Drug-polymer amorphous solid dispersions using linear poly(acrylic acid) polymers

Abstract

The amorphous solid dispersion comprises a linear poly(acrylic acid) and an active pharmaceutical ingredient. The linear poly(acrylic acid) used to form the amorphous solid dispersion has a Brookfield viscosity of at least 100 cP at 25° C. A method for forming such an amorphous solid dispersion of an active pharmaceutical ingredient includes forming a liquid dispersion of a linear poly(acrylic acid) having a Brookfield viscosity of at least 100 cP at 25° C., the active pharmaceutical ingredient, and a solvent system, and evaporating the solvent system from the liquid dispersion to form the amorphous solid dispersion.

Description

[Background technology]

[0001] Aspects of the exemplary embodiments relate to amorphous solid dispersions of active pharmaceutical ingredients and methods of forming amorphous solid dispersions of active pharmaceutical ingredients.

[0002] Many drugs have been developed that have poor water solubility and therefore poor oral bioavailability. These are generally classified as Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) in the Biopharmaceutical Classification System (BCS). The pharmaceutical industry faces the challenge of formulating such drugs into finished pharmaceutical products.

[0003] Increasing the solubility of drug candidates while maintaining efficacy has proven to be a complex problem to solve. Approaches proposed to address this problem include: a) salt formation for ionizable drugs, b) solutions in solvents, cosolvents, and lipids, c) micellar systems, d) particle size reduction, e) complexation, f) prodrugs, g) amorphous solid dispersions. However, all of these techniques have limitations such as poor aqueous solubility and therefore poor oral bioavailability of physically stable dosage forms.

[0004] WO 2005 / 117834 A1, entitled SOLID DISPERSIONS OF A BASIC DRUG COMPOUND AND A POLYMER CONTAINING ACIDIC GROUPS, describes solid dispersions comprising at least one basic drug compound and at least one pharma- ceutically acceptable water-soluble polymer containing acidic groups, such as polyacrylic acid or polymethacrylic acid. The solid dispersion is formed by blending the ingredients, extruding the blend at a temperature in the range of 20-300°C, grinding the extrudate, and optionally sieving the particles.

[0005] U.S. Patent Publication No. 2010 / 0280047A1, published Nov. 4, 2010, and entitled "SALTS OF ACTIVE INGREDIENTS WITH POLYMERIC COUNTER-IONS" by Kolter et al., describes polymeric water-soluble salts of drugs that are poorly soluble in water, including polymers having anionic character that are soluble in water at pH values ​​between 2 and 13, such as polyacrylic acid, and poorly soluble drugs that are cationic. The salts are formed by dissolving the polymer and drug in a solvent and precipitating the salt from solution.

[0006] U.S. Patent Publication No. 2015 / 0011525A1, published on January 8, 2015 and entitled "SOLID DISPERSION OF POORLY SOLUBLE COMPOUNDS COMPRISING CROSPOVIDONE AND AT LEAST ONE WATER-SOLUBLE POLYMER" by Bi et al., describes a stable ternary solid dispersion composition comprising 1-50% by weight of one or more poorly soluble pharmaceutical active ingredients belonging to BCS Class II and / or IV, 11-50% by weight of at least one water-soluble polymer, such as a homopolymer or copolymer of acrylic acid or methacrylic acid, and 20-99% by weight of cross-linked polyvinylpyrrolidone (crospovidone, a water-insoluble polymer). The method of forming the solid dispersion includes preparing a homogenous aqueous and / or organic solution of the polymer and the pharma- ceutical active ingredient, suspending crosslinked polyvinylpyrrolidone in the resulting solution to obtain a suspension or dispersion, and spray drying the resulting suspension or dispersion to obtain a dry powder form of the solid dispersion composition.

[0007] WO2014 / 135545, entitled "SOLID DISPERSION COMPRISING AMORPHOUS LORCASERIN HYDROCHLORIDE," describes an amorphous solid dispersion comprising lorcaserin hydrochloride and a pharma- ceutically acceptable water-soluble polymer, such as polyacrylic acid. A method of forming the solid dispersion includes forming a solution of lorcaserin in a suitable solvent, adding a solution providing hydrogen chloride, optionally concentrating the resulting composition, adding a water-soluble polymer and a suitable solvent, and optionally spray drying the composition.

[0008] U.S. Patent Publication No. 2017 / 0014346A1, published on January 19, 2017, and entitled "SPRAY DRYING PROCESS FOR PRODUCTION OF POWDERS WITH ENHANCED PROPERTIES" by Santos et al., describes a spray drying method for producing amorphous solid dispersions, including providing a feed mixture including an active pharmaceutical ingredient, one or more excipients, such as a polyacrylate or polymethacrylate, and a solvent, feeding the feed mixture into a spray drying apparatus, atomizing the feed mixture into droplets using a spray nozzle, drying the droplets with a drying gas to produce particles, providing a secondary gas stream at another location in the spray drying apparatus, and recovering the particles from the spray drying chamber.

[0009] U.S. Patent Publication No. 2016 / 0256433A1, published Sep. 8, 2016, by Staric et al. and entitled "FORMULATIONS CONTAINING AMORPHOUS DAPAGLIFLOZIN," describes amorphous solid dispersions containing dapagliflozin and a polymer, such as polyacrylic acid. A method for forming the amorphous solid dispersion includes preparing a solution of dapagliflozin and a polymer in a suitable solvent, spraying or dispersing the solution onto carrier particles to form granules, evaporating the solvent, and blending the resulting composition with one or more pharma- ceutically acceptable excipients. WO 97 / 44014 A1, entitled "ANTIFUNGAL COMPOSITIONS WITH INCREASED BIOAVAILABILITY," describes compositions comprising itraconazole and a water-soluble polymer formed by melt extrusion. Tian Xie et al., "Improved Release of Celecoxib from High Drug Loading Amorphous Solid Dispersions Formulated with Polyacrylic Acid and Cellulose Derivatives," MOLECULAR PHARMACEUTICS, vol. 13, no. 3, pp. 873-884 (2016) describes an amorphous solid dispersion using a binary combination of polyacrylic acid and hydroxypropyl methylcellulose as a stabilizer. Although several solid dispersions containing drugs and polymers are known in the art, there remains a need to improve the drug loading levels in amorphous solid dispersions while maintaining sufficient storage stability of the amorphous solid dispersions.A formulation method is described that is applicable to a wide range of pharmaceutical active ingredients and drug candidates belonging to BCS classes II and IV, with flexibility (wide range) of drug loading levels and acceptable storage stability. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2005 / 117834 [Patent Document 2] US Patent Application Publication No. 2010 / 0280047 [Patent Document 3] US Patent Application Publication No. 2015 / 0011525 [Patent Document 4] International Publication No. 2014 / 135545 [Patent Document 5] US Patent Application Publication No. 2017 / 0014346 [Patent Document 6] US Patent Application Publication No. 2016 / 0256433 Summary of the Invention [Means for solving the problem]

[0011] According to one aspect of the exemplary embodiment, the amorphous solid dispersion comprises a linear poly(acrylic acid) and an active pharmaceutical ingredient, wherein the linear poly(acrylic acid) has a Brookfield viscosity of at least 100 cP at 25°C.

[0012] In various embodiments of the amorphous solid dispersion, a) the weight ratio of pharma- ceutical active ingredient:poly(acrylic acid) in the amorphous solid dispersion is at least 1:10, or at least 1:6, or at least 1:3, or at least 1:1.5, or at least 1:1, or at least 2:1, or at least 3:1, or at least 4:1, or at most 6:1, or at most 5:1, or at most 4.5:1, for example, from 1:10 to 5:1, or from 1:6 to 4.5:1; b) the linear poly(acrylic acid) has a Brookfield viscosity at 25° C. of at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP, and / or the linear poly(acrylic acid) has a Brookfield viscosity at 25° C. of 3000 cP or less, or 2,500 cP or less, or 2200 cP or less, or 2100 cP or less, e.g., from 200 cP to 3000 cP, or from 250 cP to 2,500 cP; c) the amorphous solid dispersion comprises at least 10% by weight of linear poly(acrylic acid), alternatively at least 15% by weight of linear poly(acrylic acid), alternatively at least 20% by weight of linear poly(acrylic acid), alternatively at least 25% by weight of linear poly(acrylic acid); and / or the amorphous solid dispersion comprises 95% by weight or less of linear poly(acrylic acid), alternatively at least 80% by weight of linear poly(acrylic acid), alternatively at least 60% by weight of linear poly(acrylic acid), alternatively at least 50% by weight of linear poly(acrylic acid), alternatively at least 40% by weight of linear poly(acrylic acid), alternatively at least 30% by weight of linear poly(acrylic acid), for example, 10% to 95% by weight of linear poly(acrylic acid), alternatively at least 15% to 80% by weight of linear poly(acrylic acid); d) the linear poly(acrylic acid) and the active agent together constitute at least 80% by weight of the amorphous solid dispersion, or at least 90% by weight, or at least 95% by weight, or up to 100% by weight of the amorphous solid dispersion; e) the amorphous solid dispersion contains 10% by weight or less of water, alternatively 5% by weight or less of water, alternatively 1% by weight or less of water, or no water; f) the pharmacologic active ingredient is BCS class II or BCS class IV; g) A product comprising the amorphous solid dispersion described, and optionally at least one excipient or adjuvant; h) the product is in a form selected from granules, capsules, pellets, tablets, films, and implants; i) a method of administering a pharma- ceutical active ingredient to a human or non-human animal in need of treatment, comprising orally administering to the human or animal an amorphous solid dispersion as described or a product as described, and A combination of these aspects.

[0013] In another aspect of the exemplary embodiment, a method of forming an amorphous solid dispersion of an active pharmaceutical ingredient includes forming a liquid dispersion of a linear poly(acrylic acid), the active pharmaceutical ingredient, and a solvent system, the linear poly(acrylic acid) having a Brookfield viscosity of at least 100 cP at 25° C., and evaporating the solvent system from the liquid dispersion to form the amorphous solid dispersion.

