Naproxen formuation

Abstract

Here described is a pharmaceutical composition comprising a fill material comprising: a salt of one or more pharmaceutically active agents; and a lipid-based water-soluble surfactant. The fill material may further comprise a lipid-based oil and wetting agent. The lipid-based oil may be medium-chain triglycerides and the wetting agent may be lecithin.

Description

NAPROXEN FORMUATIONTechnical Field

[0001] The present application relates to a formulation of naproxen in soft gelatin capsules.Background

[0002] Naproxen sodium, a nonsteroidal anti-inflammatory drug with unique analgesic properties, is particularly effective in treating the symptoms of acute and chronic rheumatoid arthritis, osteoarthritis, primary dysmenorrhea, and mild to moderate discomfort. Its rapid absorption and utilization of analgesia set it apart from other medications.

[0003]

[0002] Naproxen sodium's chemical name is (-)-6-methoxy-alpha-methyl-2- napthaleneacetic acid sodium salt, and its chemical formula is C14H13NaO3. At neutral pH, naproxen sodium is a white to creamy white crystalline solid freely soluble in water.

[0004] Naproxen anion suppresses the synthesis of prostaglandins, fatty acid- derived molecules implicated in the sense of pain and the generation of fever and inflammation, but the route of action is unknown. Naproxen and naproxen sodium are accessible as both prescription and over-the-counter medications. Anaprox, Anaprox OS, Apo-NaproNa, Novo-Naprox Sodium, Synflex, and Synflex OS are significant brand medications in the prescription market. In the prescription division, naproxen sodium is intended for mild to moderate pain, whereas in the OTO sector, it is indicated for minor aches and pains and fever reduction, and it may also be used to treat osteoarthritis, rheumatoid arthritis, juvenile arthritis, gout, and primary dysmenorrhea.

[0005] Hydrophilic or polar solvents, such as sorbitol, glycerol, propylene glycol, polyethylene glycol, and ethanol, are commonly used to develop clear soft gelatin capsules. Among them, polyethylene glycol (PEG) stands out as a suitable choice due to its molecular weight versatility, ranging from 200 to 4000 Daltons, and its hydrophilic nature. Naproxen is freely soluble in PEGs, with a molecular weight of400 or 600 Daltons. At acidic pH, naproxen sodium, naproxen, or comparable active moieties, such as ibuprofen, acetylsalicylic acid, or diclofenac, are free acids, and their ionizable derivatives tend to form esters with primary and secondary alcohols, including polyethylene glycol. Naproxen ester with polyethylene glycol has been demonstrated as the main degradant of current formulations of Naproxen 220 mg and 275 mg soft gelatin capsules manufactured by Patheon with about 0.4-0.5wt% after 3-months of stability at 40°C / 75% RH.

[0006] To avoid the formation of different ester impurities, there is an unmet need for a solvent system containing a medicament that minimizes the formation of PEG esters, i.e., a new naproxen formulation without excipients or solvent systems containing primary or secondary alcohols. These factors were taken into consideration during the development of the naproxen formulation described herein.

[0007] It is understood that the aspects described below are not limited to implementations which solve any or all of the disadvantages of the known approaches described above.

[0008] This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to determine the scope of the claimed subject matter; variants and alternative features which facilitate the working of the invention and / or serve to achieve a substantially similar technical effect should be considered as falling into the scope of the invention disclosed herein.

[0009] The development of new pharmaceutical compositions, which minimize the formation of PEG esters and do not contain primary or secondary alcohol groups susceptible to react in the formation of ester, is a significant advancement. These factors were carefully considered to ensure the formulation's effectiveness and safety.

[0010] These new pharmaceutical compositions, which can be administered insemisolid form or can be used for preparing capsules, are described herein. In one aspect, the pharmaceutical composition may be a soft gel capsule encapsulating a semisolid fill material.

[0011] Another aspect is a pharmaceutical composition comprising a fill material comprising: a salt of one or more pharmaceutically active agents; and a lipid-based water-soluble surfactant. The fill material may further comprise a lipid and wetting agent. The lipid may be medium-chain triglycerides and the wetting agent may be lecithin.

[0012] Another aspect is a pharmaceutical composition comprising a fill material comprising: a salt of one or more pharmaceutically active agents; and a lipid-based water-soluble surfactant. The fill material may further comprise a propylene glycol monocaprylate.

[0013] Another aspect is a method for making a pharmaceutical composition, the method comprising: (a) mixing together (i) about 40% by weight of a salt of one or more pharmaceutically active agents, (ii) about 12% to about 22% of a lipid-based water-soluble surfactant by weight, (iii) about 1% to about 25% by weight of wetting agent, and (iv) less than about 40% by weight of a lipid; and (b) encapsulating the mixture in a softgel capsule using rotary die encapsulation.

[0014] Another aspect is a method for making a pharmaceutical composition, the method comprising: (a) mixing together (i) about 40% by weight of a salt of one or more pharmaceutically active agents, (ii) about 30% to about 45% of a lipid-based water-soluble surfactant by weight, and (iii) about 15% to about 30% by weight of propylene glycol monocaprylate; and (b) encapsulating the mixture in a softgel capsule using rotary die encapsulation.

[0015] Another aspect is an oral dosage form of the pharmaceutical composition produced by the method described herein. The pharmaceutical composition may be administered to treat pain, inflammation, or fever according to one or more aspects described herein.

[0016] The aspects described herein may be combined as appropriate, as would beapparent to a skilled person, and may be combined with any of the other aspects of the present invention.Detailed Description

[0017] Aspects of the present invention are described below by way of example only. These examples represent the suitable modes of putting the invention into practice that are currently known to the Applicant although they are not the only ways in which this could be achieved.

[0018] Pharmaceutically active agents (APIs) may be available in various oral forms, including tablets and gelatin capsules. The latter typically consists of a hydrophilic fill, a mixture of excipients such as polyethylene glycol, ionizing agents, solubilizing agents (alcohols), neutralizing agents, and stabilizing polymers. The capsule shell comprises gelatin and plasticizers like glycerol, sorbitol, and water. The hydrophilic fill is encapsulated into soft gelatin capsules to create a pharmaceutical oral product.

