DRUG-POLYMER AMORPHOUS SOLID DISPERSIONS USING LINEAR POLY(ACRYLIC ACID) POLYMERS

Abstract

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

Claims

1. An amorphous solid dispersion comprising: at least 10 wt. % of a linear poly(acrylic acid); and an active pharmaceutical ingredient, wherein: the linear poly(acrylic acid) has a Brookfield viscosity at 25° C. of at least 100 cP, the linear poly(acrylic acid) and the active pharmaceutical ingredient together comprise at least 80 wt. % of the amorphous solid dispersion, and the linear poly(acrylic acid) has a weight average molecular weight, as determined by size exclusion chromatography on a liquid sample of 1.5 g/L polymer in 0.1M NaNO.sub.3 at pH 10, of least 200,000 Da.

2. The amorphous solid dispersion of claim 1, wherein a ratio by weight of active pharmaceutical ingredient:poly(acrylic acid) in the amorphous solid dispersion is at least or up to 6:1.

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

4-6. (canceled)

7. The amorphous solid dispersion of claim 1, wherein the linear poly(acrylic acid) and the active pharmaceutical ingredient together comprise at least 90 wt. % of the amorphous solid dispersion.

8. The amorphous solid dispersion of claim 1, wherein the amorphous solid dispersion comprises 0-10 wt. % water.

9. The amorphous solid dispersion of claim 1, wherein the active pharmaceutical ingredient is in BCS class II or BCS class IV.

10. A product comprising the amorphous solid dispersion of claim 1 and at least one excipient or adjuvant.

11. (canceled)

12. The product of claim 10, 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 an active pharmaceutical ingredient to a person or non-human animal in need of treatment comprising orally administering the amorphous solid dispersion of claim 1 to the person or non-human animal.

14. A method of forming an amorphous solid dispersion of an active pharmaceutical ingredient, the method comprising: 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 at 25° C. of at least 100 cP and a weight average molecular weight, as determined by size exclusion chromatography on a liquid sample of 1.5 q/L polymer in 0.1M NaNO.sub.3 at pH 10, of least 200,000 Da; and evaporating the solvent system from the liquid dispersion to form an amorphous solid dispersion in which the linear poly(acrylic acid) and the active pharmaceutical ingredient together comprise at least 80 wt. % of the amorphous solid dispersion.

15. The method of claim 14, wherein a weight ratio of active pharmaceutical ingredient:linear poly(acrylic acid) in the liquid dispersion is at least 50:50.

16-18. (canceled)

19. The method of claim 14, wherein the linear poly(acrylic acid) is one which has been formed in a solvent system which is substantially free of water.

20. The method of claim 14, wherein the linear poly(acrylic acid) is one which has been formed in a solvent system selected from the group consisting of: a) ethyl acetate and b) a mixture of ethyl acetate and cyclohexane.

21. (canceled)

22. (canceled)

23. The method of claim 14, wherein the linear poly(acrylic acid) and the active pharmaceutical ingredient together comprise at least 90 wt. % of the amorphous solid dispersion.

24. The method of claim 14, wherein the amorphous solid dispersion comprises 0-1 wt. % water.

25. The method of claim 14, 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 in the solvent system.

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

27. The method of claim 26, wherein the solvent system comprises at least one of: at least one organic polar protic solvent selected from the group consisting of C.sub.1-C.sub.6 alcohols, and mixtures thereof; and at least one polar aprotic solvent selected from the group consisting of dichloromethane, C.sub.3-C.sub.8 ketones, C.sub.3-C.sub.8 ethers, and mixtures thereof.

28. (canceled)

29. The method of claim 14, wherein the active pharmaceutical ingredient is in BCS class II or BCS class IV.

30. The method of claim 14, wherein the evaporating of the solvent system from the liquid dispersion comprises spray drying.

31. The method of claim 14, further comprising preparing a product comprising the amorphous solid dispersion, the product being selected from granules, capsules, pellets, tablets, films, and implants.

32-34. (canceled)

35. A method of administering an active pharmaceutical ingredient to a person or animal in need of treatment comprising orally administering an amorphous solid dispersion formed by the method of claim 14 to the person or animal.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1 is a flow chart illustrating a method of forming a solid dispersion of an active pharmaceutical ingredient and in accordance with one aspect of the exemplary embodiment;

[0051] FIGS. 2-7 are photographs of spray-dried products at the same scale: FIG. 2 shows a product produced from 40% Itraconazole (ITZ) and 60% Soluplus® polymer; FIG. 3 shows a product produced from 40% ITZ and 60% Affinisol® polymer; FIG. 4 shows a product produced from 40% ITZ and 60% poly(acrylic acid) PAA (high molecular weight, formed in ethyl acetate cyclohexane cosolvent: HMW-CO); FIG. 5 shows a product produced from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate cyclohexane cosolvent: MMW-CO); FIG. 6 shows a product produced from 40% ITZ and 60% PAA (low molecular weight, formed in ethyl acetate cyclohexane cosolvent LMW-CO); and FIG. 7 shows a product produced from 40% ITZ and 60% PAA (medium molecular weight, formed in ethyl acetate: MMW-EA);

[0052] FIGS. 8-10 show XRPD plots for products made from ITZ and PAA (high molecular weight, prepared in cosolvent: HMW-CO): FIG. 8 shows plots for ITZ alone, a physical mixture of 15% ITZ and 85% PAA, and a spray-dried solid dispersion of 15% ITZ and 85% PAA; FIG. 9 shows plots for ITZ alone, a physical mixture of 30% ITZ and 70% PAA, and a spray-dried solid dispersion of 30% ITZ and 70% PAA; and FIG. 10 shows plots ITZ alone, a physical mixture of 50% ITZ and 50% PAA, and a spray-dried solid dispersion of 50% ITZ and 50% PAA;

[0053] FIGS. 11-15 show Differential Scanning calorimetry (DSC) plots: FIG. 11 shows a plot for a spray dried mixture of 70% ITZ and 30% PAA (medium molecular weight, formed in ethyl acetate: MMW-EA); FIG. 12 shows a plot for a spray dried mixture of 80% ITZ and 20% PAA (MMW-EA); FIG. 13 shows a plot for a spray dried mixture of 90% ITZ and 10% PAA (MMW-EA); FIG. 14 shows a plot for a spray dried mixture of 80% ITZ and 20% Soluplus® polymer; and FIG. 15 shows a plot for a spray dried mixture 80% ITZ and 20% Affinisol® polymer;

[0054] FIG. 16 shows chromatograms of the ITZ assay from 40% ITZ-60% PAA (prepared in cosolvent, at high molecular weight, medium molecular weight, and low molecular weight: HMW-CO, MMW-CO and LMW-CO);

[0055] FIG. 17 shows mean release of ITZ in 0.1N 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 (ASDs) (high molecular weight, prepared in co-solvent: HMW-CO), and ITZ neat and 100% ITZ spray dried formulations;

[0056] FIG. 18 shows mean ITV release under non-sink conditions in 0.1N HCl from 40% ITZ-60% PAA spray dried ASDs (at high, medium, and low molecular weight, prepared in co-solvent: HMW-CO, MMW-CO, and LMW-CO), a 40% ITZ-60% spray dried Soluplus® ASD, and a spray dried 40% ITZ-60% Affinisol® ASD;

[0057] FIG. 19 shows mean 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 cosolvent: LMW-CO), a 40% ITZ-60% Soluplus® ASD, and a 40% ITZ-60% Affinisol® ASD;

[0058] FIG. 20 shows mean ITZ release (under non-sink conditions in 0.1 N HCl from 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 ASDs;

[0059] FIG. 21 shows ITZ release under non-sink conditions in HCl 0.1N from 80% ITZ-20% PAA spray dried ASDs (low, medium, and high molecular weight PAA formed in ethyl acetate: LMW-EA, MMW-EA and HMW-EA);

[0060] FIG. 22 shows mean release of ITZ in 0.1N HCl under non-sink conditions from 80% ITZ-20% PAA (MMW-EA) ASD as prepared (0 Months) and after 6 months storage in accelerated conditions (40° C./75% RH);

[0061] FIG. 23 shows mean release of ITZ in 0.1N HCl under non-sink conditions from 40% ITZ-60% Soluplus® ASD as prepared (0 Months) and after 6 months storage in accelerated conditions (40° C./75% RH);

[0062] FIG. 24 shows mean release of ITZ in 0.1N HCl under non-sink conditions from 40% ITZ-60% Affinisol® ASD as prepared (0 Months) and after 6 months storage in accelerated conditions (40° C./75% RH);

[0063] FIG. 25 shows a Differential Scanning calorimetry (DSC) plot for 80% ITZ-20% Soluplus® spray dried material stored at 40° C./75% RH for 3 months; and

[0064] FIG. 26 shows a Differential Scanning calorimetry (DSC) plot for 80% ITZ-20% Affinsiol® spray dried material stored at 40° C./75% RH for 3 months.