[0014] In various embodiments of the method, a) the weight ratio of pharma- ceutical active ingredient:linear poly(acrylic acid) in the liquid dispersion is at least 15:85, or at least 30:70, or at least 40:60, or at least 50:50, or at least 70:30, and / or the weight ratio of pharma- ceutical active ingredient:linear poly(acrylic acid) in the liquid dispersion is 90:10 or less, or 85:15 or less, e.g., from 15:85 to 90:10, or from 30:70 to 85:15; b) the linear poly(acrylic acid) has a Brookfield viscosity at 25° C. of at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP, and / or the linear poly(acrylic acid) has a Brookfield viscosity of 3000 cP or less, or 2,500 cP or less, or 2200 cP or less, or 2100 cP or less, e.g., from 200 cP to 3000 cP, or from 250 cP to 2,500 cP; c) the linear poly(acrylic acid) was formed in a substantially water-free solvent system; d) a linear poly(acrylic acid) formed in a solvent system selected from a) ethyl acetate and b) a mixture of ethyl acetate and cyclohexane; e) the amorphous solid dispersion comprises at least 10% by weight of linear poly(acrylic acid), alternatively at least 15% by weight of linear poly(acrylic acid), alternatively at least 20% by weight of linear poly(acrylic acid), alternatively at least 25% by weight of linear poly(acrylic acid), and / or up to 95% by weight of linear poly(acrylic acid), alternatively at most 80% by weight of linear poly(acrylic acid), alternatively at most 60% by weight of linear poly(acrylic acid), alternatively at most 50% by weight of linear poly(acrylic acid), alternatively at most 40% by weight of linear poly(acrylic acid), alternatively at most 30% by weight of linear poly(acrylic acid), for example, from 10% to 95% by weight of linear poly(acrylic acid), alternatively at most 15% to 80% by weight of linear poly(acrylic acid), alternatively at most 10% to 60% by weight of linear poly(acrylic acid); f) the linear poly(acrylic acid) and the active agent together constitute at least 80% by weight, or at least 90% by weight, or at least 95% by weight, of the amorphous solid dispersion, and / or constitute up to 100% by weight of the amorphous solid dispersion; g) the amorphous solid dispersion contains 10% by weight or less of water, alternatively 5% by weight or less of water, alternatively 1% by weight or less of water, or no water; h) forming a dispersion of linear poly(acrylic acid) and a pharma- ceutical active ingredient includes dissolving linear poly(acrylic acid) in powder form in the solvent system or at least one of the solvents used in the solvent system; i) the solvent system comprises at least one of an organic polar protic solvent and a polar aprotic solvent; j) the solvent system comprises at least one organic polar protic solvent selected from C1-C6 alcohols, and mixtures thereof; k) the solvent system comprises at least one polar aprotic solvent selected from dichloromethane, C3-C8 ketones, C3-C8 ethers, and mixtures thereof; l) the pharmacologic active ingredient is BCS class II or BCS class IV; m) evaporating the solvent system from the liquid dispersion includes spray drying; n) the method further comprises preparing a product comprising the amorphous solid dispersion, the product being selected from a granule, a capsule, a pellet, a tablet, a film, and an implant; o) an amorphous solid dispersion formed by the described method; p) the product comprises an amorphous solid dispersion and at least one excipient or adjuvant; q) the product is in a form selected from granules, capsules, pellets, tablets, films, and implants; and It's a combination of these aspects.

[0015] According to another aspect of the exemplary embodiment, the linear polyacrylic acid that stabilizes BCS Class II and IV active pharmaceutical ingredients as amorphous solid dispersions has a Brookfield viscosity at 25° C. of at least 100 cP, or at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP, such as 3000 cP or less, or 2,500 cP or less, or 2200 cP or less, or 2100 cP or less, such as from 200 cP to 3000 cP, or from 250 cP to 2,500 cP.

[0016] In various embodiments, a) the linear polyacrylic acid is formed by a process in which precursor monomers are polymerized in a substantially water-free solvent system; b) the solvent system is selected from ethyl acetate and a mixture of ethyl acetate and cyclohexane; c) a Brookfield viscosity of 3000 cP or less, or 2,500 cP or less, or 2200 cP or less, or 2100 cP or less; and A combination of these aspects. [Brief description of the drawings]

[0017] [Figure 1] 1 is a flow chart illustrating a method of forming a solid dispersion of an active pharmaceutical ingredient, according to one aspect of the exemplary embodiment. [Diagram 2] Photographs of the spray-dried products are shown at the same scale. Figure 2 shows a product made from 40% itraconazole (ITZ) and 60% Soluplus® polymer. Figure 3 shows a product made from 40% ITZ and 60% Affinisol® polymer. Figure 4 shows a product made from 40% ITZ and 60% poly(acrylic acid) PAA (high molecular weight, formed in ethyl acetate cyclohexane cosolvent: HMW-CO). Figure 5 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-CO). Figure 6 shows a product made from 40% ITZ and 60% PAA (low molecular weight, formed in ethyl acetate cyclohexane cosolvent: LMW-CO). Figure 7 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-EA). [Diagram 3] Photographs of the spray-dried products are shown at the same scale. Figure 2 shows a product made from 40% itraconazole (ITZ) and 60% Soluplus® polymer. Figure 3 shows a product made from 40% ITZ and 60% Affinisol® polymer. Figure 4 shows a product made from 40% ITZ and 60% poly(acrylic acid) PAA (high molecular weight, formed in ethyl acetate cyclohexane cosolvent: HMW-CO). Figure 5 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-CO). Figure 6 shows a product made from 40% ITZ and 60% PAA (low molecular weight, formed in ethyl acetate cyclohexane cosolvent: LMW-CO). Figure 7 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-EA). [Figure 4]Photographs of the spray-dried products are shown at the same scale. Figure 2 shows a product made from 40% itraconazole (ITZ) and 60% Soluplus® polymer. Figure 3 shows a product made from 40% ITZ and 60% Affinisol® polymer. Figure 4 shows a product made from 40% ITZ and 60% poly(acrylic acid) PAA (high molecular weight, formed in ethyl acetate cyclohexane cosolvent: HMW-CO). Figure 5 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-CO). Figure 6 shows a product made from 40% ITZ and 60% PAA (low molecular weight, formed in ethyl acetate cyclohexane cosolvent: LMW-CO). Figure 7 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-EA). [Diagram 5] Photographs of the spray-dried products are shown at the same scale. Figure 2 shows a product made from 40% itraconazole (ITZ) and 60% Soluplus® polymer. Figure 3 shows a product made from 40% ITZ and 60% Affinisol® polymer. Figure 4 shows a product made from 40% ITZ and 60% poly(acrylic acid) PAA (high molecular weight, formed in ethyl acetate cyclohexane cosolvent: HMW-CO). Figure 5 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-CO). Figure 6 shows a product made from 40% ITZ and 60% PAA (low molecular weight, formed in ethyl acetate cyclohexane cosolvent: LMW-CO). Figure 7 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-EA). [Figure 6]Photographs of the spray-dried products are shown at the same scale. Figure 2 shows a product made from 40% itraconazole (ITZ) and 60% Soluplus® polymer. Figure 3 shows a product made from 40% ITZ and 60% Affinisol® polymer. Figure 4 shows a product made from 40% ITZ and 60% poly(acrylic acid) PAA (high molecular weight, formed in ethyl acetate cyclohexane cosolvent: HMW-CO). Figure 5 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-CO). Figure 6 shows a product made from 40% ITZ and 60% PAA (low molecular weight, formed in ethyl acetate cyclohexane cosolvent: LMW-CO). Figure 7 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-EA). [Figure 7] Photographs of the spray-dried products are shown at the same scale. Figure 2 shows a product made from 40% itraconazole (ITZ) and 60% Soluplus® polymer. Figure 3 shows a product made from 40% ITZ and 60% Affinisol® polymer. Figure 4 shows a product made from 40% ITZ and 60% poly(acrylic acid) PAA (high molecular weight, formed in ethyl acetate cyclohexane cosolvent: HMW-CO). Figure 5 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-CO). Figure 6 shows a product made from 40% ITZ and 60% PAA (low molecular weight, formed in ethyl acetate cyclohexane cosolvent: LMW-CO). Figure 7 shows a product made from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-EA). [Figure 8]The XRPD plots of products made from ITZ and PAA (high molecular weight, prepared with co-solvent: HMW-CO) are shown: FIG. 8 shows the plot of ITZ only, a physical mixture of 15% ITZ and 85% PAA, and a spray-dried solid dispersion of 15% ITZ and 85% PAA. FIG. 9 shows the plot of ITZ only, a physical mixture of 30% ITZ and 70% PAA, and a spray-dried solid dispersion of 30% ITZ and 70% PAA. FIG. 10 shows the plot of ITZ only, a physical mixture of 50% ITZ and 50% PAA, and a spray-dried solid dispersion of 50% ITZ and 50% PAA. [Figure 9] The XRPD plots of products made from ITZ and PAA (high molecular weight, prepared with co-solvent: HMW-CO) are shown: FIG. 8 shows the plot of ITZ only, a physical mixture of 15% ITZ and 85% PAA, and a spray-dried solid dispersion of 15% ITZ and 85% PAA. FIG. 9 shows the plot of ITZ only, a physical mixture of 30% ITZ and 70% PAA, and a spray-dried solid dispersion of 30% ITZ and 70% PAA. FIG. 10 shows the plot of ITZ only, a physical mixture of 50% ITZ and 50% PAA, and a spray-dried solid dispersion of 50% ITZ and 50% PAA. [Figure 10] The XRPD plots of products made from ITZ and PAA (high molecular weight, prepared with co-solvent: HMW-CO) are shown: FIG. 8 shows the plot of ITZ only, a physical mixture of 15% ITZ and 85% PAA, and a spray-dried solid dispersion of 15% ITZ and 85% PAA. FIG. 9 shows the plot of ITZ only, a physical mixture of 30% ITZ and 70% PAA, and a spray-dried solid dispersion of 30% ITZ and 70% PAA. FIG. 10 shows the plot of ITZ only, a physical mixture of 50% ITZ and 50% PAA, and a spray-dried solid dispersion of 50% ITZ and 50% PAA. [Figure 11]Differential scanning calorimetry (DSC) plots are shown: FIG. 11 shows a plot of a spray-dried mixture of 70% ITZ and 30% PAA (medium molecular weight, formed in ethyl acetate: MMW-EA). FIG. 12 shows a plot of a spray-dried mixture of 80% ITZ and 20% PAA (MMW-EA). FIG. 13 shows a plot of a spray-dried mixture of 90% ITZ and 10% PAA (MMW-EA). FIG. 14 shows a plot of a spray-dried mixture of 80% ITZ and 20% Soluplus® polymer. FIG. 15 shows a plot of a spray-dried mixture of 80% ITZ and 20% Affinisol® polymer. [Figure 12] Differential scanning calorimetry (DSC) plots are shown: FIG. 11 shows a plot of a spray-dried mixture of 70% ITZ and 30% PAA (medium molecular weight, formed in ethyl acetate: MMW-EA). FIG. 12 shows a plot of a spray-dried mixture of 80% ITZ and 20% PAA (MMW-EA). FIG. 13 shows a plot of a spray-dried mixture of 90% ITZ and 10% PAA (MMW-EA). FIG. 14 shows a plot of a spray-dried mixture of 80% ITZ and 20% Soluplus® polymer. FIG. 15 shows a plot of a spray-dried mixture of 80% ITZ and 20% Affinisol® polymer. [Figure 13] Differential scanning calorimetry (DSC) plots are shown: FIG. 11 shows a plot of a spray-dried mixture of 70% ITZ and 30% PAA (medium molecular weight, formed in ethyl acetate: MMW-EA). FIG. 12 shows a plot of a spray-dried mixture of 80% ITZ and 20% PAA (MMW-EA). FIG. 13 shows a plot of a spray-dried mixture of 90% ITZ and 10% PAA (MMW-EA). FIG. 14 shows a plot of a spray-dried mixture of 80% ITZ and 20% Soluplus® polymer. FIG. 15 shows a plot of a spray-dried mixture of 80% ITZ and 20% Affinisol® polymer. [Figure 14]Differential scanning calorimetry (DSC) plots are shown: FIG. 11 shows a plot of a spray-dried mixture of 70% ITZ and 30% PAA (medium molecular weight, formed in ethyl acetate: MMW-EA). FIG. 12 shows a plot of a spray-dried mixture of 80% ITZ and 20% PAA (MMW-EA). FIG. 13 shows a plot of a spray-dried mixture of 90% ITZ and 10% PAA (MMW-EA). FIG. 14 shows a plot of a spray-dried mixture of 80% ITZ and 20% Soluplus® polymer. FIG. 15 shows a plot of a spray-dried mixture of 80% ITZ and 20% Affinisol® polymer. [Figure 15] Differential scanning calorimetry (DSC) plots are shown: FIG. 11 shows a plot of a spray-dried mixture of 70% ITZ and 30% PAA (medium molecular weight, formed in ethyl acetate: MMW-EA). FIG. 12 shows a plot of a spray-dried mixture of 80% ITZ and 20% PAA (MMW-EA). FIG. 13 shows a plot of a spray-dried mixture of 90% ITZ and 10% PAA (MMW-EA). FIG. 14 shows a plot of a spray-dried mixture of 80% ITZ and 20% Soluplus® polymer. FIG. 15 shows a plot of a spray-dried mixture of 80% ITZ and 20% Affinisol® polymer. [Figure 16] Chromatograms of ITZ assay of 40% ITZ-60% PAA (prepared in co-solvents, high, medium, low molecular weight: HMW-CO, MMW-CO, LMW-CO) are shown. [Figure 17] Figure 1 shows the average release of ITZ in 0.1 N HCl under non-sink conditions from 15, 30 and 50% ITZ-PAA physical mixtures, 15, 30 and 50% ITZ-PAA spray dried amorphous solid dispersions (ASD) (high molecular weight, prepared in co-solvent: HMW-CO), as well as ITZ neat and 100% ITZ spray dried formulations. [Figure 18]Figure 1 shows the average ITV release under non-sink conditions in 0.1 N HCl from 40% ITZ-60% PAA spray-dried ASD (high, medium, and low molecular weight, prepared in co-solvents: HMW-CO, MMW-CO, and LMW-CO), 40% ITZ-60% spray-dried Soluplus® ASD, and spray-dried 40% ITZ-60% Affinisol® ASD.

