Mini softgel naproxen composition

Abstract

To provide a mini softgel pharmaceutical composition that is stable and displays target pharmacokinetic parameters, a method for preparing the composition, and a method for treating conditions with the composition.SOLUTION: In certain embodiments, the present disclosure may be directed to a pharmaceutical composition comprising a softgel and a fill composition. The fill composition may comprise a reaction product of naproxen free acid and potassium hydroxide. The molar ratio of potassium hydroxide to naproxen free acid in the reaction may be less than about 1. The softgel may have a size of 8 to 14. The fill composition may have a weight of from about 200 mg to about 800 mg. The pharmaceutical composition may be a mini softgel shaped in an oblong shape or in an oval shape. In some embodiments, the fill composition may comprise naproxen salt at a concentration of about 55 wt.% to about 75 wt.%, based on the total combined weight of naproxen free acid and naproxen salt.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application was filed on April 26, 2019, which is incorporated herein by reference in its entirety. Priority is claimed to filed U.S. Provisional Patent Application No. 62 / 839,198.

[0002] The present invention relates to the field of mini softgel pharmaceutical compositions containing naproxen. It also relates to methods of preparing and using such pharmaceutical compositions. [Background technology]

[0003] Soft gelatin capsules (also called liquid gels or softgels) are different from tablets, hard gels, It offers clear advantages over conventional dosage forms such as capsules and liquids. A unique drug delivery system. Softgels are sealed, one-piece capsules that deliver liquid or semi-solid Filled with solids. Softgels contain two main components: a shell composition and a fill composition. An exemplary shell composition may include gelatin, a plasticizer, and water. The fill composition may include a wide variety of vehicles and may be either a solution or a suspension. That's fine.

[0004] Soft gelatin capsules facilitate oral administration of drugs, at least in part because they are easy to swallow. Therefore, soft gelatin tablets may be preferred by many people, especially for the elderly. Soft gel capsules make capsules easier to swallow than tablets or hard capsules. Capsules can be made easier to swallow by reducing their size. To achieve a high concentration solution in the fill composition, the active pharmaceutical ingredient and the solvent are mixed together. It may be advantageous to optimize the amount of softgel used. Higher doses can be achieved with more concentrated fill compositions without sacrificing ease . Summary of the Invention [Problem to be solved by the invention]

[0005] OBJECTS AND SUMMARY OF THEINVENTION An embodiment of the present disclosure is a mini softgel pharmaceutical formulation that is stable and exhibits target pharmacokinetic parameters. The present invention is directed to compositions, methods of preparing said compositions, and methods of treating conditions with said compositions. obtain. [Means for solving the problem]

[0006] In certain embodiments, the present disclosure is directed to pharmaceutical compositions comprising softgels and fill compositions. The fill composition may comprise the reaction product of naproxen free acid and potassium hydroxide. The molar ratio of potassium hydroxide to naproxen free acid in the reaction is less than about 1. It may be about 0.55 to about 0.75, about 0.6 to about 0.7, or about 0.65. The gel may have a size of 8 to 14, or 10 to 12. The filling composition is about 200 ml. g to about 800 mg, about 400 mg to about 800 mg, or about 600 mg to about 700 mg The pharmaceutical composition may be a mini softgel formed into an oval or egg shape. In some embodiments, the fill composition comprises naproxen free acid and naproxen. About 55% by weight to about 75% by weight, about 60% by weight to about 70% by weight, based on the total weight of the salts. %, or about 65% by weight of the naproxen salt.

[0007] In certain embodiments, the target pharmacokinetic parameters include the mean T max , average C max Pharmacokinetic values ​​include naproxen free acid or administering to subjects in a fed or fasted state a dose of 200 mg of a pharma- ceutical acceptable salt thereof. In certain embodiments, the administration of the medicament to a population of max (Feeding status The incubation time may range from about 1 hour to about 6 hours, or from about 2 hours to about 5 hours. In this embodiment, the average C max (Fed state) is about 20 μg / mL to about 55 μg / mL, In certain embodiments, AU may range from about 25 μg / mL to about 50 μg / mL. C (fed state) is about 400 μg·h / mL to about 1000 μg·h / mL, or about 50 In certain embodiments, the range may be from 0 μg·hr / mL to about 950 μg·hr / mL. average T max (Fasting state) is about 0.5 hours to about 4 hours, or about 1 hour to about 2.5 hours In certain embodiments, the average C max (fasting state) is about 25μg / mL to about 70 μg / mL, or about 30 μg / mL to about 60 μg / mL In certain embodiments, the AUC(fasted state) is from about 450 μg·hr / mL to about 1000 μg·hr / mL. g·hr / mL, or in the range of about 500 μg·hr / mL to about 975 μg·hr / mL good.

[0008] In certain embodiments, the present disclosure provides a method for preparing naproxen free acid and potassium hydroxide in a minisoft solution. Any of the pharmaceutical compositions disclosed herein can be administered by incorporating them into a gel capsule. Methods of preparation are of interest.

[0009] In certain embodiments, the present disclosure provides a method for administering to a patient in need thereof a pharmaceutical composition disclosed herein. The present invention may be directed to a method of treating a condition by administering any of the compositions.

[0010] definition As used herein, the singular forms "a," "an," and " "The" includes plural references unless the context clearly indicates otherwise. Thus, for example, a reference to an "active pharmaceutical ingredient" includes a single active pharmaceutical ingredient as well as two In the present invention, the term "excipient" includes a mixture of one or more different active pharmaceutical ingredients, and references to "excipient" include references to a single excipient, as well as mixtures of two or more different excipients.