DETAILED DESCRIPTION

[0065] Aspects of the exemplary embodiment relate to an amorphous solid dispersion of an active pharmaceutical ingredient, to a method for forming an amorphous solid dispersion of an active pharmaceutical ingredient, and to an amorphous solid dispersion formed by the method.

[0066] The exemplary amorphous solid dispersion includes a linear poly(acrylic acid) polymer and an active pharmaceutical ingredient. The polymer can stabilize drugs in amorphous form at up to 80% drug loading level, or more. The exemplary amorphous solid dispersion is formed by spray-drying, which is a reproducible and scalable pharmaceutical manufacturing process.

[0067] The exemplary method has several advantages over existing methods for preparing formulations of active pharmaceutical ingredients. These may include: improved aqueous solubility and thus improved oral bioavailability of a physically stable drug form (avoiding crystallization or phase separation of the amorphous drug); flexibility in drug loading levels (e.g., up to 80% or higher drug loading level) while maintaining stability of the amorphous solid dispersion; and manufacture of an amorphous solid dispersion by a reproducible and scalable process.

[0068] An “active pharmaceutical ingredient” (API) or “drug,” as used herein, can be any substance or mixture of substances intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient in the drug product. Such substances are intended to furnish 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.

[0069] The API may belong to BCS class II (high permeability, low solubility) or BCS class IV (low permeability, low solubility). A candidate API can be any substance or mixture of substances intended to be used in the manufacture of a drug product, which are being developed/undergoing testing for such use.

[0070] According to the US Food and Drug Administration, a drug in a solid dosage form is considered to be highly soluble when its highest clinical dose strength is soluble in 250 mL or less of aqueous media over a pH range of 1-6.8 at 37±1° C., and it is considered to be highly permeable if the absorption of an orally administered dose in humans (denoted f.sub.a) is 85% or more, based on a mass balance determination (along with evidence showing stability of the drug in the GI tract) or in comparison to an intravenous reference dose. (See, “Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System: Guidance for Industry,” U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), at p. 3 (2017)), hereinafter “USFDA 2017”.

[0071] In accordance with USFDA 2017, a low permeability API is one where the f.sub.a is less than 50%, determined in accordance with the method outlined in USFDA 2017. A low solubility API is considered herein to be one in which its highest clinical dose strength (as applicable in 2019) is not soluble in 250 mL or less of aqueous media over a pH range of 1-6.8 at 37±1° C., determined in accordance with the method outlined in USFDA 2017. The aqueous solubility of the API may be less than 0.1 g/L or less than 0.05 g/L over a pH range of 1-6.8 at 37±1° C.

[0072] The active pharmaceutical ingredient may be an analgesic, anti-inflammatory agent, anthelmintic, anti-arrhythmic agent, antibacterial agent, antiviral agent, anticoagulant, antidepressant, antidiabetic agent, antiepileptic agent, antifungal agent, antigout agent, antihypertensive agent, antimalarial agent, antimigraine agent, antimuscarinic agent, antineoplastic agent, erectile dysfunction improvement agent, immune suppressant, antiprotozoal agent, antithyroid agent, anxiolytic agent, sedative, hypnotic, neuroleptic agent, β-blocker, cardiac inotropic agent, corticosteroid, diuretic, antiparkinsonian agent, gastro-intestinal agent, histamine receptor antagonist, keratolytic, lipid regulating agent, antianginal agent, Cox-2 inhibitor, leukotriene inhibitor, macrolide, muscle relaxant, opioid analgesic, protease inhibitor, sex hormone, muscle relaxant, antiosteoporosis agent, anti-obesity agent, cognition enhancer, anti-urinary incontinence agent, anti-benign prostate hypertrophy agent, antipyretic, muscular relaxant, anticonvulsant, antiemetic, anti-Alzheimer agent, or combination thereof.

[0073] Examples of BCS class II drugs include aceclofenac, acetaminophen, acyclovir, albendazole, am isulpride, aripiprazole, atorvastatin, azithromycin, benidipine, bicalutamide, candesartan cilexetil, carbamazepine, carvedilol, cefdinir, cefuroxime axetil, celecoxib, chloroquine, chlorpromazine, cilostazol, clarithromycin, clofazimine, clopidogrel, clozapine, cyclosporine, cyproterone, cisapride, danazol, dexamethasone, diazepam, diclofenac, diloxanide, ebastine, efavirenz, epalrestat, ethyl icosapentate, ezetimibe, fenofibrate, fluconazole, flurbiprofen, gefitinib, glibenclamide, glyburide, gliclazide, glimepiride, glipizide, griseofulvin, haloperidol, hydroxyzine, ibuprofen, imatinib, indinavir, irbesartan, isotretinoin, itraconazole, ketoconazole, ketoprofen, lamotrigine, levodopa, levothyroxine sodium, lopinavir, loratadine, lorazepam, manidipine, mebendazole, medroxyprogesterone, meloxicam, metaxalone, methylphenidate, metoclopramide, mosapride, mycophenolate mofetil, naproxen, nelfinavir, nevirapine, nicergoline, niclosamide, nifedipine, nisoldipine, olanzapine, orlistat, oxcarbazepine, phenytoin, pioglitazone, pranlukast, praziquantel, pyrantel, pyrimethamine, quetiapine, quinine, raloxifene, rebamipide, risperidone, ritonavir, rofecoxib, simvastatin, spironolactone, sulfasalazine, tacrolimus, tamoxifen, telmisartan, teprenone, ticlopidine, ursodeoxycholic acid, valproic acid, valsartan, verapamil, warfarin, and pharmaceutically acceptable salts thereof.

[0074] APIs that belong to BCS Class II are poorly soluble but are absorbed from the solution by the lining of the stomach and/or intestine.

[0075] Examples of BCS class IV drugs include acetazolamide, allopurinol, amphotericin B, atovaquone, bifonazole, bleomycin, buparvaquone, cefuroxime, chloroquine, chlorothiazide, cyclosporin, dapsone, diminazene stearate, dim inazene oleate, doxycycline, furosemide, mefloquine, metronidazole, mitoxantrone, 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.

[0076] In the following examples, itraconazole (C.sub.35H.sub.38Cl.sub.2N.sub.8O.sub.4) is used as an example BCS class II API and ritonavir (C.sub.37H.sub.48N.sub.6O.sub.5S.sub.2) as an example BCS class IV API. Itraconazole (ITZ) is a broad spectrum anti-fungal compound with a melting point of 170° C. ITZ is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. The solubility of ITZ in water is about 1-4 ng/mL. ITZ exhibits very poor oral bioavailability owing to its insolubility in intestinal fluids. Ritonavir (RTV), sold under the trade name Norvir™, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir exhibits low and variable oral bioavailability due to its poor aqueous solubility.

[0077] As used herein, “poly(acrylic acid)” (PAA) is a homopolymer of acrylic acid. By “homopolymer” it 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.

[0078] The exemplary PAA is linear, i.e., has substantially no crosslinking. By this, it is meant that crosslinking (or branching) occurs, on average (mean), at fewer than one in ten of the poly(acrylic acid) units in the longest chain of the polymer, or at fewer than one in twenty or one in fifty of the poly(acrylic acid) units in the longest chain of the polymer. The cross-link density can also be defined as the inverse of the molecular weight between cross-links (Mc), and may be no more than 0.0014, or no more than 0.0007.