[0018] [Figure 19] Average ITZ release under non-sink conditions in 0.1 N HCl from 40% ITZ-60% PAA spray dried ASD (medium molecular weight, formed in ethyl acetate: MMW-EA), 40% ITZ-60% PAA spray dried ASD (low molecular weight, formed in co-solvent: LMW-CO), 40% ITZ-60% Soluplus® ASD, and 40% ITZ-60% Affinisol® ASD. [Figure 20] Average ITZ release is shown (under non-sink conditions in 0.1 N HCl for 80% ITZ-20% PAA spray dried ASD (medium molecular weight PAA formed in ethyl acetate: MMW-EA), 40% ITZ-60% PAA spray dried ASD (medium molecular weight, formed in ethyl acetate: MMW-EA), 70% ITZ-30% PAA spray dried ASD medium molecular weight, formed in ethyl acetate: MMW-EA, and 40% ITZ-60% Soluplus® and 40% ITZ-60% Affinisol® spray dried ASD). [Figure 21] 1 shows the average ITZ release from 80% ITZ-20% PAA spray-dried ASD (low, medium, and high molecular weight PAA: LMW-EA, MMW-EA, and HMW-EA formed in ethyl acetate) under non-sink conditions in 0.1 N HCl. [Figure 22] Figure 1 shows the average release of ITZ in 0.1 N HCl under non-sink conditions from 80% ITZ-20% PAA (MMW-EA) ASD as prepared (0 months) and after 6 months of storage at accelerated conditions (40 °C / 75% RH). [Diagram 23]Average release of ITZ in 0.1 N HCl under non-sink conditions for 40% ITZ-60% Soluplus® ASD as prepared (0 months) and after 6 months of accelerated storage (40° C. / 75% RH). [Figure 24] 1 shows the average release of ITZ in 0.1 N HCl under non-sink conditions for 40% ITZ-60% Affinisol® ASD as prepared (0 months) and after 6 months of accelerated storage (40° C. / 75% RH). [Diagram 25] 1 shows a differential scanning calorimetry (DSC) plot of 80% ITZ-20% Soluplus® spray dried material stored at 40° C. / 75% RH for 3 months. [Figure 26] 1 shows a differential scanning calorimetry (DSC) plot of 80% ITZ-20% Affinsiol® spray dried material stored at 40° C. / 75% RH for 3 months. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Aspects of the exemplary embodiments relate to amorphous solid dispersions of active pharmaceutical ingredients, methods for forming amorphous solid dispersions of active pharmaceutical ingredients, and amorphous solid dispersions formed by the methods.

[0020] An exemplary amorphous solid dispersion includes a linear poly(acrylic acid) polymer and an active pharmaceutical ingredient. The polymer can stabilize the amorphous form of the drug at drug loading levels of up to 80% or more. An exemplary amorphous solid dispersion is formed by spray drying, a reproducible and scalable pharmaceutical manufacturing process.

[0021] The exemplary method has several advantages over existing methods for preparing formulations of pharmaceutical active ingredients, including: improved water solubility and therefore improved oral bioavailability of physically stable drug forms (avoiding crystallization or phase separation of amorphous drug), flexibility in drug loading levels (e.g., up to 80% or higher drug loading levels) while maintaining the stability of the amorphous solid dispersion, and production of amorphous solid dispersions through a reproducible and scalable process.

[0022] As used herein, an "active pharmaceutical ingredient" (API) or "drug" may be any substance or mixture of substances intended for use in the manufacture of a drug product, which, when used in the manufacture of a drug, becomes an active ingredient of the drug product. Such substances are intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body of an animal, such as a human.

[0023] The API may belong to BCS class II (high permeability, low solubility) or BCS class IV (low permeability, low solubility). A candidate API is any substance or mixture of substances intended for use in the manufacture of a drug product and is being developed / tested for such use.

[0024] According to the U.S. Food and Drug Administration, a drug in a solid dosage form is considered very soluble if its highest clinical dose strength dissolves in 250 mL or less of aqueous medium over the pH range of 1 to 6.8 at 37 ± 1 °C and is suitable for oral administration to humans (f aPermeability is considered to be high if absorption of the immediate release solid oral dosage form (labeled as 100 mg / kg / day) is 85% or more (with evidence of drug stability in the GI tract) or compared to an intravenous reference dose. (Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System: Guidance for Industry, US Food and Drug Administration, Center for Drug Evaluation and Research (CDER), p.3(2017)), see USFDA 2017.

[0025] In accordance with USFDA 2017, low permeability APIs were determined according to the method outlined in USFDA 2017, f a A low-solubility API is an API whose solubility is less than 50%. A low-solubility API is considered herein to be one whose highest clinical dose strength (applicable for 2019) is not soluble in 250 mL or less of aqueous media over a pH range of 1 to 6.8 at 37±1°C, according to the methods outlined in USFDA 2017. The water solubility of the API may be less than 0.1 g / L or less than 0.05 g / L over a pH range of 1 to 6.8 at 37±1°C.

[0026] The pharmacologic active ingredients include analgesics, anti-inflammatory agents, analgesics, antiarrhythmic agents, antibacterial agents, antiviral agents, anticoagulants, antidepressants, antidiabetic agents, antiepileptic agents, antifungal agents, antigout agents, antihypertensive agents, antimalarial agents, antimigraine agents, antimuscarinic agents, antineoplastic agents, erectile dysfunction improving agents, immunosuppressants, antiprotozoal agents, antithyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids, diuretics, antiparkinsonian agents, antispasmodics ... The therapeutic agent may be an anti-anginal agent, a gastrointestinal agent, a histamine receptor antagonist, a keratolytic agent, a lipid regulating agent, an anti-anginal agent, a Cox-2 inhibitor, a leukotriene inhibitor, a macrolide, a muscle relaxant, an opioid analgesic, a protease inhibitor, a sex hormone, a muscle relaxant, an anti-osteoporosis agent, an anti-obesity agent, a cognitive enhancer, an anti-urinary incontinence agent, an anti-benign prostatic hyperplasia agent, an antipyretic agent, a muscle relaxant, an anticonvulsant, an anti-emetic agent, an anti-Alzheimer's agent, or a combination thereof.

[0027] Examples of BCS class II drugs include aceclofenac, acetaminophen, acyclovir, albendazole, amisulpride, aripiprazole, atorvastatin, azithromycin, benidipine, bicalutamide, candesartan cilexetil, carbamazepine, carvedilol, cefdinir, cefuroxime axetil, sel, clopidogrel, clozapine, cyclosporine, cyproterone, cisapride, danazol, dexamethasone, diazepam, diclofenac, diloxanide, ebastine, efavirenz, epalrestat, ethyl icosapentate, glibenide, ezetimibe, fenofibrate, fluconazole, flurbigriseofulvin, haloperidol, hydroxyzine, ibuprofen, imatinib, indinavir, irbesartan, isotretinoin, itra Conazole, ketoconazole, ketoprofen, lamotrigine, levodopa, levothyroxine sodium, methachlorpromazine, lopinavir, loratadine, lorazepam, manidipine, mebendazole, mycophenolate mofetil, naproxen, nelfinavir, nevirapine, nicergoline, niclosamide, nifedipine, nisoldipine, olanzapine, orlistat, oxcarbazepine, phenytoin, pioglitazone, pranlukast, praziquantel, pyrantel, pyrimethamine, simfiazine, quetiapine, quinine, raloxifene, rebamipide, tacrolimus, tamoxifen, telmisartan, teprenone, ticlopidine, ursodeoxycholic acid, valproic acid, valsartan, verapamil, warfarin, and pharma- ceutically acceptable salts thereof.

[0028] APIs belonging to BCS Class II are poorly soluble but are absorbed from solution by the lining of the stomach and / or intestine.

[0029] Examples of BCS class IV drugs include acetazolamide, allopurinol, amphotericin B, atovaquone, bifonazole, bleomycin, buparvaquone, cefuroxime, chloroquine, chlorothiazide, cyclosporine, dapsone, diminazene stearate, diminazene oleate, doxycycline, furosemide, mefloquinone, metronidazole, methoxantrone, nalidixic acid, nimorazole, paclitaxel, paracetamol, pentamidine, primaquine, proteinase inhibitors, ritonavir, tinidazole, titanium metallocene dichloride, tobramycin, prostaglandins, saquinavir, vinblastine, vincristine, vindesine, vancomycin, vecuronium, and pharmaceutically acceptable salts thereof.

[0030] In the following example, itraconazole (C 35 H 38 Cl2N8O4) is used as an example of a BCS class II API, and ritonavir (C 37 H 48 N6O5S2) is used as an example of a BCS class IV API. Itraconazole (ITZ) is a broad-spectrum antifungal compound with a melting point of 170 °C. ITZ is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each with three chiral centers. The solubility of ITZ in water is approximately 1-4 ng / mL. ITZ has very low oral bioavailability due to its insolubility in intestinal fluids. Ritonavir (RTV), sold under the trade name Norvir™, is an antiretroviral drug used with other drugs to treat HIV / AIDS. This combination therapy is known as highly active antiretroviral therapy (HAART). Ritonavir has low and variable oral bioavailability due to its poor water solubility.

[0031] As used herein, "poly(acrylic acid)" (PAA) is a homopolymer of acrylic acid. By "homopolymer" is meant that at least 90 mol% of the units in the polymer are derived from acrylic acid, or at least 95 mol%, or at least 98 mol%, or 100 mol% of the units in the polymer are derived from acrylic acid.