[0011] As used herein, the term "about" in connection with a measured quantity refers to the purpose and The degree of measurement and care required to achieve the desired results is consistent with the accuracy of the measuring equipment. In certain embodiments, the term "about" refers to "about Inclusive of the recited number ±5%, so that "10" includes 9.5 to 10.5.

[0012] As used herein, "active agent," "active ingredient," "active pharmaceutical ingredient," "AP I," and the term "drug" is approved by a government agency for that purpose. Intended to produce a therapeutic, preventative, or other intended effect, whether or not These terms, referring to a particular drug, include all pharma- ceutical active substances. The present invention relates to a pharmaceutical agent, and all pharma- ceutically acceptable salts, complexes, stereoisomers, crystalline forms, cocrystals, acetals, and the like thereof. These forms include esters, hydrates, solvates, and mixtures thereof, and are not intended to be used as pharmaceutical agents. It is biologically active.

[0013] As used herein, the term "stereoisomer" refers to a compound having a different orientation of its atoms in space. A general term for all isomers of individual molecules that differ only in their structure. Isomers of compounds that are not mirror images of one another and have one or more chiral centers (diastereoisomers Includes Ma.

[0014] The term "enantiomer" or "enantiomeric" refers to a substance that is superimposable with its mirror image. and therefore optically active, the more the enantiomers align the plane of polarized light in one direction. A molecule that rotates the plane of polarized light by 10 degrees and its mirror image rotates the plane of polarized light by the same degree but in the opposite direction.

[0015] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0016] The term "patient" refers to a person who is clinically diagnosed with a particular symptom or symptoms indicating the need for treatment. exhibiting symptoms, being treated preventatively or prophylactically for a condition, or The term "subject" refers to a subject, animal or human, who has been diagnosed with a condition to be treated. , includes the definition of the term "patient" and does not exclude otherwise healthy individuals.

[0017] "Pharmaceutically acceptable salts" include, but are not limited to, hydrochloride and hydrobromide. Inorganic acid salts such as formates, acetates, trifluoroacetates, and maleates. Salts, tartrates and other organic acid salts; methanesulfonates, benzenesulfonates, p-toluenesulfonates Sulfonates, such as benzosulfonates; alginates, aspartates, glutamates Amino acid salts such as; metal salts such as sodium salts, potassium salts, cesium salts; calcium salts , alkaline earth metal salts such as magnesium salts; triethylamine salts, pyridine salts, picolines Salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N and organic amine salts such as '-dibenzylethylenediamine salt.

[0018] The recitation of ranges of values ​​herein includes each individual value within the range unless otherwise indicated herein. is merely intended to serve as a shorthand way of referring to the values ​​of individually, with each individual value being All of the above-mentioned references are incorporated herein by reference as if each reference were individually set forth herein. All methods are herein incorporated by reference unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided herein, as well as The use of exemplary language (e.g., "including") is merely intended to identify particular materials and methods. The disclosure of this specification is intended to be illustrative, not limiting. It is understood that no unclaimed element is essential to the practice of the disclosed materials and methods. It should not be interpreted.

[0019] The term "condition" or "conditions" refers to an alleviation or remission of a condition that can be ameliorated by administration of an effective amount of an active agent to a subject. These include those medical conditions that can be treated or prevented by administering a therapeutic agent such as a medicament for treating pain.

[0020] The terms "treatment of" and "treating" refer to the reduction or cessation of the severity of a condition, or includes the reduction or cessation of the severity of the symptoms of the condition.

[0021] The terms "prevention of" and "preventing" include the avoidance of the onset of a condition.

[0022] A "therapeutically effective amount" refers to an amount sufficient to administer, e.g., to treat or prevent a condition, or to administer a therapeutically effective amount to a subject. The amount of an active agent, or a combination of active agents, to treat the symptoms of a condition. It is intended.

[0023] The term "pharmacologically acceptable" means, within the bounds of sound medical judgment, a substance that is free from excessive toxicity, irritation, or irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio Those compounds, materials, and methods suitable for use in contact with human and animal tissues without The term "drugs," "compositions," and / or "dosage forms" refers to the ingredients, compositions, and / or dosage forms. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Embodiments of the present disclosure relate to pharmaceutical compositions that include a softgel and a fill composition. In some embodiments, the fill composition comprises a reaction between an active pharmaceutical ingredient (API) in free acid form and a base. The reaction product may be a salt form of the API. After reaction of the free acid form of the PI with a base, the salt form of the API and the free acid form of the API form the fill composition. The free acid form may be in molar excess compared to the base so as to coexist in the composition.

[0025] The API in the fill compositions disclosed herein is naproxen free acid and / or its In some embodiments, the salt form of the API (e.g., A salt of naproxen is a salt of an API (e.g., naproxen free acid) in its free acid form and Approximately 55% by weight, calculated based on the total weight of the salt forms of the PI (e.g., naproxen salts) Weight% ~ Approx. 75%, Approx. 60% ~ Approx. 70%, Approx. 55% ~ Approx. 65%, Approx. 55% by weight, approximately 56% by weight, approximately 57% by weight, approximately 58% by weight, approximately 59% by weight, approximately 60% by weight , about 61% by weight, about 62% by weight, about 63% by weight, about 64% by weight, about 65% by weight, about 66% by weight Amount%, about 67% by weight, about 68% by weight, about 69% by weight, about 70% by weight, about 71% by weight, about 7 2% by weight, about 73% by weight, about 74% by weight, or about 75% by weight, or any of Subranges, or single concentration values ​​therein, may be present in the fill composition.