[0079] The PAA polymer can thus be generally described by the formula:

##STR00001##

[0080] where n may 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 10,000, or at least 12,000, or at least 14,000, or up to 80,000.

[0081] The PAA used to form the amorphous solid dispersion (ASD) may have a high molecular weight, which can be expressed as a weight average molecular weight (M.sub.w) or a number average molecular weight (M.sub.n).

[0082] As used herein, the weight average molecular weight (M.sub.w) is determined by size exclusion chromatography (SEC), as follows: a liquid sample is prepared of about 1.5 g/L (0.15%) polymer in 0.1M NaNO.sub.3 at pH 10. The sample is filtered, prior to injection. 100 μL of the filtered sample is injected into the column (TOSOH Bioscience, 2× TSKgel PW.sub.XL columns plus TSKgel Guard) using 0.1M NaNO.sub.3 in deionized water at pH 10 as the mobile phase. The flow rate is 0.7 mL/min. A Viscotek Triple Detector Array (TDA) (Malvern Panalytical) is used as the detector. This detector incorporates RI, Light Scattering, and Viscosity detectors. The instrument is calibrated with a single narrow MW standard of polyethylene oxide (PEO). A commercially-available sample of polyacrylic acid is used as a linear reference polymer. Mobile phase (and sample) enters the TDA and passes through the GPC/SEC chromatography columns. The columns are maintained at the same temperature as the detectors (40° C.). After eluting from the column, the dissolved polymer molecules, now separated by size, pass through the three detectors. Finally, the mobile phase passes through the viscometer before going to waste.

[0083] The RI detector gives information about the concentration of the components in the sample. The light scattering detectors respond to the intensity of light scattered by the sample which is related to molecular weight and also allows the Rg of large molecules to be calculated. The viscometer measures the changing solution viscosity to calculate the intrinsic viscosity of the sample (not used for viscosity determination herein).

[0084] The M.sub.w of the PAA 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. The M.sub.w may be up to 10,000,000, or up to 5,000,000, or up to 3,000,000, or up to 2,000,000, or up to 1,500,000 Da. In one exemplary embodiment, the M.sub.w ranges from 500,000 to 1,500,000.

[0085] As used herein, the number average molecular weight (M.sub.n) is determined by the same method used for determining M.sub.w. The M.sub.n of the PAA 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. The M.sub.n may be up to 1,000,000, or up to 800,000, or up to 500,000 Da. In one exemplary embodiment, the M.sub.n ranges from 150,000 to 500,000 Da.

[0086] As used herein, Brookfield viscosity is measured using a Brookfield viscometer model DV2TRV, 20 rpm, at 25° C. on an aqueous solution containing 4 wt. % of the PAA at pH 7.5. The spindles used with this model are RV01-RV07 with the following viscosity range covered: 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 the PAA in water and adjusting the pH to 7.5 using an 18% aqueous solution of NaOH.

[0087] The PAA used to form the amorphous solid dispersion may have a Brookfield viscosity of at least 100 cP (cP=mPa.Math.s), or at least 200 cP, or at least 250 cP, or at least 300 cP, or at least 400 cP, by this method. The viscosity may be up to 3,000 cp, or up to 2,500 cP, or up to 2200 cP or up to 2100 cP. In one exemplary embodiment, the Brookfield viscosity ranges from 200 to 2,200 cP.

[0088] Brookfield viscosity correlates well with molecular weight. Brookfield viscosity is proportional to molecular weight, as determined by the described methods. For example, a linear PAA polymer having a Brookfield viscosity of 200 cP has an M.sub.n of 162,048 Da and an M.sub.W of 545,692 Da; and a linear PAA polymer having a Brookfield viscosity of 2075 cP has an M.sub.n of 527,772 Da and an M.sub.w 1,071,000 Da.

[0089] Since Brookfield viscosity is more readily determined than molecular weight (M.sub.n or M.sub.w), it can be used as a molecular weight indicator.

[0090] PAA linear polymers, within the range of molecular weights stated above, may be described herein as low molecular weight (LMW), medium molecular weight (MMW), or high molecular weight (HMW). An example LMW polymer may have a Brookfield viscosity of 180-350 cP. An example MMW polymer may have a Brookfield viscosity of 400-1,000 cP. An example HMW polymer may have a Brookfield viscosity of 1,200-2,200 cP.

[0091] The exemplary linear PAA is in the form of a fine powder, which includes no more than 5 wt. % water, such as no more than 3 wt. % water, or no more than 2 wt. % water, or no more than 1 wt. % water. A water content of 2-3% water may occur due to the polymer hygroscopicity rather than a result of the synthesis. Water content is determined by the Loss on Drying method (LOD).

[0092] An “amorphous solid dispersion” (ASD), as used herein is, a dispersion of an API in a solid polymer matrix, which has substantially no crystalline character, as evidenced, for example, by commonly-used qualitative indicators of crystallinity, such as X-ray powder diffraction (XRPD), as described below, and Differential Scanning calorimetry (DSC). In particular, crystalline character of a crystalline dispersion is evidenced by characteristic, well-defined peaks of the drug in the XRPD pattern and an obvious melting endotherm in the DSC thermogram. Absence of these indicators after spray-drying with linear PAA is consistent with an amorphous material. DSC may also be used to determine the glass transition temperature (Tg) of amorphous materials, which is not present in highly crystalline samples. An amorphous solid dispersion is also distinct from a physical blend of PAA and drug, in which the PAA and drug are simply combined by powder mixing.

[0093] 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 Sóti, et al., “Comparison of Spray-drying, Electroblowing and Electrospinning for Preparation of Eudragit E and Itraconazole Solid Dispersions,” Int. J. Pharm. 494:23, pp 1-27 (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).

[0094] Transmission or backscattering Raman spectroscopy may 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). As determined using transmission Raman spectroscopy, e.g., according to the method of Netchacovitch, et al., the percentage crystallinity of the amorphous sold dispersion may be less than 10%, or less than 5%, or less than 1%.

[0095] The exemplary amorphous solid dispersion includes, consists of, or consists essentially of poly(acrylic acid) and an API (or a mixture of APIs). By consists essentially of, it is meant that the polymer and API(s) together account for at least 90 wt. % (or at least 95 wt. %, or at least 98 wt. %) of the amorphous solid dispersion.

[0096] The amorphous solid dispersion may include at least 0.01 wt. % API, or at least 0.1 wt. % API, or at least 1 wt. % API, or at least 5 wt. % API, or at least 10 wt. % API, or at least 15 wt. % API, or at least 20 wt. % API, or at least 30 wt. % API or at least 40 wt. % API, or at least 50 wt. % API, or at least 60 wt. % API, or at least 70 wt. % API. The amorphous solid dispersion may include up to 90 wt. % API, or up to 85 wt. % API, or up to 80 wt. % API. As used herein the wt. % API (drug loading) is the weight of pure (undiluted) API(s) in the ASD. High loadings of API (e.g., 90 wt. % API, or above) may, in some cases, result in the solid dispersion being partially crystalline in character, which is undesirable for good solubility and absorption of the API. A rate of release of the drug from the solid dispersion is lower when the solid dispersion is partially crystalline.

[0097] The amorphous solid dispersion (ASD) may include at least 10 wt. % PAA polymer, or at least 15 wt. % PAA polymer, or at least 20 wt. % PAA polymer, or at least 25 wt. % PAA polymer. The ASD may include up to 99 wt. % PAA polymer, or up to 95 wt. % PAA polymer, or up to 80 wt. % PAA polymer, or up to 60 wt. % PAA polymer, or up to 50 wt. % PAA polymer, or up to 40 wt. % PAA polymer, or up to 30 wt. % PAA polymer.

[0098] A ratio, by weight, of active pharmaceutical ingredient: poly(acrylic acid) in the amorphous solid dispersion may 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.

[0099] The exemplary amorphous solid dispersion includes no more than 5 wt. % water, or no more than 2 wt. % water, or no more than 1 wt. % water, such as no water.

