Modified release fill compositions for dosage forms and methods of preparation and use thereof

Abstract

Disclosed herein are embodiments of a soft gel dosage form that includes a soft gel capsule and a fill composition within the soft gel capsule. The filling composition may include a matrix material and a solvent. The filling composition can flow at a temperature of at least about 40 DEG C and is solid or semi-solid under ambient conditions. Also disclosed are methods of making and using the same, as well as filling compositions for use in such soft gel dosage forms and methods.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480038379.7 (22) Application Date 2024.06.04 (30) Priority Data 63 / 471,799 2023.06.08 US (85) PCT International Application Entering National Phase Date 2025.12.08 (86) PCT International Application Application Data PCT / US2024 / 032389 2024.06.04 (87) PCT International Application Publication Data WO2024 / 254056 EN 2024.12.12 (71) Applicant: Cartalent Ontario Ltd. Address: Ontario, Canada (72) Inventors: S.A. Kim, Q.Fang, K. Sukuru (74) Patent Agency: Beijing Liu Shen Law Firm 11105 Patent Attorney Qin Jian (51) Int.Cl. A61K 9 / 48 (2006.01) A61K 31 / 138 (2006.01) A61K 31 / 167 (2006.01) A61K 31 / 192 (2006.01) (54) Invention Title: Modulating Filler Composition for Dosage Forms and its Preparation and Use Methods (57) Abstract: This document discloses an embodiment of a soft gel dosage form comprising a soft gel capsule and a filler composition within the soft gel capsule. The filler composition may comprise a matrix material and a solvent. The filler composition is flowable at a temperature of at least about 40°C and is solid or semi-solid under ambient conditions. Methods for its preparation and use, as well as the filler composition used in such soft gel dosage forms and methods, are also disclosed. Claims (17 pages), Description (24 pages), Drawings (7 pages), CN 121358469 A 2026.01.16 CN 1 21 35 84 69 A

Claims

1. A softgel dosage form comprising: a softgel capsule; and a fill composition within the softgel capsule, the fill composition comprising: a matrix material; and a solvent, wherein the fill composition is capable of flowing at a temperature of at least about 40 °C and is a solid or semi-solid under ambient conditions.

2. The softgel dosage form of claim 1, wherein the softgel dosage form further comprises at least one active agent.

3. The softgel dosage form of claim 2, wherein the at least one active agent is contained in a) the softgel capsule, b) the fill composition, c) a film on the surface of the softgel capsule, d) a film on the surface of one or more subunits of the softgel capsule or film composition, or e) a combination of a) through d).

4. The softgel dosage form of any one of the preceding claims, further comprising diphenhydramine, ibuprofen, or acetaminophen.

5. The softgel dosage form of any one of claims 2 to 4, wherein the at least one active agent comprises at least one pharmaceutically active agent, at least one nutritional agent, or a combination thereof.

6. The softgel dosage form of any one of claims 2 to 5, wherein the at least one active agent is hydrophilic or hydrophobic.

7. The softgel dosage form of any of the preceding claims, further comprising a hydrophilic active agent comprising diphenhydramine, ibuprofen, acetaminophen, an antihistamine, a decongestant, an anti-inflammatory, a stimulant, a central nervous system stimulant, caffeine, amphetamine, methamphetamine, lisdexamfetamine dimesylate, armodafinil, atomoxetine, methylphenidate, modafinil, oxybate, pitolisant, verapamil, cefdinir, propaphenone, hydroxyurea, hydrocodone, delavirdine, nelfinavir, pentosan polysulfate sodium, tocainide, quetiapine fumarate, fexofenadine, carafate, rifampin, moxifloxacin, praziquantel, ciprofloxacin, sodium / phosphorus, methenamine mandelate, sotalol, cefprozil, cefadroxyl, metformin, irbesartan, nefazodone, gatifloxacin, didanosine, modafinil, efavirenz, methataxalone, amantadine, morphine, mefenamic acid, dithiazem, sevelamer, albendazole, amoxicillin, potassium clavulanate, lithium carbonate, lamivudine, sumatriptan, nabumetone, zidovudine, cimetidine,chlorpromazine, valaciclovir, bupropion, ranitidine, abacavir, acyclovir, potassium aminobenzoate, pyridostigmine bromide, isosorbide mononitrate, nisin, demelclocycline hydrochloride, cefixime, sodium naproxen, naproxen, tetracycline hydrochloride, cefuroxime axetyl, propoxyphen napsylate, pyrazinamide, acetic acid flecainide, simethicone, mebendazole, methdopa, chlorathiazide, indinavir, penicilla, metyrosine, losartan, thiabendazole, norfloxacin, hydroxyurea, procainamide, entacapone, valsartan, terbinafine, metoprolol, ofloxacin, levofloxacin, chlorzoxazone, tolmetine, tramadol, bepridil, phenytoin, atorvastatin, celecoxib, fluconazole, doxepin, trovafloxacin mesylate, azithromycin, sertraline, rifabutine, cefpodoxime proxetil, mesalamine, disodium etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline, nizatidine, creatine, quinidine,mesuximod, ganciclovir, saquinavir mesylate, tolcapone, ticlopidine, valganciclovir, capecitabine, orlistat, colesevelam, irbesartan, succimer, meperidine, hydroxychloroquine, guaifenesin, eprosartan, amiodarone, felbamate, pseudoephedrine sulfate, carisoprodol, venlafaxine, propanolol hydrochloride, etodolac, acebutolol, chondroitin, pyruvate, opioid analgesic, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene,ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl and derivatives thereof, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, naltrexone, naloxone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, complexes (e.g. complexes with cyclodextrins), stereoisomers, ethers, esters, hydrates, solvates and mixtures thereof, opioid antagonists, dextrorphan, dextromethorphan, 3-(1 -naphthyl)-5-(phosphonormethyl)-L-phenylalanine, 3-(1 -naphthyl)-5-(phosphonormethyl)-DL-phenylalanine, 1 -(3,5-dimethylphenyl)naphthalene,2-(3,5-dimethylphenyl)naphthalene, 2SR,4RS-4-(((lH-tetrazol-5-yl)methyl)oxy)piperidine-2- carboxylic acid, 2SR,4RS-4-((((lH-tetrazol-5-yl)methyl)oxy)methyl)piperidine-2-carboxylic acid, E and Z 2SR-4-(O-(lH-tetrazol-5-yl)methyl)ketoximino)piperidine-2-carboxylic acid, 2SR,4RS-4-((lH-tetrazol-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-((lH-tetrazol-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-lH-tetrazol-l-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-2H-tetrazol-2-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-lH-tetrazol-l-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-2H-tetrazol-2-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(((lH-tetrazol-5-yl)thio)methyl)piperidine-2-carboxylic acid, 2SR,4RS-4-((5-mercapto-lH-tetrazol-l-yl)methyl)piperidine-2-carboxylic acid, 2SR,4RS-4-((5-mercapto-2H-tetrazol-2-yl)methyl)piperidine-2-carboxylic acid, any pharmaceutically acceptable salt, isomer, enantiomer, ester, prodrug, and / or derivative thereof, or a combination of any two or more of the foregoing.

