released incrementally over an extended period (e.g., 4, 6, 8, 10, 12, or 24 hours).
The term “oral bioavailability” refers to the degree to which a drug becomes available to the systemic circulation after being absorbed from the gastrointestinal tract. Poor oral bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly water soluble.
The term “total number of donor hydrogen” refers to the total number of nitrogen-hydrogen and oxygen-hydrogen bonds in a molecule.
In one aspect, the invention provides a pharmaceutical composition. The composition comprises:
The PSD may be selected from either Class II or Class IV of the Biopharmaceutical Classification System (BCS). Both classes are known for their low solubility in water. Examples of such drugs include aprepitant, aripiprazole, carbamazepine, cyclosporine, dolutegravir, rifaximin, sirolimus, and tacrolimus.
The PSD may have a solubility in the SAIB of at least 0.1 mg/g, at least 0.4 mg/g, at least 1.0 mg/g, at least 1.5 mg/g, at least 2.0 mg/g, at least 10 mg/g, at least 20 mg/g, at least 30 mg/g, at least 50 mg/g, at least 75 mg/g, at least 100 mg/g, at least 150 mg/g, or at least 200 mg/g, at 130° C. or 150° C. and atmospheric pressure.
In various embodiments, the PSD can have a molecular mass of at least 500 g/mol, at least 750 g/mol, at least 1000 g/mol, or at least 1200 g/mol. Surprisingly, it has been discovered that the molecular mass of the PSD can have a positive effect on its solubility in the SAIB. As the molecular mass of the PSD increases, its solubility in the SAIB can also increase.
In various embodiments, the PSD can have a total number of donor hydrogen (TNDH) of at least 1, at least 2, at least 3, at least 4, or at least 5 per molecule. Surprisingly, it has been discovered that the TNDH in a PSD molecule can have a positive effect on its solubility in the SAIB. As the TNDH increases, the solubility of the PSD in the SAIB can also increase.
In various embodiments, the PSD can have a melting point of 250° C. or less, 225° C. or less, 200° C. or less, 195° C. or less, 190° C. or less, 185° C. or less, 180° C. or less, 175° C. or less, 170° C. or less, 165° C. or less, 160° C. or less, 155° C. or less, or 150° C. or less. Alternatively, or additionally, the PSD can have a melting point of at least 140° C., at least 145° C., at least 150° C., at least 155° C., at least 160° C., at least 165° C., at least 170° C., at least 175° C., at least 180° C., at least 185° C., at least 190° C., at least 195° C., at least 200° C., at least 205° C., at least 210° C., at least 215° C., at least 220° C., at least 225° C., at least 230° C., at least 235° C., at least 240° C., or at least 245° C. Surprisingly, it has been discovered that the melting point of the PSD can have a negative effect on its solubility in the SAIB. Generally, the higher the melting point of the PSD, the lower its solubility can be in the SAIB when solubilized at the same temperature.
In various embodiments, the PSD can have a partition coefficient (log P) of 2.6 to 3.3. Surprisingly, it has been discovered that too high or too low of a log P can have a negative effect on the PSD's solubility in the SAIB. For example, PSDs that have a log P below 2.6 or above 3.3 tend to have very little or negligible solubility in the SAIB.
The PSD may advantageously have any combination of two or more of the solubility, molecular mass, total number of hydrogen donor, melting point, and log P parameters described herein.
The mass ratio of PSD to SAIB in the pharmaceutical composition can also range from 0.1:1 to 1:4, from 0.1:1 to 1:3, from 0.1:1 to 1:2, or from 0.1:1 to 1:1.
In various embodiments, the pharmaceutical composition comprises 0.001 wt % or less of solvent, based on the total weight of the pharmaceutical composition.
In various embodiments, the pharmaceutical composition is free of solvent.
In various embodiments, the pharmaceutical composition is free of cellulose ester.
In various embodiments, the pharmaceutical composition is free of cellulose acetate butyrate.
In various embodiments, the pharmaceutical composition is stable when stored in an open container at 40° C. and 75% relative humidity for at least one week.
In various embodiments, the pharmaceutical composition is stable when stored in a sealed container at room temperature and ambient humidity for at least 6 months, at least 12 months, at least 18 months, or at least 24 months.