[0100] In some embodiments, a formulation which includes the amorphous solid dispersion may further include one or more pharmaceutically acceptable excipients and/or adjuvants. The pharmaceutically acceptable excipient is an inert additive included in solid formulations to increase the bulk of the formulation comprising the ASD. The pharmaceutically acceptable adjuvant enhances the effectiveness of the API. The excipient(s) and/or adjuvant(s) may be added during or after the preparation of the spray-dried form of the amorphous solid dispersion.

[0101] In one embodiment, adjuvants and/or excipients may be present at up to a total of 99 wt. % of the formulation comprising the ASD, such as up to 20 wt. %, or up to 10 wt. %, or up to 5 wt. %. In one embodiment, adjuvants and/or excipients may be at least 0.01 wt. % of the formulation.

[0102] The exemplary amorphous solid dispersion may be formed from a liquid dispersion. 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, a solvent system). The two phases may be in the same or different states of matter. Liquid dispersions may be classified in a number of ways, including how large the particles are in relation to the particles of the continuous phase, whether or not precipitation occurs, and the presence of Brownian motion. In general, liquid dispersions of particles sufficiently large for sedimentation are referred to herein as suspensions, while those of smaller particles (which may be as little as on molecule in size) are referred to herein as colloidal mixtures or solutions.

[0103] The exemplary amorphous solid dispersion is formed by a solvent evaporation method, such as spray drying (SD). The amorphous solid dispersion may be in the form of an as-formed spray-dried powder, or may be further processed, e.g., to reduce the particle size and/or to form a product, e.g., in the form of granules, capsules, pellets, tablets, a film, a medical or dental implant, a dispersion of the ASD in a liquid medium, or an injectable product formulated for intravenous introduction to a human or non-human animal.

[0104] FIG. 1 illustrates a method of forming the amorphous solid dispersion. The method begins at S100.

[0105] At S102, PAA is provided. This may include forming a 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.

[0106] At S104, the PAA and API are combined in a suitable organic solvent system, such as a single solvent or solvent mixture, to form a liquid dispersion, such as a solution, colloidal mixture, or suspension.

[0107] At S106, the liquid dispersion containing PAA polymer, API, and solvent is formed into ASD particles by spray drying or other solvent evaporation method.

[0108] At S108, a product comprising the thus-formed ASD may be prepared. This may include one or more of grinding, compacting into tablets, adding excipients and/or adjuvants, encapsulating the ASD in a shell, such as a material with a different solubility in water or stomach acid from the ASD, combinations thereof, and the like.

[0109] The method ends at S110.

Preparation of PAA

[0110] The linear PAA polymer may be formed in solution, without addition of a cross-linking agent. The resulting linear PAA may be in the form of a powder.

[0111] Various methods exist for forming linear PAAs, which can be used to form a high molecular weight PAA. The PAA may be synthesized in a pharmaceutically-acceptable solvent system in which the starting material (e.g., acrylic acid monomer) is soluble. In one embodiment, the solvent is an organic solvent or mixture of organic solvents. Example 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. A ratio, by weight, of ethyl acetate: cyclohexane in the CO mixture may be from 30:70 to 100:0. The dispersion (e.g., solution) containing the monomer and solvent may be substantially free of water (non-aqueous). By this, it is meant that the solution includes no more than 10 wt. % water, or no more than 5 wt. %. water, or no more than 2 wt. % water, or 0 wt. % added water.

[0112] The PAA may be formed from acrylic acid monomer in the selected organic solvent in a free radical process, using an initiator, such as an organic peroxide. The reaction may be carried out at about room temperature, or above (e.g., 18-70° C.). The acrylic acid may be partially pre-neutralized, prior to the polymerization, e.g., with sodium hydroxide. 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 an organic solvent, such as ethyl acetate, the PAA forms as a precipitate, which can be used directly (after low temperature drying to remove most of the organic solvent) in the formation of the ASD, without the need for removing water from the PAA. For example, in the case of ethyl acetate and cyclohexane, drying may be performed at a temperature of below 90° C. for less than 1 hour.

[0113] In other embodiments, the free radical reaction can also be carried out with the pure monomer (bulk polymerization), or by polymerization in an aqueous solution or an emulsion.

[0114] Poly(acrylic acid) may also be synthesized by anionic polymerization of t-butyl acrylate (e.g., with an organolithium reagent or other adduct initiator, and methyl alcohol) followed by acid hydrolysis of the tert-butyl group.

[0115] In another embodiment, the PAA is formed by a reversible addition-fragmentation transfer polymerization (RAFT) of acrylic acid, in the presence of a RAFT agent, such as trithiocarbonate. The molecular weight (Mn) of the resulting polymer 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). In the method of Ji, the chain transfer to solvent or polymer is suppressed during the polymerization process, thus high linear PAA with high molecular weight and low polydispersivity index (PDI) can be obtained. Moreover, using the generated PAA as a macro RAFT agent, the chain extension polymerization of PAA with fresh acrylic acid displays controlled behavior, demonstrated the ability of PAA to reinitiate sequential polymerization.

[0116] Poly(acrylic acid) with a volume average molecular weight (Mv) of about 130,000, about 250,000, about 450,000, about 1,250,000, and about 3 million and about 4 million are available from Millipore Sigma or Sigma-Aldrich.

Solvent Evaporation

[0117] Spray drying (SD) is a solvent evaporation process of producing a dry powder from a liquid by rapidly drying with a hot gas. While spray drying is used in the exemplary embodiment, other solvent evaporation processes which incorporate the evaporation of the solvent, e.g., a non-aqueous (organic) solvent are contemplated, e.g., under heat and/or vacuum, such as oven drying (e.g., film casting followed by oven drying which results in dry films of drug/polymer ASD); fluid bed drying (using a flow of air or other gas, resulting in dry powder); tumble drying (employing mechanical agitation, resulting in dry powder); electrospinning (resulting in nano- or micron-size fibers containing the ASD of drug/PAA); or electrospraying (resulting in a dry powder).

[0118] In the exemplary embodiment, where spray drying is used, the liquid supplied to the spray drier for spray drying includes PAA, at least one API, and a solvent, or mixture of solvents, in which the poly(acrylic acid) and API are soluble, specifically, more soluble than in water. Suitable solvents include polar protic organic solvents, such as C.sub.1-C.sub.6 alcohols, e.g., as ethanol, and polar (hydrophilic) aprotic solvents, such as dichloromethane (DCM), C.sub.3-C.sub.8 ketones, C.sub.3-C.sub.8 ethers, and other low-boiling organic solvents (e.g., a boiling point of less than 90° C.), and mixtures thereof. The solvent(s) evaporate from the liquid and thus are not present, or present only in minor amounts, in the amorphous solid dispersion. For example, the amorphous solid dispersion comprises less than 5 wt. % solvent, or less than 1 wt. % solvent.

[0119] For example, ethanol is a suitable solvent for RTV and a mixture of dichloromethane and ethanol is suitable for ITZ. A weight ratio of (Ethanol:DCM) in such a solvent system may be from 1:10 to 10:1, such as from 5:1 to 1:2, although any suitable solvent or solvent ratio which dissolves both the drug and polymer can be used.

[0120] A ratio of the combined weight of PAA and API to weight of solvent in the spray drying solution (or other dispersion) formed at S104 is not critical and may be, for example at least 0.015:1, or at least 0.02:1, and may be up to 0.2:1 or up to 0 1:1. A ratio of PAA to solvent, by weight, in the spray drying solution is not critical and may be, for example at least 0.01:1, or at least 0.02:1, and may be up to 0.19:1 or up to 0.09:1. A ratio of API to solvent, by weight, in the spray drying solution is not critical and may be, for example at least 0.008:1, or at least 0.015:1, and may be up to 0.09:1 or up to 0.07:1. A ratio of API to PAA in the spray drying solution may be selected based on the desired ratio in the ASD. For example, the ratio may be from 10:90 to 85:15 to achieve corresponding ratios of API to PAA in the ASD.

[0121] To form the spray drying solution, the PAA (e.g., in the form of a powder), and API may first be dissolved in respective solvent(s) (which may be the same or different) and the two liquids combined. In another embodiment, the neat API is added to a solution containing the PAA and solvent(s). In another embodiment, PAA in little or no solvent is added to a solution containing the API and a solvent. In some embodiments, the solution containing the PAA and API may incorporate one or more excipients and/or adjuvants or precursors therefor.