8. The softgel dosage form of any one of the preceding claims, further comprising a hydrophilic nutritional agent comprising a water-soluble vitamin, Vitamin C (ascorbic acid), Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine), Vitamin B7 (biotin), Vitamin B9 (folate - folic acid), Vitamin B 12 (cobalamin), creatine, isoflavones, betaine, psyllium, pantothenic acid, zinc chloride, zinc gluconate, zinc sulfate, phytoestrogens, pyradoxine, proanthocyanidins, theanine, methylthioninium, L-glutamine, Korosutorumu, biotin, amino acids, serine, threonine, asparagine, L-carnitine, acetyl-L-carnitine, inositol, L-tyrosine, s-adenosylmethionine, bromelain, 2-dimethylaminoethanol, chromium picolinate, herbs, ginseng, guarana, taurine, protein hydrolysates, herbs, prebiotics, dietary fiber, or any pharmaceutically acceptable salt, isomer, enantiomer, ester, prodrug, and / or derivative thereof and combinations of any two or more of the foregoing.

9. The softgel dosage form of any of the preceding claims, further comprising a hydrophobic active agent comprising an antihistamine, a decongestant, an anti-inflammatory agent, a stimulant, a central nervous system stimulant, loratadine, an antiproliferative, paclitaxel, sirolimus, everolimus, biolimus A9, zotarolimus, tacrolimus, pimecrolimus, an analgesic and anti-inflammatory, aioxiprin, auranofin, azapropazone, benorylate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate, mefenamic acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac, an anti-arrhythmic agent, amiodarone HCl, disopyramide, flecainide acetate, quinidine sulphate, an antibacterial agent, benethamine penicillin, cinoxacin, ciprofloxacin HCl, enoxacin, norfloxacin, ofloxacin, perfloxacin, pefloxacin, temidoxane, an anticholinergic agent, atropine, hyoscine, ipratropium bromide, tiotropium bromide, an antidiabetic agent, chlorpropamide, glibenclamide, tolbutamide, an antihypertensive agent, clonidine, diazoxide, guanabenz, guanadrel, guanethidine, methyldopa, minoxidil, reserpine, a beta-blocker, atenolol, metoprolol, propranolol, a diuretic, chlorpropamide, ethacrynic acid, furosemide, a bronchodilator, albuterol, formoterol, salmeterol, a corticosteroid, beclometasone, fluticasone, a non-steroidal anti-inflammatory agent, aloe vera, arnica, arnica montana, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata, arnica unbellata,HCl), clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulfabenzamide, sulfadoxine, sulfamethizole, sulfacetamide, sulfadiazine, sulfisoxazole, sulfapyridine, tetracycline, trimethoprim, anticoagulants, dicoumarol, dipyridamole, nicoumalone, phenindione, antihypertensives, amlodipine, benidipine, darodipine, dilitazem HCl, diazoxide, felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine, terazosin HCl, anti-muscarinic agents, atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencylcimine HCl, procyclidine HCl, trihexepenidyl HCl, antipsychotics, chlorpromazine, chloφromethiazine, clozapine, fluphenazine, haloperidol, mesoridazine, molindone, pericyazine, perphenazine, pimozide, pipotiazine, prochlorperazine, spiperone, sulpiride, thioridazine, thiothixene, trifluoperazine, trifluperidol, antithyroid agents, methimazole, propylthiouracil, antiviral agents, acyclovir, ganciclovir, ribavirin, antidiabetics, chlorpropamide, glibenclamide, tolazamide, tolbutamide, antihistamines, brompheniramine, chlorpheniramine, dexchlorpheniramine, tripelennamine, antiparkinsonian agents, amantadine, benserazide, carbidopa, levodopa, selegiline, antipyrine, aminoglutethimide, anastrozole, exemezole, formestane, fadrozole, letrozole, megestrol, tamoxifen, testolactone, toremifene, triptorelin, antithyroid agents, methimazole, propylthiouracil, antiviral agents, acyclovir, ganciclovir, ribavirin, antidiabetics, chlorpropamide, glibenclamide, tolazamide, tolbutamide, antihistamines, brompheniramine, chlorpheniramine, dexchlorpheniramine, tripelennamine, antiparkinsonian agents, amantadine, benserazide, carbidopa, levodopa, selegiline,HCl), tropicamide; antineoplastic and immunosuppressive agents such as aminoglutethimide, amsacrine, azathioprine, busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate, testolactone, beta-blockers, acebutolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, cardiotonic agents, amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin, corticosteroids, beclomethasone, betamethasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, lipid-regulating agents, bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol, antianginal agents, amyl nitrate, isosorbide dinitrate, isosorbide mononitrate, nifedipine, nicorandil, nitroprusside, perhexiline, ranolazine, antiarrhythmic agents, amiodarone, disopyramide, flecainide, procainamide, propafenone, quinidine, sotalol, antihypertensive agents, amiloride, clonidine, diazoxide, guanabenz, guanadrel, guanethidine, methyldopa, minoxidil, reserpine, thiazide diuretics, aliskiren, candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, benazepril, cilazapril, delapril, pentopril, spirapril, aliskiren, candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, benazepril, cilazapril, delapril, pentopril, spirapril,nitrate), nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate, an agent for treating hypertension, guanethidine. In particular embodiments, the hydrophobic active agent comprises a chemotherapeutic agent, fluorouracil, carmustine, or any pharmaceutically acceptable salt, isomer, enantiomer, ester, prodrug, and / or derivative thereof, or a combination of any two or more of the foregoing.

10. The softgel dosage form of any one of the preceding claims, further comprising a hydrophobic nutritional agent comprising a fat soluble vitamin, Vitamin A (retinol, retinyl ester), Vitamin D (calciferol), Vitamin E (a-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol), Vitamin Kl (phytonadione), Vitamin K2 (menaquinone), omega-3 eicosapentaenoic acid, omega-3 docosahexaenoic acid, coenzyme QlO, lutein, zeaxanthin, an amino acid, or any pharmaceutically acceptable salt, isomer, enantiomer, ester, prodrug, and / or derivative thereof, or a combination of any two or more of the foregoing.

11. The softgel dosage form of any one of the preceding claims, wherein the fill composition is capable of flowing at a temperature of at least about 37 °C, at least about 45 °C, at least about 50 °C, at least about 55 °C, at least about 60 °C, or at least about 70 °C.

12. The softgel dosage form of any one of the preceding claims, wherein the fill composition is a solid or semi-solid at a temperature of about 15 °C to about 35 °C, about 18 °C to about 30 °C, or about 20 °C to about 25 °C.

13. The softgel dosage form of any one of the preceding claims, wherein the fill composition has a viscosity at a temperature of 40 °C of less than about 100,000 cp, less than about 80,000 cp, less than about 50,000 cp, less than about 25,000 cp, less than about 15,000 cp, less than about 12,000 cp, or less than about 10,000 cp when viscosity is determined using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate at 40 °C with a shear stress of 10 Pa and an oscillation frequency of 1 Hz.

14. The softgel dosage form of any one of the preceding claims, wherein the fill composition has a viscosity at a temperature of 60 °C of less than about 100,000 cp, less than about 80,000 cp, less than about 50,000 cp, less than about 25,000 cp, less than about 15,000 cp, less than about 12,000 cp, or less than about 10,000 cp when viscosity is determined using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate at 60 °C with a shear stress of 10 Pa and an oscillation frequency of 1 Hz.

15. The softgel dosage form of any one of the preceding claims, wherein the softgel dosage form provides modified release of the active agent.