[0026] The above ranges are intended to provide a stable softgel napkinase that exhibits the target pharmacokinetic parameters described herein. It is advantageous to obtain a roxene composition. When naproxen salts that can be used are included (naproxen free acid and naproxen in the fill composition), (based on total weight including salt), softgels are unstable and may melt under accelerated conditions On the other hand, when the softgel pharmaceutical composition contains less than about 55% by weight of a naproxen salt ( based on the total combined weight of naproxen free acid and naproxen salt in the fill composition), Softgels are less effective in treating and / or preventing the target condition. may not be able to meet the pharmacokinetic performance described in more detail below (i.e., it may not be able to meet the pharmacokinetic performance described in more detail below). may not be shown).

[0027] In certain embodiments, the filled composition can be stored at 40° C. and 75% relative humidity (RH) for one month. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0028] In certain embodiments, the filled composition can be stored at 40° C. and 75% relative humidity (RH) for two months. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0029] In certain embodiments, the filled composition can be stored at 40° C. and 75% relative humidity (RH) for three months. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0030] In certain embodiments, the filled composition can be stored at 40° C. and 75% relative humidity (RH) for six months. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0031] In certain embodiments, the filled composition can be stored at 40° C. and 75% relative humidity (RH) for 9 months. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0032] In certain embodiments, the filled composition can be stored at 30° C. and 65% relative humidity (RH) for one month. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0033] In certain embodiments, the filled composition can be stored at 30° C. and 65% relative humidity (RH) for two months. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0034] In certain embodiments, the filled composition can be stored at 30° C. and 65% relative humidity (RH) for three months. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0035] In certain embodiments, the filled composition can be stored at 30° C. and 65% relative humidity (RH) for six months. After storage, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen free at least about 90%, at least about 95% of the amount of the potassium salt of naproxen; Maintain at least about 98%, or at least about 99%.

[0036] In certain embodiments, the filled composition is resistant to aging at 30° C. and 65% relative humidity (RH) for 9 months. After storage for a period of time, naproxen or a pharma- ceutically acceptable salt thereof (e.g., naproxen capsules) may be at least about 90%, at least about 95% of the amount of the potassium salt of naproxen or , at least about 98%, or at least about 99%.

[0037] The base in the fill composition disclosed herein is selected based on its strength and its interaction with the API. For example, the majority of the free acid form of the API (e.g., naproxen free acid) can be selected. A salt that is strong enough to convert (and maintain) the compound into its salt form (e.g., naproxen salt). In addition, when combined, it may be advantageous to select a salt form of the API. forms (e.g., naproxen salts) and the free acid form of the API (e.g., naproxen free acid It may be advantageous to select a base that enhances the solubility of the hydroxyl group. The solubility is useful for forming concentrated solutions of the API and its pharma- ceutically acceptable salts. Such concentrated solutions may allow for the delivery of high doses of pharmaceutical compositions in dosage forms having smaller sizes. may be useful in forming .

[0038] In one embodiment, the base may be potassium hydroxide. Potassium hydroxide is used to The free acid form of naproxen can be neutralized to form the potassium salt form of naproxen. The potassium salt of naproxen is not a substitute for certain other salts of naproxen, e.g., sodium naproxen. It has better solubility in low molecular weight polyethylene glycol solvents compared to the tetrahydrofuran salt. Therefore, potassium hydroxide may be useful in naproxen pharmaceutical compositions. Furthermore, the combination of naproxen free acid and naproxen potassium salt has the same efficacy as the individual components. The fill composition is therefore more soluble in low molecular weight polyethylene glycol than in low molecular weight polyethylene glycol. By combining the potassium salt of naproxen and the free acid form of naproxen in and a pharmaceutical composition having a higher concentration of naproxen API or a pharma- ceutical acceptable salt thereof. It is possible to obtain products that lack the free acid of naproxen or that have a different (compared to pharmaceutical compositions containing the salt form).

[0039] The size and shape of the final softgel capsule can vary. The capsule shape can be circular or round. The shape may be, but is not limited to, round, oval, elliptical, or non-standard. Suitable softgel capsule shapes and sizes may be as shown in Table 1 below. , but not limited to these.

[0040] [Table 1]

[0041] As mentioned above, concentrated solutions are available in smaller volumes and correspondingly smaller sized soft In some embodiments, the gel capsules described herein allow for high doses to be included. The softgel capsule sizes disclosed in the present application range from 8 to 14, 10 to 12, and and all sizes in between, e.g. 8, 9, 10, 11, 12, 13, or 14 In certain embodiments, the softgel capsules disclosed herein may have a size of The size may be about 20% to about 30% smaller than existing equivalent dosage forms (e.g., Ale Approximately 20% to 30% more effective than VE® Liquid Gel Naproxen Sodium 220 mg small).

[0042] In some embodiments, the fill compositions disclosed herein comprise from about 200 mg to about 80 mg. 0mg, about 300mg to about 750mg, about 400mg to about 700mg, about 400mg to about 800mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg , about 450mg, about 500mg, about 550mg, about 600mg, about 610mg, about 620 mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 6 80 mg, about 690 mg, about 700 mg, about 750 mg, or about 800 mg, or Any subrange or single weight value therein.