[0019] Despite their widespread use, soft gelatin capsules can introduce water into the fill formulation, given its hydrophilic nature. For active ingredients prone to hydrolysis, (trans-)esterification, or (trans-)amidation, this can lead to unstable formulations. For APIs such as naproxen or naproxen sodium, for example, the presence of water, polyethylene glycol, and solubilizing agents can cause the formation of undesirable naproxen-ester side products.

[0020] The present application addresses this by combining solid and liquid lipid- based excipients to produce a semisolid fill formulation, preventing the formation of ester side products. This formulation comprises a mixture of liquid and solid lipid- based excipients, which creates a semisolid, chemically and physically stable fill when combined with the API.

[0021] The use of lipid excipients, especially the combination of oils and surfactants, such as medium-chain triglycerides oil, propylene glycol monocaprylate, lecithin, and lauroyl macrogol-32 glycerides, may enhance the adsorption rate of naproxen sodium. This is because when the capsule is opened in the stomach, formulation components can emulsify and form various types of micellar structures, which canaid in keeping naproxen sodium in a dissolved state, therefore facilitation its absorption rate. A faster absorption rate or quicker onset of action can provide benefits or should be taken into consideration when treating acute pain.

[0022] The present formulation as described herein is more stable than any existing soft gelatin product. In particular, the degradants do not increase significantly after 12 months of stability at 25 degrees 160% Relative Humidity, RH (ICH climatic zone II) and after 9 months at 30 degrees 165% RH (ICH climatic zone IV). ICH climatic zone refers to a climate zone associated with International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The present formulation is stable at 25°C and 60% relative humidity (Zone I), 30°C and 65% relative humidity (Zone II), 30°C and 75% relative humidity (Zone III), and 30°C and 70% relative humidity (Zone I a) or 30°C and 75% relative humidity (Zone IVb) for at least 9 months. Moreover, the overall size of the soft gelatin capsule size is reduced by the formation, with about 30% reduction in comparability.

[0023] In one aspect, fill material of the formulation may comprise about 40% by weight of naproxen sodium; about 10% to 22% of polyoxylglycerides (or lauroyl polyoxyl-32 glycerides). Polyoxylglycerides (or lauroyl polyoxyl-32 glycerides) may also be about 12% to 18%, 12% to 20%, 12% to 22%, 14% to 18%, 14% to 20%, 14% to 22%, 16% to 18%, 16% to 20%, 16% to 22%, 18% to 20%, or 18% to 22%; about 1% to about 15%, to about 20%, or to about 25% by weight of lecithin (soybean); and less than about 40% by weight of medium-chain triglycerides.

[0024] Lauroyl polyoxyl-32 glycerides are subjected to controlled preheating and mixing. Lauroyl polyoxyl-32 glycerides are combined with medium-chain triglycerides , lecithin, and naproxen sodium. This mixture undergoes a heating and mixing process to ensure all components are well-integrated and uniformly dispersed. The next step is deaeration and low-speed mixing, which removes any trapped air bubbles and ensures the mixture of the fill material maintains a smooth consistency.

[0025] In another aspect, fill material may comprise about 40% by weight of naproxen sodium; about 30% to about 45% of polyoxylglycerides; about 15% to about 30% by weight of propylene glycol monocaprylate.

[0026] In another aspect, a softgel capsule (gel mass) may comprise gelatin, glycerol, water, and colorant. The capsule may comprise sorbitol and / or pacifier.

[0027] Gelatin, glycerol, sorbitol (liquid), and purified water are combined and subjected to mixing and heating, which ensures that the gelatin dissolves completely and interacts with the other components properly to form a uniform gel mass. This mixture is then deaerated to remove any air bubbles that may have been introduced during the mixing process, which is crucial to maintain the integrity and consistency of the gel. Following deaeration, the gel mass undergoes a transfer process, ensuring it is properly prepared for the next production stage.

[0028] The fill material would be encapsulated in the softgel capsule to form the pharmaceutical composition. This is done using rotary die encapsulation.

[0029] In another aspect is a pharmaceutical composition comprising a fill material comprising: a salt of one or more pharmaceutically active agents; and a lipid-based water-soluble surfactant. The fill material may further comprise a lipid and wetting agent. The lipid may be medium-chain triglycerides and the wetting agent may be lecithin.

[0030] In another aspect is a pharmaceutical composition comprising a fill material comprising: a salt of one or more pharmaceutically active agents; and a lipid-based water-soluble surfactant. The fill material may further comprise a propylene glycol monocaprylate.

[0031] In another aspect is a method for making a pharmaceutical composition, the method comprising: (a) mixing together (i) about 40% by weight of a salt of one or more pharmaceutically active agents, (ii) about 12% to about 22% of a lipid-based water-soluble surfactant by weight, (iii) about 1% to about 25% by weight of wetting agent, and (iv) less than about 40% by weight of a lipid; and (b) encapsulating the mixture in a softgel capsule using rotary die encapsulation.

[0032] In another aspect is a method for making a pharmaceutical composition, the method comprising: (a) mixing together (i) about 40% by weight of a salt of one or more pharmaceutically active agents, (ii) about 30% to about 45% of a lipid-basedwater-soluble surfactant by weight, and (iii) about 15% to about 30% by weight of propylene glycol monocaprylate; and (b) encapsulating the mixture in a softgel capsule using rotary die encapsulation.

[0033] In another aspect is an oral dosage form of the pharmaceutical composition produced by the method described herein. The pharmaceutical composition may be administered to treat pain, inflammation, or fever according to one or more aspects described herein.