16. The softgel dosage form of any one of the preceding claims, wherein the softgel dosage form releases active agent over a period of at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 14 hours, at least about 16 hours, or at least about 24 hours, as measured by in-vitro dissolution at about 37°C in about 500 ml to about 900 ml water or buffer in a USP Apparatus II (paddle method) at about 75 RPM.

17. The softgel dosage form of any one of the preceding claims, wherein the softgel dosage form releases about 40% or less, 30% or less, 20% or less, or 10% or less of active agent over about 1 hour, as measured by in-vitro dissolution at about 37°C in about 500 ml to about 900 ml water or buffer in a USP Apparatus II (paddle method) at about 75 RPM.

18. The softgel dosage form of any one of the preceding claims, wherein the softgel dosage form releases about 80% or more, 85% or more, 95% or more, or 100% or more of active agent over about 12 hours, as measured by in-vitro dissolution at about 37°C in about 500 ml to about 900 ml water or buffer in a USP Apparatus II (paddle method) at about 75 RPM.

19. The softgel dosage form of any one of the preceding claims, wherein the softgel dosage form releases about 80% or more, 85% or more, 95% or more, or 100% or more of active agent over about 24 hours, as measured by in-vitro dissolution at about 37°C in about 500 ml to about 900 ml water or buffer in a USP Apparatus II (paddle method) at about 75 RPM.

20. The softgel dosage form of any one of the preceding claims, wherein the fill composition provides modified release of active agent.

21. The softgel dosage form of any one of the preceding claims, wherein the fill composition releases active agent over a period of at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 14 hours, at least about 16 hours, or at least about 24 hours, as measured by in-vitro dissolution at about 37°C in about 500 ml to about 900 ml water or buffer in a USP Apparatus II (paddle method) at about 75 RPM.

22. The softgel dosage form of any one of the preceding claims, wherein the fill composition releases about 40% or less, 30% or less, 20% or less, or 10% or less of active agent over about 1 hour, as measured by in-vitro dissolution at about 37°C in about 500 ml to about 900 ml water or buffer in a USP Apparatus II (paddle method) at about 75 RPM.

23. The softgel dosage form of any one of the preceding claims, wherein the fill composition releases about 80% or more, 85% or more, 95% or more, or 100% or more of the active agent within about 12 hours, as measured by in-vitro dissolution at about 37 °C in about 500 ml to about 900 ml water or buffer in a USP Apparatus II (paddle method) at about 75 RPM.

24. The softgel dosage form of any one of the preceding claims, wherein the fill composition releases about 80% or more, 85% or more, 95% or more, or 100% or more of the active agent within about 24 hours, as measured by in-vitro dissolution at about 37 °C in about 500 ml to about 900 ml water or buffer in a USP Apparatus II (paddle method) at about 75 RPM.

25. The softgel dosage form of any one of the preceding claims, wherein the softgel capsule comprises gelatin, carrageenan, starch, maltodextrin, or a combination thereof, or wherein the softgel capsule is gelatin-free.

26. The softgel dosage form of any one of the preceding claims, wherein the matrix material comprises a polymer comprising polyethylene oxide, a cellulose derivative, a natural gum, a synthetic gum, or a combination thereof, and / or wherein the matrix material comprises a wax comprising paraffin wax, hard fat, carnauba wax, beeswax, stearic acid, cetyl alcohol, cetearyl alcohol, glyceryl monostearate, or a combination thereof.

27. The softgel dosage form of any one of the preceding claims, wherein the matrix material comprises: a polyethylene oxide having a molecular weight of about 90,000 Da to about 7,000,000 Da, or a plurality of polyethylene oxides each having a different molecular weight ranging from about 90,000 Da to about 7,000,000 Da.

28. The softgel dosage form of claim 27, comprising the polyethylene oxide or plurality of polyethylene oxides in an amount of about 5 wt% to about 50 wt% or about 10 wt% to about 50 wt%, based on the total weight of the fill composition.

29. The softgel dosage form of any one of the preceding claims, wherein the softgel capsule comprises gelatin, and wherein the fill composition is flowable at a temperature of about 35 °C to about 45 °C, about 38 °C to about 42 °C, or about 40 °C.

30. The softgel dosage form of claims 27 to 29, wherein the fill composition is hydrophilic.

31. The softgel dosage form of any one of the preceding claims, wherein the cellulose derivative comprises hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, sodium croscarmellose, or a combination of any two or more thereof.

32. The softgel dosage form of any one of the preceding claims, wherein the matrix material comprises: a hydroxypropyl methylcellulose having a molecular weight of about 10,000 Da to about 1,500,000 Da, or a hydroxypropyl methylcellulose having a molecular weight of about 10,000 Da to about 1,500,000 Da, or a plurality of hydroxypropyl methylcelluloses each having a different molecular weight in the range of about 10,000 Da to about 1,500,000 Da.

33. The softgel dosage form of any one of the preceding claims, wherein the matrix material comprises: ethylcellulose having a molecular weight of about 10,000 Da to about 200,000 Da, or a plurality of ethylcelluloses each having a different molecular weight in the range of about 400 Da to about 2,000,000 Da.

34. The softgel dosage form of any one of the preceding claims, wherein the matrix material comprises at least one hydroxypropyl methylcellulose and at least one ethylcellulose, optionally wherein the weight ratio of the at least one hydroxypropyl methylcellulose to the at least one ethylcellulose is about 1: 100 to about 100: 1, about 1:50 to about 50: 1, about 1:25 to about 25: 1, about 1:20 to about 20: 1, about 1: 15 to about 15: 1, about 1: 10 to about 10: 1, about 1:5 to about 5: 1, or about 1:

1.

35. The softgel dosage form of claim 34, comprising one or more of: (a) a hydroxypropyl methylcellulose that provides a viscosity of about 4 cp to about 6 cp when used in a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose at 20 °C with a shear stress of 10 Pa and an oscillation frequency of 1 Hz using a HAAKE RheoStress 6000 parallel plate of Thermo Fisher Scientific, (b) a hydroxypropyl methylcellulose that provides a viscosity of about 12 cp to about 18 cp when used in a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose at 20 °C with a shear stress of 10 Pa and an oscillation frequency of 1 Hz using a HAAKE RheoStress 6000 parallel plate of Thermo Fisher Scientific, or (c) a hydroxypropyl methylcellulose that provides a viscosity of about 80 cp to about 120 cp when used in a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose at 20 °C with a shear stress of 10 Pa and an oscillation frequency of 1 Hz using a HAAKE RheoStress 6000 parallel plate of Thermo Fisher Scientific, optionally wherein the weight ratio of (a):(b) is 1: 100 to about 100: 1, about 1:50 to about 50: 1, about 1:25 to about 25: 1, about 1:20 to about 20: 1, about 1: 15 to about 15: 1, about 1: 10 to about 10: 1, about 1:5 to about 5: 1, or about 1: 1, and the weight ratio of (a):(c) is 1: 100 to about 100: 1, about 1:50 to about 50: 1, about 1:25 to about 25: 1, about 1:20 to about 20: 1, about 1: 15 to about 15: 1, about 1: 10 to about 10: 1, about 1:5 to about 5: 1, or about 1:

1.