[0043] In certain embodiments, a salt relative to the free acid form of the API (e.g., naproxen free acid). The molar ratio of the group (e.g., potassium hydroxide) may be less than about 1. For example, the molar ratio of base (e.g., potassium hydroxide) to naproxen free acid is about 0. .55~approx.0.75, approx.0.6~approx.0.7, approx.0.55, approx.0.56, approx.0.57, approx.0 .58, approx. 0.59, approx. 0.60, approx. 0.61, approx. 0.62, approx. 0.63, approx. 0.64, Approximately 0.65, approximately 0.66, approximately 0.67, approximately 0.68, approximately 0.69, approximately 0.70, approximately 0.7 1, about 0.72, about 0.73, about 0.74, or about 0.75, or any of them It may be a subrange or a single molar ratio value.

[0044] In softgel pharmaceutical compositions, the base (water) for the API (e.g., naproxen free acid) When the molar ratio of potassium hydroxide, etc., exceeds about 0.75, the pH and API The salt (e.g. naproxen salt) content is too high, causing the softgel capsule to become unstable. On the other hand, in softgel pharmaceutical compositions, the API (e.g., naproxen free acid) may be When the molar ratio of base (such as potassium hydroxide) to hydroxyapatite is less than about 0.55, the fill composition The API salt (e.g. naproxen salt) content may be too low and the pharmaceutical composition may not be able to deliver the targeted may be less effective in treating and / or preventing the condition (i.e., may not exhibit the pharmacokinetic properties described in more detail below).

[0045] In one embodiment, the pharmaceutical composition may include naproxen free acid and naproxen salts. The reaction product of naproxen free acid with potassium hydroxide is shown in the chemical reaction below. It is possible that the potassium salt of naproxen is the same as that of naproxen. The amount of sodium salt is related to the amount of naproxen free acid and potassium hydroxide in the fill composition. It is possible that.

[0046] Naproxen free acid + KOH → naproxen potassium salt + H2O In some embodiments, the pharmaceutical compositions disclosed herein are used to treat a target condition (such as pain). The API (e.g., naproxen or its pharma- ceutical acceptable salts) may be effective in treating The compound (a compound which is an acceptable salt) may be present in a pharmaceutical composition in a therapeutically effective amount, so that the compound is The composition is capable of targeting a drug after oral administration to a population of subjects in a fed and / or fasted state. Kinetic parameters (e.g., mean T max , average C max , and / or average AUC) It may be shown.

[0047] For example, the pharmaceutical compositions disclosed herein may comprise naproxen free acid or its pharma- ceutical derivatives. Approximately 1 hour after oral administration of a 200 mg dose of an acceptable salt to a population of subjects in a fed state Average T in the range of about 2 to about 5 hours or about 6 hours max may be shown.

[0048] For example, the pharmaceutical compositions disclosed herein may comprise naproxen free acid or a pharma- ceutical acceptable salt thereof. After oral administration of a 200 mg dose of the tolerated salt to a population of fasting subjects, Average T in the range of 1 hour to about 4 hours, or 1 hour to about 2.5 hours max may be shown.

[0049] For example, the pharmaceutical compositions disclosed herein may comprise naproxen free acid or its pharma- ceutical derivatives. Based on a dose of 200 mg of acceptable salt, following oral administration to a population of subjects in a fed state about 20 μg / mL to about 55 μg / mL, or about 25 μg / mL to about 50 μg / mL Average C range max may be shown.

[0050] For example, the pharmaceutical compositions disclosed herein may comprise naproxen free acid or its pharma- ceutical derivatives. Based on a dose of 200 mg of acceptable salt, following oral administration to a population of subjects in the fasting state 25 μg / mL to 70 μg / mL, or 30 μg / mL to 60 μg / mL Average C range max may be shown.

[0051] For example, the pharmaceutical compositions disclosed herein may comprise naproxen free acid or its pharma- ceutical derivatives. Based on a dose of 200 mg of acceptable salt, following oral administration to a population of subjects in a fed state 400 μg·h / mL to 1000 μg·h / mL, or 500 μg·h / mL The mean AUC range may be between 1.5 and approximately 950 μg·h / mL.

[0052] For example, the pharmaceutical compositions disclosed herein may comprise naproxen free acid or its pharma- ceutical derivatives. Based on a 200 mg dose of an acceptable salt, following mass oral dosing of fasting subjects: Approximately 450 μg·h / mL to approximately 1000 μg·h / mL, or approximately 500 μg·h / mL A mean AUC in the range of approximately 975 μg·h / mL may be demonstrated.

[0053] The pharmaceutical compositions disclosed herein may further comprise a pharma- ceutically acceptable solvent. Suitable solvents are those that dissolve the other components of the pharmaceutical composition to obtain a clear solution in liquid form. Exemplary solvents include, but are not limited to, low molecular weight polyethylene glycols. Polyethylene glycol has a molecular weight of about 200 to about 800 daltons and about 400 to about 70 Polyethylene having an average molecular weight of about 600 Daltons or thereabouts. The glycol may have any subrange or single value in the molecular weight range. Liquid polyethylene glycols include, but are not limited to, PEG200, PEG300, PEG400, PEG600, PEG800, and combinations thereof.

[0054] In certain embodiments, the pharmaceutical compositions disclosed herein include softgel and fill compositions. The fill composition can consist essentially of (or consist of) naproxen. The reaction product of the free acid or a pharma- ceutically acceptable salt thereof with potassium hydroxide is essentially The fill composition may comprise (or consist of) the reaction product, in addition to a solvent. (e.g., polyethylene glycol and / or water) The size of the softgel capsule, the amount of ingredients, and the pharmaceutical composition The pharmacokinetic properties of may include any of those described herein.

