RU2833036C2 - Stabilization of dosage form based on solid or semi-liquid lipid by curing and addition of surfactant (surfactants), having low value of hlb - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: group of inventions relates to pharmaceutics. Object 1 is a method for stabilizing the release profile of a dosage form, according to which a surfactant and glyceryl distearate are included in a dosage form containing an active pharmaceutical ingredient, and the dosage form is cured, where the surfactant has an HLB value of less than about 10 and is selected from sorbitan fatty acid esters and combinations thereof, and where curing is carried out at a temperature in the range of about 30 °C to about 60 °C for about 3 hours to about 7 days. Objects 2–4 are embodiments of a method for preparing a dosage form with a stabilized release profile with the inclusion of an active pharmaceutical ingredient, at least one surfactant with an HLB value of less than 10 and glyceryl distearate, including curing of the dosage form.

EFFECT: maintaining the release profile of the active pharmaceutical ingredient of the dosage form containing a surfactant and glyceryl distearate for 1, 2 and 3 months.

28 cl, 3 dwg, 8 tbl, 1 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to the field of solidified pharmaceutical compositions that contain an active pharmaceutical ingredient dispersed in a matrix containing a solid or semi-solid lipid and a surfactant with an HLB (hydrophilic-lipophilic balance) value of less than 10. The present invention also relates to methods for producing and methods for using such pharmaceutical compositions.

LEVEL OF TECHNOLOGY

When using solid and semi-solid lipid-based matrices, changes in the release profile may occur during shelf life due to changes in the crystalline form of the lipid. As a result, a drug product may have one release profile, and after storage for a year, the same drug product may have a different release profile. Such changes in the release profile may be extremely dangerous to the subject. For example, if the release becomes slower after a year, the patient may not receive enough of the active pharmaceutical ingredient in a timely manner. Alternatively, if the release becomes faster after a year, the patient may receive an excessive amount of the active pharmaceutical ingredient too quickly and an overdose may occur.

Various approaches have been studied to stabilize the release profile of dosage forms containing solid or semi-solid lipid matrices. One approach has investigated the possibility of solidifying the dosage form by heating it at an elevated temperature for an extended period of time. Another approach has investigated the possibility of using surfactants with HLB values less than 10, or surfactants with HLB values greater than 10, to stabilize the release profile of the active pharmaceutical ingredient contained in the dosage form. However, none of these approaches have resulted in dosage forms containing solid or semi-solid lipid matrices having a stable release profile of the active pharmaceutical ingredient.

What is needed is a dosage form that contains solid or semi-solid lipid based matrices and ensures the maintenance of a stable release profile of the active pharmaceutical ingredient over a long period of time.

OBJECTIVES AND SUMMARY OF THE ESSENCE OF THE INVENTION

In some embodiments of the present invention, the objective is to prepare a dosage form comprising a solid or semi-solid lipid matrix that provides a sustained release profile of an active pharmaceutical ingredient over a period of time.

In some embodiments of the present invention, another object is to provide a method for stabilizing the release profile of an active pharmaceutical ingredient of a dosage form comprising a solid or semi-solid lipid matrix over a certain period of time.

In some embodiments of the present invention, another object is to provide a method for preparing a dosage form comprising a solid or semi-solid lipid matrix that provides a sustained release profile of an active pharmaceutical ingredient over a period of time.

In some embodiments of the present invention, another object is to prepare a dosage form in which the amount of solubility-enhancing and/or bioavailability-enhancing materials used is maximized and the amount of non-influencing excipients is minimized, while also providing the patient with the appropriate quality of the drug.

The above-described objects of the present invention, as well as other objects, can be solved by the present invention, which combines the inclusion of a surfactant with an HLB value of less than 10 in a dosage form containing a solid or semi-solid lipid and the curing of this dosage form. It is shown that the combination of the inclusion of a surfactant with an HLB value of less than 10 and curing provides stabilization of the release profile of the active pharmaceutical ingredient of the dosage form containing a matrix based on a solid or semi-solid lipid.

In some embodiments, the present invention relates to a dosage form comprising an active pharmaceutical ingredient dispersed in a homogeneous matrix comprising a surfactant with an HLB value of less than 10 and at least one solid or semi-solid lipid.

In some embodiments, the present invention relates to a method for stabilizing the release profile of an active pharmaceutical ingredient of a dosage form. The method may include including in the dosage form a surfactant with an HLB value of less than 10 and at least one solid or semi-solid lipid and hardening the dosage form. The release profile of the active pharmaceutical ingredient from the dosage form stabilized by this method after conducting an accelerated stability study may be comparable to its release profile before conducting the accelerated stability study (e.g., when compared with the release profile of the active pharmaceutical ingredient before conducting the accelerated stability study, the release profile of the active pharmaceutical ingredient after conducting the accelerated stability study may have a similarity factor (f2) of at least 50).

In some embodiments, the present invention relates to a method for preparing a dosage form. In some embodiments, the method may include mixing an active pharmaceutical ingredient with a surfactant with an HLB value of less than 10 and at least one solid or semi-solid lipid to form a mixture. The method may further include heating the mixture to melt the at least one solid or semi-solid lipid to form a molten mixture. The method may further include molding the molten mixture to form a dosage form and curing the dosage form. Molding the molten mixture to form a dosage form may include dispensing the molten mixture into a pre-prepared blister cavity or encapsulating the molten mixture into a hard-shell capsule or a soft-shell capsule.

In some embodiments, the method of preparation may include mixing the active pharmaceutical ingredient with a surfactant with an HLB value of less than 10 and at least one solid or semi-solid lipid in an extruder. The method may further include extruding the active pharmaceutical ingredient, the surfactant, and at least one solid or semi-solid lipid to obtain a dosage form. The method may further include curing the dosage form.

In some embodiments, the method of preparation may include dissolving an active pharmaceutical ingredient, a surfactant with an HLB value of less than 10, and at least one solid or semi-solid lipid in a solvent. The method may further include spray drying or spray freezing the dissolved active pharmaceutical ingredient, the surfactant with an HLB value of less than 10, and at least one solid or semi-solid lipid to obtain a powder. The method may further include solidifying the powder.

The release profile of the active pharmaceutical ingredient of the dosage form prepared in accordance with the methods disclosed in the present invention after conducting an accelerated stability study may be comparable to its release profile before conducting an accelerated stability study (for example, when compared with the release profile of the active pharmaceutical ingredient before conducting an accelerated stability study, the release profile of the active pharmaceutical ingredient after conducting an accelerated stability study may have a similarity factor (f2) of at least 50).

In some embodiments, the present invention relates to a method of treatment comprising administering to a patient in need thereof any of the dosage forms disclosed herein in a therapeutically effective amount.

DEFINITIONS

As used in the present invention, singular terms include plural terms unless otherwise indicated. Thus, for example, reference to an "active pharmaceutical ingredient" includes reference to a single active pharmaceutical ingredient as well as a mixture of two or more different active pharmaceutical ingredients, and reference to an "inert filler" includes reference to a single filler as well as a mixture of two or more different inert fillers, etc.

As used in the present invention, "about" with respect to a measured value means the measured value with a typical deviation, as it can be expected by a person with general training in the art, performing the measurements and making the evaluation in accordance with the purpose of the measurement and the accuracy of the measuring equipment. In some embodiments, the term "about" includes the stated value ± 10%, thus the value "about 10" includes values from 9 to 11.

As used herein, the terms "active agent," "active ingredient," "active pharmaceutical ingredient," and "drug" mean any substance that is intended to provide a therapeutic, prophylactic, or other desired effect, whether or not approved by a governmental agency for use for that purpose. These terms, when used with respect to specific agents, include all pharmaceutically active agents, all pharmaceutically acceptable salts, complexes, stereoisomers, crystalline forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof, where they are pharmaceutically active.

As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the arrangement of their atoms in space. It includes enantiomers and isomers of compounds containing one or more chiral centers that are mirror images of each other (diastereoisomers).

The term "enantiomer" or "enantiomeric" means a molecule that is not superimposable on its mirror image and is therefore optically active if the enantiomer rotates the plane of polarized light through a certain angle in one direction and its mirror image rotates the plane of polarized light through the same angle in the opposite direction.

The term "chiral center" refers to a carbon atom to which four different groups are attached.

The term "patient" means a subject, animal or human, who exhibits a clinical manifestation of a specified symptom or symptoms suggesting the need for treatment, who is receiving preventive or prophylactic treatment for a pathological condition, or who has been diagnosed with a pathological condition that requires treatment. The term "subject" is included in the definition of the term "patient" and does not exclude individuals who are otherwise healthy.

Pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; salts derived from organic acids such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; salts derived from amino acids such as arginate, aspartate, glutamate, etc.; metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dichlorhexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

The indication of ranges of values in the present invention is used only to briefly indicate specifically all individual values within that range, unless otherwise indicated herein, and each individual value is incorporated into the description as if it were specifically indicated herein. All procedures described in the present invention may be performed in any suitable order, unless otherwise indicated herein or unless clearly contradicted by context. The use of any and all examples or indications of typical values (e.g., "such as") in the present invention is intended only to describe particular materials and methods and does not impose a limitation on the scope of the present invention. No expression in the description should be construed as indicating any unclaimed element important to the practice of the disclosed materials and methods.

The term "pathological condition" or "pathological conditions" means those pathological conditions that can be treated or prevented by administering to a subject an active agent in an effective amount.