36. The softgel dosage form of claim 34, comprising at least one of: about 5 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt% of the hydroxypropyl methylcellulose providing a viscosity of about 4 cp to about 6 cp, based on the total weight of the fill composition, about 5 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt% of the hydroxypropyl methylcellulose providing a viscosity of about 12 cp to about 18 cp, based on the total weight of the fill composition, or about 5 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt% of the hydroxypropyl methylcellulose providing a viscosity of about 80 cp to about 120 cp, based on the total weight of the fill composition.

37. The softgel dosage form of any one of claims 34 to 36, comprising ethyl cellulose providing a viscosity of about 9 cp to about 11 cp when measured using a HAAKE RheoStress 6000 parallel plate at a shear stress of 10 Pa and an oscillation frequency of 1 Hz at 20 °C.

38. The softgel dosage form of any one of the preceding claims, wherein the solvent comprises an aqueous component, an oil, an alcohol, a low molecular weight polymer, an emulsifier, a surfactant, or a combination thereof.

39. The softgel dosage form of claim 38, wherein the oil comprises soybean oil, mineral oil, olive oil, vegetable oil, sesame oil, sunflower seed oil, rapeseed oil, corn oil, oleic acid oil, coconut oil, almond oil, avocado oil, grape seed oil, or palm oil, or a combination of any two or more of the foregoing.

40. The softgel dosage form of any one of the preceding claims, wherein the solvent comprises water, soybean oil, ethanol, low molecular weight polyethylene glycol, triethyl citrate, or a combination of any two or more thereof.

41. The softgel dosage form of any one of the preceding claims, wherein the solvent comprises at least one of: soybean oil in an amount of about 20 wt% to about 90 wt%, about 30 wt% to about 80 wt%, about 40 wt% to about 70 wt%, or about 50 wt% to about 65 wt%, based on the total weight of the fill composition; water in an amount of about 0.1 wt% to about 30 wt%, about 0.5 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, based on the total weight of the fill composition, or ethanol in an amount of about 0 wt% to about 40 wt%, about 1 wt% to about 30 wt%, about 5 wt% to about 20 wt%, based on the total weight of the fill composition.

42. The softgel dosage form of any one of the preceding claims, wherein the fill composition further comprises at least one pharmaceutically acceptable excipient.

43. The softgel dosage form of claim 42, wherein the at least one pharmaceutically acceptable excipient comprises a plasticizer, a colorant, a lubricant, a thermal lubricant, an antioxidant, a buffering agent, a disintegrant, a granulating agent, a binding agent, a diluent, an anti-tacking agent, a sweetening agent, a chelating agent, a granulating agent, a filler, a suspending agent, a flavoring agent, a surfactant, a solubilizing agent, a stabilizing agent, an absorption enhancer, a preservative, an absorbent, a cross-linking agent, a pore-forming agent, an osmotic agent, a polycarboxylic acid, an emulsion stabilizer, a suspending agent, a heat stabilizer, a viscosity-increasing agent, a drying agent, a solubility enhancer, and a combination of any two or more of the foregoing.

44. The softgel dosage form of any one of the preceding claims, further comprising a heat stabilizer comprising silicon dioxide, colloidal silicon dioxide, a wax, a cyclodextrin, microcrystalline cellulose, sodium carboxymethylcellulose, an alginate, a pectin, or a combination of any two or more thereof.

45. The softgel dosage form of any one of the preceding claims, further comprising a surfactant comprising cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, sorbitan fatty acid ester, sorbitan monooleate, polyoxyethylene sorbitan fatty acid ester, polysorbate 20, polysorbate 80, polyoxyethylene glycerol fatty acid ester, macrogol cetostearyl ether, macrogol cetostearyl ether phosphate, glycerol monostearate, polyoxyethylene fatty acid ester, polyoxyethylene 40 stearate, polyoxyethylene fatty alcohol ether, polyoxyethylene oleyl ether, glycerol fatty acid ester, glycerol monostearate, glycerol dibehenate, or a combination of two or more thereof.

46. The softgel dosage form of any one of the preceding claims, further comprising a plasticizer comprising triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, stearic acid, one or more low molecular weight polymers, a low molecular weight oligomer, a low molecular weight copolymer, an oil, an organic small molecule, a low molecular weight polyol having one or more aliphatic hydroxyl groups, an ester-type plasticizer, a glycol ether, poly(propylene glycol), a low molecular weight poly(ethylene glycol), a citrate ester-type plasticizer, triacetin, propylene glycol, glycerol, ethylene glycol, 1,2-butanediol, 2,3-butanediol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, a poly(ethylene glycol) compound, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, allyl glycolate, or a combination of any two or more thereof.

47. The softgel dosage form of any one of the preceding claims, further comprising a suspending agent comprising silicon dioxide, colloidal silicon dioxide, wax, acacia, agar, alginic acid, aluminum monostearate, bentonite, camphor, carbomer, carrageenan, starch, corn starch, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, magnesium aluminum silicate, methyl cellulose, pectin, polyvinyl alcohol, povidone, sodium alginate, sodium hyaluronate, tragacanth, xanthan gum, or a combination of any two or more thereof.

48. The softgel dosage form of any one of the preceding claims, wherein the matrix material comprises one or more esters of fatty acids and glycerol, one or more triglycerides, long chain fatty acids, or a combination thereof.

49. The softgel dosage form of claim 47 or 48, wherein the one or more esters of fatty acids and glycerol comprises an ester of linolenic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, lauric acid, hexanoic acid, octanoic acid, decanoic acid, or a combination of two or more thereof, a monoglyceride, a diglyceride, a monoacylglycerol, a diacylglycerol, a stearyl polyoxylglycerol, a lauryl polyoxylglycerol, a stearyl polyoxyl-32 glycerol, a lauryl polyoxyl-32 glycerol, glyceryl monostearate, glyceryl monocaprylocaprate, glyceryl dioctanoate, glyceryl monooleate, or a combination of two or more thereof.

50. The softgel dosage form of any one of claims 47 to 49, wherein the one or more triglycerides comprises a medium chain triglyceride, a caprylocapryl triglyceride, a caprylocapric triglyceride, a triglyceride of one or more of linolenic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, hexanoic acid, octanoic acid, decanoic acid, or lauric acid, and one or more medium chain fatty acids having about 6 to about 12 carbon atoms, a caprylocapryl / capric triglyceride, a caprylocapric triglyceride, a caprylocapryl / capric triglyceride, or a combination of any two or more thereof.

51. The softgel dosage form of any one of claims 47 to 50, wherein the wax comprises paraffin wax, beeswax, jojoba oil, lanolin, whale wax, or a combination of any two or more thereof.

52. The softgel dosage form of any one of the preceding claims, comprising at least one of: about 0.1 wt% to about 20 wt%, about 0.5 wt% to about 10 wt%, or about 1 wt% to about 5 wt% of one or more esters of fatty acids and glycerol; about 0.1 wt% to about 50 wt% or about 1 wt% to about 30 wt% of a surfactant; about 1 w% to about 80 wt%, about 5 wt% to about 70 wt%, or about 10 wt% to about 60 wt% of a medium chain triglyceride; or about 0 wt% to about 20 wt% or about 0 wt% to about 10 wt% of a plasticizer.

53. The softgel dosage form of claim 52, wherein the one or more esters of fatty acids and glycerol comprises stearoyl polyoxyl-32 glycerides, the surfactant comprises glyceryl dibehenate, and the plasticizer comprises stearic acid.