In various embodiments, the pharmaceutical composition of the invention may have a higher dissolution rate in water than an equivalent pharmaceutical composition without the SAIB.
In various embodiments, the pharmaceutical composition of the invention may have a higher dissolution rate in water than an equivalent pharmaceutical composition comprising a physical mixture of the same ingredients.
In various embodiments, the pharmaceutical composition does not comprise the at least one excipient.
In various embodiments, the pharmaceutical composition is or comprises an amorphous solid solution (AmSSol).
In various AmSSol embodiments, the pharmaceutical composition has an extended-release profile.
In various AmSSol embodiments, the composition comprises:
In various AmSSol embodiments, the pharmaceutical composition comprises 0.001 wt % or less of solvent, based on the total weight of the pharmaceutical composition.
In various AmSSol embodiments, the pharmaceutical composition is free of solvent.
In various AmSSol embodiments, the pharmaceutical composition is free of cellulose ester.
In various AmSSol embodiments, the pharmaceutical composition is free of cellulose acetate butyrate.
An excipient may be added to the AmSSol to make an amorphous solid dispersion (AmSD). Excipients can alter the rate of water penetration into the amorphous hydrophobic drug contained in the solid dispersion, thereby changing the dissolution behavior of the formulation.
It may be desirable to incorporate more than one excipient from the same category or excipients from two or more different categories to achieve a specific dissolution profile. For example, lactose and mannitol belong to the same category of diluents, but they may be used together. Sodium lauryl sulfate and microcrystalline cellulose, on the other hand, belong to the different categories of surfactant and diluent, respectively, but they may also be used together. Microcrystalline cellulose, croscarmellose, and sodium lauryl sulfate belong to three different classes of excipients, but they may also be used together.
The excipient is desirably insoluble in the SAIB and is present in disperse form.
The excipient is also desirably insoluble in the organic solvent(s), if used.
Thus, in various AmSD embodiments, the composition comprises:
The pharmaceutical composition in the form of an AmSD can have an immediate-release profile or an extended-release profile.
Dissolution of the PSD can be modulated by the relative proportion of excipients to SAIB. Generally, higher proportions of the excipient(s) favor faster penetration of water and subsequent diffusion of the PSD into the bulk medium—hence, producing an immediate dissolution profile.
For an immediate-release profile, the mass ratio of excipient(s) to SAIB can range from 5:1 to 100:1, from 10:1 to 100:1, from 20:1 to 100:1, from 30:1 to 100:1, from 40:1 to 100:1, from 50:1 to 100:1, from 60:1 to 100:1, from 70:1 to 100:1, from 80:1 to 100:1, or from 90:1 to 100:1.
On the other hand, for an extended dissolution of the drug, the mass ratio of excipient(s) to SAIB can range from 0:1 to 4:1, from 0:1 to 3:1, from 0:1 to 2:1, from 0:1 to 1:1, from 0.01:1 to 4:1, from 0.01:1 to 3:1, from 0.01:1 to 2:1, from 0.01:1 to 1:1, from 0.1:1 to 4:1, from 0.1:1 to 3:1, from 0.1:1 to 2:1, or from 0.1:1 to 1:1.
In various AmSD embodiments, the pharmaceutical composition comprises 0.001 wt % or less of solvent, based on the total weight of the pharmaceutical composition.
In various AmSD embodiments, the pharmaceutical composition is free of solvent.
In various AmSD embodiments, the pharmaceutical composition is free of cellulose ester.
In various AmSD embodiments, the pharmaceutical composition is free of cellulose acetate butyrate.
In various AmSD embodiments, the pharmaceutical composition can increase the dissolution rate and extent, and the bioavailability of the PSD compared to the PSD alone or to a physical mixture of the PSD with excipient(s). An increase in oral bioavailability is indicated by area under the plasma concentration curve and maximum plasma concentration.
Amorphous solid dispersions according to the invention can show similar physical stability as that of amorphous solid dispersions based on a hydrophilic polymer, as indicated by XRPD and dissolution.
The pharmaceutical compositions of the invention may be prepared by various techniques, including high-shear granulation and hot-melt extrusion.
Thus, in another aspect, the invention provides processes for preparing the pharmaceutical compositions.