[0032] Exemplary PAAs are linear, i.e., have substantially no crosslinks. This means that crosslinks (or branches) occur, on average (average), in less than one tenth of the poly(acrylic acid) units in the longest chain of the polymer, or in less than one twentieth or one fiftieth of the poly(acrylic acid) units in the longest chain of the polymer. Crosslink density can also be defined as the reciprocal of the molecular weight (Mc) between crosslinks, and can be 0.0014 or less, or 0.0007 or less.

[0033] Thus, PAA polymers can be generally represented by the formula: [ka] wherein n can be at least 1400, or at least 2000, or at least 3000, or at least 4000, or at least 5000, or at least 6000, or at least 8000, or at least 10000, or at least 12000, or a minimum of 14000, or a maximum of 80000.

[0034] The PAA used to form the amorphous solid dispersion (ASD) may have a high molecular weight, which is the weight average molecular weight (M w ) or number average molecular weight (M n )

[0035] As used herein, the weight average molecular weight (M w) is determined by size exclusion chromatography (SEC) as follows: A liquid sample is prepared from approximately 1.5 g / L (0.15%) polymer in 0.1 M NaNO3 at pH 10. Prior to injection, the sample is filtered. 100 μL of the filtered sample is loaded onto a column (TOSOH Bioscience, 2X TSKgel PW) using 0.1 M NaNO3 in deionized water at pH 10 as the mobile phase. XL The mobile phase (and sample) enters the TDA and passes through a GPC / SEC chromatography column. The column is maintained at the same temperature (40 °C) as the detector. After elution from the column, the dissolved polymer molecules are separated by size and pass through three detectors. Finally, the mobile phase passes through a viscometer before being discarded.

[0036] The RI detector provides information about the concentration of components in the sample. The light scattering detector responds to the intensity of light scattered by the sample which relates to molecular weight and can also calculate the Rg of large molecules. The viscometer measures the viscosity of a changing solution to calculate the intrinsic viscosity of the sample (not used here to determine viscosity).

[0037] PAA's M w may be at least 120,000, or at least 150,000, or at least 200,000, or at least 250,000, or at least 300,000, or at least 400,000, or at least 500,000, or at least 600,000, or at least 800,000, or at least 1,000,000 Da. wmay be up to 10,000,000, up to 5,000,000, or up to 3,000,000, or up to 2,000,000, or up to 1,500,000 Da. w is in the range of 500,000 to 1,500,000.

[0038] As used herein, number average molecular weight (M n ) is M w It is determined by the same method used to determine the M of PAA. n may be at least 100,000 Da, or at least 120,000, or at least 140,000, or at least 150,000, or at least 160,000, or at least 180,000. n may be up to 1,000,000, up to 800,000, or up to 500,000 Da. In one exemplary embodiment, M n ranges from 150,000 to 500,000 Da.

[0039] As used herein, Brookfield viscosity is measured on an aqueous solution containing 4 wt% PAA at pH 7.5 using a Brookfield Viscometer Model DV2TRV, 20 rpm, 25 °C. The spindles used in this model are RV01-RV07, covering the following viscosity ranges: RV-01, up to 500 cP; RV-02, up to 2000 cP; RV-03, up to 5000 cP; RV-04, up to 10,000 cP; RV-05, up to 20,000 cP; RV-06, up to 50,000 cP, and RV-07, up to 200,000 cP. The aqueous solution is formed by dissolving PAA in water and adjusting the pH to 7.5 using an 18% aqueous solution of NaOH.

[0040] The PAA used to form the amorphous solid dispersion according to this method may have a Brookfield viscosity of at least 100 cP (cP=mPa·s), or at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP. The viscosity is up to 3,000 cP, or up to 2,500 cP, or up to 2200 cP, or up to 2100 cP. In an exemplary embodiment, the Brookfield viscosity is in the range of 200-2,200 cP.

[0041] Brookfield viscosity correlates well with molecular weight. Brookfield viscosity is proportional to molecular weight as measured by the method described. For example, a linear PAA polymer with a Brookfield viscosity of 200 cp has an M of 162,048 Da. n and M of 545,692 Da. W The linear PAA polymer has a Brookfield viscosity of 2075 cP and an M n and M of 1,071,000 Da w has.

[0042] Brookfield viscosity is determined by the molecular weight (M n or M w ) and can therefore be used as an indicator of molecular weight.

[0043] PAA linear polymers within the above molecular weight ranges can be described herein as low molecular weight (LMW), medium molecular weight (MMW), or high molecular weight (HMW). Exemplary LMW polymers can have a Brookfield viscosity of 180-350 cP. Exemplary MMW polymers can have a Brookfield viscosity of 400-1,000 cP. Exemplary HMW polymers can have a Brookfield viscosity of 1,200-2,200 cP.

[0044] Exemplary linear PAAs are in the form of fine powders containing 5% or less water by weight, e.g., 3% or less water by weight, or 2% or less water by weight, or 1% or less water by weight. There may be 2-3% water content due to the hygroscopic nature of the polymer, not as a result of synthesis. The water content is determined by Loss on Drying (LOD).

[0045] As used herein, an "amorphous solid dispersion" (ASD) is a dispersion of an API in a solid polymer matrix that is substantially free of crystallinity, as evidenced by commonly used qualitative indicators of crystallinity, such as, for example, X-ray powder diffraction (XRPD), described below, and differential scanning calorimetry (DSC). In particular, the crystalline character of the crystalline dispersion is evidenced by a characteristic, well-defined peak of the drug in the XRPD pattern and a clear melting endotherm in the DSC thermogram. The absence of these indicators of linear PAA after spray drying is consistent with an amorphous material. DSC can also be used to determine the glass transition temperature (Tg) of the amorphous material, which is absent in highly crystallized samples. Amorphous solid dispersions are also distinct from physical blends of PAA and drug, where the PAA and drug are simply combined by powder mixing.

[0046] The use of DSC and XRPD to characterize solid dispersions is well known. For example, the application of XRPD and DSC to solid dispersions is described in Soti et al., "Comparison of Spray-drying, Electroblowing and Electrospinning for Preparation of Eudragit E and Itraconazole Solid Dispersions," Int. J. Pharm 494:23, pp1-27 (2015), and Wlodarski et al., "Synergistic Effect of Polyvinyl Alcohol and Copovidone in Itraconazole Amorphous Solid Dispersions," Pharm. Res., 35:16, pp.1-15 (2018).

[0047] Transmission or backscattering Raman spectroscopy can also be used. See, for example, Netchacovitch et al., "Development of an analytical method for crystalline content determination in amorphous solid dispersions produced by hot-melt extrusion using transmission Raman spectroscopy: A feasibility study," Int. J. Pharm. 15, 530(1-2), pp. 249-255 (2017). The percentage of crystallinity of an amorphous solid dispersion, determined using transmission Raman spectroscopy, for example according to the method of Netchacovitch et al., can be less than 10%, or less than 5%, or less than 1%.

[0048] Exemplary amorphous solid dispersions comprise, consist of, or consist essentially of poly(acrylic acid) and an API (or mixture of APIs), where essentially consisting means that the polymer and API together account for at least 90% by weight (or at least 95% by weight, or at least 98% by weight) of the amorphous solid dispersion.

[0049] The amorphous solid dispersion may contain at least 0.01 wt% of API, or at least 0.1 wt% of API, or at least 1 wt% of API, or at least 5 wt% of API, or at least 10 wt% of API, or at least 15 wt% of API, or at least 20 wt% of API, or at least 30 wt% of API, or at least 40 wt% of API, or at least 50 wt% of API, or at least 60 wt% of API, or at least 70 wt% of API. The amorphous solid dispersion may contain up to 90 wt% of API, or up to 85 wt% of API, or up to 80 wt% of API. As used herein, weight % API (drug loading) is the weight of pure (undiluted) API in the ASD. High loading of API (e.g., 90 wt% or more API) may result in the solid dispersion being partially crystalline in nature in some cases, which is undesirable for good solubility and absorption of the API. When the solid dispersion is partially crystalline, the release rate of the drug from the solid dispersion is lower.

[0050] The amorphous solid dispersion (ASD) may contain at least 10% by weight of the PAA polymer, or at least 15% by weight of the PAA polymer, or at least 20% by weight of the PAA polymer, or at least 25% by weight of the PAA polymer. The ASD may contain up to 99% by weight of the PAA polymer, or up to 95% by weight of the PAA polymer, or up to 80% by weight of the PAA polymer, or up to 60% by weight of the PAA polymer, or up to 50% by weight of the PAA polymer, or up to 40% by weight of the PAA polymer, or up to 30% by weight of the PAA polymer.

[0051] The weight ratio of pharma- ceutical active ingredient:poly(acrylic acid) in the amorphous solid dispersion can be at least 1:10, or at least 1:6, or at least 1:3, or at least 1:1.5, or at least 1:1, or at least 2:1, or at least 3:1, or at least 4:1, or up to 6:1, or up to 5:1, or up to 4.5:1.

[0052] Exemplary amorphous solid dispersions contain 5% water by weight or less, or 2% water by weight or less, or 1% water by weight or less (eg, no water).

[0053] In some embodiments, the formulation comprising the amorphous solid dispersion may further comprise one or more pharma- ceutically acceptable excipients and / or adjuvants. Pharmaceutically acceptable excipients are inert additives included in solid formulations to increase the bulk of the formulation comprising the ASD. Pharmaceutically acceptable adjuvants enhance the efficacy of the API. Excipients and / or adjuvants can be added during or after the preparation of the spray-dried form of the amorphous solid dispersion.

[0054] In one embodiment, the adjuvant and / or excipient may be present at up to 99% by weight of the total formulation including the ASD, such as up to 20% by weight, or up to 10% by weight, or up to 5% by weight, In one embodiment, the adjuvant and / or excipient may be at least 0.01% by weight of the formulation.

[0055] Exemplary amorphous solid dispersions can be formed from liquid dispersions. A "liquid dispersion" is a system in which distributed particles of one material (here at least the API and PAA) are dispersed in a continuous phase of another material (here the solvent system). The two phases can be in the same or different states of matter. Liquid dispersions can be classified in a variety of ways, including by the size of the particles relative to the particles of the continuous phase, whether or not sedimentation occurs, and the presence of Brownian motion. In general, liquid dispersions of particles large enough to sediment are referred to herein as suspensions, while liquid dispersions of smaller particles (which can be as small as the size of molecules) are referred to herein as colloidal mixtures or solutions.

[0056] Exemplary amorphous solid dispersions are formed by solvent evaporation methods such as spray drying (SD). The amorphous solid dispersions may be in the form of an as-formed spray-dried powder or may be further processed, for example, to reduce particle size and / or to form a product, for example, in the form of a granule, capsule, pellet, tablet, film, medical or dental implant, dispersion of ASD in a liquid medium, or injectable product formulated for intravenous introduction into humans or non-human animals.

[0057] Figure 1 shows a method for forming an amorphous solid dispersion. The method begins with S100.

[0058] In S102, the PAA is prepared. This may include forming the PAA with a molecular weight and / or Brookfield viscosity as discussed above, or obtaining a preformed PAA. The PAA may be dissolved in a solvent or mixture of solvents in which the API is soluble.

[0059] In S104, the PAA and API are combined in a suitable organic solvent system, such as a single solvent or a mixture of solvents, to form a liquid dispersion, such as a solution, a colloidal mixture, or a suspension.

