Pharmaceutical composition containing isoretinoic acid as well as preparation method and application thereof

Abstract

The present invention provides a high dose oral pharmaceutical composition and high drug loading isoretinoic acid as well as capsules of low fill weight and smaller size. The invention also provides methods of making the disclosed oral pharmaceutical compositions, and methods of treating conditions and diseases, such as skin conditions, including acne, by oral administration of the disclosed pharmaceutical compositions to patients in need thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to Indian Provisional Patent Application Serial No. 202221038020 filed on July 1, 2022, the entire disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to pharmaceutical compositions comprising high dose and high drug load of isotretinoin or a pharmaceutically acceptable salt or ester thereof as an active agent, methods for preparing the same, and methods for using the same. Background Art

[0004] Isotretinoin (13-cis retinoic acid or 13-cis vitamin A) is a retinoid and is naturally present in small amounts in the body. Isotretinoin, its isomers and some of its analogs are widely known to be therapeutically active in the treatment of severe skin conditions such as acne (e.g. nodular or spherical acne or acne with a risk of permanent scarring), lupus erythematosus and icthyosis [Peck G.L. & DiGiovanna (1994) Synthetic retinoids in dermatology in dermatology. In: Sporn, MB, Roberts, AB & Goodman, DS, eds. The Retinoids: Biology, Chemistry, and Medicine. 2nd Ed. New York, Raven Press, pp. 631-658]. Its use has also been reported for childhood neuroblastoma, cutaneous T-cell lymphoma, squamous cell skin cancer, and is also being studied for the treatment of various other cancers [Hong WK ​​& TM LM (1994) Retinoids and human cancer. In: Sporn, MB, Roberts, AB & Goodman, DS, eds. The Retinoids: Biology, Chemistry, and Medicine. 2nd Ed. New York, Raven Press, pp. 597-630].

[0005] In 1982, the FDA approved the drug in capsule form. Isotretinoin is used in strengths of 10 mg, 20 mg, and 40 mg to treat nodular acne. Each capsule of contains beeswax, butylated hydroxyanisole, disodium edetate, hydrogenated soybean oil flakes, hydrogenated vegetable oil and soybean oil. Isotretinoin is highly lipophilic and has low oral bioavailability. Its absorption is enhanced when taken with a high-fat meal. Oral bioavailability can be highly variable depending on food intake, which can lead to unpredictable toxicity and teratogenicity associated with isotretinoin [Jerry Tan & Sanja Knezevic; Improving bioavailability with a novel isotretinoinformulation (isotretinoin-Lidose); Skin Therapy Lett. 2013 Sep-Oct; 18(6): 1-3]. FDA approved it in 2012. is a hard gelatin capsule formulation of isotretinoin that is claimed to have a reduced food effect. Available in 10mg, 20mg, 25mg, 30mg, 35mg and 40mg strengths.

[0006] Hoffman-La Roche, US Patent No. 4,322,438 discloses a method of treating nodulocystic and globular acne by orally administering an amount of 13-cis-retinoic acid for a period of time effective to provide complete remission from the condition even after administration of the compound has ceased.

[0007] PCT Publication No. WO00 / 25772 filed by Hoffman-La Roche relates to soft gel capsules of isotretinoin having improved bioavailability. The formulation had an average particle size of 100 μm and had a bioavailability of only about 20%. The present invention also discloses a method for further reducing the particle size of isotretinoin to a range of about 5 μm to about 30 μm, thereby increasing the bioavailability of isotretinoin.

[0008] U.S. Patent No. 7,435,427 and its family members disclose The invention relates to a isotretinoin preparation related to a commercially available preparation of isotretinoin. These patents disclose capsules containing a semisolid suspension of isotretinoin, which contain at least two lipid excipients, one having a hydrophilic lipophilic balance (HLB) value equal to or greater than 10, and the other being an oily vehicle. These patents disclose the use of "Lidose technology" to provide an isotretinoin preparation with enhanced bioavailability by preparing a hard gelatin capsule filled with a liquid or semi-liquid lipid content, the lipid content comprising an active substance mixed with a melted excipient. The mixture is then filled into a hard gelatin capsule and then cooled under specific conditions and constant conditions.