One such process comprises:
In order to facilitate dissolution of the PSD and for the PSD to exist in the molecular or amorphous state in the SAIB upon mixing, the SAIB may be advantageously heated to an elevated temperature. The temperature to which the SAIB should be heated depends upon the PSD to be dissolved. Some PSDs may benefit from higher temperatures than others to dissolve and exist in the molecular or amorphous state in the SAIB. The precise temperature for a particular PSD may be determined by routine experimentation.
Generally, the SAIB may be heated to a temperature, such as from 60 to 200° C., from 70 to 200° C., from 80 to 200° C., from 90 to 200° C., from 100 to 200° C., from 110 to 200° C., from 120 to 200° C., from 130 to 200° C., from 140 to 200° C., from 150 to 200° C., from 80 to 175° C., from 90 to 175° C., from 100 to 175° C., from 110 to 175° C., from 120 to 175° C., from 130 to 175° C., from 140 to 175° C., from 150 to 175° C., from 80 to 160° C., from 90 to 160° C., from 100 to 160° C., from 110 to 160° C., from 120 to 160° C., from 130 to 160° C., from 140 to 160° C., from 150 to 160° C., from 80 to 150° C., from 90 to 150° C., from 100 to 150° C., from 110 to 150° C., from 120 to 150° C., from 130 to 150° C., or from 140 to 150° C.
In many cases, it may be sufficient to heat the SAIB to a temperature of 80 to 175° C., 90 to 175° C., 100 to 175° C., 110 to 175° C., 120 to 175° C., 130 to 175° C., 80 to 160° C., 90 to 160° C., 100 to 160° C., 110 to 160° C., 120 to 160° C., 130 to 160° C., 80 to 150° C., 90 to 150° C., 100 to 150° C., 110 to 150° C., 120 to 150° C., or 130 to 150° C.
The manner of adding the PSD to the heated SAIB is not particularly limiting. The PSD may be added all at once or incrementally.
The mixture of the PSD and the heated SAIB may be mixed or blended using any conventional apparatus, such as a high-shear mixer, until the PSD is dissolved in the SAIB. The dissolution of the PSD may be confirmed by various techniques including visually and/or analytically.
The cooling step may be performed by terminating or removing the heat supply to the SAIB and/or exposing the mixture to any suitable cooling medium or apparatus.
In various embodiments, the process is carried out in the absence of an organic solvent.
In various embodiments, the process is carried out in the absence of cellulose ester.
In various embodiments, the process is carried out in the absence of cellulose acetate butyrate.
In various embodiments, one or more steps of the process may be advantageously carried out in a hot-melt extruder. For example, the heating and/or mixing steps may be conducted in an extruder, such as a twin-screw extruder. Following extrusion, the PSD/SAIB/excipient(s) mixture may be shaped and cooled or cooled and shaped as tablets, granules, pellets, sheets, strands, sticks, or powder. These intermediate forms may be further processed using conventional techniques into oral dosage forms such as tablets and capsules.
Another process for preparing the pharmaceutical compositions described herein comprises:
The organic solvent is desirably miscible with SAIB and can aid in solubilizing the PSD and/or in dispersing the other components of the formulation in the SAIB. A single organic solvent or a mixture of organic solvents may be used. Useful amounts of the organic solvent, relative to the SAIB, include a mass ratio of 0.1:1 to 1:1.
The forming and granulating steps may be performed in any suitable mixing device, such as a blender or a high-shear granulator.
The organic solvent may be removed by using techniques such as heating (e.g., at 25 to 65° C.), vacuum-drying, or both. Other solvent removal techniques include freeze-drying or spray-drying. It is desirable to remove as much solvent as possible since some solvents may not be well tolerated by some patients. The dried granules may be further processed using conventional techniques into oral dosage forms such as tablets and capsules.
In yet another aspect, the invention provides an oral dosage form comprising the pharmaceutical composition of the invention.
The oral dosage form may be a tablet or a capsule. In various embodiments, the oral dosage form is a tablet.
The oral dosage form may contain the PSD in an amount ranging from 0.5 to 500 mg, 0.5 to 450 mg, 0.5 to 400 mg, 0.5 to 350 mg, 0.5 to 300 mg, 0.5 to 250 mg, 0.5 to 200 mg, 0.5 to 150 mg, 0.5 to 100 mg, or 0.5 to 50 mg.
In various embodiments, the oral dosage form comprises 0.01 wt % or less of solvent, based on the total weight of the oral dosage form.
