A modified release-filling composition for a dosage form, and a method for preparing and using the same.

Abstract

Disclosed herein are embodiments of softgel dosage forms comprising softgel capsules and FDL compositions within softgel capsules. The FDL composition may include a matrix material and a solvent. The FDL composition is fluid at a temperature of at least about 40°C and solid or semi-solid under ambient conditions. Methods for preparing and using such softgel dosage forms and methods, as well as FDL compositions, are also disclosed.

Claims

1. It is a softgel dosage form, Soft gel capsules and The filling composition within the soft gel capsule comprises, Matrix material and, A solvent, and The filling composition is a soft gel formulation, wherein it is fluid at a temperature of at least about 40°C and solid or semi-solid under ambient conditions.

2. The softgel dosage form according to claim 1, wherein the softgel dosage form further comprises at least one activator.

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

4. A softgel dosage form according to any one of the prior claims, further comprising diphenhydramine, ibuprofen, or acetaminophen.

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

6. The soft gel dosage form according to any one of claims 2 to 5, wherein the at least one activator is hydrophilic or hydrophobic.

7. Diphenhydramine, ibuprofen, acetaminophen, antihistamines, decongestants, anti-inflammatory agents, stimulants, central nervous system stimulants, caffeine, amphetamine, methamphetamine, lisdexamfetamine dimesylate, almodafinil, atomoxetine, methylphenidate, modafinil, oxybate, pitrisant, verapamil, cefdinir, propafenone, hydroxyurea, hydrocodone, delavirdin, nelfinavir, sodium pentosan polysulfate, tokainide, quetiapine fumarate, fexofenadine, carafe Ethate, rifampin, moxifloxacin, praziquantel, ciprofloxacin, sodium phosphate / potassium, methenamine mandelaate, sotalol, cefprodil, cefadroxil, metformin, irbesartan, nefazodone, gatifloxacin, didanosine, modafinil, efavirenz, metataxalon, amantadine, morphine, mefenamic acid, dithiazem, sevelamer, albendazole, amoxicillin, potassium clavulanate, lithium carbonate, lamivudine, sumatriptan, nabumetone, zidovudine, cimetidine, clotramine Lupromazine, Valacyclovir, Bupropion, Ranitidine, Abacavir, Acyclovir, Potassium aminobenzoate, Pyridostigmine bromide, Isosorbide mononitrate, Nisin, Demeclocycline hydrochloride, Cefixime, Sodium naproxen, Naproxen, Tetracycline hydrochloride, Cefuroxime axetil, Propoxyfen napsylate, Pyrazinamide, Flecainide acetate, Simethicone, Mebendazole, Metadopa, Chloratiazide, Indinavir, Penicilla, Methylosine, Losartan, Thiabendazole Zol, norfloxacin, hydroxyurea, procainamide, entacapone, valsartan, terbinafine, metoprolol, ofloxacin, levofloxacin, chlorzoxazone, tolmetine, tramadol, bepridil, phenytoin, atorvastatin, celecoxib, fluconazole, doxepin, trovafloxacin mesylate, azithromycin, sertraline, rifabutin, cefpodoxime proxetil, mesalamine, disodium etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline,Nizatidine, creatine, quinidine, methocarbamol mycophenolate tomofetil, ganciclovir, saquinavir mesylate, tolcapone, ticlopidine, valganciclovir, capecitabine, orlistat, coleseveram, irbesartan, succimer, meperidine, hydroxychloroquine, guaifenesin, eprosartan, amiodarone, ferbamate, pseudoephedrine sulfate, carisoprodol, venlafaxine, propanolol hydrochloride, etodolac, acebutrol, chondroitin, pill Bate, opioid analgesics, alfentanil, allylprozine, alphaprozine, anilelysine, benzylmorphine, vegitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezosine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, eptazosine, etoheptadine, ethylmethylthiambutene, ethylmorphine, etonitazene, Thorphine, dihydroethorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levofenacylmorphan, lofentanyl, meperidine, meptazinol, metazosine, methadone, methopone, morphine, mirofin, narcein, nicomorphine, norlevorphinol, normethadone, nalolphine, nalbufen, normorphine, norpipanone, naltrexone, naloxone, opium, oxycodone, oxymorphone, papaveretam, Pentazocine, phenadoxone, phenomorphan, phenazosin, phenoperidine, piminodin, pyritramide, propeptadine, promedol, properidine, propoxyfen, sufentanil, tyridine, tramadol, their pharmaceutically acceptable salts, complexes (e.g., with cyclodextrin), stereoisomers, ethers, esters, hydrates, solvates, and mixtures, opioid antagonists, dextroorphan, dextromethorphan, 3-(1-naphthalenyl)-5-(phosphonomethyl)-L-phenylalanine,3-(1-naphthalenyl)-5-(phosphonomethyl)-DL-phenylalanine, 1-(3,5-dimethylphenyl)naphthalene, 2-(3,5-dimethylphenyl)naphthalene, 2SR,4RS-4-(((1H-tetrazole-5-yl)methyl)oxy)piperidine-2-carboxylic acid, 2SR,4RS-4-((((1H-tetrazole-5-yl)methyl)oxy)methyl)piperidine-2-carboxylic acid, E and Z 2SR-4-(O-(1H-tetrazole-5-yl)methyl)ketoximino)piperidine-2-carboxylic acid, 2SR,4RS-4-((1H-tetrazole-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-((1H-tetrazole-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-tetrazole-1-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-2H-tetrazole-2-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-tetrazole-1-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-tetrazole-1-yl)piperidine-2-carboxylic acid A softgel dosage form according to any one of the prior claims, further comprising a hydrophilic surfactant comprising any pharmaceutically acceptable salt, isomer, enantiomer, ester, prodrug, and / or derivative thereof, or any combination of two or more of the foregoing.