54. The softgel dosage form of any one of the preceding claims, comprising at least one of: about 1 wt% to about 50 wt%, about 5 wt% to about 40 wt%, or about 10 wt% to about 30 wt% of the wax; about 0.1 wt% to about 20 wt%, about 0.5 wt% to about 10 wt%, or about 1.0 wt% to about 5 wt% of hydroxypropyl methylcellulose; about 0.1 wt% to about 20 wt%, about 0.5 wt% to about 10 wt%, or about 1.0 wt% to about 5 wt% of one or more esters of fatty acids and glycerol; about 1 wt% to about 80 wt%, about 5 wt% to about 70 wt%, or about 10 wt% to about 60 wt% of medium chain triglycerides; or about 0 wt% to about 20 wt% or about 0 wt% to about 10 wt% of a plasticizer.

55. The softgel dosage form of claim 54, wherein the wax comprises paraffin wax, the hydroxypropyl methylcellulose provides a viscosity of about 80 cp to about 120 cp when used in a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose at 20 °C with a shear stress of 10 Pa and an oscillation frequency of 1 Hz using a HAAKE RheoStress 6000 parallel plate from Thermo Fisher Scientific, the one or more esters of fatty acids and glycerol comprises lauroyl polyoxylglycerides, and the plasticizer comprises stearic acid.

56. The softgel dosage form of any one of the preceding claims, wherein the fill composition comprises a solid, a semi-solid, a liquid, or a combination thereof.

57. The softgel dosage form of claim 56, wherein the solid comprises one or more of: a granule, a fine particle, a powder, a bead, a microsphere, an extrudate, a multiparticulate, a microtablet, or a combination thereof.

58. The softgel dosage form of claim 55 or 56, wherein the semi-solid comprises a gel dispersed in a semi-solid medium, a hydrogel, an organic solvent-based gel, a granule, a fine particle, a powder, a bead, a microsphere, an extrudate, and / or a multiparticulate, or a combination thereof.

59. The softgel dosage form of any one of claims 55 to 58, wherein the liquid comprises a serum, a viscous liquid, or a combination thereof.

60. The softgel dosage form of any one of the preceding claims, wherein the softgel capsule comprises a first capsule shell portion, a second capsule shell portion, and a seal attaching the first capsule shell portion to the second capsule shell portion, or wherein the softgel capsule is seamless.

61. The softgel dosage form of any one of the preceding claims, wherein the softgel dosage form does not provide immediate release of an active agent.

62. The softgel dosage form of any of the preceding claims, wherein the softgel dosage form is solidified at about 40 °C to about 75 °C or about 50 °C to about 65 °C for about 15 minutes to about four days or about 1 hour to about 24 hours.

63. A method of encapsulating a modified release fill composition in a softgel capsule to form a softgel dosage form of any of the preceding claims, the method comprising: heating the modified release fill composition to a temperature of at least about 40 °C, at least about 45 °C, at least about 50 °C, at least about 55 °C, or at least about 60 °C to provide a flowable liquid; and encapsulating the flowable liquid in the softgel capsule.

64. The method of claim 63, further comprising cooling the softgel dosage form to ambient temperature.

65. The method of claim 63 or 64, wherein the flowable liquid forms a solid or semi-solid at ambient temperature.

66. The method of claim 63, wherein encapsulating the flowable liquid comprises filling a first capsule shell portion of the softgel capsule with the flowable liquid; and sealing a second capsule shell portion to the first capsule shell portion to form a seal.

67. A method of treating pain, the method comprising: administering a softgel dosage form of any of the preceding claims to a subject in need thereof, wherein the softgel dosage form comprises a pharmaceutically active agent suitable for treating pain.

68. A fill composition for encapsulation within a softgel capsule, the fill composition comprising: a matrix material; and a solvent, wherein the fill composition is flowable at a temperature of at least about 40 °C and is a solid or semi-solid under ambient conditions.

69. The fill composition of claim 68, further comprising at least one active agent.

70. The fill composition of claim 69, wherein the at least one active agent is comprised in a) subunits dispersed in the fill composition, b) a film on the surface of one or more subunits in the fill composition, c) a loose medium of the fill composition, or d) a combination of a) to c).

71. The fill composition of claim 68 or 69, further comprising diphenhydramine, ibuprofen, or acetaminophen.

72. The fill composition of any of claims 69 to 71, wherein the at least one active agent comprises at least one pharmaceutically active agent, at least one nutraceutical agent, or a combination thereof.

73. The fill composition of any of claims 69 to 72, wherein the at least one active agent is hydrophilic or hydrophobic.

74. The filling composition of any one of claims 68-73, further comprising a hydrophilic active agent comprising diphenhydramine, ibuprofen, acetaminophen, antihistamines, decongestants, anti-inflammatory agents, stimulants, central nervous system stimulants, caffeine, amphetamines, methamphetamine, lisdexamfetamine, amobarbital, tomoxetine, methylphenidate, modafinil, hydroxybutyrate, tilomisole, verapamil, cefdinir, propafenone, hydroxyurea, hydrocodone, delavirdine, nelfinavir, pentosan polysulfate sodium, tocainide, quetiapine fumarate, fexofenadine, ranitidine, rifampin, moxifloxacin, praziquantel, ciprofloxacin, sodium / phosphorus, methenamine hippurate, sotalol, cefprozil, cefadroxil, metformin, irbesartan, nefazodone, gatifloxacin, didanosine, modafinil, efavirenz, metaxalone, amantadine, morphine, mefenamic acid, diltiazem, sevelamer, albendazole, amoxicillin, potassium clavulanate, lithium carbonate, lamivudine, sumatriptan, nabumetone, zidovudine, cimetidine, chloφromazine, valacyclovir, bupropion, ranitidine, abacavir, acyclovir, potassium aminobenzoate, pyridostigmine bromide, isosorbide mononitrate, nisoxetine, demeclocycline hydrochloride, cefixime, naproxen sodium, naproxen, tetracycline hydrochloride, cefuroxime axetil, propoxyphene napsylate, pyrazinamide, flurcazamide acetate, simethicone, mefenidne, methyldopa, chlorothiazide, indinavir, penicillin, methyldopa, losartan, thiambuten, norfloxacin, hydroxyurea, procainamide, entacapone, valsartan, terbinafine, metoprolol, ofloxacin, levofloxacin, chlorzoxazone, tolcapone, tramadol, bepridil, phenytoin, atorvastatin, celecoxib, fluconazole, doxepin, trovafloxacin mesylate, azithromycin, sertraline, rifabutin, cefpodoxime proxetil, mesalamine, etidronate disodium, furadantin, choline magnesium trisalicylate, theophylline, nizatidine, creatine, quinidine, methocarbamol meptin, ganciclovir, saquinavir mesylate, tolcapone, tioclomide, valganciclovir, capecitabine, orlistat, colesevelam, irbesartan, succinimide, pethidine, hydroxychloroquine, guaifenesin, eprosartan, amiodarone, phenyramidol, pseudoephedrine sulfate, carisoprodol, venlafaxine, propranolol hydrochloride, etodolac, acebutolol, hyaluronan, pyruvate, opioid analgesics, alfentanil, allylprodine, alphaprodine, anileridine, benzylmoφhine, benzymin, buprenorphine, butorphanol, clonitazene, codeine, desomethane, dextromoramide, dezocine, diamorphone, dihydrocodeine, dihydromorphine, demexiphyline, dimenoxadol, dipipanone, dipanone, ethoheptazine, ethoxazene, ethylmoφhine, etonitazene, etoφhine, dihydroetoφhine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol,Levoφhanol, loφhanol, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, normoφhanol, normethadone, nalorphine, nalbupine, normorphine, norpipanone, naltrexone, naloxone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenazocine, phenomorphan, phenazocine, piminodine, prodine, propiram, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts, complexes (e.g., complexes with cyclodextrins), stereoisomers, ethers, esters, hydrates, solvates, and mixtures thereof, opioid antagonists, dextroφhanol, dextromethorphan, 3-(1-naphthyl)-5-(phosphonomethyl)-L-phenylalanine, 3-(1-naphthyl)-5-(phosphonomethyl)-DL-phenylalanine, 1-(3,5-dimethylphenyl)naphthalene, 2-(3,5-dimethylphenyl)naphthalene, 2SR,4RS-4-(((1H-tetrazol-5-yl)methyl)oxy)piperidine-2-carboxylic acid, 2SR,4RS-4-((((1H-tetrazol-5-yl)methyl)oxy)methyl)piperidine-2-carboxylic acid, E and Z 2SR-4-(O-(1H-tetrazol-5-yl)methyl)ketoximino)piperidine-2-carboxylic acid, 2SR,4RS-4-((1H-tetrazol-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-((1H-tetrazol-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-tetrazol-1-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-2H-tetrazol-2-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-tetrazol-1-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-2H-tetrazol-2-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(((1H-tetrazol-5-yl)thio)methyl)piperidine-2-carboxylic acid, 2SR,4RS-4-((5-mercapto-1H-tetrazol-1-yl)methyl)piperidine-2-carboxylic acid, 2SR,4RS-4-((5-mercapto-2H-tetrazol-2-yl)methyl)piperidine-2-carboxylic acid, any pharmaceutically acceptable salts, isomers, enantiomers, esters, prodrugs, and / or derivatives thereof, or a combination of any two or more of the foregoing.