[0122] As an example, to form the spray drying solution, the PAA (e.g., in the form of a powder), and API may first be dissolved in respective solvent(s) (which may be the same or different) and the two liquids combined. Alternatively, the PAA may be dissolved in the solution of API in one solvent, and then the second solvent is added. The resulting mixture is pumped to a spray dryer to evaporate off the solvent(s) at temperature higher than the boiling point of the solvent(s) used, and the spray dried ASD is collected. For example, the inlet (maximum) temperature of the spray dryer may be at least 80° C., or at least 90° C. in the case of ethanol (or ethanol:DCM mixtures). Ethanol boils at about 78° C., under atmospheric conditions. The inlet (maximum) temperature of the spray dryer may be up to 120° C., or up to 100° C. for such solvents.

[0123] Residual organic solvent in the formed ASD may be less than 5 wt. %, or less than 2 wt. %, or less than 1 wt. %. The level of acceptable residual solvent(s) may depend on the type of solvent used (e.g., the acceptable amount for a class 1 or 2 solvent may be lower than for a (less toxic) class 3 solvent, as stipulated by pharmacopeial and/or regulatory guidance).

[0124] An active pharmaceutical ingredient may be administered orally to a person or animal in need of treatment in the form of a spray-dried amorphous solid dispersion formed by the exemplary method or in the form of a product formed from the spray-dried amorphous solid dispersion or administered by implanting an implant, such as a mesh or a tube of electrospun fibers, containing the ASD.

[0125] Without intending to limit the scope of the exemplary embodiment, the following examples demonstrate the drug loadings which can be achieved in an amorphous solid dispersion comprising poly(acrylic acid).

Examples

[0126] 1. Preparation of PAAs

[0127] Eight linear PAAs (PAAs 1-8) are synthesized in different solvents at a range of molecular weights (expressed as Brookfield viscosity, determined by the method described above). TABLE 1 shows the exemplary PAAs formed. EA denotes ethyl acetate and CO denotes a mixture of ethyl acetate and cyclohexane (e.g., EA: 30 wt. %, cyclohexane 70 wt. %). The poly(acrylic acid) products are defined as low (LMW), medium (MMW), or high (HMW) molecular weight, based on the Brookfield viscosity (determined as described above).

TABLE-US-00001 TABLE 1 Linear poly(acrylic acid) polymers Synthesis Brookfield viscosity Product Solvent (cP), 4% aq. pH 7.5 MW Designation PAA-1 EA 200 LMW PAA-2 EA 450 MMW PAA-3 EA 840 MMW PAA-4 EA 908 MMW PAA-5 EA 2075 HMW PAA-6 CO 278 LMW PAA-7 CO 750 MMW PAA-8 CO 1500 HMW

[0128] 2. Model APIs

[0129] 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]methoxylphenyl)piperazin-1-yl]phenyl}-4, 5-dihydro-1H-1, 2, 4-triazol-5-one), from Ra Chem Pharma Ltd. and SMS Pharma, and 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), from LGM Pharma, polymorphic form II, were selected as low solubility model drugs. Properties of the two drugs are shown in TABLE 2.

TABLE-US-00002 TABLE 2 Model APIs Name Itraconazole Ritonavir Property synthetic triazole agent with antiretroviral antimycotic properties MW (g/moL) 705.6 720.9 pKa 3.7 2.8 Aqueous solubility 1-4 μg/L 0.00126 g/L logP 5.66 3.9 Glass transition 52 45 temperature, Tg (° C.) Tm (° C.) 166.8 125

[0130] The linear PAAs (in their respective synthesis solvents) are combined with the selected API and spray dried to obtain stable ASDs at various drug loadings (15 wt. %, 30 wt. %, 40 wt. %; 50 wt. % and 80 wt. %).

[0131] For comparison, spray dried mixtures of the drug alone and with other polymers: polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG) (Soluplus®, BASF) and hydroxypropyl methyl cellulose (Affinisol®, Dow) are also prepared (TABLE 3). These two polymers are commonly used to stabilize ASDs.

TABLE-US-00003 TABLE 3 Comparative Polymers Trade name Solupluse ® Affinisole ®15 LV HME MW (kDa) 90-140 75 Tg (° C.) 70 110-115 Water solubility Y Y Brookfield <50 15 viscosity (cP)

[0132] 3. Preparation of Amorphous Dispersions and Other Formulations

[0133] Spray dried formulations are prepared as follows.

[0134] For spray drying Ritonavir and PAA, the PAA (in the form of a powder) is dissolved in ethanol. The Ritonavir is also dissolved in ethanol. The two solutions are combined. The resulting solution is pumped to a spray-dryer (Büchi B-290) to evaporate off the solvent at temperature higher than the boiling point of the solvents used, and the spray dried dispersions are collected as powders.

[0135] For spray drying 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 to form a solution. The resulting solution is pumped to a spray-dryer (Büchi B-290) to evaporate off the solvents at temperature higher than the boiling point of the solvents used, and the spray dried dispersions are collected as powders.

[0136] For spray drying 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 to a spray-dryer (Büchi B-290) to evaporate off the solvent at temperature higher than the boiling point of the solvents used, and the spray dried dispersions are collected as powders.

[0137] TABLE 4 shows the specific spray drying conditions for formulations F1-F15, prepared with ITZ. Dichloromethane (DCM) is used as the solvent for ITZ alone and a mixture of dichloromethane and ethanol, in various weight ratios (Ethanol:DCM), is used as a solvent for PAA:ITZ mixtures. TABLE 5 shows the spray drying conditions for formulations F16-F19, prepared with RTV, where ethanol is used as a solvent. TABLE 6 shows the spray drying conditions for formulations F20-F23, prepared with Affinisol® and Soluplus® polymers, where DCM is used as a solvent.

TABLE-US-00004 TABLE 4 Spray Drying of ITZ and ITZ—PAA ASDs Process Formulations parameters Fl F2 F3 F4 F5 Drug, PAA ITZ 15% ITZ, 30% ITZ, 40% ITZ, 50% ITZ, 85% PAA-8 70% PAA-8 60% PAA-8 50% PAA-8 Solvent system DCM Ethanol: Ethanol: Ethanol: Ethanol: DCM 3:1 DCM 2:1 DCM 2:1 DCM 2:1 Solvent (g) 185 300:104* 200:104 200:100 g 200:104 ITZ (g) 10 3 3.6 4.8 7.5 PAA (g) — 17 8.4 7.2 7.5 Wt. ratio of PAA: — 0.042 0.028 0.024 0.025 solvent Wt. ratio of ITZ: 0.054 0.007 0.012 0.016 0.025 solvent Wt. ratio of PAA + ITZ: solvent 0.054 0.050 0.040 0.040 0.049 Inlet Temp. (° C.) 60 95 95 95 95 Outlet Temp. (° C.) 45 64 65 52 60 Pump Rate 5 3 3 6 3 (setting) Aspirator rate 100% 100% 100% 100% 100% Yield 5.18 g 11.5 g 11.10 g 11.02 g 11.7 g (51.8%) (86.2%) (92.5%) (91.8%) (78.0%) Drug, PAA 40% ITZ, 40% ITZ, 40% ITZ, 70% ITZ, 80% ITZ, 60% PAA-6 60% PAA-7 60% PAA-2 30% PAA-2 20% PAA-2 Solvent system Ethanol: Ethanol: Ethanol: Ethanol: Ethanol: DCM 2:1 DCM 2:1 DCM 1:1 DCM 1.17:1 DCM 1:1 Solvent (g) 200:100 200:100 200:201 234:200 200:200 ITZ (g) 4.8 4.8 4.8 8.4 9.6 PAA (g) 7.2 7.2 7.2 3.6 2.4 Wt. ratio of PAA: 0.024 0.024 0.018 0.008 0.006 solvent Wt. ratio of ITZ: 0.016 0.016 0.012 0.019 0.024 solvent Wt. ratio of 0.040 0.040 0.030 0.028 0.030 PAA + ITZ: solvent Inlet Temp. (° C.) 95 95 95 95 95 Outlet Temp. (° C.) 60 60 49 52 52 Pump Rate 6 6 6 6 6 (setting) Aspirator rate 100% 100% 100% 90% 100% Yield 11.10 g 11 g 10.28 g 4.80 g 3.50 g (92.5%) (91.7%) (85.7%) (40%) (29.2%) Drug, PAA 80% ITZ, 90% ITZ, 80% ITZ, 80% ITZ, 80% ITZ, 20% PAA-5 10% PAA-2 20% PAA-1 20% PAA-4 20% PAA-3 Solvent system Ethanol: Ethanol: Ethanol: Ethanol: Ethanol: DCM 1:1 DCM 1:1 DCM DCM 1:1 DCM 1:1 1.25:1 Solvent (g) 200:200 200:200 250:200 200:200 200:200 ITZ (g) 9.6 10.8 9.64 g 9.60 g 9.60 g PAA (g) 2.4 1.2 2.43 g 2.40 g 2.42 g Wt. ratio of PAA: 0.006 0.003 0.005 0.006 0.006 solvent Wt. ratio of ITZ: 0.024 0.027 0.021 0.024 0.024 solvent Wt. ratio of PAA + ITZ: solvent 0.030 0.030 0.027 0.030 0.030 Inlet Temp. (° C.) 95 95 95 95 95 Outlet Temp. (° C.) 49 54 61 61 58 Pump Rate 6 6 6 6 6 (setting) Aspirator rate 100% 100% 80% 85% 90% Yield 11.02 g 5.70 g 9.44 g 7.82 g 8.49 g (91.8%) (47.5%) (78.7%) (65.2%) (70.8%) * Sprayed only ⅔.sup.rd of amount prepared so 13.34 g equivalent solution was sprayed therefore, yield as calculated based on that.