The terms "treatment" and "treat" include reducing the severity of or eliminating a pathological condition, or reducing the severity of or eliminating the symptoms of a pathological condition.

The terms "prevention" and "prevent" include preventing the occurrence of a pathological condition.

"Therapeutically effective amount" includes an amount of an active agent, or an amount of a combination of active agents, such as those intended to treat or prevent a pathological condition or treat the symptoms of a pathological condition in a subject.

The expression "pharmaceutically acceptable" means those compounds, materials, compositions and/or dosage forms that, according to basic medical principles, are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic reaction or other difficulties or complications, with a reasonable benefit/risk ratio.

The term "extended release" means that the active agent is released over a period of time, such as in a once-daily or twice-daily dosage form.

The term "immediate release" means that the dosage form allows the drug to dissolve in the gastrointestinal tract and is not intended to slow or prolong the dissolution or absorption of the drug. For example, this means releasing at least 85%, at least 90%, or at least 95% of the active agent within about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, or about 60 minutes, as determined by an in vitro dissolution test using USP Apparatus Type 1 (with a No. 40 mesh basket), USP Apparatus Type 2 (with paddles), or USP Apparatus Type 3 (with a reciprocating cylinder), in an aqueous medium (pH = 1-8) at room temperature.

BRIEF DESCRIPTION OF DRAWINGS

The above and other features of the present invention, their nature and various advantages will become more apparent upon consideration of the following detailed description together with the accompanying drawings, where:

Fig. 1A shows the solubility profile of the uncured comparative composition obtained in an accelerated solubility study.

Fig. 1B shows the solubility profile of the cured comparative composition obtained by conducting an accelerated solubility study.

Fig. 2A shows a solubility profile of an uncured composition according to one embodiment of the present invention obtained in an accelerated solubility study.

Fig. 2B shows a solubility profile of a cured composition according to one embodiment of the present invention obtained by conducting an accelerated solubility study.

Fig. 3A shows a solubility profile of an uncured composition according to one embodiment of the present invention obtained in an accelerated solubility study.

Fig. 3B shows a solubility profile of a cured composition according to one embodiment of the present invention obtained in an accelerated solubility study.

DETAILED DESCRIPTION OF THE INVENTION

Dosage forms

In various embodiments, the present invention relates to a dosage form comprising an active pharmaceutical ingredient dispersed in a matrix. The matrix may comprise a surfactant and at least one solid or semi-solid lipid. The dosage form may be solidified.

The surfactant may have an HLB value of less than 10. The surfactant with an HLB value of less than 10, without limitation, may be selected from the group consisting of ethylene oxide/propylene oxide (EO/PO) copolymers, glycerol monocaprylate, glycerol monocaprate, glycerol caprylate/caprate, glycerol monooleate, glycerol monostearate, glycerol laurate, glycerol monolinoleate, glycerol behenate, glycerol palmitostearate, petrolatum and lanolin alcohols, polyoxyethylene alkyl ethers (e.g. polyoxyl-4-lauryl ether, polyoxyl-2-cetyl ether, polyoxyl-2-stearyl ether, polyoxyl-2-oleyl ether), esters sorbitan and fatty acid (e.g. sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan diisostearate, sorbitan dioleate, sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate), sucrose esters, (ethylene glycol)-(propylene glycol)-(ethylene glycol) block copolymers (Pluronic Copolymers), lecithin, phospholipids, steareth-2, oleth-2, ceteth-2, PEG-30-dipolyhydroxystearate (PEG = polyethylene glycol), propylene glycol monocaprylate, propylene glycol dilaurate, propylene glycol monolaurate, propylene glycol monostearate, propylene glycol isostearate, alpha-tocopherol, mixed tocopherols, tricaprylin, nonionic emulsifying waxes, anionic emulsifying waxes, sorbitan monooleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan tristearate, sorbitan trioleate, and combinations thereof.

A surfactant with an HLB value of less than 10 can be present in the dosage form at a concentration in the range of from about 1 to about 60% w/w, from about 1 to about 10% w/w, from about 10 to about 30% w/w, from about 15 to about 25% w/w, from about 5 to about 15% w/w, from about 25 to about 35% w/w, from about 40 to about 50% w/w, from about 50 to about 60% w/w, from about 10 to about 50% w/w, from about 20 to about 40% w/w based on the total weight of the dosage form, or any subrange specified herein.

In some embodiments, the active pharmaceutical ingredient may have a half-life of less than about 12 hours, less than about 10 hours, or less than about 8 hours. The active pharmaceutical ingredient may be contained in the dosage form at a concentration in the range of 0.0001 to 90.0% w/w, such as from about 0.001% w/w, about 0.01% w/w, about 0.1% w/w, about 0.5% w/w, about 1.0% w/w, about 3.0% w/w, about 5.0% w/w, about 8.0% w/w, or about 10.0% w/w. up to about 15.0% w/w, about 20.0% w/w, about 25.0% w/w, about 30.0% w/w, about 35.0% w/w, about 40.0% w/w, about 50.0% w/w, about 60.0% w/w, about 70.0% w/w, about 80.0% w/w, or about 90.0% w/w based on the total weight of the dosage form.

The present invention encompasses the development of dosage forms having a higher concentration of active pharmaceutical ingredient than the concentration in currently marketed dosage forms, in order to reduce the number of single dosage forms that a patient must take, or in order to reduce the number of times a patient must take a dosage form (e.g., if a currently marketed dosage form contains about 4 mg of active pharmaceutical ingredient and is intended to be administered twice daily, then the dosage form of the present invention may contain about 8 mg of active pharmaceutical ingredient and is intended to be administered once daily).

For the purposes of the present invention, any pharmaceutically active ingredient can be used, including those that are soluble in water and those that are slightly soluble in water. Suitable pharmaceutically active ingredients include, but are not limited to, analgesics and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmics, antibacterials, anticoagulants, antidepressants, antidiabetics, antidiarrheals, antiepileptics, antifungals, antigout agents, antihypertensives, antimalarial agents, antimigraine agents, antimuscarinics, antineoplastic agents and immunosuppressants, antiprotozoals, antirheumatic agents, antithyroid agents, antivirals, tranquilizers, sedatives, hypnotics and neuroleptics, beta blockers, cardiac inotropic agents, corticosteroids, cough suppressants, cytotoxic agents, decongestants, diuretics, enzymes, antiparkinsonian agents, gastrointestinal agents, histamine receptor antagonists, lipid modulating agents, local anesthetics, neuromuscular agents, nitrates and antianginal agents, nutritional agents, opioid analgesics, oral vaccines, proteins, peptides and recombinant drugs, sex hormones and contraceptives, spermicides, stimulants and their combinations.

In some embodiments, the active pharmaceutical ingredient may be, without limitation, selected from the group consisting of dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurin, azimadoline, beclomethasone, apremilast, sapacitabine, lincitinib, abiraterone, vitamin D analogs (e.g., calcifediol, calcitriol, paricalcitol, doxercalciferol), COX-2 inhibitors (e.g., celecoxib, valdecoxib, rofecoxib), tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof, and combinations thereof.

In some embodiments, the lipids contained in the dosage form, without limitation, may be selected from the group consisting of almond oil, argan oil, avocado oil, borage seed oil, canola oil, cashew nut oil, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hempseed oil, hydroxylated lecithin, lecithin, flaxseed oil, macadamia nut oil, mango butter, manila hemp oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, hydrogenated vegetable oil, nut oil and watermelon oil. Other oils and fats may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats such as those in their hydrogenated form, free fatty acids and mono-, di- and triglycerides of fatty acids _C8 , _C10 , _C12 , _C14 , _C16 , _C16 , _C20 and _C22 , and combinations thereof.

In some embodiments, the active agents may include lipid-lowering agents, including, but not limited to, statins (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin), fibrates (e.g., clofibrate, ciprofibrate, bezafibrate, fenofibrate, and gemfibrozil), niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols and their pharmaceutically acceptable salts, hydrates, solvates, and prodrugs, mixtures of any of the foregoing, and the like.

Suitable nutritional actives may include, but are not limited to, 5-hydroxytryptophan, acetyl-L-carnitine, alpha lipoic acid, alpha-ketoglutarates, bee products, betaine hydrochloride, bovine cartilage, caffeine, cetyl myristoleate, charcoal, chitosan, choline, chondroitin sulfate, coenzyme Q10, collagen, colostrum, creatine, cyanocobalamin (vitamin B12), dimethylaminoethanol, fumaric acid, germanium sesquioxide, glandular products, glucosamine-HCI, glucosamine sulfate, hydroxymethylbutyrate, immunoglobulin, lactic acid, L-carnitine, liver-derived products, malic acid, maltose anhydrous, mannose (d-mannose), methylsulfonylmethane, phytosterols, picolinic acid, pyruvate, red yeast extract, S-adenosylmethionine, selenium-containing yeast, shark cartilage, theobromine, vanadyl sulfate and yeast.

Suitable active ingredients that are nutritional supplements may include vitamins, minerals, fiber, fatty acids, amino acids, herbal remedies, or a combination thereof.

Suitable vitamin actives may include, but are not limited to, ascorbic acid (vitamin C), B vitamins, biotin, fat soluble vitamins, folic acid, hydroxycitric acid, inositol, mineral ascorbates, mixed tocopherols, niacin (vitamin B3), orotic acid, para-aminobenzoic acid, pantothenates, pantothenic acid (vitamin B5), pyridoxine hydrochloride (vitamin B6), riboflavin (vitamin B2), synthetic vitamins, thiamine (vitamin B1), tocotrienols, vitamin A, vitamin D, vitamin E, vitamin F, vitamin K, vitamin-containing oils, and oil soluble vitamins.