75. The filling composition of any one of claims 68-74, further comprising a hydrophilic nutrient comprising a water-soluble vitamin, Vitamin C (ascorbic acid), Vitamin Bl (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine), Vitamin B7 (biotin), Vitamin B9 (folate - folic acid), Vitamin B 12 (cobalamin), creatine, isoflavones, betaine, psyllium, pantothenic acid, zinc chloride, zinc gluconate, zinc sulfate, phytoestrogens, pyradoxine, proanthocyanidins, theanine, methionine, L-glutamine, Korosutorumu, biotin, amino acids, serine, threonine, asparagine, L-carnitine, acetyl-L-carnitine, inositol, L-tyrosine, s-adenosylmethionine, bromelain, 2-dimethylaminoethanol, chromium picolinate, herbs, ginseng, guarana, taurine, protein hydrolysates, herbs, prebiotics, dietary fiber, or any pharmaceutically acceptable salt, isomer, enantiomer, ester, prodrug, and / or derivative thereof and combinations of any two or more of the foregoing.

76. The filling composition of any one of claims 68-75, further comprising a hydrophobic active agent comprising an antihistamine, a decongestant, an anti-inflammatory agent, a stimulant, a central nervous system stimulant, loratadine, an anti-proliferative agent, paclitaxel, sirolimus, everolimus, umirolimus A9, zotarolimus, tacrolimus, pimecrolimus, an analgesic and anti-inflammatory, aurothioglucose, benorylate, azapropazone, bromfenac, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate acid, mefenamic acid, nabumetone, naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac, an antiarrhythmic agent, amiodarone hydrochloride, disopyramide, flecainide acetate, quinidine sulfate, an antibacterial agent, penicillin benzathine, cinoxacin hydrochloride, clinafloxacin hydrochloride, clarithromycin, clofazimine, cloxacillin, dehydroemetine, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampin, spiramycin, sulfabenzamide, sulfadimethoxine, sulfamethazine, sulfacetamide, sulfadiazine, sulfisoxazole, sulfapyridine, tetracycline, trimethoprim, an anticoagulant, dicumarol, dipyridamole, acenocoumarol, phenindione, an antihypertensive agent, amlodipine, benidipine, darodipine, diltiazem hydrochloride, diazoxide, felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine hydrochloride, nifedipine, nimodipine, phenoxybenzamine hydrochloride, prazosin hydrochloride, reserpine, terazosin hydrochloride, an antimuscarinic agent, atropine, benzhexol hydrochloride, biperiden, ethopropazine hydrochloride, hyoscyamine, mepenzolate bromide, orphenadrine hydrochloride, pirenzepine, an antineoplastic agent and immunosuppressive agent, such as aminoglutethimide, azacytidine, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, procarbazine hydrochloride, tamoxifen citrate, testolactone, a beta-blocker, acebutolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, a cardiotonic agent, amrinone, digitoxin, digoxin, enoximone, lanatoside C, metildigoxin, a corticosteroid, beclomethasone dipropionate, betamethasone, budesonide, cortisone acetate, dexa-methasone, dexamethasone, fluocinolone acetonide, flunisolide, flurandrenolide, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone acetonide, a lipid regulating agent, bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol, an antianginal agent, amylnitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate, an agent for the treatment of hypertension, guanethidine.In particular embodiments, the hydrophobic active agent comprises a chemotherapeutic agent, fluorouracil, carmustine, or any pharmaceutically acceptable salt, isomer, enantiomer, ester, prodrug, and / or derivative thereof, or a combination of any two or more of the foregoing.

77. The filling composition of any one of claims 68-76, further comprising a hydrophobic nutrient comprising a fat-soluble vitamin, Vitamin A (retinol, retinyl ester), Vitamin D (calciferol), Vitamin E (a-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol), Vitamin Kl (phytonadione), Vitamin K2 (menaquinone), omega-3 eicosapentaenoic acid, omega-3 docosahexaenoic acid, coenzyme QlO, lutein, zeaxanthin, amino acids, or any pharmaceutically acceptable salt, isomer, enantiomer, ester, prodrug, and / or derivative thereof or combinations of any two or more of the foregoing.

78. The filling composition of any one of claims 68-77, wherein the filling composition is capable of flowing at a temperature of at least about 45 °C, at least about 50 °C, at least about 55 °C, at least about 60 °C, or at least about 70 °C.

79. The filling composition of any one of claims 68-78, wherein the filling composition is a solid or semi-solid at a temperature of about 15 °C to about 35 °C, about 18 °C to about 30 °C, or about 20 °C to about 25 °C.

80. The filling composition of any one of claims 68-79, wherein the filling composition has a viscosity at a temperature of 40 °C of less than about 100,000 cp, less than about 80,000 cp, less than about 50,000 cp, less than about 25,000 cp, less than about 15,000 cp, less than about 12,000 cp, or less than about 10,000 cp when viscosity is determined using a HAAKE RheoStress 6000 parallel plate at 40 °C with a shear stress of 10 Pa and an oscillation frequency of 1 Hz.

81. The fill composition of any one of claims 68-80, wherein the fill composition has a viscosity at a temperature of 60 °C of less than about 100,000 cp, less than about 80,000 cp, less than about 50,000 cp, less than about 25,000 cp, less than about 15,000 cp, less than about 12,000 cp, or less than about 10,000 cp when the viscosity is determined using a HAAKE RheoStress 6000 parallel plate at 60 °C with a shear stress of 10 Pa and an oscillation frequency of 1 Hz.