[0034] With respect to aspects described herein, in an option, where the fill material further comprises a lipid-based oil. Another option is where the lipid-based oil comprises medium-chain triglycerides. Another option is where the medium-chain triglycerides are present in amount of about less than 40% by weight. Another option is where the lipid-based water-soluble surfactant comprises polyoxylglycerides. Another option is where the polyoxylglycerides are Lauroyl polyoxyl-32 glycerides that are present in amount from about 12% to about 22% by weight. Another option is where the fill material further comprises a wetting agent. Another option is where the wetting agent comprises a lecithin. Another option is where the lecithin is present in amount from about 1% to 25% by weight. Another option is where the lecithin is present in amount of about 10% by weight. Another option is where the fill material further comprises a propylene glycol monocaprylate. Another option is where the propylene glycol monocaprylate is present in amount from about 15% to about 30% by weight. Another option is where the propylene glycol monocaprylate is present in amount of 24% by weight. Another option is where the lipid-based water-soluble surfactant comprises polyoxylglycerides present in amount from about 30% to about 45% by weight. Another option is where wherein the pharmaceutically active agent is a salt of the pharmaceutically active agent. Another option is where the salt is naproxen sodium. Another option is where the naproxen salt is about 40% by weight. In another option, further comprising a gel comprises gelatin, glycerol, water, and colorant. Another option is where the gel further comprises sorbitol. Another option is where the gel further comprises opacifier.

[0035] Another option is where the naproxen salt is naproxen sodium. Another option is where the naproxen sodium is about 40% by weight. Another option is where thelipid-based water-soluble surfactant comprises Lauroyl polyoxyl-32 glycerides that are present in amount from about 12% to about 22% by weight. Preferably about 16% to 18%. Another option is where the Lauroyl polyoxyl-32 glycerides are present in amount of 17.85% by weight. Another option is where the lipid comprises mediumchain triglycerides. Another option is where the medium-chain triglycerides are present in amount from about 27% to 41% by weight. Another option is where the medium-chain triglycerides are present in amount from about 27% or 40% by weight. Another option is where the wetting agent comprises a lecithin. Another option is where the lecithin is present in amount from about 1% to 25% by weight. Preferably about 1% to 20%. More preferably about 1% to 15%. Another option is where the lecithin is present in amount from about 10% by weight.

[0036] Another option is where the naproxen salt is naproxen sodium. Another option is where the naproxen sodium is about 40% by weight. Another option is where the lipid-based water-soluble surfactant comprises lauroyl polyoxyl-32 glycerides that are present in amount from about 15% to about 30% by weight. Another option is where the Lauroyl polyoxyl-32 glycerides are present in amount of 36% by weight. Another option is where the propylene glycol monocaprylate is present in amount 24% by weight.

[0037] Another option is where the lipid-based water-soluble surfactant is Lauroyl polyoxyl-32 glycerides in amount of 17.85% by weight. Another option is where the wetting agent is lecithin is in amount of 10% by weight. Another option is where the lipid-based oil is in amount of 32.15% by weight.

[0038] Another option is where the lipid-based water-soluble surfactant is Lauroyl polyoxyl-32 glycerides in amount of 36% by weight. Another option is where the propylene glycol monocaprylate is in amount of 24% by weight.

[0039] Another option is where the composition described herein remains stable after 9-months at 30°C and 65% relative humanity with individual degradation products content equal to about 0.15% or less than about 0.15% by weight. As another option is where individual degradation products content of about 0.15% in one or more ICH climatic zones. Another option is where gel stability is based ontemperature and relative humidity corresponding to that of ICH climatic zones l-IVb, optionally for a period no less than 9 months. Another option is where the capsule comprises individual degradation products content equal to about 0.15% or less than about 0.15% by weight.

[0040] It is understood that herein described options may be combined with respect to one or more aspects of the formulation as appropriate, as would be apparent to a skilled person, and may be combined with any of the other options in the same or similar appropriate manner.

[0041] The preparation process for the formulation aspects and / or options described herein may involve several steps. For example, in the first step, the solid excipient, lauroyl polyoxyl-32 glycerides, is preheated. Next, liquid excipients, including medium-chain triglycerides oil and lecithin, are added to a medicine tank set to 50±5 degrees Celsius. The melted solid excipient is then added to the preheated medicine tank, followed by the homogenization of the excipients. API is mixed into the medicine / gel reactor until homogeneous. This is followed by encapsulation of the fill at 30±5 degrees Celsius using standard equipment. The capsules are then dried until they attain adequate hardness. In the final step, post-production activities are carried out. The resulting product, soft gelatin capsules, is suitable for oral use. The following are exemplary pharmaceutical compositions in relation to one or more aspects described herein.

[0042] It is understood that ranges of % by weight of the excipient(s) herein described would include each integer and fraction within the specified % range. For example, polyoxylglycerides may comprise about 16 to 22% by weight, 16%, 17%, 18%, or about 16-17%, 16-18%, 16-18%, 16-19%, 16-20%, 16-21%, 16-22%, 17- 18%, 17-19%, 16-20%, 17-21%, 17-22%, 18-19%, 18-20%, 18-21%, 18-22%, 19-20%, 19-21%, 19-22%, 20-21%, 20-22%, and 21-22%. In some cases, % by weight may be equivalent to the total mass of a fill or shell, including each integer and fraction within these specified values and ranges.I. CompositionA. Fill Materials1. Drugs to be Formulated

[0043] The formulation can contain one or more APIs, such as therapeutic, diagnostic, prophylactic or nutraceutical agent. Exemplary agents include, but are not limited to, analeptic agents; analgesic agents; anesthetic agents; antiasthmatic agents; antiarthritic agents; anticancer agents; anticholinergic agents; anticonvulsant agents; antidepressant agents; antidiabetic agents; antidiarrheal agents; antiemetic agents; antihelminthic agents; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents; anti-inflammatory agents; antimigraine agents; antineoplastic agents; antiparkinson drugs; antipruritic agents; antipsychotic agents; antipyretic agents; antispasmodic agents; antitubercular agents; antiulcer agents; antiviral agents; anxiolytic agents; appetite suppressants (anorexic agents); attention deficit disorder and attention deficit hyperactivity disorder drugs; cardiovascular agents including calcium channel blockers, antianginal agents, central nervous system ("CNS") agents, beta-blockers and antiarrhythmic agents; central nervous system stimulants; diuretics; genetic materials; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; muscle relaxants; narcotic antagonists; nicotine; nutritional agents; parasympatholytics; peptide drugs; psychostimulants; sedatives; sialagogues, steroids; smoking cessation agents; sympathomimetics; tranquilizers; vasodilators; beta-agonist; and tocolytic agents.