[0060] In S106, the liquid dispersion containing the PAA polymer, API, and solvent is formed into ASD particles by spray drying or other solvent evaporation methods.

[0061] At S108, a product containing the ASD thus formed can be prepared, which may include one or more of milling, compression into a tablet, addition of excipients and / or adjuvants, encapsulation of the ASD in a shell, such as a material having a different solubility in water or gastric acid than the ASD, combinations thereof, and the like.

[0062] The method ends at S110.

[0063] Preparation of PAA The linear PAA polymer can be formed in solution without the addition of a crosslinker, and the resulting linear PAA can be in the form of a powder.

[0064] Various methods exist for forming linear PAA and can be used to form high molecular weight PAA. PAAs can be synthesized in a pharma- ceutically acceptable solvent system in which the starting materials (e.g., acrylic acid monomers) are soluble. In one embodiment, the solvent is an organic solvent or mixture of organic solvents. Examples of organic solvents include ethyl acetate (EA) alone or in combination with a co-solvent, such as a mixture of cyclohexane and ethyl acetate. A mixture of ethyl acetate and cyclohexane is referred to herein as CO. The weight ratio of ethyl acetate:cyclohexane in the CO mixture can be from 30:70 to 100:0. A dispersion (e.g., solution) comprising monomer and solvent can be substantially free of water (non-aqueous). This means that the solution contains 10% water by weight or less, or 5% water by weight or less, or 2% water by weight or less, or 0% added water by weight.

[0065] PAA can be formed from acrylic acid monomers in a selected organic solvent in a free radical process using an initiator such as an organic peroxide. The reaction can be carried out at about room temperature or above (e.g., 18-70°C). The acrylic acid can be partially preneutralized, for example with sodium hydroxide, prior to polymerization. The degree of neutralization can be used to control the molecular weight of the PAA polymer. See, for example, Khanlari et al., "Effect of pH on Poly(acrylic acid) Solution Polymerization," J. Macromolecular Science, Part A, 52:8, 587-592 (2015). In organic solvents such as ethyl acetate, PAA is formed as a precipitate and can be used directly to form ASD without the need to remove water from the PAA (to remove most of the organic solvent after low temperature drying). For example, with ethyl acetate and cyclohexane, drying can be performed at temperatures below 90°C for less than an hour.

[0066] In other embodiments, the free radical reaction can also be carried out using pure monomers (bulk polymerization) or by polymerization in aqueous solution or emulsion.

[0067] Poly(acrylic acid) can also be synthesized by anionic polymerization of t-butyl acrylate (eg, with an organolithium reagent or other addition initiator, and methyl alcohol), followed by acid hydrolysis of the tert-butyl groups.

[0068] In another embodiment, PAA is formed by reversible addition-fragmentation transfer polymerization (RAFT) of acrylic acid in the presence of a RAFT agent such as a trithiocarbonate. The molecular weight (M n) can be controlled by selecting the ratio of [AA]:[RAFT agent]. See, for example, Ji et al., "Efficient Synthesis of Poly(acrylic acid) in Aqueous Solution via a RAFT Process," J. Macromolecular Science, Part A, 47:5, 445-451 (2010). Ji's method allows for the production of highly linear PAA with high molecular weight and low polydispersity index (PDI) because chain transfer to the solvent or polymer is suppressed during the polymerization process. Furthermore, when the generated PAA was used as a macro-RAFT agent, the chain-extension polymerization of PAA with novel acrylic acid showed controlled behavior, indicating the ability of PAA to resume continuous polymerization.

[0069] Volume average molecular weight (M v Poly(acrylic acid) with molecular weights of about 130,000, about 250,000, about 450,000, about 1.25 million, and about 3 million and about 4 million are available from Millipore Sigma or Sigma-Aldrich.

[0070] Evaporation of the solvent Spray drying (SD) is a solvent evaporation process that produces a dry powder from a liquid by rapid drying with hot gas. Although spray drying is used in the exemplary embodiment, other solvent evaporation processes involving evaporation of a solvent, such as, for example, a non-aqueous (organic) solvent, are contemplated, such as, for example, oven drying under heat and / or vacuum (e.g., film casting followed by oven drying to obtain a dry film of the drug / polymer ASD), fluidized bed drying (using a flow of air or other gas to produce a dry powder), tumble drying (using mechanical agitation to produce a dry powder), electrospinning (to produce nano- or micron-sized fibers containing the ASD of the drug / PAA), or electrospraying (to produce a dry powder).

[0071] In an exemplary embodiment where spray drying is used, the liquid fed to the spray dryer for spray drying includes the PAA, at least one API, and a solvent or mixture of solvents in which the poly(acrylic acid) and API are soluble, particularly more soluble than water. Suitable solvents include polar protic organic solvents such as C1-C6 alcohols, polar (hydrophilic) aprotic solvents such as ethanol, dichloromethane (DCM), C3-C8 ketones, C3-C8 ethers, and other low boiling organic solvents (e.g., boiling point below 90°C), and mixtures thereof. Solvents evaporate from the liquid, so they are absent or present in small amounts in the amorphous solid dispersion. For example, the amorphous solid dispersion contains less than 5% by weight of solvent, or less than 1% by weight of solvent.

[0072] For example, ethanol is a suitable solvent for RTV, and a mixture of dichloromethane and ethanol is suitable for ITZ. The weight ratio of (ethanol:DCM) in such a solvent system can be 1:10 to 10:1, such as 5:1 to 1:2, although any suitable solvent or solvent ratio that dissolves both the drug and polymer can be used.

[0073] The ratio of the total weight of PAA and API to the weight of the solvent in the spray-drying solution (or other dispersion) formed in S104 is not critical, and can be, for example, at least 0.015:1, or at least 0.02:1, and can be up to 0.2:1 or up to 0.1:1. The weight ratio of PAA to the solvent in the spray-drying solution is not critical, and can be, for example, at least 0.01:1, or at least 0.02:1, and can be up to 0.19:1 or up to 0.09:1. The weight ratio of API to the solvent in the spray-drying solution is not critical, and can be, for example, at least 0.008:1, or at least 0.015:1, and can be up to 0.09:1 or up to 0.07:1. The ratio of API to PAA in the spray-drying solution can be selected based on the desired ratio in the ASD. For example, the ratio can be 10:90 to 85:15 to achieve the corresponding ratio of API to PAA in the ASD.

[0074] To form a spray-drying solution, the PAA (e.g., in powder form) and the API can first be dissolved in their respective solvents (which can be the same or different) and the two liquids combined. In another embodiment, neat API is added to a solution containing PAA and a solvent. In another embodiment, PAA with little or no solvent is added to a solution containing API and a solvent. In some embodiments, the solution containing PAA and API can incorporate one or more excipients and / or their adjuvants or precursors.

[0075] As an example, to form a spray-dried solution, the PAA (e.g., in powder form) and the API can be first dissolved in their respective solvents (which can be the same or different) and the two liquids combined. Alternatively, the PAA can be dissolved in a solution of the API in one solvent and then the second solvent can be added. The resulting mixture is pumped to a spray dryer to evaporate the solvent at a temperature higher than the boiling point of the solvent used and collect the spray-dried ASD. For example, the inlet (maximum) temperature of the spray dryer can be at least 80°C, or at least 90°C for ethanol (or ethanol:DCM mixtures). Ethanol boils at about 78°C under atmospheric conditions. The inlet (maximum) temperature of the spray dryer can be up to 120°C, or up to 100°C for such solvents.

[0076] Residual organic solvents in the formed ASD may be less than 5% by weight, or less than 2% by weight, or less than 1% by weight. Acceptable residual solvent levels vary depending on the type of solvent used (e.g., as specified by pharmacopoeias and / or regulatory guidance, the allowable amount of Class 1 or 2 solvents may be less than (less toxic) Class 3 solvents).

[0077] The active pharmaceutical ingredient, in the form of a spray dried amorphous solid dispersion formed by the exemplary methods, or in the form of a product formed from the spray dried amorphous solid dispersion, can be administered orally to a human or animal in need of treatment, by implanting an implant, such as a mesh or tube of electrospun fibers containing the ASD.

[0078] Without intending to limit the scope of the exemplary embodiments, the following examples demonstrate the drug loading that can be achieved in amorphous solid dispersions containing poly(acrylic acid). EXAMPLES

[0079] 1. Preparation of PAA Eight linear PAAs (PAA1-8) are synthesized in a range of different molecular weights (expressed as Brookfield viscosity measured by the method described above) in various solvents. Table 1 shows examples of PAAs formed. EA indicates ethyl acetate and CO indicates a mixture of ethyl acetate and cyclohexane (e.g., EA: 30 wt%, cyclohexane: 70 wt%). Poly(acrylic acid) products are defined as low molecular weight (LMW), medium molecular weight (MMW), or high molecular weight (HMW) based on their Brookfield viscosity (determined as described above). [Table 1]

[0080] 2. Model API Itraconazole (ITZ) (1-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one) from Ra Chem Pharma Ltd and SMS Pharma, and LGM Ritonavir (RTV) (5-thiazolylmethyl ((alphaS)-alpha-((1S,3S)-1-hydroxy-3-((2S)-2-(3-((2-isopropyl-4-thiazolyl)methyl)-3-methylureido)-3-methylbutyramido)-4-phenylbutyl)phenethyl)carbamate) polymorphic form II from Pharma was selected as a low-solubility model drug. The properties of the two drugs are shown in Table 2. [Table 2]

[0081] Linear PAA (in the respective synthesis solvent) is combined with the selected API and spray dried to obtain stable ASDs with various drug loadings (15 wt%, 30 wt%, 40 wt%, 50 wt%, 80 wt%).

[0082] For comparison, spray-dried mixtures of the drug alone and with other polymers were also prepared: polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG) (Soluplus®, BASF) and hydroxypropyl methylcellulose (Affinisol®, Dow) (Table 3). These two polymers are commonly used to stabilize ASDs. [Table 3]

[0083] 3. Preparation of Amorphous Dispersions and Other Formulations The spray dried formulation is prepared as follows.

[0084] For spray drying of Ritonavir and PAA, PAA (in powder form) is dissolved in ethanol. Ritonavir is also dissolved in ethanol. The two solutions are combined. The resulting solution is pumped into a spray dryer (BUCHI B-290) where the solvent is evaporated at a temperature higher than the boiling point of the solvent used and the spray dried dispersion is collected as a powder.

[0085] For spray drying of ITZ and PAA, ITZ is dissolved in DCM. PAA is dispersed in the resulting solution. Ethanol is added to the dispersion of PAA in ITZ-DCM to dissolve the PAA and form a solution. The resulting solution is pumped into a spray dryer (BUCHI B-290) where the solvent is evaporated at a temperature higher than the boiling point of the solvent used and the spray dried dispersion is collected as a powder.

[0086] For spray drying of ITZ and Soluplus® or ITZ and Affinisol®, ITZ is dissolved in DCM. The polymer (Soluplus® or Affinisol®) is dissolved in DCM. The two solutions are combined. The resulting solution is pumped into a spray dryer (BUCHI B-290) where the solvent is evaporated at a temperature higher than the boiling point of the solvent used and the spray dried dispersion is collected as a powder.