Suitable active ingredients that are herbal remedies may include, but are not limited to, arnica, bilberry, black cohosh, cat's claw, chamomile, echinacea, evening primrose oil, fenugreek, flaxseed, feverfew, garlic, ginger root, ginkgo biloba, ginseng, goldenrod, hawthorn, kava kava, licorice, milk thistle, plantain, rauwolfia, senna, soybean, St. John's wort, saw palmetto, turmeric, valerian.

Active agents that are minerals may include, but are not limited to, boron, calcium, chelating minerals, chloride, chromium, coated minerals, cobalt, copper, dolomite, iodine, iron, magnesium, manganese, mineral premixes, mineral products, molybdenum, phosphorus, potassium, selenium, sodium, vanadium, malic acid, pyruvate, zinc and other minerals.

Examples of other possible active agents include, but are not limited to, antihistamines (e.g., ranitidine, dimenhydrinate, diphenhydramine, chlorpheniramine, and dexchlorpheniramine maleate), nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox-2 inhibitors, diclofenac, benoxaprofen, flurbiprofen, fenoprofen, flubufen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, fluprofen, buloxic acid, indomethacin, sulindac, zomepirac, tiopinac, zidomethacin, acemetacin, fentiazac, clidanac, oxpinac, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, aceclofenac, aloxiprine, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, etodolac, etoricoxib, faislamin, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, mefenamic acid, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, salicyl salicylate, sulindac, sulfinpyrazone, tenoxicam, tiaprofenic acid, tolmetin, their pharmaceutically acceptable salts and mixtures thereof), acetaminophen, antiemetics (eg, metoclopramide, methylnaltrexone), antiepileptics (eg, phenytoin, meprobamate, and nitrazepam), vasodilators (eg, nifedipine, papaverine, diltiazem, and nicardipine), antitussives and expectorants (eg, codeine phosphate), antiasthmatics (eg, theophylline), antacids, antispasmodics (eg, atropine, scopolamine), antidiabetics (eg, insulin), diuretics (eg, ethacrynic acid, bendrofluthiazide), antihypertensives (eg, propranolol, clonidine), hypertensives (eg, clonidine, methyldopa), bronchodilators (eg, albuterol), steroids (eg, hydrocortisone, triamcinolone, prednisone), antibiotics (eg, tetracycline), antihemorrhoidal agents, hypnotics, psychotropic agents, antidiarrheals, mucolytics, sedatives, decongestants (eg, pseudoephedrine), laxatives, vitamins, stimulants (including appetite suppressants such as phenylpropanolamine) and cannabinoids, as well as their pharmaceutically acceptable salts, hydrates, solvates and prodrugs.

The active agent may also be a benzodiazepine, barbiturate, stimulant, or mixtures thereof. The term "benzodiazepines" means benzodiazepine and drugs that are benzodiazepine derivatives that have the ability to depress central nervous system functions. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate, as well as their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Benzodiazepine antagonists that can be used as the active agent include, but are not limited to, flumazenil, as well as its pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof.

The term "barbiturates" means sedative-hypnotic drugs formed from barbituric acid (2,4,6-trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbital, butabarbital, butalbital, methohexital, mephobarbital, metarbital, pentobarbital, phenobarbital, secobarbital, and their pharmaceutically acceptable salts, hydrates, solvates, prodrugs, and mixtures thereof. Barbiturate antagonists that can be used as the active agent include, but are not limited to, amphetamines, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

The term "stimulants" includes, but is not limited to, amphetamines such as dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, and their pharmaceutically acceptable salts, hydrates, and solvates, and mixtures thereof. Stimulant antagonists that may be used as an active agent include, but are not limited to, benzodiazepines, and their pharmaceutically acceptable salts, hydrates, solvates, and mixtures thereof.

The dosage forms provided in the present invention include various active agents and pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, etc.; salts derived from organic acids such as formate, acetate, trifluoroacetate, maleate, tartrate, etc.; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; salts derived from amino acids such as arginate, aspartate, glutamate, etc.; and metal salts such as sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dichlorhexylamine salt, N,N'-dibenzylethylenediamine salt, etc.

The dosage form can be stored at elevated temperatures and/or elevated humidity and still retain the appropriate release profile of the active pharmaceutical ingredient over time. In some embodiments, the dosage form may be suitable for pediatric use. The dosage form may be in a form suitable for administration by the oral route, the sublingual route, the buccal route, the vaginal route, or the rectal route. In some embodiments, the dosage form may be suitable for administration by the oral route and may be chewable.

In some embodiments, the finished dosage form may have a shape, without limitation, selected from the group consisting of round, oval, oblong, capsule-shaped, tubular, and teardrop-shaped. In some embodiments, the finished dosage form includes one compartment. In other embodiments, the finished dosage form includes a plurality of compartments (also referred to as chambers). For example, the finished dosage form may include two, three, four, or more chambers.

In some embodiments, the dosage form may further comprise fillers and/or excipients. Fillers and/or excipients, individually or together, may be present in the dosage form at a concentration of about 20% w/w or less, about 15% w/w or less, about 10% w/w or less, about 5% w/w or less, about 4% w/w or less, about 3% w/w or less, about 2% w/w or less, about 1% w/w or less, about 0.5% w/w or less, about 0.1% w/w or less, based on the total weight of the dosage form. In some embodiments, the dosage form may be free of fillers (e.g., may contain 0% w/w). In some embodiments, the dosage form may be free of excipients (e.g., may contain 0% w/w). In some embodiments, the dosage form may contain fillers and/or excipients, individually or together, in an amount in the range of, for example, from about 2 to about 50% w/w, from about 6 to about 40% w/w, from about 10 to about 30% w/w, from about 10 to about 40% w/w, from about 15 to about 35% w/w, from about 20 to about 30% w/w, from about 20 to about 25% w/w, or from about 15 to about 25% w/w, based on the total weight of the dosage form.

Typical fillers may be selected without limitation from the group consisting of lactose, microcrystalline cellulose and combinations thereof.

Typical excipients may be selected, without limitation, from the group consisting of high melting point fats (e.g., triglycerides having a melting point above 25°C), waxes, low melting point oils (e.g., triglycerides having a melting point below 25°C), liquid lipids, surfactants with HLB values greater than 10, solvents, cosolvents, solid high molecular weight polyethylene glycol, liquid polyethylene glycol, lubricants, blowing agents, dispersing agents, gelatin, gum, water-soluble polymers, water, glycerol, sorbitol, cyclodextrins, flavoring agents, disintegrating agents, and combinations thereof. In some embodiments, the dosage form may contain additional excipients such as solubility enhancers, solubilizers (e.g., caprylocaproyl polyoxyl-8-glycerides and polyethyleneglycol monostearate), bioavailability enhancers, plasticizers, coloring agents, opacifying agents, flavoring agents, enzymes, sweeteners, spices, vitamins, preservatives, stabilizers, antioxidants, release agents (e.g., a lipid-based matrix for providing extended release, such as glyceryl distearate), bulking agents, cross-linking agents, anti-caking agents, bioavailability enhancers, diluents, antifoams, buffering agents, foaming agents, bulking agents, excipients, flow-improving agents, mold release agents, granulating agents, binders, oils/fats, pH modifiers, absorbents, glidants (e.g., silicon dioxide), adhesives, anti-adherents (e.g., talc, corn starch, colloidal silicon dioxide (Cab-O-Sil™), DL-leucine, sodium lauryl sulfate, and metallic stearates), acidulants, emollients, resins, demulcents, emulsifiers, osmotic agents, elastomers, bleaching agents (e.g., sodium metabisulfite, sodium bisulfite, or others), aversives such as bitter tastants (e.g., denatonium salts such as denatonium benzoate, denatonium saccharide, and denatonium chloride; sucrose octaacetate; quinine; flavonoids such as quercetin and naringenin; and quassinoids such as quassin and brucine), pungent flavoring agents (e.g. capsaicin, piperine, allyl isothiocyanate and resiniferatoxin), combinations thereof and other functional ingredients in amounts suitable for the purposes for which they are intended. Suitable excipients may be in liquid, semi-liquid and/or solid form.

Typical solvents and/or cosolvents, without limitation, may be selected from the group consisting of ethanol, propylene glycol, glycerol, polyethylene glycol and combinations thereof.

A typical high molecular weight solid polyethylene glycol may, without limitation, be selected from the group consisting of PEG 3350, PEG 4000, PEG 4600, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG up to 10000, and combinations thereof.

A typical liquid polyethylene glycol, without limitation, may be selected from the group consisting of PEG 200, PEG 300, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 2000 and combinations thereof.

Typical water-soluble polymers, without limitation, may be selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), gum, and combinations thereof.

Typical disintegrants, without limitation, may be selected from the group consisting of crosscarmellose, pregelatinized starch, starch, sodium stearyl fumarates, and combinations thereof.