[0044] A first class of drugs is selected based on inclusion in the molecule of a weakly acidic, basic or amphoteric group that can form a salt. Any drug that bears an acidic or a basic functional group, for example, an amine, imine, imidazoyl, guanidine, piperidinyl, pyridinyl, quaternary ammonium, or other basic group, or a carboxylic, phosphoric, phenolic, sulfuric, sulfonic or other acidic group, can react with the de-ionizing agent.

[0045] Some specific drugs that bear acidic or basic functional groups and thus may be converted to the corresponding salt for use in the described formulations include, but are not limited to, Acetaminophen, Acetylsalicylic acid, Alendronic acid, Alosetron, Amantadine, Amlopidine, Anagrelide, Argatroban, Atomoxetine, Atrovastatin, Azithromycin dehydrate, Balsalazide, Bromocriptan, Bupropion, Candesartan, Carboplatin, Ceftriaxone, Clavulonic acid, Clindamycin, Cimetadine,Dehydrocholic (acid), Dexmethylphenidate, Diclofenac, Dicyclomine, Diflunisal, Diltiazem, Donepezil, Doxorubicin, Doxepin, Epirubicin, Etodolic acid, Ethacrynic acid, Fenoprofen, Fluoxetine, Flurbiprofen, Furosemide, Gemfibrozil, Hydroxyzine, Ibuprofen, Imipramine, Indomethacin, Ketoprofen, Levothyroxine, Maprolitline, Meclizine, Methadone, Methylphenidate, Minocycline, Mitoxantone, Moxifloxacin, Mycophenolic acid, Naproxen, Niflumic acid, Ofloxacin, Ondansetron, Pantoprazole, Paroxetine, Pergolide, Pramipexole, Phenytoin, Pravastain, Probenecid, Rabeprazole, Risedronic acid, Retinoic acid, Ropinirole, Selegiline, Sulindac, Tamsulosin, Telmisertan, Terbinafine, Theophyline, Tiludronic Acid, Tinzaparin, Ticarcillin, Tometin, Valproic acid, Salicylic acid, Sevelamer, Ziprasidone, Zoledronic acid, Acetophenazine, Albuterol, Almotriptan, Amitriptyline, Amphetamine, Atracurium, Beclomethasone, Benztropine, Biperiden, Bosentan, Bromodiphenhydramine, Brompheniramine carbinoxamine, Caffeine, Capecitabine, Carbergoline, Cetirizine, Chlocylizine, Chlorpheniramine, Chlorphenoxamine, Chlorpromazine, Citalopram, Clavunate potassium, Ciprofloxacin, Clemastine, Clomiphene, Clonidine, Clopidogrel, Codeine, Cyclizine, Cyclobenzaprine, Cyproheptadine, Delavirdine, Diethylpropion, Divalproex, Desipramine, Dexmethylphenidate, Dexbrompheniramine, Dexchlopheniramine, Dexchlor, Dextroamphetamine, Dexedrine, Dextromethorphan, Fiflunisal, Diphemanil methylsulphate, Diphenhydramine, Dolasetron, Doxylamine, Enoxaparin, Ergotamine, Ertepenem, Eprosartan, Escitalopram, Esomeprazole, Fenoldopam, Fentanyl, Fexofenadine, Flufenamic acid, Fluvastatin, Fluphenazine, Fluticasone, Fosinopril, Frovatriptan, Gabapentin, Galatamine, Gatifloxacin, Gemcitabine, Haloperidol, Hyalurondate, Hydrocodone, Hydroxychloroquine, Hyoscyamine, Imatinib, Imipenem, Ipatropin, Lisinopril, Leuprolide, Levopropoxyphene, Losartan, Meclofenamic acid, Mefanamic acid, Mesalamine, Mepenzolate, Meperidine, Mephentermine, Mesalimine, Mesoridazine, Metaproteranol, Metformin, Methdialazine, Methscopolamine, Methysergide, Metoprolol, Metronidazole, Mibefradil, Montelukast, Morphine, Mometasone, Naratriptan, Nelfinavir, Nortriptylene, Noscapine, Nylindrin, Omeprazole, Orphenadrine, Oseltamivir, Oxybutynin, Papaverine, Pentazocine, Phendimetrazine, Phentermine, Pioglitazone, Pilocarpine, Prochloroperazine, Pyrilamine, Quetapine, Ranitidine, Rivastigmine, Rosiglitazone, Salmetrol, Sertaline, Sotalol, Sumatriptan, Tazobactam, Tacrolimus,Tamoxifen, Ticlopidine, Topiramate, Tolterodine, Triptorelin, Triplennamine, Triprolidine, Tramadol, Trovofloxacin, Ursodiol, Promazine, Propoxyphene, Propanolol, Pseudoephedrine, Pyrilamine, Quinidine, Oxybate sodium, Sermorelin, Tacrolimus, Tegaseroid, Teriparatide, Tolterodine, Triptorelin pamoate, Scoplolamine, Venlafaxine, Zamivir, Aminocaproic acid, Aminosalicylic acid, Hydromorphone, Isosuprine, Levorphanol, Melhalan, Nalidixic acid, and Paraaminosalicylic acid.2. Excipient

[0046] Fill composition may comprise one or more excipients, such as emulsifier or emulsifying lipid, lipid-based water-soluble surfactants, and wetting agents, where at least one of the materials is (semi-)solid at room temperature. Some exemplary excipients may include but are not limited to medium-chain triglycerides oil, Lauroyl polyoxyl-32 glycerides (also known as lauroyl macrogol-32 glycerides, Lauroyl macrogol-32 glycerides), lecithin (i.e. soybean or rapeseed lecithin), and propylene glycol monocaprylate. The lauroyl macrogol-32 glycerides may be semisolid at room temperature.