[0087] Table 4 shows the specific spray drying conditions for formulations F1-F15 prepared with ITZ. Dichloromethane (DCM) is used as the solvent for the ITZ only, and a mixture of dichloromethane and ethanol at various weight ratios (ethanol:DCM) is used as the solvent for the PAA:ITZ mixture. Table 5 shows the spray drying conditions for formulations F16-F19 prepared with RTV, where ethanol is used as the solvent. Table 6 shows the spray drying conditions for formulations F20-F23 prepared with Affinisol® and Soluplus® polymers using DCM as the solvent. [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

[0088] Physical mixtures of linear PAA and drug (without spray drying) are also prepared for comparison with formulations made by spray drying. The selected drug and polymer are weighed separately and mixed gently using a mortar and pestle using the geometric dilution method. Table 7 lists these formulations. [Table 9]

[0089] 4. Product Evaluation The resulting ASDs and comparative examples are tested for stability at 40°C / 75%RH and analyzed by appearance, differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and drug dissolution. All drug-PAA ASDs prepared by spray drying show stability over time. Stabilization of high drug loading (above 80%) was achieved only with linear PAA.

[0090] A. Physical properties (appearance, crystallinity, thermal behavior) Table 8 shows the physical properties of the ITZ-PAA physical mixtures and spray dried amorphous solid dispersions. The PAA type indicates the molecular weight designation and the solvent (Ethyl acetate: EA, Ethyl acetate cyclohexane co-solvent: CO) used to form the PAA. The physical form of the product is identified visually (e.g., solid powder) and by XRPD and / or DSC (to assess the amorphous or crystalline state). The Tg values ​​are estimates from the DSC curves.

[0091] The results for the comparative polymers are shown in Table 9. [Table 10-1] [Table 10-2]

[0092] The results suggest that API / linear PAA ASDs with drug loadings of up to 80 wt% can be achieved by spray drying without losing the amorphous character of the product. The API / linear PAA physical mixtures exhibit some crystallinity due to the API.

[0093] Formulations F9 and F10 were placed on accelerated stability (40° C. / 75% RH) and analyzed at 2 weeks. This informal stability study showed no significant changes (still amorphous). [Table 11]

[0094] In the case of 80% ITZ Soluplus® or Affinisol® spray-dried materials (F21 and F23, Table 9), the XRPD shows an amorphous system and the DSC shows broader features with a melting peak characteristic of crystalline ITZ (Figures 14 and 15). Combining these two results supports the conclusion that a heterogeneous amorphous system with amorphous-amorphous phase separation with ITZ amorphous drug occurs in the 80% ITZ Soluplus® or Affinisol® spray-dried materials. The same features are present in the XRPD and DSC of the spray-dried material with 90% ITZ and PAA (F12, Table 8, Figure 13).

[0095] These results suggest that at high drug loadings, spray-dried ASD cannot be achieved with Soluplus® and Affinisol® polymers without phase separation of the drug. From a physical stability perspective, phase separation is undesirable as it impacts drug dissolution and long-term stability, increasing the likelihood of drug crystallization over time.

[0096] For the 80% ITZ-PAA amorphous solid dispersion, DSC shows no melting peak characteristic of crystalline ITZ (Figure 12) and XRPD shows amorphous material. These results indicate that 80% ITZ-PAA is a homogeneous single-phase amorphous solid dispersion with no drug phase separation. Thus, PAA is a more effective polymer in maintaining the physical stability of drug-polymer ASDs at higher drug loading levels than the benchmarks Soluplus® and Affinisol®.

[0097] Figures 2 to 7 are photographs of spray-dried products on the same scale. Figure 2 shows product F20 (40% ITZ-60% Soluplus®). Figure 3 shows product F22 (40% ITZ-60% Affinisol®). Figure 4 shows product F4 (40% ITZ-60% PAA (HMW-CO)). Figure 5 shows product F7 (40% ITZ-60% PAA (MMW-CO)). Figure 6 shows product F6 (40% ITZ-60% PAA (LMW-CO)). Figure 7 shows product F8 (40% ITZ-60% PAA (MMW-EA)).

[0098] X-ray powder diffraction (XRPD) was performed using Panalytical's X'Pert 3This was done using powder XRPD. Figures 8-10 show XRPD plots of various formulations made with ITZ and PAA-8. In Figure 8, plots are shown for ITZ only (neat IZT, formulation F25), a physical mixture of 15% ITZ and 85% PAA (PM 15%, formulation F26), and a spray-dried solid dispersion of 15% ITZ and 85% PAA (ASD 15%, formulation F2). In Figure 9, plots are shown for ITZ only (neat IZT, formulation F25), a physical mixture of 30% ITZ and 70% PAA (PM 30%, formulation F27), and a spray-dried solid dispersion of 30% ITZ and 70% PAA (ASD 30%, formulation F3). In FIG. 10, plots of spray dried solid dispersions of ITZ only (neat IZT, Formulation F25), a physical mixture of 50% ITZ and 50% PAA (PM 50%, Formulation F28), and 50% ITZ and 50% PAA (ASD 50%, Formulation F5) are shown.

[0099] The plot shows that the exemplary ASD is substantially amorphous (no large peaks in the spectrum) even at high drug loading (50% ITZ). In contrast, both the ITZ and the physical mixture show significant crystalline characteristics, as evidenced by the large peaks.

[0100] Figures 11-13 show the DSC plots of formulations F9 (spray dried ASD, 70% ITZ-30% PAA (MMW-EA)), F10 (spray dried ASD, 80% ITZ-20% PAA (MMW-EA)) and F12 (spray dried 90% ITZ-10% PAA (MMW-EA) respectively). Figures 14 and 15 show the DSC plots of formulations F21 (spray dried 80% ITZ 20% Soluplus®) and F23 (spray dried 80% ITZ-20% Affinisol®) materials respectively. The DSC plots show that when Affinisol® or Soluplus® polymers are spray dried with 80% drug, recrystallization and melting point peaks of ITZ are observed. These peaks are absent when linear PAA is spray dried with 80% API.

[0101] B. Assay and Drug Recovery from Spray-Dried ASD To assess the drug content of the formulations, 25 mg of formulation sample (equivalent to 10 mg API) is added to a 50 mL volumetric flask. 5 mL of solvent (1:2 DCM:ethanol, by volume) is added to dissolve the sample and the mixture is briefly sonicated. Each sample is made up to volume in the flask with diluent (70:30 methanol:0.1 N HCl, by volume) and mixed well. The mixtures are analyzed by HPLC using the Assay / Related Substances method. A Waters Alliance HPLC is used. Table 10 shows the results of the ITZ assay. [Table 12]

[0102] FIG. 16 shows the chromatograms of the ITZ assay of formulations F4, F7, and F6.

[0103] C. Drug dissolution test The results of drug dissolution studies indicate that model drugs are released more effectively from spray-dried linear PAA ASDs than from dispersions made with conventional polymers and from physical mixtures. A dissolution bath is used in these studies (Distek Model 6100 or 7100).

[0104] i) Itraconazole: 15% by weight, 30% by weight, 50% by weight, ITZ-Linear PAA ASD The method is carried out under non-sink conditions. The solubility limit of ITZ in the equilibrium dissolution medium (750 mL 0.1 N HCl, 37 °C) is approximately 4-6 μg / mL, and the ITZ concentration in the vessel is approximately 50 μg / mL.

[0105] Weigh out product equivalent to approximately 37.5 mg of itraconazole into a 50 mL plastic centrifuge tube (i.e., 15% fill = 250 mg, 30% fill = 125 mg, 50% fill = 75 mg). Remove 40 mL of equilibrated media from the 750 mL container. Add approximately 10 mL of the removed equilibrated media to the tube vial to pre-wet the drug. Shake the tube by hand to transfer the contents to the container. Rinse the tube with the remaining 40 mL of media and return the contents to the container. Mix the sample using Apparatus II (paddle) at 75 rpm.

[0106] Samples (three of each) are removed from the vessel at 5, 10, 15, 30, 45, 60, and 120 min. Sampling is performed using a 10 μm cannula tip filter and a 0.2 μm regenerated cellulose (Thermo F2513-8) filter for post sample collection. To collect the sample, the cannula is purged 1-2 times and then 5 mL is collected into a disposable syringe. The disposable syringe is removed from the cannula and the cellulose filter is attached to the syringe. The filter is flushed with approximately 4 mL of the collected sample and returned to the vessel. The remaining 1 mL of sample is collected in a glass vial. The collected sample is diluted 1:1 with ACN by transferring 750 μL of sample to an HPLC vial and adding 750 μL of ACN. Mix the diluted sample using a vortex and perform the HPLC analysis.

[0107] FIG. 17 shows the release of ITZ (average of three samples), spray dried (SD) ASD (formulations F2, F3, and F5), ITZ neat (formulation F25), and ITZ SD (formulation F1) in 0.1 N HCl under non-sink conditions from ITZ-PAA (co-solvent) physical mixtures (PM) (formulations F26, F27, and F28).

[0108] ii) Itraconazole-40% ITZ-60% linear PAA polymer ASD, Itraconazole-40% ITZ-60% polymer (Soluplus® or Affinisol®) dispersion, and Itraconazole-80%-20% linear PAA polymer ASD The method is carried out under non-sink conditions. Add the product equivalent to 100 mg ITZ (40% loading = 250 mg; 80% loading = 125 mg) to the centrifuge. Immediately before dissolution, remove approximately 40 mL of equilibrated medium from each container and add a small amount (approximately 10 mL) to a tube vial to pre-wet the product and transfer it to the container by shaking by hand. This is repeated with the remaining medium, and all the medium initially removed from the container is returned to the container. Two equilibrated dissolution media are used: 900 mL of pH 6.8 phosphate buffer at 37 °C and 900 mL of 0.1 N HCl at 37 °C. Mix the sample using Apparatus II (paddle) at 75 rpm.

[0109] As described in i) above, samples (triplicates each) are removed from the vessel at 5, 10, 15, 30, 45, 60 and 120 minutes.

[0110] FIG. 18 shows ITZ release (average of 3 samples) under non-sink conditions with 0.1 N HCl from 40% ITZ-60% PAA (Formulations F4: co-solvent HMW; F6: co-solvent, LMW; and F7: co-solvent, MMW) spray-dried ASD, and 40% ITZ-60% Soluplus® ASD (Formulation F20) and 40% ITZ-60% Affinisol® ASD (Formulation F22).

[0111] FIG. 19 shows the average ITZ release (of three samples) under non-sink conditions in 0.1 N HCl from 40% ITZ-60% PAA (Formulation F8: ethyl acetate; MMW) spray-dried ASD, 40% ITZ-60% Soluplus® ASD (Formulation F20), 40% ITZ-60% Affinisol® ASD (Formulation F22), and 40% ITZ-60% PAA ASD (Formulation F6).

[0112] iii) Ritonavir-15%, 30%, 50% RTV-Linear PAA ASD The method is carried out under non-sink conditions. The solubility limit of RTZ in the equilibrium dissolution medium (pH 6.8 phosphate buffer at 37° C.) is approximately 1 μg / mL, and the concentration of ITZ in the vessel is approximately 13 μg / mL.