Plasticizers

Typical plasticizers that may be contained in the dosage form may include, but are not limited to, a hydroxy sugar plasticizer such as isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or a polyol plasticizer such as diglycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol with a MW (molecular weight) of up to 10,000, neopentyl glycol, propylene glycol, 1,3 propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyol, ethanolamines; and mixtures thereof. Other typical plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols containing aliphatic hydroxy groups, ester plasticizers, glycol ethers, poly(propylene glycol), multiblock copolymers, monoblock polymers, ester plasticizers - citrates and triacetin. Such plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, 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, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

Coloring agents

Coloring agents in the present invention may also be called "dyes or pigments" or "colorants". Coloring agents mean substances that impart color and/or aesthetic appeal to the dosage form. A dye is a colored substance that has an affinity for the substrate to which it is applied. A dye can be used in an aqueous solution and requires a fixative designed to improve the durability of the dye on the substrate. A pigment is a material that changes the color of reflected or transmitted light as a result of absorption at a certain wavelength. This physical phenomenon differs from fluorescence, phosphorescence and other forms of luminescence, which are based on the emission of light by a material. Both dyes and pigments are colored because they absorb light at some wavelengths to a greater extent than others. Unlike a dye, a pigment is usually insoluble and has no affinity for the substrate.

Typical coloring agents that may be contained in the dosage form may include, but are not limited to, those providing colors such as, for example, white, black, yellow, blue, green, pink, red, orange, purple, dark blue, and brown. In preferred embodiments, the color of the dosage form may indicate the components contained therein (e.g., one or more active ingredients).

Flavoring agents

The term "flavoring agent" means a substance capable of imparting flavor. In addition to providing the consumer with an attractive and pleasant taste, a flavoring substance may also mask the unpleasant taste of the components of the dosage form. A flavoring agent may include natural flavoring agents (e.g., extracts).

The term "aromatic extract" means a flavoring agent obtained by extracting part of a starting material, such as animal or plant material, often using a solvent such as ethanol or water. Most natural essences are obtained by extracting the essential oil from flowers, fruits, roots, etc., or from whole plants, by four methods: expression (when the oil content is large and easy to obtain, as in the case of lemon peel), absorption (usually carried out by immersion in alcohol, as in the case of vanilla beans), maceration (used to obtain smaller parts of the whole, as in extracting peppermint, etc.), and distillation (used in conjunction with maceration, but in many cases requiring specialized chemistry and the assembly of expensive distillation apparatus).

Typical flavoring agents that may be contained in the dosage form may include, but are not limited to, breath freshening compounds such as menthol, mint and cinnamon, coffee beans, other flavorings or fragrances such as fruit flavors (e.g., cherry, orange, grape, etc.), especially those used for oral hygiene, as well as active substances used for cleaning teeth and cleaning the oral cavity, such as quaternary ammonium bases. The effect of flavorings can be enhanced by the use of flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

Fragrances

Typical fragrances that may be contained in the dosage form include, but are not limited to, natural and/or synthetic raw fragrances. For example, these may be oil-soluble perfume oils, which may or may not be in admixture with water-soluble perfume oils. Oil-soluble perfume oils are natural or nature-identical essential oils such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaf oil, peppermint oil, cedarwood oil, rosemary oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, geranium oil, menthol and marjoram oil. A fragrance of animal origin is, for example, musk, castoreum, ambergris or civet. Essences of fresh medicinal plants are also known in the art. They are obtained by fermenting certain herbs, which are then processed to obtain the finished product. Synthetic fragrances are, for example, synthetic essential oils, such as those consisting of individual compounds such as linalool, terpineol, nerol, citronellal, benzaldehyde, cinnamaldehyde, vanillin, ethyl vanillin or methyl acetophenone. Fragrances can also be synthetic oil-soluble perfume oils selected from the usual group consisting of the following: aromatic hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, polyene derivatives. Other odorants that can be used are catalogued and described in publications and databases such as S. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; reprint 2000); Allured's Flavor and Fragrance Materials (2005); and the database maintained by the Research Institute for Fragrance Materials, available at www.rifm.org.

Sweeteners

The term "sweetener" means a substance capable of providing an attractive and pleasant taste to the consumer and/or capable of masking the unpleasant taste of the components of the dosage form. Typical sweeteners that may be contained in the dosage form may include, but are not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame and its various salts such as the potassium salt (marketed under the name Sunett®), alitame, aspartame (marketed under the names NutraSweet® and Equal®), aspartame-acesulfame salt (marketed under the name Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts such as the sodium salt (marketed under the name Sweet'N Low®), stevia, chlorinated sucrose derivatives such as sucralose (marketed under the names Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); honey stevia (stevioside), natural intense sweeteners such as monk fruit, polyols such as sorbitol, mannitol, xylitol, erythritol, etc.

Vitamins

As used herein, the term "vitamin" means an organic compound required by the body as a vital nutrient in limited quantities. An organic chemical compound (or set of related compounds) is called a vitamin if it cannot be synthesized by the body in sufficient quantities and must be obtained from food. Thus, the meaning of the term depends on both the circumstances and the particular organism. For example, ascorbic acid (vitamin C) is a vitamin for humans, but not for most other animals, and biotin and vitamin D are required in the human diet only under certain circumstances.

Typical human-grade vitamins that may be contained in the dosage form may include, but are not limited to, vitamin A (e.g., retinol, retinal, and 4 carotenoids including beta-carotene), vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (e.g., niacin and niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (e.g., pyridoxine, pyridoxamine, and pyridoxal), vitamin B7 (biotin), vitamin B9 (e.g., folic acid and folinic acid), vitamin B12 (e.g., cyanocobalamin, hydroxocobalamin, and methylcobalamin), vitamin C (ascorbic acid), vitamin D (cholecalciferol), vitamin E (e.g., tocopherols and tocotrienols), and vitamin K (e.g., phylloquinone, phytonadione, and menaquinones).

Preservatives

The term "preservative" as used herein means an agent that provides for an extension of the shelf life of a dosage form by delaying or preventing deterioration in taste, color, odor, texture, appearance, therapeutic value or safety. It is necessary that the preservative provide a lethal, irreversible effect resulting in partial or complete destruction of microbial cells or impairment of their activity. Sterilants, disinfectants, sanitizers, spore killers, antivirals and tuberculosis destroyers have an irreversible effect, sometimes called a "bactericidal" effect. In contrast, a preservative may have an inhibitory and bacteriostatic effect, which is reversible in the sense that the target microbes can resume proliferation if the preservative is removed. The fundamental difference between a preservative and a disinfectant is mainly in the mode of action (a preservative prevents the growth of microorganisms, rather than destroying them) and the duration of action (a preservative acts for several days to months, whereas a disinfectant acts for no more than a few minutes).