8. Water-soluble vitamins, Vitamin C (ascorbic acid), Vitamin B1 (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine), Vitamin B7 (biotin), Vitamin B9 (folate), Vitamin B12 (cobalamin), creatine, isoflavones, betaine, psyllium, pantothenic acid, zinc chloride, zinc gluconate, zinc sulfate, phytoestrogens, pycnogenol, proanthocyanidins, suntheanine, methylsulfonyl meta, L-glutamine, colostrum, biotin, amino acids, ce A softgel dosage form according to any one of the prior claims, further comprising a hydrophilic nutritional supplement comprising phosphorus, threonine, asparagine, L-carnitine, acetyl-L-carnitine, inositol, L-tyrosine, S-adenosylmethionine, bromelain, 2-dimethylaminoethanol, chromium picolinate, medicinal herbs, ginseng, guarana, taurine, protein hydrolysates, medicinal herbs, prebiotics, dietary fiber, or pharmaceutically acceptable salts, isomers, enantiomers, esters, prodrugs, and / or derivatives thereof, and any two or more combinations thereof.

9. Antihistamines, decongestants, anti-inflammatory agents, stimulants, central nervous system stimulants, loratadine, antiproliferative agents, paclitaxel, sirolimus, everolimus, biolimus A9, zotarolimus, tacrolimus, pimecrolimus, analgesics and anti-inflammatory agents, alloxiprine, auranofin, azapropazon, benolilate, diflunisal, etodolac, fenbufen, fenoprofencalcim, flurbiprofen, ibuprofen, indomethacin, ketop Lofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxyfenbutazone, phenylbutazone, piroxicam, sulindac, antiarrhythmic agents, amiodarone HCl, disopyramide, flecainide acetate, quinidine sulfate, antibacterial agents, benetamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacin, demeclocycline, doxycycline, erythromycin Icin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulfabenzamide, sulfadoxine, sulfamerazine, sulfacetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim, anticoagulants, dicumarol, dipyridamole, nicumaron, phenindione, antihypertensives, amlodipine, benidipine, dalodi Pine, diritazem HCl, diazoxide, felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine, terazosin HCl, antimuscarinic agents, atropine, benzhexol HCl, biperiden, etopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencilcymine HCl, tropicamide;Antitumor agents and immunosuppressants, such as aminoglutethimide, amsacrin, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate, testolactone, beta-blockers, acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, cardiac stimulants, amrinone, digitoxin, digoxin, enoximon, lanatoside C, medigoxin, corticosteroids, beclomethasone, beta A softgel dosage form according to any one of the prior claims, further comprising metasone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, lipid modifiers, bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol, antianginal agents, amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate, agents for the treatment of hypertension, and hydrophobic agents including guanethidine. In certain embodiments, hydrophobic agents include chemotherapeutic agents, fluorouracil, carmustine, or pharmaceutically acceptable salts, isomers, enantiomers, esters, prodrugs, and / or derivatives thereof, or any combination of two or more of the above.

10. A softgel dosage form according to any one of the prior claims, further comprising a hydrophobic nutritional supplement comprising a fat-soluble vitamin, vitamin A (retinol, retinyl ester), vitamin D (calciferol), vitamin E (α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol), vitamin K1 (phytonadione), vitamin K2 (menaquinone), omega-3 eicosapentaenoic acid, omega-3 docosahexaenoic acid, coenzyme Q10, lutein, zeaxanthin, amino acids, or pharmaceutically acceptable salts, isomers, enantiomers, esters, prodrugs, and / or derivatives thereof, or any two or more combinations thereof.

11. The soft gel dosage form according to any one of the prior claims, wherein the filling composition is fluid 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 soft gel dosage form according to any one of the prior claims, wherein the filling composition is 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 filling composition is a soft gel formulation according to any one of the prior claims, wherein the viscosity is determined at a temperature of 40°C using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate with a shear stress of 10 Pa and an vibration frequency of 1 Hz, and the viscosity at 40°C is 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.

14. The filling composition is a soft gel formulation according to any one of the prior claims, wherein the viscosity is determined at a temperature of 60°C using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate with a shear stress of 10 Pa and an vibration frequency of 1 Hz, and the viscosity at 60°C is 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.

15. The softgel dosage form according to any one of the prior claims, wherein the softgel dosage form provides controlled release of the activator.

16. The softgel dosage form according to any one of the prior claims, wherein the softgel dosage form releases an activator 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 instrument II (paddle) at about 75 RPM in about 500 ml to about 900 ml of water or buffer at about 37°C.

17. The softgel dosage form according to any one of the prior claims, wherein when the softgel dosage form is measured by in vitro dissolution in a USP instrument II (paddle) at approximately 75 RPM in approximately 500 ml to approximately 900 ml of water or buffer at approximately 37°C, it releases approximately 40% or less, 30% or less, 20% or less, or 10% or less of the activator within approximately one hour.

18. The softgel dosage form according to any one of the prior claims, wherein when the softgel dosage form is measured by in vitro dissolution in a USP instrument II (paddle) at approximately 75 RPM in approximately 500 ml to approximately 900 ml of water or buffer at approximately 37°C, it releases approximately 80% or more, 85% or more, 95% or more, or 100% or more of the activator within approximately 12 hours.

19. The softgel dosage form according to any one of the prior claims, wherein when the softgel dosage form is measured by in vitro dissolution in a USP instrument II (paddle) at approximately 75 RPM in approximately 500 ml to approximately 900 ml of water or buffer at approximately 37°C, it releases approximately 80% or more, 85% or more, 95% or more, or 100% or more of the activator within approximately 24 hours.

20. The softgel dosage form according to any one of the prior claims, wherein the filling composition provides controlled release of the activator.

21. The softgel dosage form according to any one of the prior claims, wherein the filling composition releases an activator 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, when measured by in vitro dissolution in a USP instrument II (paddle) at about 75 RPM in about 500 ml to about 900 ml of water or buffer at about 37°C.

22. The softgel dosage form according to any one of the prior claims, wherein the filling composition releases about 40% or less, 30% or less, 20% or less, or 10% or less of the activator within about 1 hour when measured by in vitro dissolution in a USP instrument II (paddle) at about 75 RPM in about 500 ml to about 900 ml of water or buffer at about 37°C.