[0113] Weigh out product equivalent to approximately 10 mg of ritonavir into a 50 mL plastic centrifuge tube (i.e., 15% fill = 66.66 mg, 30% fill = 33.33 mg, 50% fill = 20 mg). Immediately prior to dissolution, remove 40 mL of equilibrated media from the vessel containing 750 mL. Add approximately 10 mL of the removed equilibrated media to the tube vial to pre-wet the drug. Shake the tube by hand to transfer the contents to the vessel. Rinse the tube with the remaining 40 mL of media and return the contents to the vessel. Use Apparatus II (paddle) at 75 rpm to mix the sample.

[0114] Samples (triplicates each) are removed from the vessels at 5, 10, 15, 30, 45, 60, and 120 minutes. Sampling is performed as described in i) above using a 10 μm cannula tip filter and a 0.45 μm PVDF w / GMF (Whatman Cat#6872-2504) filter after sample collection.

[0115] Figure 20 shows ITZ release (average of 3 samples) under non-sink conditions in 0.1 N HCl from 80% ITZ-20% PAA spray-dried ASD (formulation F10: ethyl acetate MMW PAA), 40% ITZ-60% PAA spray-dried ASD (formulation F8: ethyl acetate MMW PAA); 70% ITZ-30% PAA spray-dried ASD (formulation F9: ethyl acetate MMW PAA); and 40% ITZ-60% Soluplus® and 40% ITZ-60% Affinisol® spray-dried ASD (formulations F20 and F22). Soluplus® and Affinisol® were not suitable for preparing ASDs with 80% drug loading.

[0116] FIG. 21 shows ITZ release (average of 3 samples) under non-sink conditions in 0.1 N HCl from 80% ITZ-20% PAA spray dried ASD (Formulation F13: ethyl acetate LMW PAA, Formulation F14: ethyl acetate MMW PAA, Formulation F15: ethyl acetate MMW PAA, and Formulation F11: ethyl acetate HMW PAA).

[0117] D. Stability studies Product samples will be stored in 1 oz (~28 gm) glass bottles with screw tops for the duration of the study. For itraconazole, approximately 0.4-1.1 g of sample will be used per bottle. For ritonavir, approximately 0.3-0.5 g will be used. Containers will be stored in a stability chamber (Caron 7000-50-1, Darwin Chambers ICH-G2HD-11X11) at 40-45°C / 75% RH and will be tested at T0, 1 month, 2 months, 3 months, and in some cases up to 6 months. Tests performed include appearance, dissolution, DSC, and XRPD.

[0118] XRPD XRPD is performed using a Si zero background holder. 2Theta positioning is performed using a Panalytical Si reference standard disk. The XRPD instrument configuration is Bragg-Brentano geometry. Table 11 shows the parameters used. [Table 13]

[0119] DSC Differential scanning calorimetry (DSC) is performed on a Mettler-Toldeo DSC-1 instrument (without modulated DSC software) using sample amounts of 5-10 mg. Pan type is aluminum, 40 μL. Contents are crimped and lids are perforated. Samples are heated in the pans to 25-250 °C, increasing at 5 degrees / min under a nitrogen purge. Temperature and heat of fusion are calibrated using appropriate standards (indium).

[0120] ITZ-PAA (co-solvent) samples at 15%, 30%, 50%, and 100% ITZ are tested at 40°C / 75%RH. Both XRPD and DSC show that the 100% ITZ spray-dried formulation converted from amorphous to crystalline form at 1 month, with no further morphological changes observed at 2 and 3 months. All spray-dried formulations containing ITZ and PAA remained amorphous throughout the study period. Dissolution data supports the XRPD and DSC observations. 30% and 50% ITZ-PAA ASDs did not show any meaningful change in dissolution pattern. 15% ITZ-PAA ASDs showed a decrease in drug release after 3 months, but XRPD and DSC indicated that the amorphous state was maintained.

[0121] Samples of 40%, 60%, and 80% ITZ-PAA (MMW-EA) spray-dried ASD are tested at accelerated stability conditions (40°C / 75%RH) for 6 months. Both XRPD and DSC show that all spray-dried formulations containing ITZ and PAA remain amorphous for the duration of the study. Dissolution data confirms the XRPD and DSC observations, with no significant decrease in dissolution rate (e.g., 80% ITZ-PAA ASD, see Figure 22).

[0122] Samples of 40% ITZ-Soluplus and 40% ITZ-Affinisol® spray-dried ASD tested at accelerated stability conditions (40° C. / 75% RH) for 6 months show that they remain amorphous for the duration of the study, however, a decrease in drug release was observed at the 6 month time point (FIG. 23, FIG. 24).

[0123] The prepared spray-dried 80% ITZ-Soluplus® and 80% ITZ-Affinisol® materials are heterogeneous amorphous systems with amorphous-amorphous phase separation including the ITZ amorphous drug (Figures 14 and 15, Table 9). This may be undesirable for some applications as it impacts long-term stability and increases the likelihood of drug crystallization over time. Storage of the spray-dried 80% ITZ-Soluplus® and 80% ITZ-Affinisol® materials at 40°C / 75% RH for 3 months increased recrystallization upon heating and affected thermal behavior (Figures 25, 26).

[0124] 15%, 30%, 50%, and 100% RTV-PAA (co-solvent) samples are tested at 45°C / 75%RH. Both XRPD and DSC show that the 100% RTV spray-dried formulation converts from amorphous to crystalline form I at 2 months, with no morphological change observed at 3 months. All spray-dried formulations containing RTV and PAA remain amorphous throughout the study period. Dissolution data supports the XRPD and DSC observations. The 15% and 30% RTV-PAA ASDs show no meaningful change in dissolution pattern. The 50% RTV-PAA ASD shows a decrease in drug release at 2 months, but no change between 2 and 3 months. However, XRPD and DSC show that the amorphous state is maintained.

[0125] The decrease in dissolution observed for the 15% ITZ-PAA ASD and 50% RTV-PAA may be related to the "clumping" of the material upon storage. Changes in surface area may affect the initial wettability of the powder, leading to changes in the dissolution profile.

[0126] fruitUnless otherwise expressly indicated in the examples or otherwise, all numerical values ​​in this description specifying amounts of materials, reaction conditions, molecular weights, number of carbon atoms, etc., should be understood to be modified by the word "about". Unless otherwise specified, each chemical or composition referred to herein should be interpreted as a commercial grade material that may contain isomers, by-products, derivatives, and other such materials that are normally understood to be present in commercial grades. However, unless otherwise indicated, the amount of each chemical component is presented excluding any solvents and diluents that may be customarily present in commercially available materials. It should be understood that the upper and lower limits of amounts, ranges, and ratios described herein may be independently combined. Similarly, the ranges and amounts of each element of the present invention may be used with any ranges or amounts of the other elements.

[0127] In one embodiment, for example, the following items are provided: (Item 1) 1. An amorphous solid dispersion comprising a linear poly(acrylic acid) and an active pharmaceutical ingredient, wherein the linear poly(acrylic acid) has a Brookfield viscosity of at least 100 cP at 25° C. (Item 2) 2. The amorphous solid dispersion according to item 1, wherein the weight ratio of pharma- ceutically active ingredient to poly(acrylic acid) in said amorphous solid dispersion is at least 1:10, or at least 1:6, or at least 1:3, or at least 1:1.5, or at least 1:1, or at least 2:1, or at least 3:1, or at least 4:1, or at most 6:1, or at most 5:1, or at most 4.5:1. (Item 3) 3. The amorphous solid dispersion according to item 1 or 2, wherein the Brookfield viscosity of the linear poly(acrylic acid) at 25° C. is at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP. (Item 4) 4. The amorphous solid dispersion according to any one of items 1 to 3, wherein the linear poly(acrylic acid) has a Brookfield viscosity at 25° C. of 3000 cP or less, or 2,500 cP or less, or 2200 cP or less, or 2100 cP or less. (Item 5) 5. The amorphous solid dispersion according to any one of items 1 to 4, wherein the amorphous solid dispersion comprises at least 10% by weight of linear poly(acrylic acid), or at least 15% by weight of linear poly(acrylic acid), or at least 20% by weight of linear poly(acrylic acid), or at least 25% by weight of linear poly(acrylic acid). (Item 6) 6. The amorphous solid dispersion according to any one of items 1 to 5, wherein the amorphous solid dispersion comprises 95% by weight or less of linear poly(acrylic acid), or 80% by weight or less of linear poly(acrylic acid), or 60% by weight or less of linear poly(acrylic acid), or 50% by weight or less of linear poly(acrylic acid), or 40% by weight or less of linear poly(acrylic acid), or 30% by weight or less of linear poly(acrylic acid). (Item 7) 7. The amorphous solid dispersion according to any one of items 1 to 6, wherein the linear poly(acrylic acid) and the pharma- ceutical active ingredient together constitute at least 80% by weight, or at least 90% by weight, or at least 95% by weight of the amorphous solid dispersion. (Item 8) 8. The amorphous solid dispersion according to any one of items 1 to 7, wherein the amorphous solid dispersion comprises 10% by weight or less of water, or 5% by weight or less of water, or 1% by weight or less of water, or no water. (Item 9) 9. The amorphous solid dispersion according to any one of items 1 to 8, wherein the pharma- ceutical active ingredient is BCS class II or BCS class IV. (Item 10) A product comprising the amorphous solid dispersion according to any one of items 1 to 9. (Item 11) 11. The product according to item 10, further comprising at least one excipient or adjuvant. (Item 12) 12. The product according to item 10 or 11, wherein the product is in a form selected from the group consisting of granules, capsules, pellets, tablets, films, and implants. (Item 13) A method for administering a pharma- ceutical active ingredient to a human or a non-human animal in need of treatment, comprising orally administering to said human or animal the amorphous solid dispersion according to any one of items 1 to 9, or the product according to any one of items 10 to 12. (Item 14) 1. A method for forming an amorphous solid dispersion of a pharmaceutical active ingredient, comprising the steps of: forming a liquid dispersion comprising a linear poly(acrylic acid), an active pharmaceutical ingredient, and a solvent system, the linear poly(acrylic acid) having a Brookfield viscosity of at least 100 cP at 25° C.; and evaporating the solvent system from the liquid dispersion to form an amorphous solid dispersion. (Item 15) 15. The method of claim 14, wherein the weight ratio of pharma- ceutical active ingredient to linear poly(acrylic acid) in the liquid dispersion is at least 15:85, or at least 30:70, or at least 40:60, or at least 50:50, or at least 70:30. (Item 16) 16. The method according to item 14 or 15, wherein the weight ratio of pharma- ceutically active ingredient to linear poly(acrylic acid) in the liquid dispersion is 90:10 or less, or 85:15 or less. (Item 17) 17. The method of any one of items 14 to 16, wherein the linear poly(acrylic acid) has a Brookfield viscosity at 25° C. of at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP. (Item 18) 18. The method of any one of items 14 to 17, wherein the linear poly(acrylic acid) has a Brookfield viscosity of 3000 cP or less, or 2,500 cP or less, or 2200 cP or less, or 2100 cP or less. (Item 19) 19. The method of any one of items 14 to 18, wherein the linear poly(acrylic acid) is formed in a substantially water-free solvent system. (Item 20) 20. The method of any one of items 14 to 19, wherein the linear poly(acrylic acid) is formed in a solvent system selected from a) ethyl acetate and b) a mixture of ethyl acetate and cyclohexane. (Item 21) 21. The method according to any one of items 14 to 20, wherein the amorphous solid dispersion comprises at least 10% by weight of linear poly(acrylic acid), or at least 15% by weight of linear poly(acrylic acid), or at least 20% by weight of linear poly(acrylic acid), or at least 25% by weight of linear poly(acrylic acid). (Item 22) 22. The method according to any one of items 14 to 21, wherein the amorphous solid dispersion comprises 95% by weight or less of linear poly(acrylic acid), or 80% by weight or less of linear poly(acrylic acid), or 60% by weight or less of linear poly(acrylic acid), or 50% by weight or less of linear poly(acrylic acid), or 40% by weight or less of linear poly(acrylic acid), or 30% by weight or less of linear poly(acrylic acid). (Item 23) 23. The method according to any one of items 14 to 22, wherein the linear poly(acrylic acid) and the active agent together constitute at least 80% by weight, or at least 90% by weight, or at least 95% by weight of the amorphous solid dispersion. (Item 24) 23. The method according to any one of items 14 to 22, wherein the amorphous solid dispersion comprises 10% by weight or less of water, or 5% by weight or less of water, or 1% by weight or less of water, or no water. (Item 25) 25. The method of any one of items 14 to 24, wherein the forming of the dispersion of the linear poly(acrylic acid) and the active pharmaceutical ingredient comprises dissolving the linear poly(acrylic acid) in powder form in the solvent system or in at least one of the solvents used in the solvent system. (Item 26) 26. The method according to any one of items 14 to 25, wherein the solvent system comprises at least one of an organic polar protic solvent and a polar aprotic solvent. (Item 27) The solvent system is 1 -C 6 27. The method according to claim 26, further comprising at least one organic polar protic solvent selected from the group consisting of alcohols, and mixtures thereof. (Item 28) The solvent system is dichloromethane, 3 -C 8 Ketone, C 3-C 8 28. The method according to claim 26 or 27, comprising at least one polar aprotic solvent selected from the group consisting of ethers, ethers, and mixtures thereof. (Item 29) 29. The method according to any one of items 14 to 28, wherein the pharmacologic active ingredient is BCS class II or BCS class IV. (Item 30) 30. The method of any one of items 14 to 29, wherein the evaporation of the solvent system from the liquid dispersion comprises spray drying. (Item 31) 31. The method according to any one of items 14 to 30, further comprising preparing a product comprising the amorphous solid dispersion, wherein the product is selected from a granule, a capsule, a pellet, a tablet, a film, and an implant. (Item 32) 32. An amorphous solid dispersion formed by the method according to any one of items 14 to 31. (Item 33) 33. A product comprising the amorphous solid dispersion according to item 32 and at least one excipient or adjuvant. (Item 34) Item 34. The product according to item 33, wherein the product is in a form selected from the group consisting of granules, capsules, pellets, tablets, films, and implants. (Item 35) 31. A method of administering a pharma- ceutical active ingredient to a human or animal in need of treatment, comprising orally administering to said human or animal an amorphous solid dispersion formed by the method according to any one of items 14 to 30, or a product formed by the method according to item 31.