Antioxidants

Typical antioxidants that may be contained in the dosage form may include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioethers/esters, and combinations of the foregoing. Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols including, but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-dimethylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylcyclohexyl)-4,6-dimethylphenol, 2,6-dioctadecyl-4-methylphenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4-methoxymethylphenol, nonylphenols that have linear or branched side chains, such as 2,6-di-nonyl-4-methylphenol, 2,4-dimethyl-6-(1'-methylundec-1'-yl)phenol, 2,4-dimethyl-6-(1'-methylheptadec-1'-yl)phenol, 2,4-dimethyl-6-(1'-methyltridec-1-yl)phenol and mixtures thereof, alkylthiomethylphenols including but not limited to 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-dioctylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol, hydroquinones and alkylated hydroquinones including but not limited to, 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-di-tert-butyl-4-hydroxyphenyl)adipate, tocopherols including but not limited to, α-tocopherol, β-tocopherol, γ-tocopherol, 5-tocopherol and mixtures thereof (vitamin E), hydroxylated thiodiphenyl ethers, including but not limited to 2,2'-thiobis(6-tert-butyl-4-methylphenol), 2,2'-thiobis(4-ethylphenol), 4,4'-thiobis(6-tert-butyl-3-methylphenol), 4,4'-thiobis(6-tert-butyl-2-methylphenol), 4,4'-thiobis(3,6-di-sec-amylphenol), 4,4'-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide, alkylidenebisphenols including but not limited to 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 2,2'-methylenebis(6-tert-butyl-4-ethylphenol), 2,2'-methylenebis[4-methyl-6-(α-methylcyclohexyl)phenol], 2,2'-methylenebis(4-methyl-6-cyclohexylphenol), 2,2'-methylenebis(6-nonyl-4-methylphenol), 2,2'-methylenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(6-tert-butyl-4-isobutylphenol), 2,2'-methylenebis[6-(α-methylbenzyl)-4-nonylphenol], 2,2'-methylenebis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4'-methylenebis(2,6-di-tert-butylphenol), 4,4'-methylenebis(6-tert-butyl-2-methylphenol), 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-bis(3-tert-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-tris(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3'-tert-butyl-4'-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methylphenyl)-dicyclopentadiene, bis[2-(3'-tert-butyl-2'-hydroxy-5'-methylbenzyl)-6-tert-butyl-4-methylphenyl] terephthalate, 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-4-n-dodecylmercaptobutane, 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane, containing O-, N- and S-benzyl compounds including, but not limited to, 3,5,3',5'-tetra-tert-butyl 4,4'-dihydroxydibenzyl ether, octadecyl 4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl 4-hydroxy-3,5-di-tert-butylbenzyl mercaptoacetate, tris(3,5-di-tert-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl 3,5-di-tert-butyl-4-hydroxybenzyl mercaptoacetate, hydroxybenzylated malonates including but not limited to dioctadecyl 2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, dioctadecyl 2-(3-tert-butyl-4-hydroxy-5-methylbenzyl) malonate, didodecylmercaptoethyl 2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl) malonate, bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl) malonate, aromatic hydroxybenzyl compounds including but not limited to 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol, triazine compounds including but not limited to 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,3,5-triazine, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenylethyl)-1,3,5-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexahydro-1,3,5-triazine, 1,3,5-tris(3,5-dicyclohexyl-4-hydroxybenzyl)isocyanurate, benzyl phosphonates including but not limited to dimethyl 2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate dioctadecyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl 5-tert-butyl-4-hydroxy-3-methylbenzylphosphonate, calcium salt of monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzylphosphonic acid, acylaminophenols including, but not limited to, 4-hydroxylauranilide, 4-hydroxystearanilide, octyl N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamate, esters of β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid formed with mono- or polyhydric alcohols, for example, with methanol, ethanol, n-octanol, isooctanoic acid, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, esters of β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid formed with mono- or polyhydric alcohols, for example, with methanol, ethanol, n-octanol, isooctanoic acid, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexaneol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]-2,4,8,10-tetraoxaspiro-[5.5]undecane, esters of 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid formed with mono- or polyhydric alcohols, for example, with methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo-[2.2,2]octane, esters of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid formed with mono- or polyhydric alcohols, for example, with methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)-isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, amides of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, such as N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexamethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazide, N,N'-bis[2-(3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyloxy)ethyl]oxamide (Naugard®XL-1, manufactured by Uniroyal), ascorbic acid (vitamin C), amine antioxidants including, but not limited to, N,N'-diisopropyl-p-phenylenediamine, N,N'-di-sec-butyl-p-phenylenediamine, N,N'-bis(1,4-dimethylpentyl)-p-phenylenediamine, N,N'-bis(1-ethyl-3-methylpentyl)-p-phenylenediamine, N,N'-bis(1-methylheptyl)-p-phenylenediamine, N,N'-dicyclohexyl-p-phenylenediamine, N,N'-diphenyl-p-phenylenediamine, N,N'-bis(2-naphthyl)-p-phenylenediamine, N-isopropyl-N'-phenyl-p-phenylenediamine, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine, N-(1-methylheptyl)-N'-phenyl-p-phenylenediamine, N-cyclohexyl-N'-phenyl-p-phenylenediamine, 4-(p-toluenesulfamoyl)diphenylamine, N,N'-dimethyl-N,N'-di-sec-butyl-p-phenylenediamine, diphenylamine, N-allyldiphenylamine, 4-isopropoxydiphenylamine, N-phenyl-1-naphthylamine, N-(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine, octylated diphenylamine including but not limited to p,p'-di-tert-octyldiphenylamine, 4-n-butylaminophenol, 4-butyrylaminophenol, 4-Nonanoylaminophenol, 4-dodecanoylaminophenol, 4-octadecanoylaminophenol, bis(4-methoxyphenyl)amine 2,6-di-tert-butyl-4-dimethylaminomethylphenol, 2,4'-diaminodiphenylmethane, 4,4'-diaminodiphenylmethane, N,N,N',N'-tetramethyl-4,4'-diaminodiphenylmethane, 1,2-bis[(2-methylphenyl)amino]ethane, 1,2-bis(phenylamino)propane, (o-tolyl)biguanide, bis[4-(1',3'-dimethylbutyl)phenyl]amine, tert-octylated N-phenyl-1-naphthylamine, mixture of mono- and dialkylated tert-butyl/tert-octyldiphenylamines, mixture of mono- and dialkylated nonyldiphenylamines, a mixture of mono- and dialkylated dodecyldiphenylamines, a mixture of mono- and dialkylated isopropyl/isohexyldiphenylamines, a mixture of mono- and dialkylated tert-butyldiphenylamines, 2,3-dihydro-3,3-dimethyl-4H-1,4-benzothiazine, phenothiazine, a mixture of mono- and dialkylated tert-butyl/tert-octylphenothiazines, a mixture of mono- and dialkylated tert-octylphenothiazines, N-allylphenothiazine, N,N,N',N'-tetraphenyl-1,4-diaminobut-2-ene, and combinations of the foregoing.

Lubricants/release agents

Lubricants/release agents suitable for the dosage form may include, but are not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants may include, but are not limited to, glyceryl behenate (Compritol™ 888), metallic stearates (e.g., magnesium, calcium, and sodium stearates), stearic acid, hydrogenated vegetable oils (e.g., Sterotex™), talc, waxes such as beeswax and carnauba wax, silicon dioxide, finely divided silicon dioxide, colloidal silicon dioxide, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-leucine, polyethylene glycols (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv™), lauryl sulfate magnesium, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin, propylene glycol and combinations thereof.

Volumizing agents/anti-caking agents/anti-sticking agents

Bulking agents/anti-caking agents/tackifying agents suitable for the dosage form may include, but are not limited to, starches, modified starches, cross-linked polyvinylpyrrolidone, cross-linked cellulose, microcrystalline cellulose, silicon dioxide, metal oxides, calcium carbonate, talc and mica.

Thinners

Suitable diluents useful in the dosage forms of the present invention include, but are not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, calcium hydrogen phosphate dihydrate NF, sucrose based diluents, confectioners' sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, granulated calcium lactate trihydrate NF, dextrates NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed cereal products such as Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, etc.

Oils/fats

Typical oils and fats that may be contained in the dosage form may include, but are not limited to, almond oil, argan oil, avocado oil, canola oil, cashew nut oil, castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hempseed oil, hydroxylated lecithin, lecithin, flaxseed oil, macadamia nut oil, mango butter, manila hemp oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, and watermelon oil. oil. Other oils and fats that may be contained in the PVA (polyvinyl acetate) casing may include, but are not limited to, fish oil (omega-3), krill oil, animal or vegetable fats, such as those in their hydrogenated form, mono-, di- and triglycerides of fatty acids _C12 , _C14 , _C16 , _C16 , _C20 and _C22 .

pH modifiers

Typical pH modifiers that may be contained in the dosage form may include, but are not limited to, hydrochloric acid, potassium hydroxide, sodium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, and nitric acid.

Other inert fillers

Other typical excipients that may be present in the dosage form may include, but are not limited to, gelatin, vegetable proteins such as sunflower proteins, soy proteins, cottonseed proteins, peanut proteins, grape proteins, whey proteins, whey protein isolates, blood proteins, egg whites, acrylated proteins, water soluble polysaccharides such as alginates, carrageenans, guar gum, agar-agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragacanth), pectin, water soluble cellulose derivatives: alkyl celluloses, hydroxyalkyl celluloses and hydroxyalkyl alkyl celluloses such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, hydroxybutyl methylcellulose, cellulose esters and hydroxyalkyl cellulose esters such as cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose (HPMC); carboxyalkyl celluloses, carboxyalkyl alkyl celluloses, carboxyalkyl cellulose esters such as carboxymethyl cellulose and its alkali metal salts; water-soluble synthetic polymers such as polyacrylic acids, polyacrylamides and polyacrylic acid esters, polymethacrylic acids, polymethacrylamides and polymethacrylic acid esters, polyvinyl acetates, polyvinyl alcohols, polyvinyl acetate phthalates (PVAP), polyvinylpyrrolidone (PVP), PVP/vinyl acetate copolymer and polycrotonic acids; Also suitable are phthalated gelatin, gelatin succinate, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates containing, for example, a tertiary or quaternary amino group such as a diethylaminoethyl group, which may optionally be quaternized; and other similar polymers; inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium, etc.

Other pharmaceutically acceptable excipients that can be used in the dosage form can include, but are not limited to, a hydrophobic material including, but not limited to, digestible, long chain (C ₈ -C ₅₀ , preferably C ₁₂ -C ₄₀ ) saturated or unsaturated hydrocarbons such as natural or synthetic waxes (such as beeswax, Glycowax®, hydrogenated castor oil and carnauba wax), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl alcohol or, preferably, cetostearyl alcohol), fatty acids including, but not limited to, mono- and diglycerides of medium chain fatty acids (such as caprylic, capric, caproic, lauric, oleic, linoleic acid), medium chain triglycerides, fatty acid esters, fatty acid glycerides (mono-, di- and triglycerides), hydrogenated fats, hydrocarbons, common waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon chains.

Additional pharmaceutically acceptable excipients may further include polyvinyl alcohols, polyvinylpyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetates, polycarboxylic acids and their salts, acetic acid, caprylic acid, oleic acid, polyamino acids or peptides, polyamides, polyacrylamide, maleic acid/acrylic acid copolymers, polysaccharides including starch and gelatin, natural gums such as xanthan, and carrageenans. For example, the polymers may be selected from the following: polyacrylates and water-soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, maltodextrin, polymethacrylates and combinations thereof, or they may be selected from the following: polyvinyl alcohols, polyvinyl alcohol-hydroxypropyl methylcellulose (HPMC) copolymers, methacrylic acid/methyl methacrylate copolymers, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caprylocaproyl polyoxyl-8 glycerides, glyceryl distearate and combinations thereof.

Surfactants with an HLB value greater than 10

Suitable high HLB surfactants may include, but are not limited to, polysorbate 80 (polyoxyethylene (20) sorbitan monooleate), polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, caprylocaproyl macrogol glycerides, and combinations thereof.

Release rate

The dosage forms disclosed in the present invention may have an immediate release profile.

In some embodiments, when tested in an in vitro dissolution study using USP Apparatus 1 (with a #40 mesh basket), USP Apparatus 2 (with paddles), or USP Apparatus 3 (with a reciprocating cylinder), in an aqueous medium (at a pH in the range of from about 1 to about 8) at a temperature of about 37°C, the dosage forms disclosed herein release at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the active agent within 15 minutes.