23. The softgel dosage form according to any one of the prior claims, wherein the filling composition releases about 80% or more, 85% or more, 95% or more, or 100% or more of the activator within about 12 hours when measured by in vitro dissolution in a USP instrument II (paddle) at about 75 RPM in about 500 ml to about 900 ml of water or buffer at about 37°C.

24. The softgel dosage form according to any one of the prior claims, wherein the filling composition releases approximately 80% or more, 85% or more, 95% or more, or 100% or more of the activator within approximately 24 hours when measured by in vitro dissolution in a USP instrument II (paddle) at approximately 75 RPM in approximately 500 ml to approximately 900 ml of water or buffer at approximately 37°C.

25. The softgel capsule contains gelatin, carrageenan, starch, maltodextrin, or a combination thereof, or The softgel dosage form according to any one of the prior claims, wherein the softgel capsule does not contain gelatin.

26. The matrix material includes a polymer comprising polyethylene oxide, a cellulose derivative, natural gum, synthetic gum, or a combination thereof, and / or The softgel dosage form according to any one of the prior claims, wherein the matrix material comprises a wax containing paraffin wax, stearoyl polyoxyl-32 glyceride, carnauba wax, beeswax, stearic acid, cetyl alcohol, cetostearyl alcohol, glyceryl monostearate, or a combination thereof.

27. The aforementioned matrix material, Polyethylene oxide having a molecular weight of approximately 90,000 Da to approximately 7,000,000 Da, or A soft gel dosage form according to any one of the prior claims, comprising a plurality of polyethylene oxides, each having a different molecular weight in the range of approximately 90,000 Da to approximately 7,000,000 Da.

28. The soft gel dosage form according to claim 27, comprising about 5 wt% to about 50 wt%, or about 10 wt% to about 50 wt%, of the polyethylene oxide or a plurality of polyethylene oxides based on the total weight of the filling composition.

29. The softgel dosage form according to any one of the prior claims, wherein the softgel capsule contains gelatin, and the filling composition is fluid at a temperature of about 35°C to about 45°C, about 38°C to about 42°C, or about 40°C.

30. The soft gel dosage form according to any one of claims 27 to 29, wherein the filling composition is hydrophilic.

31. The soft gel dosage form according to any one of the prior claims, wherein the cellulose derivative comprises hydroxypropyl methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, or any two or more combinations thereof.

32. The aforementioned matrix material, Hydroxypropyl methylcellulose having a molecular weight of approximately 10,000 Da to approximately 1,500,000 Da, or A softgel dosage form according to any one of the prior claims, comprising 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 aforementioned matrix material, Ethyl cellulose having a molecular weight of approximately 10,000 Da to approximately 200,000 Da, or A softgel dosage form according to any one of the prior claims, comprising a plurality of ethylcelluloses, each having a different molecular weight in the range of approximately 400 Da to approximately 2,000,000 Da.

34. The softgel dosage form according to any one of the prior claims, wherein the matrix material comprises at least one hydroxypropyl methylcellulose and at least one ethylcellulose, and optionally 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. (a) A 2% (by weight) aqueous solution of hydroxypropyl methylcellulose provides a viscosity of about 4 cp to about 6 cp when a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate is subjected to a shear stress of 10 Pa and an vibration frequency of 1 Hz at 20°C, hydroxypropyl methylcellulose, (b) A 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose provides a viscosity of about 12 cp to about 18 cp when a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate is subjected to a shear stress of 10 Pa and an vibration frequency of 1 Hz at 20°C, or (c) A 2% (by weight) aqueous solution of hydroxypropyl methylcellulose comprises one or more hydroxypropyl methylcelluloses that provide a viscosity of about 80 cp to about 120 cp when a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate is subjected to a shear stress of 10 Pa and an vibration frequency of 1 Hz at 20°C, The softgel dosage form according to claim 34, wherein optionally, 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 hydroxypropyl methylcellulose provides a viscosity of about 4 cp to about 6 cp, based on the total weight of the filling composition, in amounts 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, the hydroxypropyl methylcellulose provides a viscosity of about 12 cp to about 18 cp in amounts of about 5 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt%, or The soft gel dosage form according to claim 34, comprising at least one of the hydroxypropyl methylcelluloses that provides a viscosity of about 80 cp to about 120 cp, in an amount 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.

37. A softgel formulation according to any one of claims 34 to 36, comprising ethyl cellulose that provides a viscosity of about 9 cp to about 11 cp when measured at 20°C with a shear stress of 10 Pa and an vibration frequency of 1 Hz using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate.

38. The soft gel dosage form according to any one of the prior 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 formulation according to claim 38, wherein the oil comprises soybean oil, mineral oil, olive oil, vegetable oil, sesame oil, sunflower oil, rapeseed oil, corn oil, oleic oil, coconut oil, almond oil, avocado oil, grape seed oil, or palm oil, or any two or more of the above combinations.

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

41. The aforementioned solvent Based on the total weight of the aforementioned filling composition, soybean oil in an amount of approximately 20 wt% to approximately 90 wt%, approximately 30 wt% to approximately 80 wt%, approximately 40 wt% to approximately 70 wt%, or approximately 50 wt% to approximately 65 wt%, Based on the total weight of the filling composition, an amount of water 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%, or A softgel dosage form according to any one of the prior claims, comprising at least one of ethanol in an amount of about 0 wt% to about 40 wt%, about 1 wt% to about 30 wt%, or about 5 wt% to about 20 wt%, based on the total weight of the filling composition.

42. The softgel dosage form according to any one of the prior claims, wherein the filling composition further comprises at least one pharmaceutically acceptable excipient.

43. The soft gel dosage form according to claim 42, wherein the at least one pharmaceutically acceptable excipient comprises a plasticizer, a colorant, a lubricant, a thermal lubricant, an antioxidant, a buffer, a disintegrant, a granulator, a binder, a diluent, an anti-adhesive, a sweetener, a chelating agent, a granulator, a bulking agent, a suspending agent, a flavoring agent, a surfactant, a solubilizer, a stabilizer, an absorption enhancer, a preservative, an absorbent, a crosslinking agent, a pore-forming agent, a penetrating agent, a polycarboxylic acid, an emulsifying stabilizer, a suspending agent, a thermal stabilizer, a viscosity increaser, a drying agent, a solubility enhancer, and any combination of two or more of the above.