[0009] PCT Publication WO2015 / 181802 discloses an oral pharmaceutical composition of isotretinoin dissolved or dispersed in a liquid vehicle selected from water, a water-miscible solvent and / or a mixture thereof and a carrier matrix with enhanced bioavailability. The enhancement of the bioavailability of isotretinoin of the present invention can be directly related to the reduction of the dosage of isotretinoin.

[0010] PCT Publication WO2016 / 051288 discloses a low-dose oral pharmaceutical composition of isotretinoin and a pharmaceutically acceptable excipient in the form of a dispersion, which is further filled into a capsule and is commercially available capsules, with comparable efficacy at lower doses of isotretinoin.

[0011] PCT Publication WO2016 / 016742 discloses an oral pharmaceutical composition of isotretinoin with reduced food effect. The disclosed composition comprises isotretinoin, one or more surfactants having an HLB value of 10 or greater, and one or more co-solvents, wherein the composition is substantially free of oil.

[0012] PCT Publication WO2016 / 189481 discloses a once-daily oral isotretinoin pharmaceutical composition for better patient compliance. The oral pharmaceutical composition of the present invention may be a modified release composition, or an immediate release composition, or a combination thereof.

[0013] PCT Publication WO 2010 / 134047 discloses a liquid dosage form of isotretinoin dissolved in a lipophilic carrier or a combination of lipophilic / hydrophilic carriers for better bioavailability without the use of additional surfactants or emulsifiers, substantially free of alcohol carriers and exhibiting no bitter taste.

[0014] The standard dose range of isotretinoin is 0.5 to 1 mg / kg / day given in two divided doses for 15 to 20 weeks ( label). However, adult patients with very severe acne with scarring or predominantly on the trunk may require dose adjustment up to 2 mg / kg / day, as tolerated. Thus, patients with higher body weight and severe disease may require up to 200 mg of isotretinoin in two divided doses, based on body weight.

[0015] The highest isotretinoin dosage strength available to patients is 40 mg, which is usually provided in a large size 00 capsule and is difficult to swallow. In addition, for many patients, more than one capsule is needed to adjust the dose of 0.5 to 1 mg / kg / day. Therefore, for patients who need higher doses (e.g., up to 200 mg per day), at least three capsules are needed. This higher "pill burden" can lead to reduced patient compliance, resulting in recurrence of symptoms within 2 years, requiring repeated medical intervention [Amanda Cyrulnik, Aron Gewirtzman, Kate Viola and Steven Cohen; High-Dose Isotretinoin (Accutane) Therapy: Positive Results in Nodulocystic Acne; American Academy of Dermatology; In: Peter Sonnenreich; P T. 2011 May; 36 (5): 294–296].

[0016] Therefore, there is a need for higher dose formulations and high drug load formulations with lower fill weights, smaller capsule sizes, comparable and / or better bioavailability. Summary of the invention

[0017] The disclosed formulations enable patients to take fewer capsules and smaller sized capsules when a higher dose is required. Thus, the disclosed compositions and methods have the potential to achieve better patient compliance while providing prescribers with dosage flexibility, including smaller capsule sizes, higher dose formulations, and high drug load formulations.

[0018] The present disclosure provides high-dose oral pharmaceutical compositions and high drug loads of isotretinoin or a pharmaceutically acceptable salt or ester thereof with low fill weight and smaller size capsules (e.g., size 1, 2, or 3 or smaller) with comparable and / or better bioavailability, reduced food effect, fewer capsules required, and lower toxicity.

[0019] The disclosed oral pharmaceutical composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof and other pharmaceutically acceptable excipients or carriers.