In various embodiments, the oral dosage form comprises 0.001 wt % or less of solvent, based on the total weight of the oral dosage form.
In various embodiments, the oral dosage form is free of solvent.
In various embodiments, the oral dosage form is free of cellulose ester.
In various embodiments, the oral dosage form is free of cellulose acetate butyrate.
In various embodiments, the oral dosage form of the invention may have a higher dissolution rate in water than an equivalent oral dosage form without the SAIB.
In various embodiments, the oral dosage form of the invention may have a higher dissolution rate in water than an equivalent oral dosage form comprising a physical mixture of the same ingredients.
In various embodiments, the oral dosage form of the invention may have a higher serum maximum concentration (Cmax) than an equivalent oral dosage form without the SAIB.
In various embodiments, the oral dosage form of the invention may have a higher serum maximum concentration (Cmax) than an equivalent oral dosage form comprising a physical mixture of the same ingredients.
In various embodiments, the oral dosage form of the invention may have a Cmax of at least 1.1×, at least 1.2×, at least 1.3×, at least 1.4×, at least 1.5×, at least 1.6×, at least 1.7×, at least 1.8×, at least 1.9×, or at least 2× greater than the Cmax of an equivalent oral dosage form without the SAIB.
In various embodiments, the oral dosage form of the invention may have a Cmax of at least 1.1×, at least 1.2×, at least 1.3×, at least 1.4×, at least 1.5×, at least 1.6×, at least 1.7×, at least 1.8×, at least 1.9×, or at least 2× greater than the Cmax of an equivalent oral dosage form comprising a physical mixture of the same ingredients.
In various embodiments, the oral dosage form of the invention may have a greater area under the curve (AUC) than an equivalent oral dosage form without the SAIB.
In various embodiments, the oral dosage form of the invention may have a greater area under the curve (AUC) than an equivalent oral dosage form comprising a physical mixture of the same ingredients.
In various embodiments, the oral dosage form of the invention may have an AUC of at least at least 1.1×, at least 1.2×, at least 1.3×, at least 1.4×, at least 1.5×, at least 1.6×, at least 1.7×, at least 1.8×, at least 1.9×, at least 2×, at least 2.1×, at least 2.2×, at least 2.3×, at least 2.4×, or at least 2.5× greater than the AUC of an equivalent oral dosage form without the SAIB.
In various embodiments, the oral dosage form of the invention may have an AUC of at least at least 1.1×, at least 1.2×, at least 1.3×, at least 1.4×, at least 1.5×, at least 1.6×, at least 1.7×, at least 1.8×, at least 1.9×, at least 2×, at least 2.1×, at least 2.2×, at least 2.3×, at least 2.4×, or at least 2.5× greater than the AUC of an equivalent oral dosage form comprising a physical mixture of the same ingredients.
To remove any doubt, the present invention includes and expressly contemplates and discloses any and all combinations of embodiments, features, characteristics, parameters, and/or ranges mentioned herein. That is, the subject matter of the present invention may be defined by any combination of embodiments, features, characteristics, parameters, and/or ranges mentioned herein.
It is contemplated that any ingredient, component, or step that is not specifically named or identified as part of the present invention may be explicitly excluded.
Any process/method, apparatus, compound, composition, embodiment, or component of the present invention may be modified by the transitional terms “comprising,” “consisting essentially of,” or “consisting of,” or variations of those terms.
As used herein, the indefinite articles “a” and “an” mean one or more, unless the context clearly suggests otherwise. Similarly, the singular form of nouns includes their plural form, and vice versa, unless the context clearly suggests otherwise.
While attempts have been made to be precise, the numerical values and ranges described herein may be considered approximations. These values and ranges may vary from their stated numbers depending upon the desired properties sought to be obtained by the present disclosure as well as the variations resulting from the standard deviation found in the measuring techniques. Moreover, the ranges described herein are intended and specifically contemplated to include all sub-ranges and values within the stated ranges. For example, a range of 50 to 100 is intended to include all values within the range including sub-ranges such as 60 to 90, 70 to 80, etc.
Any two numbers of the same property or parameter reported in the working examples may define a range. Those numbers may be rounded off to the nearest thousandth, hundredth, tenth, whole number, ten, hundred, or thousand to define the range.