44. A softgel dosage form according to any one of the prior claims, further comprising a heat stabilizer comprising silicon dioxide, colloidal silicon dioxide, wax, cyclodextrin, microcrystalline cellulose, sodium carboxymethylcellulose, arginate, pectin, or any two or more combinations thereof.

45. A soft gel dosage form according to any one of the prior claims, further comprising a surfactant comprising cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid ester, sorbitan monooleate, polyoxyethylene sorbitan fatty acid ester, polysorbate 20, polysorbate 80, polyoxyethylene fatty acid glyceride, polyethylene glycol hexadecyl ether, polyethylene glycol hexadecyl ether phosphate, glycerol monostearate, polyoxyethylene fatty acid ester, polyoxyl 40 stearate, polyoxyethylene fatty alcohol ether, polyoxyl oleyl ether, glycerol fatty acid ester, glycerol monostearate, glyceryl dibenate, or a combination of two or more thereof.

46. 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, low organic molecules, low molecular weight polyols having one or more aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol, glycerin, ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, di A softgel dosage form according to any one of the prior claims, further comprising a plasticizer comprising ethylene 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 two or more thereof.

47. A softgel dosage form according to any one of the prior claims, further comprising a suspension containing silicon dioxide, colloidal silicon dioxide, wax, acacia, agar, alginic acid, aluminum monostearate, bentonite, camphor, carbomer, carrageenan, starch, corn starch, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, magnesium aluminum silicate, methylcellulose, pectin, polyvinyl alcohol, povidone, sodium alginate, sodium hyaluronate, tragacanth, xanthan gum, or any two or more combinations thereof.

48. The softgel dosage form according to any one of the prior 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 according to claim 47 or 48, wherein one or more esters of the fatty acid and glycerol include esters of linolenic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, lauric acid, caproic acid, caprylic acid, capric acid, or two or more combinations thereof, monoglycerides, diglycerides, monoacylglycerols, diacylglycerols, stearoyl polyoxylglycerides, lauroyl polyoxylglycerides, stearoyl polyoxyl-32 glycerides, lauroyl polyoxyl-32 glycerides, glycerol monostearate, glycerol monocaprylate, glycerol dicaprylate, glycerol monooleate, or two or more combinations thereof.

50. The softgel dosage form according to any one of claims 47 to 49, wherein the one or more triglycerides comprises one or more triglycerol esters of medium-chain triglycerides, caprylic acid triglycerides, capric acid triglycerides, linolenic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, caproic acid, caprylic acid, capric acid, or lauric acid, and one or more medium-chain fatty acids having about 6 to about 12 carbon atoms, glyceryl tricaprylate / caprate, glycerol caprylate / caprate, caprylic acid / capric acid triglycerides, or any two or more combinations thereof.

51. The softgel formulation according to any one of claims 47 to 50, wherein the wax comprises paraffin wax, beeswax, jojoba, lanolin, gay wax, or any two or more combinations thereof.

52. Approximately 0.1 wt% to approximately 20 wt%, approximately 0.5 wt% to approximately 10 wt%, or approximately 1 wt% to approximately 5 wt%, one or more esters of fatty acids and glycerol. Approximately 0.1 wt% to approximately 50 wt%, or approximately 1 wt% to approximately 30 wt%, surfactants, Medium-chain triglycerides in amounts of approximately 1 wt% to approximately 80 wt%, approximately 5 wt% to approximately 70 wt%, or approximately 10 wt% to approximately 60 wt%, or A soft gel dosage form according to any one of the prior claims, comprising at least one of a plasticizer in an amount of approximately 0 wt% to approximately 20 wt%, or approximately 0 wt% to approximately 10 wt%.

53. The soft gel dosage form according to claim 52, wherein one or more esters of the fatty acid and glycerol comprises stearoyl polyoxyl-32 glyceride, the surfactant comprises glyceryl dibehenate, and the plasticizer comprises stearic acid.

54. The wax in an amount of approximately 1 wt% to approximately 50 wt%, approximately 5 wt% to approximately 40 wt%, or approximately 10 wt% to approximately 30 wt%, Approximately 0.1 wt% to approximately 20 wt%, approximately 0.5 wt% to approximately 10 wt%, or approximately 1.0 wt% to approximately 5 wt% of hydroxypropyl methylcellulose, One or more esters of fatty acids and glycerol in amounts of approximately 0.1 wt% to approximately 20 wt%, approximately 0.5 wt% to approximately 10 wt%, or approximately 1.0 wt% to approximately 5 wt%, Medium-chain triglycerides in amounts of approximately 1 wt% to approximately 80 wt%, approximately 5 wt% to approximately 70 wt%, or approximately 10 wt% to approximately 60 wt%, or A soft gel dosage form according to any one of the prior claims, comprising at least one of a plasticizer in an amount of approximately 0 wt% to approximately 20 wt%, or approximately 0 wt% to approximately 10 wt%.

55. The softgel formulation according to claim 54, wherein the wax comprises paraffin wax, the hydroxypropyl methylcellulose provides a viscosity of about 80 cp to about 120 cp when a 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose is subjected to a shear stress of 10 Pa and an vibration frequency of 1 Hz at 20°C using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate, the fatty acid and one or more esters of glycerol comprise lauroyl polyoxylglyceride, and the plasticizer comprises stearic acid.

56. The soft gel dosage form according to any one of the prior claims, wherein the filling composition comprises a solid, a semi-solid, a liquid, or a combination thereof.

57. The softgel dosage form according to claim 56, wherein the solid comprises one or more particles, granules, powders, beads, fine particles, extruded products, multiply particles, mini-tablets, or combinations thereof.

58. The soft gel dosage form according to claim 55 or 56, wherein the semi-solid comprises a gel, aqueous gel, organic solvent-based gel, particles, granules, powder, beads, fine particles, extruded material, and / or multiple particles dispersed in a semi-solid medium, or a combination thereof.