[0047] Some lipid-based water-soluble surfactants may include but are not limited to caprylocaproyl macrogol-8 glycerides, caprylocaproyl macrogol-6 glycerides, oleoyl macrogol-6 glycerides, lauroyl macrogol-6 glycerides. Further lipid-based water- soluble surfactants may comprise polyoxylglycerides such as lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and lauroyl macrogol-6 glycerides. Caprylocaproyl polyoxyl-8 glycerides. Additional lipid-based surfactants may comprise Vitamin E Polyethylene Glycol Succinate, Polyoxyl 40 hydrogenated castor oil, Polyoxyl 15 Hydroxystearate, Polyoxyl 35 Castor Oil, and poloxamer.

[0048] Some lipid-based water-soluble surfactants may be (semi-) solid material at room temperature, which may include, but not limited to, beeswax, hard fat, Glyceryl dibehenate, Glyceryl Monostearate, glyceryl palmitostearate, glyceryl monostearate, Vitamin E Polyethylene Glycol Succinate, Polyoxyl 40 hydrogenated castor oil, stearoyl macrogol-32 glycerides, and lauroyl macrogol-6 glycerides.

[0049] Some exemplary emulsifiers may be a lipid-based oil or lipid-based oilcomposition, which include, but are not limited to, medium-chain triglycerides, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, Lecithin (from soybean or rapeseed), Oleoyl polyoxyl-6 glycerides, Glyceryl Monocaprylocaprate Type I and Type II, Propylene glycol monocaprylate type I and II.

[0050] Some exemplary wetting agents may include lecithin from soybean, rapeseed, egg, sunflower, canola, milk, and corn. Wetting agents may also include but are not limited to phosphatidylcholine, phosphatidylethanolamine, polysorbate, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monostearate, sorbitan monooleate, glyceryl monostearate, polyoxyl stearate, and castor oil.

[0051] One example of excipient composition comprises a mixture of liquid oil and a solid lipid-based water-soluble surfactant; medium-chain triglycerides and lauroyl macrogol-32 glycerides, combined with the API to produce a semisolid formulation with a melting point between 30°C to 44°C. Lecithin may be added to enhance the wettability of the API within the liquid oil mixture and potentially confer shear thinning behavior to the formulation.

[0052] To achieve the desired viscosity and enhance the overall stability, the behavior of lauroyl macrogol-32 glycerides was examined and found to retain a dual role in the formulation, functioning as both a viscosity modifier and a wetting agent. This dual functionality significantly impacts the rheology of the suspension in a nonlinear manner. Thus, a separate wetting agent may be preferred.

[0053] When lecithin is used as the wetting agent at concentrations above 1 wt.% and within the range of 2 wt.% to 3 wt.%, while maintaining a constant amount of lauroyl macrogol-32 glycerides, which functions solely as a viscosity modifier. The lecithin content in the formulation may be increased to optimize its pseudoplastic flow characteristics, directly enhancing the ease of encapsulation. Following are some examples of fill compositions with naproxen or naproxen sodium no more than 40% by weight and expedients described herein.

[0054] In an example, effective encapsulation requires medium chain triglycerides oil to be between 27.15% and 41.15% by weight, lauroyl polyoxyl-32 glycerides between 12.85% and 20% by weight, and soybean lecithin to be between 1% and 20% byweight.

[0055] In another example, effective encapsulation requires lauroyl polyoxyl-32 glycerides to be added at 36% to 42% by weight, and propylene glycol monocaprylate to be within the range of 18% to 27% by weight, preferably 21% to 27%.

[0056] It is appreciated that stability study for some of the examples described herein demonstrates that the capsules retain quality over time under both ICH conditions. At Zone II (25±2°C, 60±5% RH), they meet all criteria with stable hardness, disintegration times, and assay values. They show similar stability at Zone IV (30±2°C, 65±5% RH). Total related substances are significantly lower than comparable products on the market, as individual degradation products content achieves less than or equal to about 0.15%, indicating superior chemical stability over these products. This is further illustrated in Table 4 and Table 5.B. Shell

[0057] Gel composition comprises a mixture of ingredients. These ingredients may include but are not limited to gelling agents like gelatin or synthetic polymers that provide structure, solvents such as water or glycerol, and additives for enhancing properties. Additives can include colorants, plasticizers for flexibility, stabilizers for consistency, and preservatives for extended shelf life. Gel composition may also comprise additives like emulsifiers and humectants may be included to improve performance. The composition is tailored to meet the desired characteristics and functional requirements of the API and provide the drug product.

[0058] One example may be a colored gel comprising primarily of base gel (99.175%), with the addition of purified water (0.5%), Eurogran Patent Blue V (E131) at 0.1%, and yellow iron oxide (E172) in glycerol (20:80% w / w) at 0.225%.

[0059] As explained in the following section, the encapsulation of the fill is conducted using an oval die suitable for a fill weight of about 550 mg, which is equivalent to 220 mg Naproxen Sodium. The gel formulation can consist of a mixture of gelatin, glycerol, sorbitol (optional), water, colorant, and optionally pacifier. Detailed gelcomposition is provided in the example above.

[0060] This exemplary fill is encapsulated at 35±5 degrees. After the medicine is encapsulated using a rotary die machine, the soft gelatin capsules are initially dried in a tumbler dryer (18-27 degrees / 15-35% RH), followed by a secondary drying in tunnels (22-28 degrees / 10-25% RH). Once soft gelatin capsules attain an acceptable hardness (8-11 N), they are inspected, and postproduction activities are carried out.

[0061] Another example may be a colored gel that has a similar composition with base gel (99.175%), purified water (0.5%), Eurogran Patent Blue V (E131) at 0.1%, and yellow iron oxide (E172) in glycerol (20:80% w / w) at 0.225%.