The content of all documents cited herein, including patents as well as non-patent literature, is hereby incorporated by reference in their entirety. To the extent that any incorporated subject matter contradicts with any disclosure herein, the disclosure herein shall take precedence over the incorporated content.
This invention can be further illustrated by the following working examples, although these examples are included merely for purposes of illustration and are not intended to limit the scope of the invention.
Analysis of drugs was performed by HPLC. The HPLC equipment used was Infinity 1260 (Agilent Technologies, CA, USA) fitted with a quaternary pump, an autosampler, and a UV detector, and a column compartment maintained at 30° C. The method was developed and validated by ICH 2005. Details of the HPLC method are shown in Table 1. Solubility was determined in three replicates for each drug.
NIR spectra of samples were obtained using modular Nicolet™ iS™ 50 system (Thermo Fisher Scientific, Austin, TX). The instrument was fitted with a scanning grating monochromator and a diffuse reflectance apparatus (rapid content analyzer). After the instrument passed the diagnostic tests and reflectance standardization, samples in 20 mL borosilicate glass vials were placed on the sample window and centered with an iris. NIR spectra ranging from 4000-10000 cm−1 with a data resolution of 4 cm−1 and 32 scans were obtained in sextet from the base of the vial, which was transparent to the NIR.
Via-Spec II Hyperspectral Imaging system was used to collect NIR hyperspectral (NIR-H) images. The images were collected from 900-2500 nm with SWIR hyperspectral camera (MRC-303-005-02, Middleton Spectral Vision, Middleton, WI). The spectral camera resolution was 384×288 pixels and pixel size were 24×24 μm. Data were collected using the following parameters: transmission mode, integration time 7.020 ms, frame rate 75 MHz and scan axis speed 0.2 inch/sec. Prior to actual sample measurements, a white reference image and a dark reference image were obtained. The data acquisition software used was Middleton Spectral Vision (Middleton Spectral Vision, Middleton, WI) and data analysis software was Prediktera Evince™ (Prediktera AB, Umea, Sweden).
Bruker D2 Phaser SSD 160 diffractometer (Bruker AXS, Madison, WI) was employed to collect spectra on the samples. The instrument was equipped with the LYNXEYE scintillation detector and Cu Kα radiation (λ=1.54184 Å) at a voltage of 30 KV and a current of 10 mA. Approximately 500 mg of a sample were placed in a sample holder and scanned over 2θ range of 5-35° with a step size of 0.020209° at 1s per step (1241 total steps). Average diffractogram was obtained by rotating samples at 15 rpm during the measurement. Diffract.Suite™ V4.2.1 (Bruker AXS, Madison, WI) and Diffract.Eva V4.2.1 (Bruker AXS, Madison, WI) software was used for data collection and analysis, respectively.
The physicochemical properties of the PSDs used in the following examples are reported in Table 2.
SAIB was heated to 150° C. (RFX, DST, DLT, CYS, ITZ, SRL, APT and CBZ) or 130° C. (TAC and APZ), followed by addition of a known amount of the drug to dissolve in 30 min. Approximately, 100 mg of each sample were transferred to a 100-mL volumetric flask, and volume was made up with the mobile phase to dissolve the drug. The amount of dissolved drug was determined by validated HPLC. The results are shown in Table 3.
The physicochemical properties of the drugs had an influence over their solubility in SAIB. The molecular weight/mass of a drug showed a positive effect on its solubility. For example, CYS, TAC, and RFX showed solubilities of 239.0±12.6, 115.1±2.3, and 36.4±0.9 mg/g, respectively. The molecular weights of CYS, TAC, and RFX are 1202.6, 804, and 785.9 g/mol, respectively. A positive correlation coefficient of 0.60 was obtained between drug solubility in SAIB and their molecular weight.
The number of donor hydrogen (total number of nitrogen-hydrogen and oxygen-hydrogen bonds) had a positive effect on the solubility of the drug in SAIB. In general, the higher the total number of donor hydrogen, the higher the solubility in SAIB. For example, CYS and TAC have five and three donor hydrogens, respectively, and their corresponding solubilities were 239.0±12.6 and 115.1±2.3 mg/g. The correlation coefficient value between hydrogen donor and solubility was 0.52.