59. The soft gel dosage form according to any one of claims 55 to 58, wherein the liquid comprises a slurry, a viscous liquid, or a combination thereof.

60. The soft gel capsule includes a first capsule shell portion, a second capsule shell portion, and a seal that attaches the first capsule shell portion to the second capsule shell portion, or The softgel dosage form according to any one of the prior claims, wherein the softgel capsule is seamless.

61. The softgel dosage form according to any one of the prior claims, wherein the softgel dosage form does not provide immediate release of the activator.

62. The soft gel dosage form according to any one of the prior claims, wherein the soft gel dosage form is cured at approximately 40°C to approximately 75°C, or approximately 50°C to approximately 65°C, for approximately 15 minutes to approximately 4 days, or approximately 1 hour to approximately 24 hours.

63. A method for encapsulating a modified release-filled composition in a softgel capsule to form a softgel dosage form according to any one of the prior claims, The adjusted release-filling composition is heated 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 fluid liquid. A method comprising encapsulating the fluid liquid in the soft gel capsule.

64. The method according to claim 63, further comprising cooling the soft gel formulation to ambient temperature.

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

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

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

68. A filling composition for encapsulation within a softgel capsule, wherein the filling composition is Matrix material and, A solvent, and The filling composition is fluid at a temperature of at least about 40°C and solid or semi-solid under ambient conditions.

69. The filling composition according to claim 68, further comprising at least one activator.

70. The filling composition according to claim 69, wherein the at least one activator is contained in a) a subunit dispersed in the filling composition, b) a film on the surface of one or more subunits in the filling composition, c) the bulk medium of the filling composition, or d) a combination of a) to c).

71. The filling composition according to claim 68 or 69, further comprising diphenhydramine, ibuprofen, or acetaminophen.

72. The filling composition according to any one of claims 69 to 71, wherein the at least one activator comprises at least one pharmaceutical activator, at least one nutritional supplement, or a combination thereof.

73. The filling composition according to any one of claims 69 to 72, wherein the at least one activator is hydrophilic or hydrophobic.

74. Diphenhydramine, ibuprofen, acetaminophen, antihistamines, decongestants, anti-inflammatory agents, stimulants, central nervous system stimulants, caffeine, amphetamine, methamphetamine, lisdexamfetamine dimesylate, almodafinil, atomoxetine, methylphenidate, modafinil, oxybate, pitrisant, verapamil, cefdinir, propafenone, hydroxyurea, hydrocodone, delavirdin, nelfinavir, sodium pentosan polysulfate, tokainide, quetiapine fumarate, fexofenadine, carafe Ethate, rifampin, moxifloxacin, praziquantel, ciprofloxacin, sodium phosphate / potassium, methenamine mandelaate, sotalol, cefprodil, cefadroxil, metformin, irbesartan, nefazodone, gatifloxacin, didanosine, modafinil, efavirenz, metataxalon, amantadine, morphine, mefenamic acid, dithiazem, sevelamer, albendazole, amoxicillin, potassium clavulanate, lithium carbonate, lamivudine, sumatriptan, nabumetone, zidovudine, cimetidine, clotramine Lupromazine, Valacyclovir, Bupropion, Ranitidine, Abacavir, Acyclovir, Potassium aminobenzoate, Pyridostigmine bromide, Isosorbide mononitrate, Nisin, Demeclocycline hydrochloride, Cefixime, Sodium naproxen, Naproxen, Tetracycline hydrochloride, Cefuroxime axetil, Propoxyfen napsylate, Pyrazinamide, Flecainide acetate, Simethicone, Mebendazole, Metadopa, Chloratiazide, Indinavir, Penicilla, Methylosine, Losartan, Thiabendazole Zol, norfloxacin, hydroxyurea, procainamide, entacapone, valsartan, terbinafine, metoprolol, ofloxacin, levofloxacin, chlorzoxazone, tolmetine, tramadol, bepridil, phenytoin, atorvastatin, celecoxib, fluconazole, doxepin, trovafloxacin mesylate, azithromycin, sertraline, rifabutin, cefpodoxime proxetil, mesalamine, disodium etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline,Nizatidine, creatine, quinidine, methocarbamol mycophenolate tomofetil, ganciclovir, saquinavir mesylate, tolcapone, ticlopidine, valganciclovir, capecitabine, orlistat, coleseveram, irbesartan, succimer, meperidine, hydroxychloroquine, guaifenesin, eprosartan, amiodarone, ferbamate, pseudoephedrine sulfate, carisoprodol, venlafaxine, propanolol hydrochloride, etodolac, acebutrol, chondroitin, pill Bate, opioid analgesics, alfentanil, allylprozine, alphaprozine, anilelysine, benzylmorphine, vegitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezosine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, dioxafetyl butyrate, dipipanone, eptazosine, etoheptadine, ethylmethylthiambutene, ethylmorphine, etonitazene, Thorphine, dihydroethorphine, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levofenacylmorphan, lofentanyl, meperidine, meptazinol, metazosine, methadone, methopone, morphine, mirofin, narcein, nicomorphine, norlevorphinol, normethadone, nalolphine, nalbufen, normorphine, norpipanone, naltrexone, naloxone, opium, oxycodone, oxymorphone, papaveretam, Pentazocine, phenadoxone, phenomorphan, phenazosin, phenoperidine, piminodin, pyritramide, propeptadine, promedol, properidine, propoxyfen, sufentanil, tyridine, tramadol, their pharmaceutically acceptable salts, complexes (e.g., with cyclodextrin), stereoisomers, ethers, esters, hydrates, solvates, and mixtures, opioid antagonists, dextroorphan, dextromethorphan, 3-(1-naphthalenyl)-5-(phosphonomethyl)-L-phenylalanine,3-(1-naphthalenyl)-5-(phosphonomethyl)-DL-phenylalanine, 1-(3,5-dimethylphenyl)naphthalene, 2-(3,5-dimethylphenyl)naphthalene, 2SR,4RS-4-(((1H-tetrazole-5-yl)methyl)oxy)piperidine-2-carboxylic acid, 2SR,4RS-4-((((1H-tetrazole-5-yl)methyl)oxy)methyl)piperidine-2-carboxylic acid, E and Z 2SR-4-(O-(1H-tetrazole-5-yl)methyl)ketoximino)piperidine-2-carboxylic acid, 2SR,4RS-4-((1H-tetrazole-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-((1H-tetrazole-5-yl)thio)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-tetrazole-1-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-2H-tetrazole-2-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-tetrazole-1-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(5-mercapto-1H-tetrazole-1-yl)piperidine-2-carboxylic acid A filler composition according to any one of claims 68 to 73, further comprising a hydrophilic surfactant comprising: (pto-2H-tetrazole-2-yl)piperidine-2-carboxylic acid, 2SR,4RS-4-(((1H-tetrazole-5-yl)thio)methyl)piperidine-2-carboxylic acid, 2SR,4RS-4-((5-mercapto-1H-tetrazole-1-yl)methyl)piperidine-2-carboxylic acid, 2SR,4RS-4-((5-mercapto-2H-tetrazole-2-yl)methyl)piperidine-2-carboxylic acid, any pharmaceutically acceptable salts, isomers, enantiomers, esters, prodrugs, and / or derivatives thereof, or any combination of two or more of the foregoing.