In some embodiments, when tested in an in vitro dissolution study using USP Apparatus 1 (with a #40 mesh basket), USP Apparatus 2 (with paddles), or USP Apparatus 3 (with a reciprocating cylinder), in an aqueous medium (at a pH in the range of from about 1 to about 8) at a temperature of about 37°C, the dosage forms disclosed herein release at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the active agent within 30 minutes.

In some embodiments, when tested in an in vitro dissolution study using USP Apparatus 1 (with a #40 mesh basket), USP Apparatus 2 (with paddles), or USP Apparatus 3 (with a reciprocating cylinder), in an aqueous medium (at a pH in the range of from about 1 to about 8) at a temperature of about 37°C, the dosage forms disclosed herein release at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the active agent within 45 minutes.

In some embodiments, when tested in an in vitro dissolution study using USP Apparatus 1 (with a #40 mesh basket), USP Apparatus 2 (with paddles), or USP Apparatus 3 (with a reciprocating cylinder), in an aqueous medium (at a pH in the range of from about 1 to about 8) at a temperature of about 37°C, the dosage forms disclosed herein release at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the active agent within 60 minutes.

The dosage forms disclosed in the present invention may have an extended release profile.

In some embodiments, the dosage form disclosed herein may release from about 10 to about 30 wt.% of the active agent in 1 hour, from about 25 to about 50 wt.% of the active agent in 2 hours, from about 40 to about 80 wt.% of the active agent in 4 hours, from about 65 to about 95 wt.% of the active agent in 8 hours, from about 80 to about 100 wt.% of the active agent in 12 hours, and more than 90 wt. % active agent in 24 hours, in each case the amount determined by an in vitro dissolution study carried out using USP apparatus 1 (with basket) at 100 rpm, using USP apparatus 2 (with paddles) at 50 rpm, 75 rpm or 100 rpm, or using USP apparatus 3 (with reciprocating cylinder), in an aqueous medium (at pH = 1-8) at 37°C.

In some embodiments, the dosage form disclosed herein can release from about 15 to about 25% by weight of the active agent in 1 hour, from about 30 to about 40% by weight of the active agent in 2 hours, from about 55 to about 75% by weight of the active agent in 4 hours, from about 75 to about 85% by weight of the active agent in 8 hours, from about 90 to about 100% by weight of the active agent in 12 hours, and more than 95% by weight of the active agent in 12 hours. % active agent in 24 hours, in each case the amount determined by an in vitro dissolution study carried out using USP apparatus 1 (with basket) at 100 rpm, using USP apparatus 2 (with paddles) at 50 rpm, 75 rpm or 100 rpm, or using USP apparatus 3 (with reciprocating cylinder), in an aqueous medium (at pH = 1-8) at 37°C.

In some embodiments, the release profile of the active pharmaceutical ingredient from the dosage form after conducting the accelerated stability study may be comparable to its release profile before conducting the accelerated stability study. In some embodiments, when comparing the release profile of the active pharmaceutical ingredient before conducting the accelerated stability study, the release profile of the active pharmaceutical ingredient from the dosage form after conducting the accelerated stability study has a similarity factor (f2) of at least about 50 (e.g., from about 50, about 55, about 60, about 65, about 70, or about 75 to about 80, about 85, about 90, about 95, or about 100). The terms "comparable" or "similarity factor (f2)" may be used interchangeably in the present invention and mean that when comparing the release profile of an active pharmaceutical ingredient before an accelerated stability study, the release profile of an active pharmaceutical ingredient after an accelerated stability study is considered similar or biologically equivalent if the f2 value is at least about 50.

The similarity coefficient (f2) can be used to compare the dissolution profiles of the test and reference products. The similarity coefficient (f2) can be calculated based on the following equation:

where n denotes the number of time points, R _t denotes the amount of dissolved reference sample at time t, and T _t denotes the amount of dissolved test sample at time t, as described in the FDA (Food and Drug Administration) Guidance to Industry, published in December 2017, regarding bioequivalence studies for solid oral dosage forms (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/waiver-vivo-bioavailability-and-bioequivalence-studies-immediate-release-solid-oral-dosage-forms, section III, part C, incorporated herein by reference).

In embodiments provided herein, the accelerated stability study can be conducted for about 2 days, about 5 days, about 7 days, about 14 days, about 21 days, about 28 days, about 56 days, about 84 days, about 112 days, about 140 days, about 168 days, about 365 days, about 1 month, about 2 months, about 3 months, about 6 months, about 12 months, about 2 days to about 12 months, about 7 days to about 12 months, about 1 month to about 12 months, about 1 month to about 6 months, or about 1 month to about 3 months. In one embodiment, the accelerated stability study can be conducted for at least about 1 month. In one embodiment, the accelerated stability study can be conducted for at least about 2 months. In one embodiment, the accelerated stability study can be conducted for at least about 3 months.

In embodiments provided by the present invention, the accelerated stability study can be conducted at a temperature in the range of about 25 to about 40°C, and at a humidity in the range of about 60 to about 75%. In some embodiments, the accelerated stability study can be conducted at a temperature of about 40°C and at a relative humidity of about 75%.

In one embodiment, the similarity factor (f2) of the release profile of the API (active pharmaceutical ingredient) from a dosage form according to one embodiment after conducting an accelerated stability study at 40°C and at a relative humidity of 75% for about 1 month and its release profile before conducting the accelerated stability study is in the range of from about 50 to about 70, from about 55 to about 65, or from about 58 to about 62.

In one embodiment, the similarity factor (f2) of the release profile of the API from a dosage form according to one embodiment after conducting an accelerated stability study at 40°C and at a relative humidity of 75% for about 2 months and its release profile before conducting the accelerated stability study is in the range of from about 50 to about 70, from about 53 to about 68, or from about 55 to about 66.

In one embodiment, the similarity factor (f2) of the release profile of the API from a dosage form according to one embodiment after conducting an accelerated stability study at 40°C and at a relative humidity of 75% for about 3 months and its release profile before conducting the accelerated stability study is in the range of from about 50 to about 95, from about 51 to about 60, from about 52 to about 55, from about 85 to about 95, or from about 88 to about 92.

The release/dissolution profile of an active pharmaceutical ingredient (API) contained in a dosage form can be determined in accordance with the FDA guidance published in December 2017 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/waiver-vivo-bioavailability-and-bioequivalence-studies-immediate-release-solid-oral-dosage-forms), incorporated herein by reference. More specifically, the release/dissolution profile of the API can be determined by an in vitro dissolution study conducted using USP Apparatus 1 (with basket) at 100 rpm, using USP Apparatus 2 (with paddles) at 50 rpm, 75 rpm or 100 rpm, or using USP Apparatus 3 (with reciprocating cylinder), in an aqueous medium (at pH = 1-8) at 37°C, using 500 ml (or 900 ml if the amounts are changed accordingly) of the following dissolution medium: (1) 0.1 N HCl solution or USP Simulated Gastric Fluid (SGF) without added enzymes, (2) a buffer having a pH of 4.5, (3) a buffer having a pH of 6.8 or USP Simulated Intestinal Fluid without added enzymes.

It should be understood that the dosage forms disclosed in the present invention have a release profile after a stability study conducted at least one temperature in the range of from about 25 to about 40°C (for example, about 40°C), and at least one humidity in the range of from about 60 to about 75% (for example, at about 75% humidity), and at least one time period selected from the following time periods: T=1 month, T=2 months, and T=3 months, comparable to the release profile before conducting the accelerated stability study. The dosage form may optionally have a release profile after a stability study conducted at each individual temperature, humidity, and time period within the specified range, comparable to the release profile before conducting the accelerated stability study. Thus, a dosage form that maintains a release profile after an accelerated stability study, for example, at 30°C, at 70% humidity, and at T=1 month, that is comparable to the release profile before the stability study, meets the specified specification, even if the same dosage form does not maintain a comparable release profile after an accelerated stability study, for example, at 35°C, at 75% humidity, and at T=3 months. Similarly, a dosage form with a similarity factor (f2) of greater than 50 after an accelerated stability study, for example, at 40°C, at 75% humidity, and at T=1 month, meets the specified specification, even if the same dosage form does not have a similarity factor (f2) of greater than 50 after an accelerated stability study, for example, at 40°C, at 75% humidity, and at T=2 months.

Methods of preparation, stabilization and treatment

In some embodiments, the present invention relates to a method for stabilizing the release profile of a dosage form. The method may include incorporating a surfactant and at least one solid or semi-solid lipid into a dosage form containing an active pharmaceutical ingredient and hardening the dosage form. The surfactant may have an HLB value of less than 10. The release profile of the active pharmaceutical ingredient from the dosage form stabilized according to this method may be comparable to its release profile before conducting an accelerated stability study.

Incorporating a surfactant together with at least one solid or semi-solid lipid may involve forming a homogeneous mixture. A matrix may be formed from the homogeneous mixture.

The curing of the dosage form can be carried out at a temperature in the range of from about 10 to about 100°C, from about 20 to about 80°C, or from about 30 to about 60°C. The curing time can be in the range of from about 1 hour to about 14 days, from about 2 hours to about 10 days, or from about 3 hours to about 7 days. In one embodiment, the curing of the dosage form can be carried out at a temperature of 50°C for about 7 days.

In some embodiments, the method of stabilizing the release profile of an active pharmaceutical ingredient from a dosage form may further comprise dissolving or suspending the active pharmaceutical ingredient in a homogeneous mixture or matrix.