TABLE-US-00005 TABLE 5 Spray Drying of RTV and RTV—PAA ASDs Process Formulation parameters F16 F17 F18 F19 Drug, PAA RTV 15% RTV, 30% RTV, 50% RTV, 85% PAA-8 70% PAA-8 50% PAA-8 Solvent system Ethanol Ethanol Ethanol Ethanol Solvent (g) 312.87 390.45 195.92 195.91 RTV (g) 8.02 1.51 1.51 2.51 PAA (g) — 8.5 3.51 2.52 Wt. ratio of PAA: solvent — 0.022 0.018 0.013 Wt. ratio of RTV: solvent 0.026 0.004 0.008 0.013 Wt. ratio of 0.026 0.026 0.26 0.026 PAA + RTV: solvent Inlet Temp. (° C.) 95 95 95 95 Outlet Temp. (° C.) 65 60 64 65 Pump Rate (setting) 5 5 5 5 Aspirator rate 85% 100% 100% 100% Yield 3.81 g (47.6%) 7.33 g (73.3%) 3.19 g (63.8%) 3.27 g (65.4%)

TABLE-US-00006 TABLE 6 Spray Drying of ITZ-Soluplus ® and ITZ —Affinisol ® Process Formulation parameters F20 F21 F22 F23 Drug, polymer 40% ITZ, 60% 80% ITZ, 20% 40% ITZ, 60% 80% ITZ, 20% Solupluse ® Solupluse ® Affinisole ® Affinisole ® Solvent system DCM DCM DCM DCM Solvent (mL) 150 g 300 g 383.5 g 250 g ITZ (g) 4.8 g 9.6 g 4.8 g 9.6 g Polymer (g) 7.2 g 2.4 g 7.25 g 2.4 g Inlet Temp. (° C.) 58 58 58 58 Outlet Temp.(° C.) 48 40 48 42 Pump Rate (setting) 8 9 8 9 Aspirator rate 90% 90% 90% 90% Yield 4.5 g (37.5%) 7 g (58.3%) 7.2 g (60%) 2 g (16.7%)

[0138] Physical mixtures of linear PAAs and drug (without spray-drying) are also prepared, for comparison with the formulations made by spray drying. The selected drug and polymer are weighed separately and, using a geometric dilution method, are gently mixed together using a mortar and pestle. TABLE 7 lists these formulations.

TABLE-US-00007 TABLE 7 Other Formulations Drug:Polymer Formulation Drug, Polymer Ratio, by wt. F24 PAA-8 (polymer powder) F25 ITZ (neat) F26 ITZ, PAA-8 (physical mixture) 15:85 F27 ITZ, PAA-8 (physical mixture) 30:70 F28 ITZ, PAA-8 (physical mixture) 50:50 F29 RTV (neat) F30 RTV, PAA-8 (physical mixture) 15:85 F31 RTV, PAA-8 (physical mixture) 30:70 F32 RTV, PAA-8 (physical mixture) 50:50

[0139] 4. Evaluation of Products

[0140] 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 (80%, or higher) was achieved only for the linear PAA.

[0141] A. Physical Properties (Appearance, Crystallinity, Thermal Behavior)

[0142] TABLE 8 shows physical properties of ITZ-PAA physical mixtures and spray dried amorphous solid dispersions. The PAA type shows the molecular weight designation and solvent (ethyl acetate: EA, ethyl acetate cyclohexane cosolvent: CO) used in formation of the PAA. The physical form of the product is identified visually (e.g., solid powder) and by XRPD and/or DSC (to assess amorphous or crystalline state). Tg values are estimates from DSC curves.

[0143] Results for the comparative polymers are shown in TABLE 9.

TABLE-US-00008 TABLE 8 Physical properties of Formulations Drug: PAA Formulation Drug PAA type (wt. ratio) Process Appearance Form Tg (° C.) F1 ITZ — 100:0 Spray White Amorphous* 57 dried powder F2 ITZ HMW-CO 15:85 Spray White, Amorphous 125 dried cotton like F3 ITZ HMW-CO 30: 70 Spray White, Amorphous 130 dried cotton like F4 ITZ HMW-CO 40:60 Spray White, Amorphous 125 dried cotton like F5 ITZ HMW-CO 50:50 Spray White Amorphous 125 dried powder F6 ITZ, LMW-CO 40:60 Spray White, Amorphous 130 dried fibrous powder F7 ITZ MMW-CO 40:60 Spray White, Amorphous 125 dried fibrous fluffy powder F8 ITZ MMW-EA 40:60 Spray White fluffy Amorphous 130 dried powder F9 ITZ MMW-EA 70:30 Spray White Amorphous 100 dried powder F10 ITZ MMW-EA 80:20 Spray White Amorphous 95 dried powder F11 ITZ HMW-EA 80:20 Spray White Amorphous 90, 110† dried powder F12 ITZ MMW-EA 90:10 Spray White static Non-uniform 75 dried powder amorphous system with an amorphous- amorphous phase separation†† F13 ITZ LMW-EA 80:20 Spray White amorphous 95 dried powder F14 ITZ MMW-EA 80:20 Spray White amorphous 95 dried powder F15 ITZ MMW-EA 80:20 Spray White amorphous 95 dried powder F16 RTV — 100:0 Spray White Amorphous* 45 dried powder F17 RTV HMW-CO 15:85 Spray White, Amorphous ~115 dried cotton like powder F18 RTV HMW-CO 30:70 Spray White, Amorphous ~120 dried cotton like powder F19 RTV HMW-CO 50:50 Spray White, Amorphous ~115 dried cotton like powder F24 — HMW-CO 0:100 Powder White Amorphous 120 powder F25 ITZ — 100:0 As purchased White Crystalline N/A powder (no Tg) F26 ITZ HMW-CO 15:85 Physical White Crystalline + 120 mixture powder amorphous** F27 ITZ HMW-CO 30:70 Physical White Crystalline + 120 mixture powder amorphous** F28 ITZ HMW-CO 50:50 Physical White Crystalline + 120 mixture powder amorphous** F29 RTV — 100:0 As purchased White Crystalline N/A powder powder (Form II) No Tg F30 RTV HMW-CO 15:85 Physical White Crystalline + Overlap mixture powder amorphous** with API Tm F31 RTV HMW-CO 30:70 Physical White Crystalline + Overlap mixture powder amorphous** with API Tm F32 RTV HMW-CO 50:50 Physical White Crystalline + Overlap Overlap mixture powder amorphous** with API Tm *Freshly spray dried ITZ and RTV are both amorphous. However, the product changes to a crystalline form very quickly upon storage. **Crystalline pattern of neat drug + amorphous halo from PAA †ITZ melt observed ††DSC suggests phase separation. PXRD shows amorphous material.