75. Water-soluble vitamins, Vitamin C (ascorbic acid), Vitamin B1 (thiamine), Vitamin B2 (riboflavin), Vitamin B3 (niacin), Vitamin B5 (pantothenic acid), Vitamin B6 (pyridoxine), Vitamin B7 (biotin), Vitamin B9 (folate), Vitamin B12 (cobalamin), creatine, isoflavones, betaine, psyllium, pantothenic acid, zinc chloride, zinc gluconate, zinc sulfate, phytoestrogens, pycnogenol, proanthocyanidins, suntheanine, methylsulfonyl meta, L-glutamine, colostrum, biotin, amino acids, ce A filler composition according to any one of claims 68 to 74, further comprising a hydrophilic nutritional supplement comprising phosphorus, threonine, asparagine, L-carnitine, acetyl-L-carnitine, inositol, L-tyrosine, S-adenosylmethionine, bromelain, 2-dimethylaminoethanol, chromium picolinate, medicinal herbs, ginseng, guarana, taurine, protein hydrolysates, medicinal herbs, prebiotics, dietary fiber, or pharmaceutically acceptable salts, isomers, enantiomers, esters, prodrugs, and / or derivatives thereof, and any two or more combinations thereof.

76. Antihistamines, decongestants, anti-inflammatory agents, stimulants, central nervous system stimulants, loratadine, antiproliferative agents, paclitaxel, sirolimus, everolimus, biolimus A9, zotarolimus, tacrolimus, pimecrolimus, analgesics and anti-inflammatory agents, alloxiprine, auranofin, azapropazon, benolilate, diflunisal, etodolac, fenbufen, fenoprofencalcim, flurbiprofen, ibuprofen, indomethacin, ketop Lofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxyfenbutazone, phenylbutazone, piroxicam, sulindac, antiarrhythmic agents, amiodarone HCl, disopyramide, flecainide acetate, quinidine sulfate, antibacterial agents, benetamine penicillin, cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacin, demeclocycline, doxycycline, erythromycin Icin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulfabenzamide, sulfadoxine, sulfamerazine, sulfacetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim, anticoagulants, dicumarol, dipyridamole, nicumaron, phenindione, antihypertensives, amlodipine, benidipine, dalodi Pine, diritazem HCl, diazoxide, felodipine, guanabenz acetate, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine, terazosin HCl, antimuscarinic agents, atropine, benzhexol HCl, biperiden, etopropazine HCl, hyoscyamine, mepenzolate bromide, oxyphencilcymine HCl, tropicamide;Antitumor agents and immunosuppressants, such as aminoglutethimide, amsacrin, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate, testolactone, beta-blockers, acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, cardiac stimulants, amrinone, digitoxin, digoxin, enoximon, lanatoside C, medigoxin, corticosteroids, beclomethasone, betamethasone A filling composition according to any one of claims 68 to 75, further comprising: tazone, budesonide, cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, lipid modifiers, bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol, antianginal agents, amyl nitrate, glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate, agents for the treatment of hypertension, and hydrophobic surfactants including guanethidine. In certain embodiments, hydrophobic agents include chemotherapeutic agents, fluorouracil, carmustine, or pharmaceutically acceptable salts, isomers, enantiomers, esters, prodrugs, and / or derivatives thereof, or any combination of two or more of the above.

77. The filling composition according to any one of claims 68 to 76, further comprising a hydrophobic nutritional supplement comprising fat-soluble vitamins, vitamin A (retinol, retinyl ester), vitamin D (calciferol), vitamin E (α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol), vitamin K1 (phytonadione), vitamin K2 (menaquinone), omega-3 eicosapentaenoic acid, omega-3 docosahexaenoic acid, coenzyme Q10, lutein, zeaxanthin, amino acids, or pharmaceutically acceptable salts, isomers, enantiomers, esters, prodrugs, and / or derivatives thereof, or any two or more combinations thereof.

78. The filling composition according to any one of claims 68 to 77, wherein the filling composition is fluid 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 according to any one of claims 68 to 78, wherein the filling composition is 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 according to any one of claims 68 to 79, wherein the viscosity is determined at a temperature of 40°C using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate with a shear stress of 10 Pa and an vibration frequency of 1 Hz, and the viscosity at 40°C is 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.

81. The filling composition according to any one of claims 68 to 80, wherein the viscosity of the filling composition is determined at a temperature of 60°C using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate with a shear stress of 10 Pa and an vibration frequency of 1 Hz, and the viscosity at 60°C is 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.

82. The filling composition according to any one of claims 68 to 81, wherein the filling composition provides controlled release of an activator.