[0062] Yet another example may be a base gel that comprises glycerol (20%), gelatin (43.4%), and purified water (36.6%). In one example, based gel may contain glycerol (10.6%), sorbitol liquid (13.9%), gelatin (43.4%), and purified water (32.1%). It may also be a composition of yellow iron oxide in glycerol, including glycerol (80%) and yellow iron oxide (20%).With respect to the % by weight of the fill, it is understood that shell weight should be separately considered. In other words, % weight of each shell composition is only with respect to the shell not the entire formulation. Equally, the % weight of each fill composition is only with respect to the % total fill composition. For example, taking into account of the % weight of shell with API at about 40% by weight will be about 27% instead. II. Methods of MakingA. Preheating

[0063] The manufacturing process for Naproxen softgel begins with the premanufacturing excipient heating, where polyoxylglycerides, or more specifically lauroyl polyoxyl-32 glycerides, are subjected to heating and mixing to achieve the desired appearance. For example, the lauroyl polyoxyl-32 glycerides are placed in a heating chamber until fully liquid / homogeneous. The temperature may be 70-80°C for not less than 12 hours. The desired appearance may be clear liquid, from colourless turning to slightly yellow.B. Fill preparation

[0064] Following this, the active fill preparation involves the heating and mixing of lauroyl polyoxyl-32 glycerides, medium chain triglyceride, lecithin, and naproxen sodium. This mixture is then deaerated and mixed at low speed, with the appearance checked at the end of the process. The following Tables 1 to 3 further illustrate the preparation process. Table 1Table 2Table 3C. Gell Mass Preparation

[0065] Next, the base gel mass preparation involves the combination of gelatin, glycerol, liquid sorbitol, and purified water. These ingredients are mixed, heated, deaerated, and then transferred, ensuring the appearance is satisfactory.Concurrently, the colored gel mass preparation uses Eurogram Patent Blue V(E131) and yellow iron oxide (E172) in glycerol (2:8 ratio), which are mixed to achieve the desired appearance.

[0066] The encapsulation process follows, which involves processing the prepared fill material and gel mass, with monitoring of parameters such as fill blend uniformity, fill weight, ribbon thickness, and seam percentage.

[0067] The prepared fill and gel mass are processed using the rotary die method, which can be performed with various equipment models, all operating on the same principle. The gel mass is heated. The molten gel is fed from a gel receiver onto two rotating cooling drums via a spreader box, forming two flat gel ribbons. These ribbons, which become the capsule shell, are encapsulated using the form-fill-seal process in the rotary die, which determines the capsule's size and shape. The ribbons may be lubricated with medium-chain triglycerides oil during encapsulation, and the capsule's outer side is lubricated with soy lecithin in medium-chain triglycerides oil mixture, traces of which may remain in the encapsulated product.

[0068] After encapsulation, the product undergoes drying and transfer, with checks for hardness and water activity. The drying process may begin with tumble dryers, where humidity is maintained between 15-35% and temperature between 18-27°C.The capsules may then be transferred to trays and spread evenly before being stacked and placed in a drying tunnel. In the drying tunnel, humidity is kept between 10-25% and temperature between 22-28°C. Once the capsules reach the target hardness, the trays may be removed from the tunnel, except for one tray, which remains for an extended drying study.

[0069] Post-production activities begin with a visual inspection to ensure the capsules meet appearance standards (i.e. Color: Blueish opaque capsule, Shape: oval), followed by manual polishing to enhance their final look. The capsules are then transferred to deeps and polished using cloths with 100% isopropyl alcohol. After polishing, they are packaged and undergo sampling to confirm they meet all required specifications. This thorough process ensures the softgels are consistently high in quality from initial preparation to final packaging.III. Methods of Use

[0070] Softgels may be used to encapsulate a wide range of APIs, nutritional agents, and personal care products. Softgel capsules may be administered orally to a patient to deliver an API.

[0071] One such API may be naproxen salt, or more specifically naproxen sodium. Naproxen sodium is an over-the-counter analgesic that temporarily relieves minor aches, pains, and reduces fever. It belongs to the group of non-steroidal antiinflammatory drugs (NSAIDs). The naproxen sodium is in solid and liquid lipid-based excipients that are combined in a manner that produces a semisolid fill formulation that prevents the formation of naproxen ester side products.

[0072] The size of the softgel capsule with naproxen sodium is reduced by approximately 30% compared other naproxen sodium products, and there is no significant increase in the amount of degradants after 12 months of stability testing at 25°C and 60% RH (ICH zone II) and after 9 months at 30°C and 65% RH (ICH zone IV).EXAMPLESExample 1 :of semisolid com

[0073] In the following examples, the fill material can be prepared by mixing a pharmaceutically active agent described herein with liquid materials (i.e. , mediumchain triglycerides, soybean lecithin, propylene glycol monocaprylate) at room temperature or higher, followed by heating up the mixture, at least, 10°C above the melting point of the (semi-)solid material (i.e., lauroyl polyoxyl-32 glycerides). The (semi-)solid material is added to the mixture and mixed until visually homogeneous; then the pharmaceutically active agent is added slowly at a temperature, at least, 10°C above the melting point of the (semi-)solid material (i.e., 55±5°C) and at a high mixing speed for, at least, one hour. The resulting suspension can be encapsulated at about 35±5°C in a softgel capsule using the appropriate gel mass.