On the other hand, the partition coefficient and the melting point of the drugs showed an inverse relationship with the drugs' solubility in SAIB. The higher the melting of a drug, the lower its solubility in the SAIB tended to be, when solubilized at the same temperature. For example, CYS, CBZ, and APT have melting point ranges of 148-151, 189-192, and 251-255° C., respectively, and their corresponding solubilities were 239.0±12.6, 76.5±4.0, and 0.4±0.0 mg/g, respectively. A higher melting point means higher lattice energy, which translated into higher thermal energy needed to overcome the forces that hold the molecules together. The correlation coefficient was −0.53 between the drugs' melting point and their solubility in the SAIB.
Similarly, the partition coefficient (log P) of a drug had to be optimum to solubilize in the SAIB. A too high or too low log P tended to have a negative impact on solubility. The log P of the studied drugs varied from 2.2 to 5.7. The drugs showing high solubility were RFX, CYS, TAC, and CBZ; the log P of these drugs varied from 2.6 to 3.3. On the other hand, the drugs having a log P below 2.6 or above 3.3 showed very little or negligible solubility. It is surprising that drugs with a high log P exhibited low solubility in SAIB even though the log P of SAIB is 6. Nevertheless, negative correlation coefficient of −0.34 was obtained between the drugs' log P and their solubility in the SAIB.
Physical mixtures and amorphous solid solutions (AmSSols) of various PSDs were prepared by a solubilization-heating method.
The physical mixtures were prepared by heating about 1 g of SAIB to 50° C., the heating was turned off, then about 1 g of the PSD was added to the heated SAIB. The mixture was stirred with a spatula as it cooled to room temperature.
The AmSSols were prepared by heating about 5 g of SAIB to 130 or 150° C., followed by addition of the PSD at 130 or 150° C. with stirring until no crystal was visually observed. The amount of each PSD added is reported in Table 4.
The prepared AmSSol samples were placed in uncapped scintillation vials and exposed to 40° C./75% RH (Model D-78502, Binder Inc, Bohemia, NY) for one week. The AmSSols were exposed to the elevated temperature and humidity to assess the phase transformation of the dissolved drug. The samples were visually examined and characterized by XRPD, NIR, and NIR-H.
For each PSD,
Unlike infrared spectrum, bands in the near infrared spectrum are broad and overlapping. This is due to bond vibration (like O—H, C—H, and N—H) due to overtones and combinations process. However, some of the peaks are sharp, e.g., nitrile group, N—H bending, methyl, methylene, and methine groups, etc. This technique is widely used for both qualitative and quantitative analysis in the pharmaceutical industry. NIR can also be used to characterize amorphous and crystalline forms of the drug. The NIR spectra of the various samples tested are shown in
In particular,
As seen from
NIR-H is a spectral imaging technique which provides spectral and spatial information about the samples. In pharmaceutical analysis, it is used for qualitative and quantitative analysis. NIR-H data need chemometric methods to construct the images. Most used methods include partial least square regression (PLSR) and principal component analysis (PCA). PCA is used for qualitative purpose, while PLSR is for quantitative analysis. Examples of qualitative analysis include grouping of similar types of samples, distribution of components in a mixture, homogeneity, etc.
PCA was applied to NIR-H data to create the images in this example. The data were mean centered and treated with standard normal variate. The PCA images of the physical mixtures and the AmSSols in this example are shown in
In particular, for each PSD tested,
As seen in
The XRPD data are shown in
In particular,
As seen in
Amorphous drug is thermodynamically instable and devitrify when exposed to exaggerated conditions, such as high temperature and humidity. These conditions increase molecular mobility by lowering the glass transition temperature. The prepared AmSSols were exposed to 40° C./75% RH to accelerate devitrification, if any. After exposure to the elevated temperature and humidity conditions, there was no sign of drug crystals in the AmSSols (
Drug (aprepitant) and various amounts of SAIB were dissolved in the least quantity of ethanol.
Hydrophilic excipient or excipients (lactose, microcrystalline cellulose, croscarmellose sodium, and/or sodium lauryl sulfate, etc.) were sieved through a #18 mesh screen and blended in a V-blender (V-blender, Model VH-2) or a high-shear granulator (KG5, KEY International Inc., NJ, USA) for 2 min, followed by granulation with a solution of the drug and the SAIB. The drug/SAIB solution was gradually added to the mixture of excipient(s) with impeller rotation (KG5, KEY International Inc., NJ, USA).