83. The filling composition according to any one of claims 68 to 82, wherein the filling composition releases an activator 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, when measured by in vitro dissolution in a USP apparatus II (paddle) at about 50 RPM in about 900 ml of 0.1 N HCl at about 37°C.

84. The filling composition according to any one of claims 68 to 83, wherein when the filling composition is measured by in vitro dissolution in a USP apparatus II (paddle) at about 50 RPM in about 900 ml of 0.1 N HCl at about 37°C, it releases about 40% or less, 30% or less, 20% or less, or 10% or less of the activator within about 1 hour.

85. The filling composition according to any one of claims 68 to 84, wherein when the filling composition is measured by in vitro dissolution in a USP apparatus II (paddle) at about 50 RPM in about 900 ml of 0.1 N HCl at about 37°C, it releases about 80% or more, 85% or more, 95% or more, or 100% or more of the activator within about 12 hours.

86. The filling composition according to any one of claims 68 to 85, wherein when the filling composition is measured by in vitro dissolution in a USP apparatus II (paddle) at about 50 RPM in about 900 ml of 0.1 N HCl at about 37°C, it releases about 80% or more, 85% or more, 95% or more, or 100% or more of the activator within about 24 hours.

87. The matrix material includes a polymer comprising polyethylene oxide, a cellulose derivative, natural gum, synthetic gum, or a combination thereof, and / or The filler composition according to any one of claims 68 to 86, wherein the matrix material comprises a wax containing paraffin wax, stearoyl polyoxyl-32 glyceride, carnauba wax, beeswax, stearic acid, cetyl alcohol, cetostearyl alcohol, glyceryl monostearate, or a combination thereof.

88. The aforementioned matrix material, Polyethylene oxide having a molecular weight of approximately 90,000 Da to approximately 7,000,000 Da, or A filler composition according to any one of claims 68 to 87, comprising a plurality of polyethylene oxides, each having a different molecular weight in the range of about 90,000 Da to about 7,000,000 Da.

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

90. The filling composition according to any one of claims 68 to 89, wherein the filling composition is fluid 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 according to any one of claims 68 to 90, wherein the filling composition is hydrophilic.

92. The filling composition according to any one of claims 68 to 91, wherein the cellulose derivative comprises hydroxypropyl methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, crosslinked sodium carboxymethylcellulose, or any two or more combinations thereof.

93. The aforementioned matrix material, Hydroxypropyl methylcellulose having a molecular weight of approximately 10,000 Da to approximately 1,500,000 Da, or A filler composition according to any one of claims 68 to 92, comprising 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.

94. The aforementioned matrix material, Ethyl cellulose having a molecular weight of approximately 10,000 Da to approximately 200,000 Da, or A filler composition according to any one of claims 68 to 93, comprising a plurality of ethylcelluloses, each having a different molecular weight in the range of about 400 Da to about 2,000,000 Da.

95. The filler composition according to any one of claims 68 to 94, wherein the matrix material comprises at least one hydroxypropyl methylcellulose and at least one ethylcellulose, and optionally 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.

96. (a) A 2% (by weight) aqueous solution of hydroxypropyl methylcellulose provides a viscosity of about 4 cp to about 6 cp when a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate is subjected to a shear stress of 10 Pa and an vibration frequency of 1 Hz at 20°C, hydroxypropyl methylcellulose, (b) A 2% (by weight) aqueous solution of the hydroxypropyl methylcellulose provides a viscosity of about 12 cp to about 18 cp when a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate is subjected to a shear stress of 10 Pa and an vibration frequency of 1 Hz at 20°C, or (c) A 2% (by weight) aqueous solution of hydroxypropyl methylcellulose comprises one or more hydroxypropyl methylcelluloses that provide a viscosity of about 80 cp to about 120 cp when a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate is subjected to a shear stress of 10 Pa and an vibration frequency of 1 Hz at 20°C, The filling composition according to claim 95, wherein optionally, 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 hydroxypropyl methylcellulose provides a viscosity of about 4 cp to about 6 cp, based on the total weight of the filling composition, in amounts 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, the hydroxypropyl methylcellulose provides a viscosity of about 12 cp to about 18 cp in amounts of about 5 wt% to about 50 wt%, about 10 wt% to about 40 wt%, or about 20 wt% to about 30 wt%, or The filling composition according to claim 95, comprising at least one of the hydroxypropyl methylcelluloses that provides a viscosity of about 80 cp to about 120 cp, in an amount 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.

98. A filler composition according to any one of claims 95 to 97, comprising ethyl cellulose that provides a viscosity of about 9 cp to about 11 cp when measured at 20°C with a shear stress of 10 Pa and an vibration frequency of 1 Hz using a Thermo Fischer Scientific HAAKE RheoStress 6000 parallel plate.

99. The filling composition according to any one of claims 68 to 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 according to claim 99, wherein the oil comprises soybean oil, mineral oil, olive oil, vegetable oil, sesame oil, sunflower oil, rapeseed oil, corn oil, oleic oil, coconut oil, almond oil, avocado oil, grape seed oil, or palm oil, or any two or more of the above combinations.

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

102. The aforementioned solvent Based on the total weight of the aforementioned filling composition, soybean oil in an amount of approximately 20 wt% to approximately 90 wt%, approximately 30 wt% to approximately 80 wt%, approximately 40 wt% to approximately 70 wt%, or approximately 50 wt% to approximately 65 wt%, Based on the total weight of the filling composition, an amount of water 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%, or The filling composition according to any one of claims 68 to 101, comprising at least one of ethanol in amounts of about 0 wt% to about 40 wt%, about 1 wt% to about 30 wt%, and about 5 wt% to about 20 wt%, based on the total weight of the filling composition.

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

104. The filler composition according to claim 103, wherein the at least one pharmaceutically acceptable excipient comprises a plasticizer, a colorant, a lubricant, a thermal lubricant, an antioxidant, a buffer, a disintegrant, a granulator, a binder, a diluent, an anti-adhesive, a sweetener, a chelating agent, a granulator, a bulking agent, a suspending agent, a flavoring agent, a surfactant, a solubilizer, a stabilizer, an absorption enhancer, a preservative, an absorbent, a crosslinking agent, a pore-forming agent, a penetrating agent, a polycarboxylic acid, an emulsifying stabilizer, a suspending agent, a thermal stabilizer, a viscosity increaser, a drying agent, a solubility enhancer, and any combination of two or more of the above.