Claims

1. 1. An amorphous solid dispersion comprising: at least 10% by weight of linear poly(acrylic acid); and a pharmacologic active ingredient, the linear poly(acrylic acid) has a Brookfield viscosity of at least 100 cP at 25° C.; said linear poly(acrylic acid) and said active pharmaceutical ingredient together constitute at least 80% by weight of said amorphous solid dispersion; The linear poly(acrylic acid) was dissolved in 0.1 M NaNO at pH 10. ３ a weight average molecular weight, as determined by size exclusion chromatography of a 1.5 grams / L liquid sample of the polymer, of at least 200,000 Da, or at least 250,000 Da, or at least 300,000 Da, or at least 400,000 Da, or at least 500,000 Da, or at least 600,000 Da, or at least 800,000 Da, or at least 1,000,000 Da; 13. An amorphous solid dispersion, wherein the weight ratio of said active pharmaceutical ingredient to said linear poly(acrylic acid) in said amorphous solid dispersion is at least 3:1 and at most 6:

1.

2. 2. The amorphous solid dispersion of claim 1, wherein the weight ratio of active pharmaceutical ingredient to linear poly(acrylic acid) in the amorphous solid dispersion is at least 4:1, or at most 5:1, or at most 4.5:

1.

3. 3. The amorphous solid dispersion of claim 1 or 2, wherein the Brookfield viscosity of the linear poly(acrylic acid) at 25° C. is at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP.

4. 4. The amorphous solid dispersion of any one of claims 1 to 3, wherein the linear poly(acrylic acid) has a Brookfield viscosity at 25°C of 3000 cP or less, or 2,500 cP or less, or 2200 cP or less, or 2100 cP or less.

5. 5. The amorphous solid dispersion of any one of claims 1 to 4, wherein the amorphous solid dispersion comprises at least 15% by weight of linear poly(acrylic acid), or at least 20% by weight of linear poly(acrylic acid), or at least 25% by weight of linear poly(acrylic acid).

6. 6. The amorphous solid dispersion of any one of claims 1 to 5, wherein the amorphous solid dispersion comprises 95% or less by weight linear poly(acrylic acid), or 80% or less by weight linear poly(acrylic acid), or 60% or less by weight linear poly(acrylic acid), or 50% or less by weight linear poly(acrylic acid), or 40% or less by weight linear poly(acrylic acid), or 30% or less by weight linear poly(acrylic acid).

7. 7. The amorphous solid dispersion of any one of claims 1 to 6, wherein the linear poly(acrylic acid) and the active pharmaceutical ingredient together constitute at least 90% by weight, or at least 95% by weight, of the amorphous solid dispersion.

8. 8. The amorphous solid dispersion of claim 1, wherein the amorphous solid dispersion comprises 10% by weight or less of water, or 5% by weight or less of water, or 1% by weight or less of water, or no water.

9. 9. The amorphous solid dispersion of any one of claims 1 to 8, wherein the pharmacologic active ingredient is BCS class II or BCS class IV.

10. A product comprising the amorphous solid dispersion according to any one of claims 1 to 9.

11. 11. The product of claim 10 further comprising at least one excipient or adjuvant.

12. 12. The product of claim 10 or 11, wherein the product is in a form selected from the group consisting of granules, capsules, pellets, tablets, films, and implants.

13. A method of administering a pharma- ceutical active ingredient to a non-human animal in need of treatment, comprising orally administering to said animal an amorphous solid dispersion according to any one of claims 1 to 9, or a product according to any one of claims 10 to 12.

14. 1. A method for forming an amorphous solid dispersion of a pharmaceutical active ingredient, comprising the steps of: forming a liquid dispersion comprising a linear poly(acrylic acid), a pharma- ceutical active ingredient, and a solvent system, the linear poly(acrylic acid) having a Brookfield viscosity of at least 100 cP at 25°C and a 0.1 M NaNO3 at pH 10; ３ wherein a weight average molecular weight, as determined by size exclusion chromatography of a 1.5 grams / L liquid sample of the polymer is at least 200,000 Da, or at least 250,000 Da, or at least 300,000 Da, or at least 400,000 Da, or at least 500,000 Da, or at least 600,000 Da, or at least 800,000 Da, or at least 1,000,000 Da; and evaporating the solvent system from the liquid dispersion to form an amorphous solid dispersion. the amorphous solid dispersion comprises at least 10% by weight of linear poly(acrylic acid); The method, wherein the weight ratio of said active pharmaceutical ingredient to said linear poly(acrylic acid) in said amorphous solid dispersion is at least 3:1 and at most 6:

1.

15. The method of claim 14, wherein the weight ratio of pharma- ceutically active ingredient to linear poly(acrylic acid) in the amorphous solid dispersion is at least 4:1, or at most 5:1, or at most 4.5:

1.

16. 15. The method of claim 14, wherein the weight ratio of pharma- ceutically active ingredient to linear poly(acrylic acid) in the liquid dispersion is 85:15 or less.

17. 17. The method of any one of claims 14 to 16, wherein the linear poly(acrylic acid) has a Brookfield viscosity at 25°C of at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP.

18. 18. The method of any one of claims 14 to 17, wherein the linear poly(acrylic acid) has a Brookfield viscosity of 3000 cP or less, or 2,500 cP or less, or 2200 cP or less, or 2100 cP or less.

19. The method of any one of claims 14 to 18, wherein the linear poly(acrylic acid) is formed in a substantially water-free solvent system.

20. 20. The method of any one of claims 14 to 19, wherein the linear poly(acrylic acid) is formed in a solvent system selected from a) ethyl acetate and b) a mixture of ethyl acetate and cyclohexane.

21. 21. The method of any one of claims 14 to 20, wherein the amorphous solid dispersion comprises at least 15% by weight of linear poly(acrylic acid), or at least 20% by weight of linear poly(acrylic acid), or at least 25% by weight of linear poly(acrylic acid).

22. 22. The method of any one of claims 14 to 21, wherein the amorphous solid dispersion comprises no more than 95% by weight linear poly(acrylic acid), or no more than 80% by weight linear poly(acrylic acid), or no more than 60% by weight linear poly(acrylic acid), or no more than 50% by weight linear poly(acrylic acid), or no more than 40% by weight linear poly(acrylic acid), or no more than 30% by weight linear poly(acrylic acid).

23. 23. The method of any one of claims 14 to 22, wherein the linear poly(acrylic acid) and the active pharmaceutical ingredient together constitute at least 80%, or at least 90%, or at least 95% by weight of the amorphous solid dispersion.

24. 23. The method of any one of claims 14 to 22, wherein the amorphous solid dispersion comprises no more than 10% by weight water, or no more than 5% by weight water, or no more than 1% by weight water, or no water.

25. 25. The method of any one of claims 14 to 24, wherein the forming of the dispersion of the linear poly(acrylic acid) and the active pharmaceutical ingredient comprises dissolving the linear poly(acrylic acid) in powder form in the solvent system or in at least one of a plurality of solvents used within the solvent system.

26. 26. The method of any one of claims 14 to 25, wherein the solvent system comprises at least one of an organic polar protic solvent and a polar aprotic solvent.

27. The solvent system is １ -C ６ 27. The method of claim 26, comprising at least one organic polar protic solvent selected from an alcohol, and mixtures thereof.

28. The solvent system is dichloromethane, ３ -C ８ Ketone, C ３ -C ８ 28. The method of claim 26 or 27, comprising at least one polar aprotic solvent selected from: ethers, and mixtures thereof.

29. The method according to any one of claims 14 to 28, wherein the pharmacologic active ingredient is BCS class II or BCS class IV.

30. The method of any one of claims 14 to 29, wherein the evaporation of the solvent system from the liquid dispersion comprises spray drying.

31. 31. The method of any one of claims 14 to 30, further comprising preparing a product comprising said amorphous solid dispersion, said product being selected from a granule, a capsule, a pellet, a tablet, a film, and an implant.

32. The method of claim 31, wherein the product further comprises at least one excipient or adjuvant.

33. 32. A method of administering a pharma- ceutical active ingredient to a non-human animal in need of treatment, comprising orally administering to said animal an amorphous solid dispersion formed by the method of any one of claims 14 to 30, or a product formed by the method of claim 31.

34. An amorphous solid dispersion according to any one of claims 1 to 9 or a product according to any one of claims 10 to 12 for administration of a pharma- ceutical active ingredient.

Images