The ethanol was removed from the granules by drying in an oven at 50° C. until loss on drying was less than 1%.
The dried granules were milled (Quadro Comil®, Model-193, Quadro Engineering Inc., Waterloo, Canada) and sieved through a #18 mesh screen.
The milled granules were further dried in a vacuum oven for 24 hours.
A super-disintegrant mixture (sodium croscarmellose/sodium starch glycolate/Kollidon) was added to the dried granules, followed by lubrication with magnesium stearate/colloidal silicon dioxide/talc for 2 min in a V-blender.
The final blend was compressed into tablets using a Mini Press-1 (Globe Pharma, New Brunswick, NJ, USA) 10-station tableting machine with 8/10 mm biconvex and punches (Natoli Engineering Company, Saint Charles, MO, USA).
The final blend was also filled into hard gelatin capsules.
The compositions of the prepared tablets/capsule are reported in Table 5.
Each of the tablets and capsule from Example 3 was added to 900 ml of a 0.4% aqueous solution of sodium lauryl sulfate at a paddle speed of 75 rpm and a temperature of 37° C. for 2 hours to determine their dissolution rate.
The dissolution rate of each formulation, F1-F4, is shown in
As seen in
The formulation F2 from Example 3 was aged at 40° C./75% RH for 1 and 3 months. The dissolution rates of the initial, 1-month-old, and 3-month-old tablets were measured according to the method described in Example 4.
The dissolution rate of each tablet is shown in
As seen from
The formulation F2 from Example 3 was aged at 25° C./60% RH for 3 months. The dissolution rates of the initial and 3-month-old tablets were measured according to the method described in Example 4.
The dissolution rate of each tablet is shown in
As seen in
The formulation F2 from Example 3 was further assessed for oral bioavailability in beagle dogs (n=4/formulation) and compared against tablets made of a physical mixture of the same drug and excipients, but without the SAIB.
The compositions of F2 and the physical mixture are reported in Table 6.
The bioavailability data for the tablets of F2 and the physical mixture are reported in Table 7.
As seen in Table 7, there was a significant increase in the bioavailability parameters when aprepitant was administered as an AmSD formulation using SAIB as a carrier compared to a physical mixture without the SAIB. The Cmax and AUC of the AmSD formulation were 2.1 and 2.6-fold those of the physical mixture, respectively.
Tablets and capsules were prepared using the procedures outline in Example 3 with tacrolimus as the PSD.
The compositions of the prepared tablet/capsules are reported in Table 8.
Each of the capsules and tablet from Example 8 was added to 900 ml of a 0.4% aqueous solution of sodium lauryl sulfate at a paddle speed of 75 rpm and a temperature of 37° C. for 2 hours to determine their dissolution rate.
The dissolution rate of each formulation, F5-F9, is shown in
As seen in
The formulation F9 from Example 8 was aged at 40° C./75% RH for 1 and 2 months. The dissolution rates of the initial, 1-month-old, and 2-month-old tablets were measured according to the method described in Example 9.
The dissolution rate of each tablet is shown in
As seen in
The formulation F9 from Example 8 was aged at 25° C./60% RH for 3 months. The dissolution rates of the initial and 3-month-old tablets were measured according to the method described in Example 9.
The dissolution rate of each tablet is shown in
As seen in
The formulation F9 from Example 8 was further assessed for oral bioavailability in beagle dogs (n=4/formulation) and compared against tablets made of a physical mixture of the same drug and excipients, but without the SAIB.
The compositions of F9 and the physical mixture are reported in Table 9.
The bioavailability data for the tablets of F9 and the physical mixture are reported in Table 10.
As seen in Table 10, the bioavailability of tacrolimus increased significantly as indicated by a significant increase in the pharmacokinetic parameters. The Cmax and AUC of the AmSD formulation of tacrolimus was 1.8 and 1.9-fold of those of the physical mixture, respectively.
Exemplary embodiments include the following:
The invention has been described in detail with particular reference to specific embodiments thereof, but it will be understood that variations and modifications can be made within the spirit and scope of the invention.
This application claims priority to U.S. Provisional Application No. 63/192,374 filed on May 24, 2021; the entire content of which is hereby incorporated by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/028570 | 5/10/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63192374 | May 2021 | US |