[0055] The pharmaceutical compositions disclosed herein may contain surfactants (HLB values ​​less than 10 or more than 10). (can be used as a solvent, co-solvent, solid high molecular weight polyethylene glycol, water-soluble polymer, flavoring agent , pH adjuster, disintegrant, plasticizer, colorant, pore former, dispersant, water-soluble polymer, water, Lycerin, sorbitol, cyclodextrin, solubility enhancers, bioavailability enhancers, Additional additives, such as opacifiers, enzymes, preservatives, stabilizers, antioxidants, bulking agents, and combinations thereof. Suitable excipients may be in liquid, semi-solid, and / or solid form. The embodiment may be in the form of

[0056] Surfactants with an HLB value of less than 10 include, but are not limited to, ethylene oxide. EO / PO copolymer, glycerol monocaprylate, glycerol Glycerol Monocaprate, Glycerol Caprylate / Caprate, Glycerol Monocaprate Glycerol monostearate, glycerol laurate, glycerol mono Linoleate, Glycerol Behenate, Glycerol Palmitostearate, Petroleum and Lanolin alcohol, polyoxyethylene alkyl ether (e.g., polyoxyl 4 lanolin) Polyoxyl 2 cetyl ether, Polyoxyl 2 stearyl ether, Polyoxyl 2 oleyl ether), sorbitan fatty acid esters (e.g., sorbitan mono Noisostearate, Sorbitan Monolaurate, Sorbitan Monopalmitate, Sorbitan Sorbitan monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate Sorbitan sesquistearate, sorbitan diisostearate, sorbitan dioleate sorbitan triisostearate, sorbitan trioleate, sorbitan tri stearate), sucrose ester, poly(ethylene glycol)-block-poly( Propylene glycol)-block-poly(ethylene glycol) (Pluronic copolymer Body), PEG-30 Dipolyhydroxystearate, Propylene Glycol Monocaprylate propylene glycol dilaurate, propylene glycol monolaurate, Pyrene glycol monostearate, propylene glycol isostearate, sorbita Sorbitan monooleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan sorbitan tristearate, sorbitan trioleate, and combinations thereof. .

[0057] Suitable surfactants with an HLB value above 10 include, but are not limited to, polysorbates. 80-Polyoxyethylene (20) Sorbitan Monooleate, Polyoxyl 40 Hydrogenated Castor oil, polyoxyl 35 castor oil, caprylocaproyl macrogol glycerides, and combinations thereof.

[0058] Exemplary solvents and / or co-solvents include, but are not limited to, ethanol, propylene glycol, ethyl acetate ... glycol, glycerin, polyethylene glycol, and combinations thereof. do.

[0059] Exemplary solid polymer polyethylene glycols include, but are not limited to, PEG335. 0, PEG4000, PEG4600, PEG5000, PEG6000, PEG700 0, PEG 8000, up to PEG 10000, and combinations thereof.

[0060] Exemplary water soluble polymers include, but are not limited to, hydroxypropylmethylcellulose. HPMC, Hydroxypropyl Cellulose (HPC), Hydroxyethyl Cellulose Examples of suitable oleic acid derivatives include oleic acid (HEC), gums, and combinations thereof.

[0061] Exemplary plasticizers include, but are not limited to, isomalt, maltitol, sorbitol. , xylitol, erythritol, adonitol, dulcitol, pentaerythritol or sugar alcohol plasticizers such as mannitol; or glycerin, diglycerin , ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene Polyethylene glycol, dipropylene glycol, up to 10,000 MW , neopentyl glycol, propylene glycol, 1,3-propanediol, 2- Methyl-1,3-propanediol, trimethylolpropane, polyether polyol , ethanolamine, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, Low molecular weight polyols with aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers Poly(propylene glycol), multi-block polymers, single block polymers mer, citrate ester type plasticizer, triacetin, 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 Citrate 80, Acetyl Triethyl Citrate, Tributyl Citrate and Allyl Glycol Citrate and mixtures thereof.

[0062] Exemplary colorants include, but are not limited to, white, black, yellow, blue, green, pink, and red. , orange, purple, indigo, and brown.

[0063] Exemplary flavorings include, but are not limited to, menthol, spearmint, and cinnamon. breath freshening compounds such as citronella, coffee beans, and fruit flavors (e.g., cherry, orange, Other flavourings or fragrances, such as grape, especially those used in oral hygiene, as well as These include actives used in dental and oral rinses such as quaternary ammonium bases. The effect of flavorings can be increased by using flavor enhancers such as tartaric acid, citric acid, vanillin, etc. Cut.

[0064] Exemplary sweeteners include, but are not limited to, one or more artificial sweeteners, one or more Sweeteners include, for example, natural sweeteners or combinations thereof. For example, acesulfame and its potassium salt (available as Sunett®) NutraSweet®, various salts such as alitame, aspartame (NutraSweet®), and Equal®), a salt of aspartame-acesulfame (available as Twinsweet®), neohesperidin dihydrochalcone Naringin dihydrochalcone, dihydrochalcone compounds, neotame, cyclamic acid Sodium, saccharin and its sodium salts (Sweet'N Low® Various salts such as stevia and chlorine derivatives of sucrose such as sucralose are available. (available as Kaltame® and Splenda®), Natural sweeteners include, for example, glucose, dextrose, and mogrosides. Roth, invert sugar, fructose, sucrose, glycyrrhizin, glycyrrhizic acid monoacetate ammonium (sold under the trade name MagnaSweet®); Stevia rebaudiana Stevia rebaudiana (stevioside), a natural strong sweetener such as monk fruit, sorbitol, Examples of polyols include glycerol, mannitol, xylitol, and erythritol.

[0065] Exemplary pH adjusters include, but are not limited to, hydrochloric acid, potassium hydroxide, sodium hydroxide, Examples of suitable nitriles include ammonium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, and nitric acid.