[0074] Example 1-1Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Medium-Chain Triglycerides oil 32.15Lauroyl polyoxyl-32 glycerides 17.85Soybean Lecithin 10.00TOTAL 100.00%Example 1-2Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Medium-Chain Triglycerides oil 41.15Lauroyl polyoxyl-32 glycerides 17.85Soybean Lecithin 1.00TOTAL 100.00%Example 1-3Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Medium-Chain Triglycerides oil 27.15Lauroyl polyoxyl-32 glycerides 17.85Soybean Lecithin 15.00TOTAL 100.00%Example 1-4Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Medium-Chain Triglycerides oil 27.15Lauroyl polyoxyl-32 glycerides 12.85Soybean Lecithin 20.00TOTAL 100.00%Example 1-5Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Medium-Chain Triglycerides oil 27.15Lauroyl polyoxyl-32 glycerides 20.00Soybean Lecithin 12.85TOTAL 100.00%Example 1-6Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Lauroyl polyoxyl-32 glycerides 36.00Propylene Glycol Monocaprylate 24.00TOTAL 100.00%Example 1-7Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Lauroyl polyoxyl-32 glycerides 33.00Propylene Glycol Monocaprylate 27.00TOTAL 100.00%Example 1-8Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Lauroyl polyoxyl-32 glycerides 39.00Propylene Glycol Monocaprylate 21.00TOTAL 100.00%Example 1-9Fill Material Ingredients % (by weight)Naproxen (or Naproxen Sodium) 40.00Lauroyl polyoxyl-32 glycerides 42.00Propylene Glycol Monocaprylate 18.00TOTAL 100.00%Example 2: Naproxen Sodium 220 mg soft gelatin capsules stability study:The long-term stability of Naproxen Sodium 220 mg soft gelatin capsules using the composition of above examples (i.e., Example 1-1) are herein described. The soft gelatin capsules were placed on stability at two ICH conditions, Zone II (25±2°C and 60±5% RH) and Zone IV (30±2°C and 65±5% RH) for 12 months. The testing points were after manufacturing (t=0), 1 month (t=1m), 3 months (t=3m), 6 months (t=6m), 9 months (t=9m), and 12 months (t=12m, only for Zone II condition). Summary results of the stability evaluation is shown in Table 4 and Table 5.Table 4. Stability results at 25±2°C and 60±5% rH*Reporting threshold 0.05% Table 5. Stability results at 30±2°C and 65±5% rH*Reporting threshold 0.05% After 12 months at 25°C / 60% RH, the present invention has a total related substance (RS) content of about 0.1%, expressed as a percentage, and with individual degradation products content less than or equal to about 0.15%. Similarly, after 9 months at 30°C / 65% RH, the total RS content (amount of impurities or degradation products) is about 0.1%. In comparison, the hydrophilic-based Naproxen 220 mg soft gelatin capsules available in the market have a total RS content of about 0.7% after12 months at 25°C / 60% RH, and about 0.8% after 9 months at 30°C / 65% RH. This evidence demonstrates that the present invention has a superior chemical stability when compared to the existing soft gelatin product.

[0075] It will be understood that the benefits and advantages described above may relate to one aspect or may relate to several aspects. The aspects are not limited to those that solve any or all of the stated problems or those that have any or all of the stated benefits and advantages. Variants should be considered to be included into the scope of the invention.

[0076] Further, it is understood that the disclosed invention is not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0077] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are as described. Publications cited herein and the materials for which they are cited are specifically incorporated by reference. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0078] Any reference to 'an' item refers to one or more of those items. The term 'comprising' is used herein to mean including the method steps or elements identified, but that such steps or elements do not comprise an exclusive list and a method or apparatus may contain additional steps or elements.

[0079] Further, as used herein, the term "exemplary", "example" or "aspects" is intended to mean "serving as an illustration or example of something". Further, to the extent that the term "includes" is used in either the detailed description or the claims, such term is intended to be inclusive in a manner similar to the term "comprising" as "comprising" is interpreted when employed as a transitional word in aclaim.

[0080] As used herein, the term “about” or “approximately” as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In one aspect, the term “about” refers to any values, including both integers and fractional components that are within a variation of up to ± 10% of the value modified by the term “about.” Alternatively, “about” can mean within 3 or more standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, in some embodiments within 5- fold, and in some embodiments within 2-fold, of a value. As used herein, the symbol means “about” or “approximately.”

[0081] All ranges disclosed herein include both end points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1- 2.0 includes 0.1 , 0.2, 0.3, 0.4 . . . 2.0. If the end points are modified by the term “about,” the range specified is expanded by a variation of up to ±10% of any value within the range or within 3 or more standard deviations, including the end points.

[0082] What has been described above includes examples of one or more aspects. It is, of course, not possible to describe every conceivable modification and alteration of the above devices or methods for purposes of describing the aforementioned aspects, but one of ordinary skill in the art can recognize that many further modifications and permutations of various aspects are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the scope of the appended

Claims

TP388606USPRV1CLAIMS1. A pharmaceutical composition comprising a fill material comprising: a pharmaceutically active agent; and a lipid-based water-soluble surfactant.

2. The pharmaceutical composition of claim 1 , wherein the fill material further comprises a lipid-based oil.

3. The pharmaceutical composition of claim 2, wherein the lipid-based oil comprises medium-chain triglycerides.

4. The pharmaceutical composition of claim 3, wherein the medium-chain triglycerides are present in amount of about less than 41 % by weight.

5. The pharmaceutical composition of claims 1 to 4, wherein the lipid-based water-soluble surfactant comprises polyoxylglycerides.

6. The pharmaceutical composition of claim 5, wherein the polyoxylglycerides are Lauroyl polyoxyl-32 glycerides that are present in amount from about 12% to about 22% by weight.

7. The pharmaceutical composition of claims 1 to 6, wherein the fill material further comprises a wetting agent.

8. The pharmaceutical composition of claim 7, wherein the wetting agent comprises a lecithin.

9. The pharmaceutical composition of claim 8, wherein the lecithin is present in amount from about 1 % to 25% by weight.

10. The pharmaceutical composition of claim 8, wherein the lecithin is present in amount of about 10% by weight.11 . The pharmaceutical composition of claim 1 , wherein the fill material furtherTP388606USPRV1 comprises a propylene glycol monocaprylate.

12. The pharmaceutical composition of claim 11 , wherein the propylene glycol monocaprylate is present in amount from about 15% to about 30% by weight.

13. The pharmaceutical composition of claim 11 , wherein the propylene glycol monocaprylate is present in amount from about 16% to about 27%.