[0144] 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 show crystallinity, attributable to the API.

[0145] Formulations F9 and F10 were placed in accelerated stability (40° C./75% RH) and analyzed at two weeks. This informal stability study showed no significant changes (still amorphous).

TABLE-US-00009 TABLE 9 Physical properties of ITZ—Polymer (Soluplus ®; Affinisol ®) spray dried solid dispersions ITZ: Polymer Formulation Polymer weight ratio Appearance Form Tg (° C.) F20 Soluplus ® 40:60 White, free amorphous ND flowing powder F21 Soluplus ® 80:20 White static Non-uniform 50 powder amorphous system with an amorphous- amorphous phase separation* F22 Affinisol ® 40:60 White, free amorphous ND flowing powder F23 Affinisol ® 80:20 White static Non-uniform ND powder amorphous system with an amorphous- amorphous phase separation* *ITZ melt observed; Recrystallization and melting endotherm. DSC suggests phase separation. PXRD shows amorphous material. ND: Could not reliably be determined from existing data

[0146] In the case of 80% ITZ Soluplus® or Affinisol® spray dried materials (F21 and F23, Table 9), XRPD shows an amorphous system, while the DSC shows broader features with a melting peak characteristic for crystalline ITZ (FIGS. 14 and 15). These two results combined support the conclusion that a non-uniform amorphous system with an amorphous-amorphous phase separation comprising ITZ amorphous drug occurs in the 80% ITZ Soluplus® or Affinisol® spray dried materials. The same features are present in XRPD and DSC of the spray dried material containing 90% ITZ and PAA (F12; Table 8; FIG. 13).

[0147] These results suggest that at high drug loading, spray dried ASD cannot be achieved with Soluplus® and Affinisol® polymers without phase separation of the drug. From a physical stability standpoint, phase separation is undesirable as it impacts drug dissolution and long-term stability, with increase potential for drug crystallization in time.

[0148] For 80% ITZ-PAA amorphous solid dispersion, DSC shows no melting peak characteristic of crystalline ITZ (FIG. 12) and the XRPD shows an amorphous material. These results indicate that 80% ITZ-PAA is a uniform, single phase amorphous solid dispersion with no drug phase separation. Thus, PAA is a more effective polymer in maintaining physical stability of drug-polymer ASDs at high drug loading levels than the benchmarks Soluplus® and Affinisol®.

[0149] FIGS. 2-7 are photographs of spray-dried products at the same scale. FIG. 2 shows product F20 (40% ITZ-60% Soluplus®); FIG. 3 shows product F22 (40% ITZ-60% Affinisol®); FIG. 4 shows product F4 (40% ITZ-60% PAA (HMW-CO)); FIG. 5 shows product F7 (40% ITZ-60% PAA (MMW-CO)); FIG. 6 shows product F6 (40% ITZ-60% PAA (LMW-CO)); and FIG. 7 shows product F8 (40% ITZ-60% PAA (MMW-EA)).

[0150] X-ray Powder Diffraction (XRPD) is performed with a Panalytical X'Pert.sup.3 Powder XRPD. FIGS. 8-10 show XRPD plots for various formulations made using ITZ and PAA-8. In FIG. 8, plots for ITZ alone (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), are shown. In FIG. 9, plots for ITZ alone (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), are shown. In FIG. 10, plots for ITZ alone (Neat IZT, Formulation F25), a physical mixture of 50% ITZ and 50% PAA (PM 50%, Formulation F28), and a spray-dried solid dispersion of 50% ITZ and 50% PAA (ASD 50%, Formulation F5), are shown.

[0151] The plots indicate that the exemplary ASDs are substantially amorphous (no large peaks in the spectrum), even at high drug loading (50% ITZ). In contrast, both the neat ITZ and physical mixtures show significant crystalline character, as evidenced by the large peaks.

[0152] FIGS. 11-13 show DSC plots for 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. FIGS. 14 and 15 show DSC plots for Formulation F21 (spray dried 80% ITZ 20% Soluplus®) and Formulation 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, ITZ recrystallization and melting point peaks are observed. These peaks are absent when linear PAA is spray dried with 80% API.

[0153] B. Assay and Drug Recovery from Spray Dried ASDs

[0154] To evaluate the drug content of the formulations, 25 mg of a formulated 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 brought to the volume of the flask with diluent (70:30 Methanol:0.1 N HCl, by volume), and mixed well. The mixture is analyzed by HPLC using the Assay/Related Substance method A Waters Alliance HPLC is used. TABLE 10 shows the results of the ITZ assay.

TABLE-US-00010 TABLE 10 ITZ Assay ITZ assay % Recovery (n = 3) Formulation F4 F7 F6 40% ITZ-60% 40% ITZ- 60% 60% ITZ-40% PAA-8 PAA-7 PAA-6 (CO-HMW) (CO-MMW) (CO-LMW) Recovery 94 92 92 (average over 3 samples)

[0155] FIG. 16 shows chromatograms of the ITZ assay of Formulations F4, F7, and F6.

[0156] C. Drug Dissolution Testing

[0157] The results of drug dissolution testing indicate that the model drugs are more effectively released from the spray dried linear PAA ASDs than from dispersions made with conventional polymers and from physical mixtures. For these tests a dissolution bath is used (Distek Model 6100 or 7100).

[0158] i) Itraconazole: 15%, 30%, 50%, by Weight, ITZ-Linear PAA ASDs

[0159] The method is performed under non-sink conditions. The solubility limit of ITZ in an equilibrated dissolution media (750 mL 0.1 N HCl, 37° C.) is about 4-6 μg/mL and the in-vessel ITZ concentration is about 50 μg/mL.

[0160] Product equivalent to about 37.5 mg of itraconazole is weighed into a 50 mL plastic centrifuge tube (i.e., for 15% loading=250 mg, for 30% loading=125 mg, and for 50% loading=75 mg). 40 mL of equilibrated media is removed from a vessel containing 750 mL. About 10 mL of the removed equilibrated media is added to the tube vial to pre-wet the drug. The tube is shaken by hand, and the contents transferred to the vessel. The tube is rinsed with the remaining portion of the 40 mL media and the contents returned to the vessel. Apparatus II (paddles) @ 75 rpm, is used to mix the sample.

[0161] Samples (3 each) are removed from the vessel at 5, 10, 15, 30, 45, 60, and 120 minutes. The sampling is performed using 10 μm cannula tip filters and 0.2 μm regenerated cellulose (Thermo F2513-8) filters for post sample collection. To take a sample, the cannula is purged 1-2 times before collecting 5 mL into a disposable syringe. The disposable syringe is removed from the cannula and the cellulose filter fitted to the syringe. The filter is flushed with ˜4 mL of collected sample, back into vessel. The remaining 1 mL of the sample is collected in a glass vial. The collected sample is diluted 1:1 with ACN by transferring 750 μL of the sample to an HPLC vial and adding 750 μL of ACN. A vortex is used to mix the diluted sample and HPLC analysis is performed.

[0162] FIG. 17 shows release of ITZ (mean of 3 samples) in 0.1N HCl under non-sink conditions from ITZ-PAA (co-solvent) physical mixtures (PM) (Formulations F26, F27, and F28), spray dried (SD) ASDs (Formulations F2, F3, and F5), ITZ neat (Formulation F25), and ITZ SD (Formulation F1).

[0163] ii) Itraconazole-40% ITZ-60% Linear PAA Polymer ASD, Itraconazole-40% ITZ-60% Polymer (Soluplus® or Affinisol®) Dispersions, and Itraconazole-80%-20% Linear PAA Polymer ASD

[0164] The method is performed under non-sink conditions. Product equivalent to 100 mg ITZ (40% loading=250 mg; 80% loading=125 mg) is added to a centrifuge. Immediately prior to dissolution, about 40 mL of equilibrated media is removed from the respective vessel and a small amount (˜10 mL) is added to the tube vial to pre-wet the product, which is shaken by hand, and transferred to the vessel. This is repeated with remaining media so that all media originally removed from the vessel is returned to the vessel. Two equilibrated dissolution media are used: 900 mL of pH 6.8 of phosphate buffer at 37° C. and 900 mL of 0.1N HCl 37° C. Apparatus II (paddles) @ 75 rpm, is used to mix the sample.