[0066] Other exemplary excipients that may be included in the pharmaceutical composition include, but are not limited to, gelatin. chin, water-soluble polysaccharides (e.g., alginic acid, carrageenan, guar gum, agar, xanthan Gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragacanthus Canth gum), pectin, etc.), water-soluble derivatives of cellulose (e.g. alkylcelluloses, cellulose, hydroxyalkyl cellulose, and hydroxyalkyl alkyl cellulose (e.g. For example, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, Hydroxypropyl cellulose, Hydroxyethyl methyl cellulose, Hydroxypropyl methylcellulose, hydroxybutylmethylcellulose, etc.), cellulose esters and and hydroxyalkyl cellulose esters (e.g., cellulose acetate phthalate (CAP) ) etc.), Hydroxypropyl methylcellulose (HPMC), Carboxyalkyl cellulose Roasted rice, carboxyalkyl alkyl cellulose, carboxyalkyl cellulose ester (e.g., carboxymethylcellulose and its alkali metal salts), water-soluble Synthetic polymers (e.g., polyacrylic acid, polyacrylamide, and polyacrylic acid) Esters, polymethacrylic acids, polymethacrylamides, and polymethacrylic acid esters etc.), polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (P Polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymers. .

[0067] In some embodiments, the excipient comprises about 20% by weight of the total pharmaceutical / fill composition. Weight% or less, about 15% by weight or less, about 10% by weight or less, about 5% by weight or less, about 4% by weight, about 3 2% by weight or less, 1% by weight or less, 0.5% by weight or less, 0.1% by weight or less In some embodiments, the fill composition may be present in the pharmaceutical / fill composition at a concentration below 0.01%. The composition may contain no excipients other than the polyethylene glycol solvent (e.g., about 0.05 wt. % polyethylene glycol solvent). The drug / fill composition may be, for example, about 2% by weight to about 5% by weight based on the total drug / fill composition weight. About 50% by weight, about 6% to about 40% by weight, about 10% to about 30% by weight, about 10% by weight ~40wt%, approx.15wt%~approx.35wt%, approx.20wt%~approx.30wt%, approx.20wt % to about 25% by weight, or from about 15% to about 25% by weight. That's fine.

[0068] In some embodiments, the API (in its free acid form and / or its salt form) is About 15% by weight to about 40% by weight, about 20% by weight to about 30% by weight, based on the total weight of the filling composition. Amount%, approximately 15% by weight, approximately 16% by weight, approximately 17% by weight, approximately 18% by weight, approximately 19% by weight, approximately 2 0% by weight, approximately 21% by weight, approximately 22% by weight, approximately 23% by weight, approximately 24% by weight, approximately 25% by weight, Approximately 26% by weight, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, approximately 30% by weight, approximately 31% by weight %, approximately 32% by weight, approximately 33% by weight, approximately 34% by weight, approximately 35% by weight, approximately 36% by weight, approximately 37 %, about 38%, about 39%, or about 40% by weight of the fill composition. You may.

[0069] In some embodiments, the fill composition comprises up to about 15%, up to about 12%, up to about 10% , maximum approximately 9%, maximum approximately 8%, maximum approximately 7%, maximum approximately 6%, maximum approximately 5%, maximum approximately 4%, maximum approximately It may have a moisture content of about 3%, up to about 2%, up to about 1%, or may be completely dehydrated. In certain embodiments, the upper range may be exceeded (i.e., 0% moisture content). The moisture content is physically stable at certain conditions (e.g., 40°C and 75% relative humidity). This may result in a softgel formulation that is not

[0070] In some embodiments, the softgel compositions disclosed herein comprise a gel of from about 2N to about 20 N, about 4N to about 15N, about 6N to about 13N, about 8N to about 12N, or a range of hardnesses It may have a hardness of any subrange included or any single value.

[0071] The hardness and / or moisture content of the dosage forms disclosed herein may be maintained for up to about 20 days, from about 1 day to about 20 days. Approximately 18 days, approximately 5 to 15 days, approximately 7 to 13 days, or approximately 10 to 12 days, or The softgel formulation is dried over a period of time within any subrange or single value included therein. It can be obtained by drying.

[0072] An embodiment of the present invention is directed to a method for stabilizing the potassium salt form of naproxen. The method may be carried out at a molar ratio of potassium hydroxide to naproxen free acid of less than about 1. The free acid form of naproxen is packaged in mini softgel capsules with potassium hydroxide base. The method may include a step of incorporating (e.g., by reacting) the mini soft gel cap. The cells may have a size of 8 to 12. The incorporation is carried out by hydroxylating the free acid form of naproxen. Mix with potassium and dissolve in a suitable solvent (e.g., low molecular weight polyethylene glycol) , reacting naproxen free acid with potassium hydroxide to produce naproxen free acid or its pharmaceutical equivalents; This may include obtaining highly concentrated solutions of environmentally acceptable salts.

[0073] Any of the other excipients disclosed herein may be used in any of the methods disclosed herein. It may be incorporated into the dosage form at various steps.

[0074] An embodiment of the present invention is a method for administering any of the pharmaceutical compositions disclosed herein to a patient in need thereof. The present invention may be directed to a method of treating a target condition (e.g., pain) by administering . EXAMPLES

[0075] The following examples are included to aid in the understanding of the present invention and are not intended to limit the scope of the invention as described herein. and should not be construed as specifically limiting the claimed invention. All equivalent replacements now known or later developed within the scope of the art Variations of the invention, including changes in formulation or slight variations in experimental design, are incorporated herein by reference. should be considered within the scope of the present invention.