In some embodiments, the method of stabilizing the release profile of an active pharmaceutical ingredient from a dosage form may further comprise dispensing the active pharmaceutical ingredient, dissolved or suspended in a homogeneous mixture or matrix, into pre-prepared cavities using a rotary tableting machine. The blister with the dose-containing cavities may then be cooled and sealed. This approach may eliminate the need for fillers, thereby maximizing the amount of dissolved and/or bioavailability-enhancing materials.

In some embodiments, the method of stabilizing the release profile of an active pharmaceutical ingredient from a dosage form may further comprise placing the active pharmaceutical ingredient, dissolved or suspended in a homogeneous mixture or in a matrix, in a soft-shell capsule or in a hard-shell capsule (e.g., in a soft gelatin capsule or in a starch or carrageenan-based capsule).

In some embodiments, the method for stabilizing the release profile of an active pharmaceutical ingredient from a dosage form may further comprise solidifying the active pharmaceutical ingredient dissolved or suspended in a homogeneous mixture or in a matrix, and compressing the solidified active pharmaceutical ingredient contained in the homogeneous mixture or in a matrix to obtain a tablet. Solidifying the active pharmaceutical ingredient dissolved or suspended in a homogeneous mixture or in a matrix may comprise drying in drying chambers, freeze drying, or cooling the active pharmaceutical ingredient dissolved or suspended in a homogeneous mixture or in a matrix.

In some embodiments, the method of stabilizing the release profile of an active pharmaceutical ingredient from a dosage form may further comprise extruding the active pharmaceutical ingredient dissolved or suspended in a homogeneous mixture or matrix.

In some embodiments, the present invention relates to a method for preparing a dosage form. One typical method may include mixing an active pharmaceutical ingredient with a surfactant and at least one solid or semi-solid lipid to form a mixture. The method may further include heating the mixture to melt the at least one solid or semi-solid lipid to form a molten mixture. The method may further include molding the molten mixture to form a dosage form and solidifying the dosage form.

In one embodiment, shaping the molten mixture to form a dosage form may include dispensing the molten mixture into a pre-formed depression of a blister. In one embodiment, shaping the molten mixture to form a dosage form may include encapsulating the molten mixture into a hard-shell capsule or a soft-shell capsule.

Another typical method may include mixing the active pharmaceutical ingredient with a surfactant with an HLB value of less than 10 and at least one solid or semi-solid lipid in an extruder. The method may further include extruding the active pharmaceutical ingredient, the surfactant and at least one solid or semi-solid lipid to form a dosage form. The method may further include solidifying the dosage form.

Another typical method may include solubilizing/dissolving an active pharmaceutical ingredient, a surfactant with an HLB value of less than 10, and at least one solid or semi-solid lipid in a solvent. The method may further include spray drying or spray freezing the solubilized/dissolved active pharmaceutical ingredient, the surfactant, and at least one solid or semi-solid lipid to obtain a powder. The method may further include solidifying the powder.

The release profile of the active pharmaceutical ingredient from a dosage form prepared according to these methods after an accelerated stability study may be comparable to its release profile before the accelerated stability study.

The curing of the dosage form carried out in the various preparation methods described in the present invention can be carried out at a temperature in the range of from about 10 to about 100°C, from about 20 to about 80°C, or from about 30 to about 60°C. The curing time can be in the range of from about 1 hour to about 14 days, from about 2 hours to about 10 days, or from about 3 hours to about 7 days. In one embodiment, the curing of the dosage form can be carried out at a temperature of 50°C for about 7 days.

Any active pharmaceutical ingredients, surfactants, solid or semi-solid lipids, solvents and other fillers and/or excipients disclosed in the present invention can be included in the dosage form at various stages of any of the processes disclosed in the present invention (e.g., various additional components can be mixed, dissolved, suspended, heated, cooled, solidified, extruded, solidified, dried, etc. together with a solid or semi-solid lipid, a surfactant with an HLB value of less than 10 and an active pharmaceutical ingredient).

In some embodiments, the present invention relates to a method of treatment comprising administering to a patient in need thereof any of the dosage forms disclosed herein in a therapeutically effective amount.

ILLUSTRATIVE EXAMPLES

The following examples are provided to facilitate understanding of the present invention and should not be construed as specifically limiting the present invention as described and claimed herein. It is intended that such modifications of the present invention as including substitution of all equivalents now known or later developed that are within the competence of those skilled in the art, and changes in compositions or minor changes in experimental design are included within the scope of the present invention as disclosed herein.

Example 1

The dissolution/release profiles for the three compositions (presented in Table 1 below) are shown in Figs. 1A, 1B, 2A, 2B, 3A, and 3B. Figs. 1A, 2A, and 3A show the dissolution/release profiles for the uncured compositions. Figs. 1B, 2B, and 3B show the dissolution/release profiles for the cured compositions. The compositions for which results are presented in Figs. 1B, 2B, and 3B were cured at a temperature of about 50°C for about 7 days. During the accelerated dissolution study, the dissolution profile for each composition (cured and uncured) was determined at 4 time points: 1) immediately after preparation (T=0), 2) after storage for 1 month (T=1 month), 3) after storage for 2 months (T=2 months), and 4) after storage for 3 months (T=3 months). During the accelerated dissolution study, the storage conditions were 40°C and 75% relative humidity. All samples were tested three times.

Fig. 1A shows the dissolution/release profile for uncured sample 1A over 12 h, determined at T=0, T=1 month, T=2 months, and T=3 months. Each sample was tested in triplicate. The average numerical values are presented in Table 2 below.

Fig. 1B shows the dissolution/release profile for cured sample 1B over 12 h, determined at T=0, T=1 month, T=2 months, and T=3 months. Each sample was tested in triplicate. The average numerical values are presented in Table 3 below.

Fig. 2A shows the dissolution/release profile for uncured sample 2A over 24 h, determined at T=0, T=1 month, T=2 months, and T=3 months. Each sample was tested in triplicate. The average numerical values are presented in Table 4 below.

Fig. 2B shows the dissolution/release profile for cured sample 2B over 24 h, determined at T=0, T=1 month, T=2 months, and T=3 months. Each sample was tested in triplicate. The average numerical values are presented in Table 5 below.

Fig. 3A shows the dissolution/release profile for uncured sample 3A over 24 h, determined at T=0, T=1 month, T=2 months, and T=3 months. Each sample was tested in triplicate. The average numerical values are presented in Table 6 below.

Fig. 3B shows the dissolution/release profile for cured sample 3B over 24 h, determined at T=0, T=1 month, T=2 months, and T=3 months. Each sample was tested in triplicate. The average numerical values are presented in Table 7 below.

The similarity coefficients for: a) T=1 month when compared with T=0, b) T=2 months when compared with T=0 and c) T=3 months when compared with T=0 for each of the samples (sample 1A, sample 1B, sample 2A, sample 2B, sample 3A and sample 3B) are presented in the table below.

As can be seen from Table 8, in the case of the comparative uncured sample 1A, a change in its API release profile is observed after the accelerated stability study (at 40°C and 75% relative humidity) at T=1 month and at T=2 months, as indicated by a similarity factor (f2) of less than 50. After processing under the accelerated stability study conditions (at 40°C and 75% relative humidity) for 3 months (T=3 months), an unintentional curing of the sample occurs, which probably leads to an improvement in the similarity factor (f2 is approximately 65).

For comparative sample 1B, curing is shown to improve the stability of the API release profile from the dosage form over time, as indicated by the f2 value for cured sample 1B of 44.24 at T=1 month, which is higher than the f2 value for uncured sample 1A of 28.14 at T=1 month. Further improvement in the f2 value for cured sample 1B is observed at T=2 months and T=3 months, likely due to unintended additional curing of the sample. However, without imposing limitations, it can be assumed that curing alone is not sufficient to provide an f2 similarity factor greater than or equal to 50 at all time points in the accelerated stability study (T=1 month, 2 months, and 3 months).

Samples 2A and 3A are samples that included a low HLB surfactant but were not cured. Without imposing limitations, it can be assumed that the inclusion of a low HLB surfactant alone is insufficient to provide an f2 similarity factor greater than or equal to 50 at all time points in the accelerated stability study (T=1 month, 2 months, and 3 months). This can be confirmed by the f2 value for sample 2A of 47.08 at T=2 months and the f2 value for sample 3A of 41.05 at T=month.

In contrast, samples 2B and 3B, which included a low HLB surfactant and were cured, respectively, had a similarity factor, f2, greater than or equal to 50 at all time points in the accelerated stability study (T=1 month, 2 months, and 3 months).

As shown in the figures and tables, the inclusion of a low HLB surfactant in the composition and curing of the composition provides for a reduction in the change in the release profile of the API over time and a stabilization of the dissolution/release profile of the active pharmaceutical ingredient contained in the dosage form over time. Without imposing limitations, it can be assumed that curing alone, carried out without including a low HLB surfactant in the composition, may be insufficient, and that only including a low HLB surfactant, without curing the dosage form, may be insufficient.

For ease of explanation, the embodiments and methods of the present invention are shown and described as a sequence of actions. However, the actions of the present invention can be performed in any order and/or simultaneously and together with other actions not shown and described herein. In addition, not all illustrated events may be required to perform the methods according to the claimed subject matter. In addition, it should be understood and obvious to those skilled in the art that the methods can alternatively be represented as a series of interrelated states in the form of a state diagram or events.