82. The fill composition of any one of claims 68-81, wherein the fill composition provides modified release of the active agent.

83. The fill composition of any one of claims 68-82, wherein the fill composition releases the active agent over a period of at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 14 hours, at least about 16 hours, or at least about 24 hours, as measured by in-vitro dissolution in a USP Apparatus II (paddle method) at about 50 RPM in about 900 ml 0.1 N HC1 at about 37 °C.

84. The fill composition of any one of claims 68-83, wherein the fill composition releases about 40% or less, 30% or less, 20% or less, or 10% or less of the active agent within about 1 hour, as measured by in-vitro dissolution in a USP Apparatus II (paddle method) at about 50 RPM in about 900 ml 0.1 N HC1 at about 37 °C.

85. The fill composition of any one of claims 68-84, wherein the fill composition releases about 80% or more, 85% or more, 95% or more, or 100% or more of the active agent within about 12 hours, as measured by in-vitro dissolution in a USP Apparatus II (paddle method) at about 50 RPM in about 900 ml 0.1 N HC1 at about 37 °C.

86. The fill composition of any one of claims 68-85, wherein the fill composition releases about 80% or more, 85% or more, 95% or more, or 100% or more of the active agent within about 24 hours, as measured by in-vitro dissolution in a USP Apparatus II (paddle method) at about 50 RPM in about 900 ml 0.1 N HC1 at about 37 °C.

87. The fill composition of any one of claims 68-86, wherein the matrix material comprises a polymer comprising poly(ethylene oxide), a cellulose derivative, a natural gum, a synthetic gum, or a combination thereof, and / or wherein the matrix material comprises a wax comprising paraffin wax, hard fat, carnauba wax, beeswax, stearic acid, cetyl alcohol, cetearyl alcohol, glyceryl monostearate, or a combination thereof.

88. The filling composition of any one of claims 68-87, wherein the matrix material comprises: a polyethylene oxide having a molecular weight of about 90,000 Da to about 7,000,000 Da, or a plurality of polyethylene oxides each having a different molecular weight ranging from about 90,000 Da to about 7,000,000 Da.

89. The filling composition of claim 88, comprising the polyethylene oxide or plurality of polyethylene oxides in an amount of about 5 wt% to about 50 wt% or about 10 wt% to about 50 wt%, based on the total weight of the filling composition.

90. The filling composition of any one of claims 68-89, wherein the filling composition is flowable at a temperature of about 35 °C to about 45 °C, about 38 °C to about 42 °C, or about 40 °C.

91. The filling composition of any one of claims 68-90, wherein the filling composition is hydrophilic.

92. The filling composition of any one of claims 68-91, wherein the cellulose derivative comprises hydroxypropyl methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, sodium croscarmellose, or a combination of any two or more thereof.

93. The filling composition of any one of claims 68-92, wherein the matrix material comprises: a hydroxypropyl methylcellulose having a molecular weight of about 10,000 Da to about 1,500,000 Da, or a plurality of hydroxypropyl methylcelluloses each having a different molecular weight ranging from about 10,000 Da to about 1,500,000 Da.

94. The filling composition of any one of claims 68-93, wherein the matrix material comprises: an ethyl cellulose having a molecular weight of about 10,000 Da to about 200,000 Da, or a plurality of ethyl celluloses each having a different molecular weight ranging from about 400 Da to about 2,000,000 Da.

95. The filling composition of any one of claims 68-94, wherein the matrix material comprises at least one hydroxypropyl methylcellulose and at least one ethyl cellulose, optionally wherein the weight ratio of the at least one hydroxypropyl methylcellulose to the at least one ethyl cellulose is about 1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:20 to about 20:1, about 1:15 to about 15:1, about 1:10 to about 10:1, about 1:5 to about 5:1, or about 1:

1.

96. The filling composition of claim 95, comprising one or more of: a hydroxypropyl methylcellulose having a molecular weight of about 10,000 Da to about 1,500,000 Da, or a plurality of hydroxypropyl methylcelluloses each having a different molecular weight ranging from about 10,000 Da to about 1,500,000 Da. (a) a hydroxypropyl methylcellulose that provides a viscosity of about 4 cp to about 6 cp when using a HAAKE RheoStress 6000 parallel plate at a shear stress of 10 Pa and an oscillation frequency of 1 Hz in a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose at 20 °C, (b) a hydroxypropyl methylcellulose that provides a viscosity of about 12 cp to about 18 cp when using a HAAKE RheoStress 6000 parallel plate at a shear stress of 10 Pa and an oscillation frequency of 1 Hz in a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose at 20 °C, or (c) a hydroxypropyl methylcellulose that provides a viscosity of about 80 cp to about 120 cp when using a HAAKE RheoStress 6000 parallel plate at a shear stress of 10 Pa and an oscillation frequency of 1 Hz in a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose at 20 °C, optionally wherein the weight ratio of (a):(b) is 1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:20 to about 20:1, about 1:15 to about 15:1, about 1:10 to about 10:1, about 1:5 to about 5:1, or about 1:1, and the weight ratio of (a):(c) is 1:100 to about 100:1, about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:20 to about 20:1, about 1:15 to about 15:1, about 1:10 to about 10:1, about 1:5 to about 5:1, or about 1:

1.

97. The filling composition of claim 95, comprising at least one of: about 5 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt%, based on the total weight of the filling composition, of the hydroxypropyl methylcellulose that provides a viscosity of about 4 cp to about 6 cp, about 5 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt%, based on the total weight of the filling composition, of the hydroxypropyl methylcellulose that provides a viscosity of about 12 cp to about 18 cp, or about 5 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt%, based on the total weight of the filling composition, of the hydroxypropyl methylcellulose that provides a viscosity of about 80 cp to about 120 cp.

98. The filling composition of any one of claims 95-97, comprising ethyl cellulose that provides a viscosity of about 9 cp to about 11 cp when measured using a HAAKE RheoStress 6000 parallel plate at a shear stress of 10 Pa and an oscillation frequency of 1 Hz at 20 °C.

99. The filling composition of any one of claims 68-98, wherein the solvent comprises an aqueous component, an oil, an alcohol, a low molecular weight polymer, an emulsifier, a surfactant, or a combination thereof.

100. The filling composition of claim 99, wherein the oil comprises soybean oil, mineral oil, olive oil, vegetable oil, sesame oil, sunflower seed oil, rapeseed oil, corn oil, oleic acid oil, coconut oil, almond oil, avocado oil, grape seed oil, or palm oil, or a combination of any two or more of the foregoing.

101. The filling composition of any one of claims 68-100, wherein the solvent comprises water, soybean oil, ethanol, low molecular weight polyethylene glycol, triethyl citrate, or a combination of any two or more thereof.

102. The filling composition of any one of claims 68-101, wherein the solvent comprises at least one of: soybean oil in an amount of about 20 wt% to about 90 wt%, about 30 wt% to about 80 wt%, about 40 wt% to about 70 wt%, or about 50 wt% to about 65 wt%, based on the total weight of the filling composition; water in an amount of about 0.1 wt% to about 30 wt%, about 0.5 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, based on the total weight of the filling composition, or ethanol in an amount of about 0 wt% to about 40 wt%, about 1 wt% to about 30 wt%, about 5 wt% to about 20 wt%, based on the total weight of the filling composition.