[0165] Samples (3 each) are removed from the vessel at 5, 10, 15, 30, 45, 60, and 120 minutes, as described for i) above.

[0166] FIG. 18 shows ITZ release (mean of 3 samples) under non-sink conditions in 0.1N HCl from 40% ITZ-60% PAA (Formulations F4: co-solvent HMW; F6: co-solvent, LMW; and F7: cosolvent, MMW) spray dried ASDs, as well as 40% ITZ-60% Soluplus® ASD (Formulation F20) and 40% ITZ-60% Affinisol® ASD (Formulation F22).

[0167] FIG. 19 shows mean ITZ release (of 3 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).

[0168] iii) Ritonavir-15%, 30% and 50% RTV-Linear PAA ASD

[0169] The method is performed under non-sink conditions. The solubility limit of RTZ in an equilibrated dissolution media (of pH 6.8 phosphate buffer 37° C.) is about 1 μg/mL and the in-vessel ITZ concentration is about 13 μg/mL.

[0170] Product equivalent to about 10 mg of ritonavir is weighed into a 50 mL plastic centrifuge tube (i.e., for 15% loading=66.66 mg, for 30% loading=33.33 mg, and for 50% loading=20 mg). Immediately prior to dissolution, 40 mL of equilibrated media is removed from a vessel containing 750 mL. About 10 mL of the removed equilibrated media is added to the tube vial to pre-wet the drug. The tube is shaken by hand, and the contents transferred to the vessel. The tube is rinsed with the remaining portion of the 40 mL media and the contents returned to the vessel. Apparatus II (paddles) @ 75 rpm, is used to mix the sample.

[0171] Samples (3 each) are removed from the vessel at 5, 10, 15, 30, 45, 60, and 120 minutes. The sampling is performed using 10 μm cannula tip filters and 0.45 μm PVDF w/GMF (Whatman Cat#6872-2504) filters for post sample collection, as described for i) above.

[0172] FIG. 20 shows ITZ release (mean of 3 samples) under non-sink conditions in 0.1N 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 ASDs (Formulations F20 and F22). Soluplus® and Affinisol® were not suitable to prepare ASDs at 80% drug loading.

[0173] FIG. 21 shows ITZ release (mean of 3 samples) under non-sink conditions in 0.1 N HCl from 80% ITZ-20% PAA spray dried ASDs (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).

[0174] D. Stability Study

[0175] Product samples are stored in 1 oz. (˜28 gm) glass jars with screw tops for the duration of the study. For itraconazole, approximately 0.4-1.1 g of sample per jar is used. For ritonavir, approximately 0.3-0.5 g is used. The containers are stored at 40-45° C./75% RH in a stability chamber (Caron 7000-50-1, Darwin Chambers ICH-G2HD-11X11) and tested at TO, 1 month, 2 months, 3 months, and in some cases up to 6 months. The tests performed include appearance, dissolution, DSC, and XRPD.

[0176] XRPD

[0177] XRPD is performed with Si zero background holders. The 2-theta position is performed with a Panalytical Si reference standard disc. The XRPD instrument configuration is Bragg-Brentano geometry. TABLE 11 shows the parameters used.

TABLE-US-00011 TABLE 11 XRPD Parameters Parameters Reflection Mode X-Ray wavelength Cu, kαKα1 (Å): 1.540598, Kα2 (Å): 1.544426, Kα2/Kα1 intensity ratio: 0.50 X-Ray tube setting 45 kV, 40 mA Divergence slit Fixed 1/8° Scan mode Continuous Scan range (° 2TH) 3-40 Scan step time (s) 18.87 Step size (° 2TH) 0.0131 Test Time 4 min 15 s

[0178] DSC

[0179] Differential Scanning calorimetry (DSC) is performed with a Mettler-Toldeo DSC-1 instrument (no modulated DSC software) using a sample amount of 5-10 mg. The pan type is aluminum, 40 μL; contents crimped, lid pierced. The sample is heated in the pan from 25-250° C., increasing at 5 deg/min under a nitrogen purge. Temperature and heat of fusion are calibrated with an appropriate reference material (indium).

[0180] 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 spray dried formulations of 100% ITZ converted from amorphous to crystalline form at one month and no further form change was observed at two months, and three months. All spray dried formulations containing ITZ and PAA remained amorphous for the duration of the study. Dissolution data support the observations made by XRPD and DSC. 30% and 50% ITZ-PAA ASDs showed no meaningful change of dissolution patterns. The 15% ITZ-PAA ASD showed a decrease in drug release after three months, however the XRPD and DSC showed amorphous state was maintained.

[0181] Samples of 40%, 60% and 80% ITZ-PAA (MMW-EA) spray dried ASDs are tested in accelerated stability conditions (40° C./75% RH) for 6 months. Both XRPD and DSC show that all spray dried formulations containing ITZ and PAA remained amorphous for the duration of the study. Dissolution data support the observations made by XRPD and DSC showing no meaningful reduction in dissolution rate (see for example 80% ITZ-PAA ASDs, FIG. 22).

[0182] Samples of 40% ITZ-Soluplus and 40% ITZ-Affinisol® spray dried ASDs tested in accelerated stability conditions (40° C./75% RH) for 6 months show they remain amorphous for the duration of study; however, a decrease of drug release was observed for the 6 months' time point (FIG. 23; FIG. 24).

[0183] As prepared spray dried 80% ITZ-Soluplus® and 80% ITZ-Affinisol® materials are non-uniform amorphous systems with an amorphous-amorphous phase separation comprising ITZ amorphous drug (FIGS. 14 and 15; Table 9). This may be undesirable for some applications as it impacts long-term stability, with increase potential for drug crystallization in time. Storage of spray dried 80% ITZ-Soluplus® and 80% ITZ-Affinisol® materials at 40° C./75% RH for 3 months affected their thermal behavior with increased recrystallization on heating (FIG. 25; FIG. 26).

[0184] RTV-PAA (co-solvent) samples at 15%, 30%, 50% and 100% are tested at 45° C./75% RH. Both XRPD and DSC show that spray dried formulations of 100% RTV converted from amorphous to crystalline form I at two months and that no form change is observed at three months. All spray dried formulations containing RTV and PAA remain amorphous for the duration of the study. Dissolution data support the observations made by XRPD and DSC. 15% and 30% RTV-PAA ASDs show no meaningful change of dissolution patterns. The 50% RTV-PAA ASD show a decrease in drug release over two months, but no change between two and three months. However, XRPD and DSC show that the amorphous state is maintained.

[0185] The reduced dissolution observed for 15% ITZ-PAA ASD and 50% RTV-PAA may be associated with a “clumping” of the material upon storage. Change in surface area may have an impact in initial wettability of the powder, which can lead to the changes in dissolution profile.

[0186] Each of the documents referred to above is incorporated herein by reference. Except in the Examples, or where otherwise explicitly indicated, all numerical quantities in this description specifying amounts of materials, reaction conditions, molecular weights, number of carbon atoms, and the like, are to be understood as modified by the word “about.” Unless otherwise indicated, each chemical or composition referred to herein should be interpreted as being a commercial grade material which may contain the isomers, by-products, derivatives, and other such materials which are normally understood to be present in the commercial grade. However, the amount of each chemical component is presented exclusive of any solvent or diluent oil, which may be customarily present in the commercial material, unless otherwise indicated. It is to be understood that the upper and lower amount, range, and ratio limits set forth herein may be independently combined. Similarly, the ranges and amounts for each element of the invention may be used together with ranges or amounts for any of the other elements.

[0187] While the invention has been explained in relation to its preferred embodiments, it is to be understood that various modifications thereof will become apparent to those skilled in the art upon reading the specification. Therefore, it is to be understood that the invention disclosed herein is intended to cover such modifications as fall within the scope of the appended claims.