[0020] The present disclosure also provides an oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof in a liquid or semisolid drug form filled in a capsule and a method for preparing the composition.

[0021] The present disclosure also provides methods for preparing the disclosed oral pharmaceutical compositions.

[0022] The present disclosure also provides methods of treating conditions and diseases, such as skin conditions, including acne, for example, by orally administering the disclosed pharmaceutical compositions to a patient in need thereof.

[0023] The present disclosure further provides methods comprising using the oral pharmaceutical compositions to treat acne conditions, such as severe, recalcitrant nodular acne, such as in patients 12 years of age and older. DETAILED DESCRIPTION

[0024] definition:

[0025] As used herein, the term "about" generally refers to a range of values ​​of + / -10% of a specified value. With respect to the amount of an active pharmaceutical ingredient, the term "about" also refers to being within the pharmaceutically acceptable limits of the United States Pharmacopeia (USP-NF 21), 2003 edition, or available at www.usp.org. With respect to blood drug concentrations, "about" means within FDA acceptable guidelines.

[0026] "Administration" or "application" refers to the step of giving (i.e., administering) a pharmaceutical composition or active ingredient to a subject. The pharmaceutical compositions disclosed herein can be administered by a number of suitable routes, including oral and intramuscular or subcutaneous routes of administration, such as by injection, topical or using implants.

[0027] The term "AUC" refers to the area under the time / plasma concentration curve following administration of a pharmaceutical composition. 0-∞ AUC represents the area under the plasma concentration-time curve from time 0 to infinity; 0-t It represents the area under the plasma concentration-time curve from time 0 to time t.

[0028] The term "C max " refers to the maximum concentration of isotretinoin in the blood after administration of the pharmaceutical composition. When the pharmaceutical composition of the present invention is administered to healthy subjects under fed and fasting conditions, its pharmacokinetic and pharmacodynamic parameters are expressed as area under the curve (AUC), maximum concentration (C max ) and maximum concentration time (T max )Report.

[0029] The term "D10" refers to the particle size of isotretinoin wherein 10% (w / v) of the particles are smaller than the defined D10 value; "D50" refers to the particle size of isotretinoin wherein 50% (w / v) of the particles are smaller than the defined D50 value; and "D90" refers to the particle size of isotretinoin wherein 90% (w / v) of the particles are smaller than the defined D90 value.

[0030] As used herein, the phrase "food effect" refers to a food-drug interaction that reduces or increases the extent of drug absorption. It refers to the area under the curve (AUC), maximum concentration (C) of the drug when the drug or its formulation is orally administered to humans, compared to the same formulation administered in the fasting state or without food, when taken with food or in the fed state. max ) and / or the relative differences.

[0031] As used herein, the phrase "high dose" refers to a dose of isotretinoin, wherein the dose is at least 45 mg, greater than 40 mg ( and The highest dose currently approved) is at least 12.5% ​​higher.

[0032] The term "isotretinoin" refers to isotretinoin in crystalline or amorphous form or mixtures thereof.

[0033] The phrase "high drug load" as used herein refers to the mass ratio of drug / isotretinoin or a pharmaceutically acceptable salt or ester thereof to the drug-loaded composition / isotretinoin or a pharmaceutically acceptable salt or ester thereof and pharmaceutical excipients filled into the capsule. High drug load capsules contain a high mass ratio of drug to drug-loaded composition filled into the capsule, which ultimately results in a smaller size of the capsule filled with the composition. The disclosed pharmaceutical composition provides a ratio of isotretinoin or a pharmaceutically acceptable salt or ester thereof to isotretinoin or a pharmaceutically acceptable salt or ester thereof and pharmaceutically acceptable excipients of 0.20:1 or greater.

[0034] "Patient" means a human or non-human subject receiving medical or veterinary care.