14. The pharmaceutical composition of claim 11 , wherein the propylene glycol monocaprylate is present in amount of 24% by weight.

15. The pharmaceutical composition of claims 11 to 14, wherein the lipid-based water-soluble surfactant comprises polyoxylglycerides present in amount from about 30% to about 45% by weight.

16. The pharmaceutical composition of claims 11 to 15, wherein the lipid-based water-soluble surfactant comprises polyoxylglycerides present in amount from about 36% to about 42% by weight.

17. The pharmaceutical composition of claims 1 to 16, wherein the pharmaceutically active agent is a salt of the pharmaceutically active agent.

18. The pharmaceutical composition of claim 17, wherein the salt is naproxen sodium.

19. The pharmaceutical composition of claim 17 or 18, wherein the naproxen salt is about or less than 40% by weight.

20. The pharmaceutical composition of claims 1 to 19, further comprising a gel comprises gelatin, glycerol, water, and colorant.21 . The pharmaceutical composition of claim 20, wherein the gel further comprises sorbitol.

22. The pharmaceutical composition of claim 20 or 21 , wherein the gel furtherTP388606USPRV1 comprises opacifier.

23. The pharmaceutical composition of any preceding claims, wherein the composition remains stable in each of ICH climatic zones I to IVb.

24. The pharmaceutical composition of any preceding claims, wherein the composition comprises individual degradation products content equal to about 0.15% or less than about 0.15% by weight.

25. A method for treating pain, inflammation, or fever comprising administering the pharmaceutical composition of claims 1 to 24 to a patient in need thereof.

26. A soft gelatin capsule comprising a fill material comprising:(a) a naproxen salt;(b) a lipid-based water-soluble surfactant;(c) a lipid-based oil; and(d) a wetting agent.

27. The capsule of claim 26, wherein the naproxen salt is naproxen sodium.

28. The capsule of claim 26, wherein the naproxen sodium is about or less than 40% by weight.

29. The capsule of claims 26 to 28, wherein the lipid-based water-soluble surfactant comprises Lauroyl polyoxyl-32 glycerides that are present in amount from about 16% to about 22% by weight.

30. The capsule of claim 29, wherein the Lauroyl polyoxyl-32 glycerides are present in amount of 17.85% by weight.31 . The capsule of claims 26 to 30, wherein the lipid-based oil comprises medium-chain triglycerides.

32. The capsule of claim 31 , wherein the medium-chain triglycerides are present in amount from about 27% to 41% by weight.

33. The capsule of claim 32, wherein the medium-chain triglycerides are presentTP388606USPRV1 in amount from about 27% by weight; or wherein the medium-chain triglycerides are present in amount from about or less than 40% by weight.

34. The capsule of claims 26 to 33, wherein the wetting agent comprises a lecithin.

35. The capsule of claim 34, wherein the lecithin is present in amount from about 1% to 25% by weight.

36. The capsule of claim 34, wherein the lecithin is present in amount from about 10% by weight.

37. The capsule of claims 26 to 36, wherein the capsule is stable at temperature and relative humidity corresponding to that of ICH climatic zones l-IVb for a period no less than 9 months.

38. The capsule of claims 26 to 37, wherein the capsule comprises individual degradation products content equal to about 0.15% or less than about 0.15% by weight.

39. A soft gelatin capsule comprising a fill material comprising:(a) a naproxen salt;(b) a lipid-based water-soluble surfactant; and(d) an emulsifier, wherein the emulsifier is a propylene glycol monocaprylate.

40. The capsule of claim 39, wherein the naproxen salt is naproxen sodium.

41. The capsule of claim 40, wherein the naproxen sodium is about or less than 40% by weight.

42. The capsule of claims 39 to 41 , wherein the lipid-based water-soluble surfactant comprises lauroyl polyoxyl-32 glycerides that are present in amount fromTP388606USPRV1 about 15% to about 30% by weight.

43. The capsule of claim 42, wherein the Lauroyl polyoxyl-32 glycerides are present in amount of 36% by weight.

44. The capsule of claims 39 to 43, wherein the propylene glycol monocaprylate is present in amount 24% by weight.

45. The capsule of claims 39 to 44, wherein the capsule comprises individual degradation products content equal to about 0.15% or less than about 0.15% at temperature and relative humidity corresponding to at least one ICH climatic zone.

46. A method for treating pain, inflammation, or fever comprising administering the capsule of claims 26 to 45 to a patient in need thereof.

47. A method for making a soft gelatin capsule, the method comprising:(a) mixing together(i) about 40% by weight of a salt of one or more pharmaceutically active agents,(ii) about 12% to about 22% of a lipid-based water-soluble surfactant by weight,(iii) about 1% to about 15% by weight of wetting agent; and(iv) about or less than 40% by weight of a lipid; and(b) encapsulating the mixture in a softgel capsule using rotary die encapsulation.

48. The method of claim 47, wherein the lipid-based water-soluble surfactant is Lauroyl polyoxyl-32 glycerides in amount of 17.85% by weight.

49. The method of claim 47 or 48, wherein the wetting agent is lecithin is in amount of 10% by weight.

50. The method of claims 47 to 49, wherein the lipid-based oil is in amount of 32.15% by weight.TP388606USPRV151. A method for making a soft gelatin capsule, the method comprising:(a) mixing together(i) about or less than 40% by weight of a salt of one or more pharmaceutically active agents,(ii) about 30% to about 45% of a lipid-based water-soluble surfactant by weight, and(iii) about 15% to about 30% by weight of propylene glycol monocaprylate; and(b) encapsulating the mixture in a softgel capsule using rotary die encapsulation.

52. The method of claim 51 , wherein the lipid-based water-soluble surfactant is Lauroyl polyoxyl-32 glycerides in amount of 36% by weight.

53. The method of claim 51 or 52, wherein the propylene glycol monocaprylate is in amount of 24% by weight.

54. The method of claims 47 to 53, wherein the soft gelatin capsule comprises individual degradation products content of about 0.15% in one or more ICH climatic zones.

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