[0076] [Example 1] Naproxen mini softgel formulation Table 2 below shows the results of the analysis of naproxen free acid in water at different molar ratios and different fill weights. Six fill compositions prepared by neutralization with potassium oxide are shown.

[0077] [Table 2]

[0078] Table 3 below lists three solutions used to encompass the fill compositions described in Table 2. The prescription for Futogel is shown.

[0079] [Table 3]

[0080] The naproxen mini softgel formulations from Tables 2 and 3 were prepared according to the following method: Ta:

[0081] Deionized water was added to an approximately 40 gallon closed mixing vessel equipped with a bottom mixer. Cool to 15° C. Apply full vacuum to the vessel and increase the temperature to 40° C. while mixing at approximately 100 RPM. The potassium hydroxide was slowly vacuum transferred to a container kept at a temperature below 100°C. Mix the potassium hydroxide / water solution until it is completely dissolved. Keep the temperature of the solution at 20-25°C. Maintained.

[0082] The polyethylene glycol 600 was vacuum transferred to a separate approximately 300 gallon closed mixing vessel. The jacket of the closed vessel was set at 27° C. The disperser and 2 While mixing under vacuum with the sweep set at 0 RPM, remove approximately half of the naproxen free acid. 100 ml of the mixture was vacuum transferred to a closed mixing vessel containing polyethylene glycol 600, still under vacuum. The mixture was mixed until uniform.

[0083] After mixing is complete, mix with the disperser at 1200 RPM and sweep at 20 RPM. Then slowly vacuum transfer about half of the potassium hydroxide solution into a 300 gallon sealed mixing tank. The temperature was maintained below about 40°C.

[0084] After mixing for approximately 10 minutes, the remainder of the naproxen free acid was added to a 300 gallon closed mixing tank. Vacuum transfer and mix until uniform.

[0085] Following the transfer of the naproxen free acid, the remainder of the potassium hydroxide is added at a temperature below 40°C. The mixture was vacuum transferred to a 300 gallon closed mixing tank containing

[0086] Mix the mixture for at least about 20 minutes until all of the naproxen free acid is completely dissolved. It came together.

[0087] The fill solution was transferred to a sealed receiver and the sealed receiver was transferred to a rotary die encapsulation machine.

[0088] The fill material was encapsulated into 10 oval dies using a fast drying gel formulation.

[0089] The softgels were dried until the filler moisture content was approximately 7%. Wood moisture and hardness are summarized in Table 4 below.

[0090] [Table 4-1]

[0091] [Table 4-2]

[0092] [Example 2] Stability study of naproxen mini-softgel formulations Two batches of 200 mg naproxen free acid (preparations from Tables 2 and 3 of Example 1) were The formulations 5 and 6) were subjected to physical and chemical stability tests. The results of the first batch were as follows: The following stability impact points were established: baseline, 1 month, 2 months, and 3 months. The results for the second batch are summarized in Table 5 below. The results for the second batch were established based on the following stability impact points: The results were: baseline, 1 month, 2 months, 3 months, 6 months, and 9 months. The results are summarized in Table 6 below. do.

[0093] [Table 5]

[0094] [Table 6]

[0095] By comparison, a marketed comparative formulation containing 200 mg of the relevant active agent was 482, assayed 104.0%, glycerin 0.11%. The total of the esters, 0.25% PEG-Nap, and 0.36% related substances were shown. The comparative formulations were purchased and tested directly from the commercial bottle.

[0096] Two batches of 200 mg naproxen free acid (stability test results are shown in Table 5 and Table 6, respectively) The first batch of 100 mg of 100% glycerol (100 mg / kg) was also subjected to dissolution testing (see Table 6). The dissolution results of the first batch were as follows: Established based on qualitative impact points: at start, 1 month, 2 months, and 3 months. 1st batch The dissolution results for the first batch are summarized in Table 7 below. The dissolution results for the second batch were as follows: The study was based on: baseline, 1 month, 2 months, 3 months, 6 months, and 9 months. The dissolution results for the batches are summarized in Table 8 below.

[0097] [Table 7]

[0098] [Table 8-1]

[0099] [Table 8-2]

[0100] By comparison, the marketed comparative formulations containing 200 mg of the relevant active agent are shown in Table 9 below. The comparative formulations were purchased and tested directly from the commercial bottle.

[0101] [Table 9]

[0102] Both batches of naproxen mini softgel formulations according to embodiments described herein (particularly The stability and dissolution results of the first batch (second batch) were compared with those of the stability test of the comparative naproxen formulation. The test results and dissolution results were comparable.

[0103] Naproxen 200 mg soft gelatin caps were analyzed using analytical method 1.1.6.211. The amount of naproxen-related substances in the cells was measured by HPLC. MC-Pack Pro C18 RS, 3 μm, 150 × 4.6 mm, 30 °C Detection was at 230 nm. Samples were kept at ambient temperature and incubated for 10 min for analysis by HPLC. A volume of 0 μL was injected.

[0104] Stock sample solutions for testing using analytical method 1.1.6.211 are prepared as follows: was prepared. Five capsules of naproxen were placed in a 500 mL volumetric flask. Add 200mL of diluent to the flask Keep the flask in the freezer until there is no more gel on the bottom of the flask and the capsules are completely dissolved. Heat in a 50°C water bath for at least 1 hour with occasional rapid rotation. The flask was removed from the water bath. Add 200 mL of methanol and shake the solution thoroughly. The flask was sonicated for 5 minutes. After the solution was returned to room temperature, the volume was adjusted with methanol and mixed well. The solution was left at room temperature for 10 minutes to allow any undissolved material to settle. At each time point, 5 mL of the supernatant of the stock sample solution was placed in a 100 mL volumetric flask and diluted with diluent. The volume was adjusted to prepare the sample to be analyzed.