[0035] The phrase "pharmaceutically acceptable carrier" is recognized in the art and includes, for example, a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in carrying or transporting any relevant composition from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the relevant composition and not harmful to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic compatible substances used in pharmaceutical formulations.

[0036] "Pharmaceutical composition" refers to a preparation having an active ingredient. The term "preparation" means that in addition to the active ingredient, at least one additional ingredient (such as, but not limited to, albumin [such as human serum albumin (HSA) or recombinant human albumin] and / or sodium chloride) is present in the pharmaceutical composition. Therefore, a pharmaceutical composition is a preparation suitable for diagnosis, treatment or cosmetic administration to a subject (such as a human patient). The pharmaceutical composition can be in a lyophilized or vacuum-dried state, for example, after the lyophilized or vacuum-dried pharmaceutical composition is reconstituted with physiological saline or water to form a solution, or in a solution state without reconstitution. As described above, the pharmaceutical composition can be a liquid, semisolid or solid. The pharmaceutical composition may be free of animal protein.

[0037] As used herein, the term "stable" refers to chemical stability, wherein no more than 1.5% w / w of total related substances are formed when stored under conditions according to the ICH guidelines. Conditions include accelerated conditions (temperature of 40° C. at 75% relative humidity) and long-term stability conditions (temperature of 25° C. at 60% relative humidity) for a period of at least three months.

[0038] The term "T max ” refers to the amount of C max Time (hours).

[0039] "Therapeutically effective amount" refers to the level, amount or concentration of active ingredient required to treat a symptom, disease, disorder or condition without causing significant negative or undesirable side effects.

[0040] "Treat," "treating," or "treatment" refers to the alleviation or reduction (which includes some reduction, significant reduction, nearly complete reduction, and complete reduction), resolution, or prevention (temporarily or permanently) of the symptoms, disease, disorder, or condition in order to achieve a desired therapeutic or cosmetic result, for example, by healing of injured or damaged tissue, or by altering, altering, enhancing, improving, ameliorizing, and / or beautifying an existing or perceived disease, disorder, or condition.

[0041] Composition

[0042] The present disclosure provides embodiments comprising a high-dose oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof. The disclosed compositions may further comprise at least one pharmaceutically acceptable excipient or carrier.

[0043] In an embodiment, the present disclosure provides a high drug load oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof.The disclosed composition may further comprise at least one pharmaceutically acceptable excipient.

[0044] In an embodiment, the present disclosure provides a high-dose oral pharmaceutical composition comprising:

[0045] a. At least 45 mg of isotretinoin or a pharmaceutically acceptable salt or ester thereof, which is higher than the currently approved highest dose and at least 12.5% ​​higher than 40 mg; and

[0046] b. at least one pharmaceutically acceptable excipient;

[0047] Wherein, when orally administered at a higher dose and with a minimum number of capsules, the composition can produce equivalent or better therapeutic effects, and equivalent and lower adverse reaction profiles.

[0048] In another embodiment, the present disclosure provides a high drug load oral pharmaceutical composition comprising:

[0049] a. 30 mg or 40 mg or 50 mg or 60 mg or more of isotretinoin or a pharmaceutically acceptable salt or ester thereof; and

[0050] b. at least one pharmaceutically acceptable excipient, which is compatible with an approved and Compared to filling into lower sized capsules;

[0051] For patients who need to take two or more capsules orally to adjust the dosage to a maximum of 2 mg / kg / day for the treatment of acne, the capsules prepared by the composition are easy to swallow, thereby improving the compliance of the patients.

[0052] In an embodiment, the present disclosure provides a high-dose oral pharmaceutical composition comprising:

[0053] a. isotretinoin or a pharmaceutically acceptable salt or ester thereof, the dosage of which is higher than that of commercially available The highest available dose for capsules (i.e., 40 mg) is 12.5% ​​to about 50% higher;

[0054] b. and a pharmaceutically acceptable excipient;

[0055] Wherein, when orally administered at a higher dose and with a minimum number of capsules, the composition can produce equivalent or better therapeutic effects, and equivalent and lower adverse reaction profiles.