105. A filling composition according to any one of claims 68 to 104, further comprising a heat stabilizer comprising silicon dioxide, colloidal silicon dioxide, cyclodextrin, microcrystalline cellulose, sodium carboxymethylcellulose, arginate, pectin, or any two or more combinations thereof.

106. A filler composition according to any one of claims 68 to 105, further comprising a surfactant comprising cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid ester, sorbitan monooleate, polyoxyethylene sorbitan fatty acid ester, polysorbate 20, polysorbate 80, polyoxyethylene fatty acid glyceride, polyethylene glycol hexadecyl ether, polyethylene glycol hexadecyl ether phosphate, glycerol monostearate, polyoxyethylene fatty acid ester, polyoxyl 40 stearate, polyoxyethylene fatty alcohol ether, polyoxyl oleyl ether, glycerol fatty acid ester, glycerol monostearate, glyceryl dibenate, or a combination of two or more thereof.

107. 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, low organic molecules, low molecular weight polyols having one or more aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), low molecular weight poly(ethylene glycol), citrate ester-type plasticizers, triacetin, propylene glycol, glycerin, ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, die A filler composition according to any one of claims 68 to 106, further comprising a plasticizer comprising ethylene 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 two or more thereof.

108. A filling composition according to any one of claims 68 to 107, further comprising a suspension containing silicon dioxide, colloidal silicon dioxide, acacia, agar, alginic acid, aluminum monostearate, bentonite, camphor, carbomer, carrageenan, starch, corn starch, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, magnesium aluminum silicate, methylcellulose, pectin, polyvinyl alcohol, povidone, sodium alginate, sodium hyaluronate, tragacanth, xanthan gum, or any combination of two or more thereof.

109. The filler composition according to any one of claims 68 to 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 according to claim 113 or 109, wherein one or more esters of the fatty acid and glycerol include esters of linolenic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, lauric acid, caproic acid, caprylic acid, capric acid, or two or more combinations thereof, monoglycerides, diglycerides, monoacylglycerols, diacylglycerols, stearoyl polyoxylglycerides, lauroyl polyoxylglycerides, stearoyl polyoxyl-32 glycerides, lauroyl polyoxyl-32 glycerides, glycerol monostearate, glyceryl monocaprylate, glycerol dicaprylate, glycerol monooleate, or two or more combinations thereof.

111. The filling composition according to any one of claims 113 to 110, wherein the one or more triglycerides comprises one or more triglycerol esters of medium-chain triglycerides, caprylic acid triglycerides, capric acid triglycerides, linolenic acid, oleic acid, palmitic acid, linoleic acid, stearic acid, caproic acid, caprylic acid, capric acid, or lauric acid, and one or more medium-chain fatty acids having about 6 to about 12 carbon atoms, glyceryl tricaprylate / caprate, glycerol caprylate / caprate, caprylic acid / capric acid triglycerides, or any two or more combinations thereof.

112. The filler composition according to any one of claims 68 to 111, wherein the wax comprises paraffin wax, beeswax, jojoba, lanolin, gay wax, or any two or more combinations thereof.

113. Approximately 0.1 wt% to approximately 20 wt%, approximately 0.5 wt% to approximately 10 wt%, or approximately 1 wt% to approximately 5 wt%, one or more esters of fatty acids and glycerol. Approximately 0.1 wt% to approximately 50 wt%, or approximately 1 wt% to approximately 30 wt%, surfactants, Medium-chain triglycerides in amounts of approximately 1 wt% to approximately 80 wt%, approximately 5 wt% to approximately 70 wt%, or approximately 10 wt% to approximately 60 wt%, or A filler composition according to any one of claims 68 to 112, comprising at least one of a plasticizer in an amount of about 0 wt% to about 20 wt%, or about 0 wt% to about 10 wt%.

114. The filling composition according to claim 113, wherein one or more esters of the fatty acid and glycerol include stearoyl polyoxyl-32 glyceride, the surfactant includes glyceryl dibehenate, and the plasticizer includes stearic acid.

115. The wax in an amount of approximately 1 wt% to approximately 50 wt%, approximately 5 wt% to approximately 40 wt%, or approximately 10 wt% to approximately 30 wt%, Approximately 0.1 wt% to approximately 20 wt%, approximately 0.5 wt% to approximately 10 wt%, or approximately 1.0 wt% to approximately 5 wt% of hydroxypropyl methylcellulose, One or more esters of fatty acids and glycerol in amounts of approximately 0.1 wt% to approximately 20 wt%, approximately 0.5 wt% to approximately 10 wt%, or approximately 1.0 wt% to approximately 5 wt%, Medium-chain triglycerides in amounts of approximately 1 wt% to approximately 80 wt%, approximately 5 wt% to approximately 70 wt%, or approximately 10 wt% to approximately 60 wt%, or A filler composition according to any one of claims 68 to 114, comprising at least one of a plasticizer in an amount of about 0 wt% to about 20 wt%, or about 0 wt% to about 10 wt%.

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

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

118. The filling composition according to claim 117, wherein the solid comprises one or more particles, granules, powders, beads, fine particles, extruded products, multiply particles, mini tablets, or combinations thereof.

119. The filling composition according to claim 117 or 118, wherein the semi-solid comprises a gel, aqueous gel, organic solvent-based gel, particles, granules, powder, beads, fine particles, extruded material, and / or multiple particles dispersed in a semi-solid medium, or a combination thereof.

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

121. The filling composition according to any one of claims 68 to 120, wherein the filling composition does not provide immediate release of the activator.

122. In capsule form, Capsule shell and A filling composition for a softgel capsule, wherein the filling composition is Matrix material and, A solvent, and The filling composition is in capsule form, wherein it is fluid at a temperature of at least about 40°C and solid or semi-solid under ambient conditions.

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