103. The filling composition of any one of claims 68-102, wherein the filling composition further comprises at least one pharmaceutically acceptable excipient.

104. The filling composition of claim 103, wherein the at least one pharmaceutically acceptable excipient comprises a plasticizer, a colorant, a lubricant, a thermal lubricant, an antioxidant, a buffering agent, a disintegrant, a granulating agent, a binder, a diluent, an anti-tacking agent, a sweetener, a chelating agent, a granulating agent, a filler, a suspending agent, a flavoring agent, a surfactant, a solubilizer, a stabilizer, an absorption enhancer, a preservative, an absorbent, a cross-linking agent, a pore former, an osmotic agent, a polycarboxylic acid, an emulsion stabilizer, a suspending agent, a thermal stabilizer, a viscosity enhancer, a drying agent, a solubility enhancer, and a combination of any two or more of the foregoing.

105. The filling composition of any one of claims 68-104, further comprising a thermal stabilizer comprising silicon dioxide, colloidal silicon dioxide, a cyclodextrin, microcrystalline cellulose, sodium carboxymethylcellulose, an alginate, pectin, or a combination of any two or more thereof.

106. The filling composition of any one of claims 68-105, further comprising a surfactant comprising cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, sorbitan fatty acid ester, sorbitan monooleate, polyoxyethylene sorbitan fatty acid ester, polysorbate 20, polysorbate 80, polyoxyethylene glycerol fatty acid ester, macrogol cetostearyl ether, macrogol cetostearyl ether phosphate, glyceryl monostearate, polyoxyethylene fatty acid ester, polyoxyethylene 40 stearate, polyoxyethylene fatty alcohol ether, polyoxyethylene oleyl ether, glycerol fatty acid ester, glyceryl monostearate, glyceryl dibehenate, or a combination of two or more thereof.

107. The filling composition of any one of claims 68-106, further comprising a plasticizer comprising triethyl citrate, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, stearic acid, one or more low molecular weight polymers, low molecular weight oligomers, low molecular weight copolymers, oils, small organic molecules, low molecular weight polyols having one or more aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, poly(propylene glycol), low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol, glycerol, ethylene glycol, 1,2-butanediol, 2,3-butanediol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, poly(ethylene glycol) compounds, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, allyl glycolate, or a combination of any two or more thereof.

108. The filling composition of any one of claims 68-107, further comprising a suspending agent comprising silicon dioxide, colloidal silicon dioxide, acacia, agar, alginic acid, aluminum monostearate, bentonite, camphor, carbomer, carrageenan, starch, corn starch, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium aluminum silicate, methyl cellulose, pectin, polyvinyl alcohol, povidone, sodium alginate, sodium hyaluronate, tragacanth, xanthan gum, or a combination of any two or more thereof.

109. The filling composition of any one of claims 68-108, wherein the matrix material comprises one or more esters of fatty acids and glycerol, one or more triglycerides, long chain fatty acids, or a combination thereof.

110. The filling composition of claim 113 or 109, wherein the one or more esters of fatty acids and glycerol comprises an ester of linolenic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, lauric acid, hexanoic acid, octanoic acid, decanoic acid, or a combination of two or more thereof, a monoglyceride, a diglyceride, a monoacylglycerol, a diacylglycerol, a stearyl polyoxylglycerol, a lauryl polyoxylglycerol, a stearyl polyoxyl-32 glycerol, a lauryl polyoxyl-32 glycerol, glyceryl monostearate, glyceryl monocaprylocaprate, glyceryl dioctanoate, glyceryl monooleate, or a combination of two or more thereof.

111. The filling composition of any one of claims 113-110, wherein the one or more triglycerides comprises a medium chain triglyceride, a tricaprylin, a tricaprin, a triglyceride of one or more of linolenic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, hexanoic acid, octanoic acid, decanoic acid, or lauric acid, and one or more medium chain fatty acids having about 6 to about 12 carbon atoms, a tricaprylin / tricaprin, a caprylocaprin, a caprylin / caprin triglyceride, or a combination of any two or more thereof.

112. The filling composition of any one of claims 68-111, wherein the wax comprises a paraffin wax, a beeswax, a jojoba oil, a lanolin, a whale wax, or a combination of any two or more thereof.

113. The filling composition of any one of claims 68-112, comprising at least one of: about 0.1 wt% to about 20 wt%, about 0.5 wt% to about 10 wt%, or about 1 wt% to about 5 wt% of one or more esters of fatty acids and glycerol; about 0.1 wt% to about 50 wt% or about 1 wt% to about 30 wt% of a surfactant; about 1 wt% to about 80 wt%, about 5 wt% to about 70 wt%, or about 10 wt% to about 60 wt% of a medium chain triglyceride; or about 0 wt% to about 20 wt% or about 0 wt% to about 10 wt% of a plasticizer.

114. The filling composition of claim 113, wherein the one or more esters of fatty acids and glycerol comprises a stearyl polyoxyl-32 glycerol, the surfactant comprises a glyceryl dibehenate, and the plasticizer comprises a stearic acid.

115. The filling composition of any one of claims 68-114, comprising at least one of: about 1 wt% to about 50 wt%, about 5 wt% to about 40 wt%, or about 10 wt% to about 30 wt% of the wax; about 0.1 wt% to about 20 wt%, about 0.5 wt% to about 10 wt%, or about 1.0 wt% to about 5 wt% of a hydroxypropyl methylcellulose; about 0.1 wt% to about 20 wt%, about 0.5 wt% to about 10 wt%, or about 1.0 wt% to about 5 wt% of one or more esters of fatty acids and glycerol; about 1 w% to about 80 wt%, about 5 wt% to about 70 wt%, or about 10 wt% to about 60 wt% medium chain triglycerides; or about 0 wt% to about 20 wt% or about 0 wt% to about 10 wt% plasticizer.

116. The fill composition of claim 115, wherein the wax comprises paraffin wax, the hydroxypropyl methylcellulose provides a viscosity of about 80 cp to about 120 cp when used at 10 Pa of shear stress and 1 Hz of oscillation frequency in a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose at 20 °C using a HAAKE RheoStress 6000 parallel plate of Thermo Fisher Scientific, the one or more esters of fatty acids and glycerol comprises lauroyl polyoxylglycerides, and the plasticizer comprises stearic acid.

117. The fill composition of any one of claims 68 to 116, wherein the fill composition comprises a solid, a semi-solid, a liquid, or a combination thereof.

118. The fill composition of claim 117, wherein the solid comprises one or more of granules, fine granules, a powder, beads, microspheres, extrudates, multiparticulates, microtablets, or a combination thereof.

119. The fill composition of claim 117 or 118, wherein the semi-solid comprises a gel, an aqueous gel, an organic solvent-based gel, granules, fine granules, a powder, beads, microspheres, extrudates, and / or multiparticulates dispersed in a semi-solid medium, or a combination thereof.

120. The fill composition of any one of claims 117 to 119, wherein the liquid comprises a slurry, a viscous liquid, or a combination thereof.

121. The fill composition of any one of claims 68 to 120, wherein the fill composition does not provide immediate release of an active agent.

122. A capsule dosage form, comprising: a capsule shell; and a fill composition within the softgel capsule, the fill composition comprising: a matrix material; and a solvent, wherein the fill composition is flowable at a temperature of at least about 40 °C and is a solid or semi-solid under ambient conditions.

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