[0056] In an embodiment, the present disclosure provides a high-dose oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition exhibits a reduced food effect, thereby providing greater flexibility to the patient.

[0057] In an embodiment, the present disclosure provides a high drug load oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the composition exhibits a reduced food effect, thereby providing greater flexibility to the patient.

[0058] In a disclosed embodiment, the present invention provides a high-dose oral pharmaceutical composition comprising:

[0059] a. isotretinoin or a pharmaceutically acceptable salt or ester thereof;

[0060] b. Oily / lipid vehicles;

[0061] c. Surfactant;

[0062] d. co-surfactant;

[0063] e. Antioxidants; and / or

[0064] f. Co-solvent.

[0065] In a disclosed embodiment, the present invention provides a high drug load oral pharmaceutical composition comprising:

[0066] a. isotretinoin or a pharmaceutically acceptable salt or ester thereof;

[0067] b. Oily / lipid vehicles;

[0068] c. Surfactant;

[0069] d. co-surfactant;

[0070] e. Antioxidants; and / or

[0071] f. Co-solvent.

[0072] In disclosed embodiments, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof in an amount of, for example, about 20 mg to about 100 mg. For example, in embodiments, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof in an amount of, for example, about 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg.

[0073] In a further embodiment, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof in an amount of about 30 mg. In another embodiment, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof in an amount of about 40 mg. In another embodiment, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof in an amount of about 60 mg.

[0074] In a disclosed embodiment, the pharmaceutical composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, wherein the ratio of isotretinoin or a pharmaceutically acceptable salt or ester thereof to isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient is 0.20:1 or greater; 0.40:1 or greater; 0.60:1 or greater; 0.80:1 or greater; 1:1 or greater, preferably 0.24:1 or greater.

[0075] In disclosed embodiments, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof, for example, in an amount from about 10% w / w to about 90% w / w of the total composition, or in an amount from about 10% w / w to about 50% w / w of the total composition, or in an amount from about 10% w / w to about 40% w / w of the total composition, preferably in an amount from about 20% w / w to about 30% w / w of the total composition.

[0076] The present disclosure provides high drug loading of isotretinoin or a pharmaceutically acceptable salt or ester thereof with low fill weight, thereby enabling the isotretinoin or a pharmaceutically acceptable salt or ester thereof composition to be filled into smaller size capsules, such as size 1, size 2, size 3 or smaller.

[0077] The present disclosure provides a composition of isotretinoin or a pharmaceutically acceptable salt or ester thereof with a high drug load, wherein the dose of isotretinoin is 30 mg to 100 mg and is compatible with currently approved and In contrast, in smaller sized capsules (eg, size 1, 2, 3 or smaller) have a low fill weight.

[0078] In one embodiment, the composition is a liquid, semisolid, solution, suspension, emulsion, microemulsion, dispersion, self-emulsifying drug delivery system Self-emulsifying microemulsion drug delivery system The composition is filled into capsules with a total fill weight of about 100 mg to about 250 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg.

[0079] In other embodiments, the composition comprises isotretinoin in crystalline form or in amorphous form or in a mixture of crystalline and amorphous forms.

[0080] In another embodiment, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof in milled or unmilled form, wherein the particle size distribution of the isotretinoin or a pharmaceutically acceptable salt or ester thereof is such that the D10 is, for example, less than 400 μm, less than 300 μm, less than 200 μm, less than 100 μm, less than 50 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm or less than 10 μm; preferably less than 70 μm, less than 60 μm, less than 50 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm or less than 10 μm.

[0081] In a further embodiment, a composition of isotretinoin or a pharmaceutically acceptable salt or ester thereof in milled or unmilled form is disclosed, wherein the particle size distribution of isotretinoin or a pharmaceutically acceptable salt or ester thereof is such that the D50 is less than, for example, 400 μm, less than 300 μm, less than 200 μm, less than 100 μm, less than 50 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm or less than 10 μm; preferably less than 150 μm, less than 50 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm or less than 10 μm.