[0105] The diluent is 2.62 g of sodium dihydrogen phosphate and 11.5 g of sodium phosphate dibasic in 1000 ml of water. 0 g of disodium phosphate in water, and mobile phase A is 0.1% H3PO4. Mobile phase B was acetonitrile. The chromatographic conditions used were as shown in Table 10 below. followed.

[0106] [Table 10]

[0107] For ease of explanation, the method embodiments of the present disclosure are depicted and described as a series of acts. However, acts according to this disclosure may be performed in various orders and / or simultaneously. as well as other actions not shown and described herein. Moreover, all illustrated acts are required to practice a methodology in accordance with the disclosed subject matter. In addition, those skilled in the art will appreciate that the methodology may be implemented in a single step via a state diagram or event diagram. Understand and recognize that the relationship can be alternatively represented as a set of interrelated states. cormorant.

[0108] In the preceding description, specific materials, dimensions, and processes have been used in order to provide a thorough understanding of the present invention. Many specific details are given, such as process parameters. Specific features, construction, materials, and The features may be combined in any suitable manner in one or more embodiments. The words "example" or "exemplary" are used herein to mean something that serves as an example, instance, or illustration. The term "example" or "exemplary" is used herein to mean that the Any aspect or design described herein is not necessarily preferred or advantageous over other aspects or designs. Rather, use of the words "example" or "exemplary" should not be construed as As used in this application, "or" is intended to present the concept concretely. The term "or" is intended to mean an inclusive "or" rather than an exclusive "or." That is, unless otherwise stated or clear from the context, "X is "Containing A or B" is intended to mean any of the natural inclusive permutations. That is, if X contains A, if X contains B, or if X contains both A and B, then In any of the above cases, "X includes A or B" is satisfied. References to an embodiment, a particular embodiment, or one embodiment relate to an embodiment. that a particular feature, structure, or characteristic described in any one of the following paragraphs is included in at least one embodiment; Thus, the terms "embodiment," "specific embodiment," "particular embodiment," and "particular embodiment" in various places throughout this specification refer to Appearances of the phrases "in one embodiment," "in one embodiment," or "in one embodiment" do not necessarily all refer to the same embodiment. is not limited to this.

[0109] The present invention has been described with reference to specific exemplary embodiments thereof. The drawings, if any, are to be regarded in an illustrative and not a limiting sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art. It is intended that any of the foregoing be apparent to those skilled in the art and fall within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising a softgel and a fill composition, said fill composition comprising a reaction product of naproxen free acid and potassium hydroxide, wherein a molar ratio of potassium hydroxide to naproxen free acid is less than 1, said fill composition having a weight of 200 mg to 800 mg, said pharmaceutical composition exhibiting a Tmax of 0.5 hours to 4 hours following oral administration to a population of subjects in a fasted state, based on a dose of 200 mg of naproxen free acid or a pharma- ceutical acceptable salt thereof, a Cmax of 25 μg / mL to 70 μg / mL, and an AUC of 450 μg-hr / mL to 1000 μg-hr / mL; 1. A pharmaceutical composition, wherein the fill composition comprises a potassium salt of naproxen, the potassium salt of naproxen being present in the fill composition at a concentration of 65% to 75% by weight, based on the total combined weight of the naproxen free acid and the potassium salt of naproxen.

2. A pharmaceutical composition comprising a softgel and a fill composition, said fill composition comprising a reaction product of naproxen free acid and potassium hydroxide, wherein a molar ratio of potassium hydroxide to naproxen free acid is less than 1, said fill composition having a weight of 200 mg to 800 mg, said pharmaceutical composition exhibiting a Tmax of 1 to 6 hours following oral administration to a population of subjects in a fed state based on a dose of 200 mg of naproxen free acid or a pharma- ceutical acceptable salt thereof, exhibiting a Cmax of 20 μg / mL to 55 μg / mL, and exhibiting an AUC of 400 μg-hr / mL to 1000 μg-hr / mL, 1. A pharmaceutical composition, wherein the fill composition comprises a potassium salt of naproxen, the potassium salt of naproxen being present in the fill composition at a concentration of 65% to 75% by weight, based on the total combined weight of the naproxen free acid and the potassium salt of naproxen.

3. A pharmaceutical composition comprising a softgel and a fill composition, the fill composition comprising a reaction product of naproxen free acid and potassium hydroxide, wherein the molar ratio of potassium hydroxide to naproxen free acid is less than 1, the fill composition having a weight of 200 mg to 800 mg, 1. A pharmaceutical composition, wherein the fill composition comprises a potassium salt of naproxen, the potassium salt of naproxen being present in the fill composition at a concentration of 65% to 75% by weight, based on the total combined weight of the naproxen free acid and the potassium salt of naproxen.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein the filling composition has a moisture content of up to 15%, up to 12%, up to 10%, up to 9%, up to 8%, up to 7%, up to 6%, up to 5%, up to 4%, up to 3%, up to 2%, up to 1%, or 0%.

5. A pharmaceutical composition described in any one of claims 1 to 4, having a hardness of 2N to 20N, 4N to 15N, 6N to 13N, or 8N to 12N.

6. A method for preparing a pharmaceutical composition according to any one of claims 1 to 5, comprising incorporating naproxen free acid and potassium hydroxide into a mini softgel capsule.