In order to provide a thorough understanding of the present invention, numerous specific features are set forth in the foregoing description, such as specific materials, dimensions, method parameters, and the like. The specific features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The words "example" or "typical" are used herein to indicate an example, instance, or illustration. Any feature or design described herein as "example" or "typical" is not necessarily preferred or advantageous over other features or designs. Rather, the use of the words "example" or "typical" is intended to describe representations in a particular manner. As used in this application, the term "or" is meant to be an inclusive "or" rather than an exclusive "or." This means that unless otherwise indicated or obvious from context, "X includes A or B" means any conventional inclusive permutation. This means that if X includes A; X includes B; or X includes both A and B, then "X includes A or B" means any of the above. In the present invention, reference to the expressions "an embodiment," "some embodiments," or "one embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, all the expressions "an embodiment," "some embodiments," or "one embodiment" in different parts of the present specification do not necessarily mean the same embodiment.

The present invention has been described with reference to specific exemplary embodiments thereof. Accordingly, the description and drawings are to be considered as illustrative and not restrictive. Various modifications of the present invention in addition to those shown and described herein will be apparent to those skilled in the art and are intended to be within the scope of the appended claims.

Claims (56)

1. A method for stabilizing the release profile of a dosage form, comprising: the inclusion of a surfactant and glyceryl distearate in the dosage form; and hardening of a dosage form containing an active pharmaceutical ingredient, wherein the release profile of the active pharmaceutical ingredient after conducting the accelerated stability study has a similarity factor (f2) of at least 50 when compared to the release profile of the active pharmaceutical ingredient before conducting the accelerated stability study, wherein the accelerated stability study is conducted at a temperature of about 40°C and at a humidity of about 75% for at least 1 month; wherein the surfactant has an HLB value of less than about 10 and is selected from sorbitan fatty acid esters, and combinations thereof; where the dosage form additionally contains inert fillers; and wherein curing is carried out at a temperature in the range of from about 30°C to about 60°C for from about 3 hours to about 7 days. 2. The method of claim 1, wherein the surfactant comprises sorbitan fatty acid esters selected from the group consisting of sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan sesquistearate, sorbitan diisostearate, sorbitan dioleate, sorbitan triisostearate, sorbitan trioleate, sorbitan tristearate, and combinations thereof. 3. The method according to claim 1 or 2, wherein the active pharmaceutical ingredient has a half-life of less than about 8 hours. 4. The method according to any one of claims 1-3, wherein the active pharmaceutical ingredient is selected from the group consisting of dabigatran, dronedarone, ticagrelor, iloperidone, ivacaftor, midostaurin, azimadoline, beclomethasone, apremilast, sapacitabine, lincitinib, abiraterone, vitamin D analogues, COX-2 inhibitors, tacrolimus, testosterone, lubiprostone, pharmaceutically acceptable salts thereof and combinations thereof. 5. The method according to claim 4, wherein the active pharmaceutical ingredient comprises vitamin D analogues selected from the group consisting of calcifediol, calcitriol, paricalcitol, doxercalciferol, their pharmaceutically acceptable salts and combinations thereof. 6. The method of claim 4, wherein the active pharmaceutical ingredient comprises COX-2 inhibitors selected from the group consisting of celecoxib, valdecoxib, rofecoxib, pharmaceutically acceptable salts thereof, and combinations thereof. 7. The method of any one of claims 1 to 6, wherein the incorporation comprises obtaining a homogeneous mixture of a surfactant and glyceryl distearate, wherein the homogeneous mixture forms a matrix. 8. The method of claim 7, further comprising dissolving or suspending the active pharmaceutical ingredient in the matrix. 9. The method of claim 7, further comprising placing the active pharmaceutical ingredient, dissolved or suspended in the matrix, into a soft-shell capsule or a hard-shell capsule. 10. The method of claim 8, further comprising solidifying an active pharmaceutical ingredient dissolved or suspended in the matrix, and compressing the solidified active pharmaceutical ingredient contained in the matrix into a tablet. 11. The method of claim 10, wherein the curing comprises drying in drying chambers, freeze drying or cooling the active pharmaceutical ingredient dissolved or suspended in the matrix. 12. The method of claim 8, further comprising extruding the active pharmaceutical ingredient dissolved or suspended in the matrix. 13. The method of any one of claims 1 to 12, wherein the dosage form comprises about 20% w/w or less, about 15% w/w or less, about 10% w/w or less, about 5% w/w or less, about 4% w/w or less, about 3% w/w or less, about 2% w/w or less, about 1% w/w or less, about 0.5% w/w or less, about 0.1% w/w or less, or 0% w/w of fillers, based on the total weight of the dosage form. 14. The method according to claim 13, wherein the fillers are selected from the group consisting of lactose, microcrystalline cellulose and combinations thereof. 15. The method according to any one of claims 1-14, wherein the dosage form further comprises inert fillers selected from the group consisting of high melting point fats, waxes, low melting point oils, surfactants with an HLB value greater than 10, solvents, cosolvents, solid high molecular weight polyethylene glycols, liquid polyethylene glycols, lubricants, blowing agents, dispersing agents, gelatin, gum, water-soluble polymers, glycerol, sorbitol, cyclodextrins, flavoring agents, disintegrants, and combinations thereof. 16. The method of claim 15, wherein the inert fillers comprise solvents and cosolvents selected from the group consisting of ethanol, polypropylene glycol, glycerin, polyethylene glycol and combinations thereof. 17. The method of claim 15, wherein the inert fillers comprise a solid high molecular weight polyethylene glycol selected from the group consisting of PEG 3350, PEG 4000, PEG 4600, PEG 5000, PEG 6000, PEG 7000, PEG 8000, PEG up to 10000, and combinations thereof. 18. The method of claim 15, wherein the inert fillers comprise water-soluble polymers selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), gum, and combinations thereof. 19. The method of claim 15, wherein the inert fillers comprise disintegrants selected from the group consisting of croscarmellose, pregelatinized starch, starch, sodium stearyl fumarates, and combinations thereof. 20. The method according to any one of claims 1-19, wherein the dosage form is suitable for administration by the oral route, the sublingual route, the buccal route, the vaginal route or the rectal route. 21. The method of claim 20, wherein the dosage form is suitable for oral administration and is chewable. 22. The method according to any one of claims 1-21, wherein the dosage form has an extended release profile. 23. The method according to any one of claims 1-21, wherein the dosage form has an immediate release profile. 24. The method according to any one of claims 1-23, wherein the accelerated stability study is conducted for about 1 month, about 2 months, or about 3 months. 25. A method for preparing a dosage form with a stabilized release profile, comprising: mixing an active pharmaceutical ingredient, at least one surfactant with an HLB value of less than 10, and glyceryl distearate to obtain a mixture; heating this mixture until the glyceryl distearate melts to form a molten mixture; forming this molten mixture into a dosed form; and curing of the dosage form, wherein the release profile of the active pharmaceutical ingredient after conducting the accelerated stability study has a similarity factor (f2) of at least 50 when compared to the release profile of the active pharmaceutical ingredient before conducting the accelerated stability study, wherein the accelerated stability study is conducted at a temperature of about 40°C and at a humidity of about 75% for at least 1 month; and wherein the surfactant has an HLB value of less than about 10 and is selected from sorbitan fatty acid esters, and combinations thereof; where the dosage form additionally contains inert fillers; and wherein curing is carried out at a temperature in the range of from about 30°C to about 60°C for from about 3 hours to about 7 days. 26. The method of claim 25, wherein forming the molten mixture into a dosage form comprises encapsulating the molten mixture in a hard-shell capsule or a soft-shell capsule. 27. A method for preparing a dosage form with a stabilized release profile, comprising: mixing the active pharmaceutical ingredient, a surfactant with an HLB value of less than 10 and glyceryl distearate in an extruder; extruding an active pharmaceutical ingredient, a surfactant with an HLB value of less than 10, and glyceryl distearate to form a dosage form; and curing of the dosage form, wherein the release profile of the active pharmaceutical ingredient after conducting the accelerated stability study has a similarity factor (f2) of at least 50 when compared to the release profile of the active pharmaceutical ingredient before conducting the accelerated stability study, wherein the accelerated stability study is conducted at a temperature of about 40°C and at a humidity of about 75% for at least 1 month; and wherein the surfactant has an HLB value of less than about 10 and is selected from sorbitan fatty acid esters, and combinations thereof; where the dosage form additionally contains inert fillers; and wherein curing is carried out at a temperature in the range of from about 30°C to about 60°C for from about 3 hours to about 7 days. 28. A method for preparing a dosage form with a stabilized release profile, comprising: dissolving an active pharmaceutical ingredient, a surfactant with an HLB value of less than 10 and glyceryl distearate in a solvent; spray drying the dissolved active pharmaceutical ingredient, a surfactant with an HLB value of less than 10, and glyceryl distearate to obtain a powder; and powder curing, wherein the release profile of the active pharmaceutical ingredient after conducting the accelerated stability study has a similarity factor (f2) of at least 50 when compared to the release profile of the active pharmaceutical ingredient before conducting the accelerated stability study, wherein the accelerated stability study is conducted at a temperature of about 40°C and at a humidity of about 75% for at least 1 month; and wherein the surfactant has an HLB value of less than about 10 and is selected from sorbitan fatty acid esters, and combinations thereof; where the dosage form additionally contains inert fillers; and wherein curing is carried out at a temperature in the range of from about 30°C to about 60°C for from about 3 hours to about 7 days.