[0082] In a further embodiment, a composition of isotretinoin or a pharmaceutically acceptable salt or ester thereof in milled or unmilled form is disclosed, wherein the particle size distribution of isotretinoin or a pharmaceutically acceptable salt or ester thereof is such that the D90 is less than 400 μm, less than 300 μm, less than 200 μm, less than 100 μm, less than 50 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm or less than 10 μm; preferably less than 300 μm, less than 100 μm, less than 50 μm, less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm or less than 10 μm.

[0083] In further embodiments, an oral pharmaceutical composition comprises isotretinoin filled into a capsule of size 1 or smaller, size 2 or smaller, size 3 or smaller, size 4 or smaller, or size 5 or smaller and a pharmaceutically acceptable excipient.

[0084] In a further embodiment, the oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient filled into a capsule, wherein the volume filled into the capsule is about 0.50 mL or less, about 0.37 mL or less, about 0.30 mL or less, about 0.21 mL or less, about 0.13 mL or less.

[0085] In a further embodiment, the oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient filled into a capsule, wherein the concentration of isotretinoin in the capsule is about 200 mg / ml to about 300 mg / ml, preferably about 220 mg / ml to about 280 mg / ml, preferably about 230 mg / ml to about 270 mg / ml, preferably about 240 mg / ml to about 260 mg / ml, preferably about 245 mg / ml, preferably about 250 mg / ml, preferably about 255 mg / ml.

[0086] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient filled into a capsule, wherein the concentration of isotretinoin in the capsule is at least 25% w / w or higher.

[0087] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, wherein the composition having an isotretinoin concentration of about 200 mg / ml to about 300 mg / ml; preferably about 220 mg / ml to about 280 mg / ml, preferably about 230 mg / ml to about 270 mg / ml, preferably about 240 mg / ml to about 260 mg / ml, preferably about 245 mg / ml, preferably about 250 mg / ml, preferably about 255 mg / ml comprises:

[0088] a. isotretinoin or a pharmaceutically acceptable salt or ester thereof;

[0089] b. Oily / lipid vehicles;

[0090] c. Surfactant;

[0091] d. co-surfactant;

[0092] e. Antioxidants; and / or

[0093] f. Co-solvent.

[0094] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, wherein the composition has a capsule fill volume of about 0.5 mL or less, about 0.37 mL or less, about 0.30 mL or less, about 0.21 mL or less, about 0.13 mL or less, comprising:

[0095] a. isotretinoin or a pharmaceutically acceptable salt or ester thereof;

[0096] b. Oily / lipid vehicles;

[0097] c. Surfactant;

[0098] d. co-surfactant;

[0099] e. Antioxidants; and / or

[0100] f. Co-solvent.

[0101] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, wherein the composition is in a suspension dosage form comprising:

[0102] a. isotretinoin or a pharmaceutically acceptable salt or ester thereof;

[0103] b. Oily / lipid vehicles;

[0104] c. Surfactant;

[0105] d. co-surfactant;

[0106] e. Antioxidants; and / or

[0107] f. co-solvent;

[0108] wherein the suspension composition has a capsule fill volume of about 0.5 mL or less, about 0.37 mL or less, about 0.30 mL or less, about 0.21 mL or less, about 0.13 mL or less, and

[0109] The concentration of isotretinoin in the capsule is about 200 mg / ml to about 300 mg / ml, preferably about 220 mg / ml to about 280 mg / ml, preferably about 230 mg / ml to about 270 mg / ml, preferably about 240 mg / ml to about 260 mg / ml, preferably about 245 mg / ml, preferably about 250 mg / ml, preferably about 255 mg / ml.

[0110] In another embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, wherein the composition is in a suspension dosage form comprising:

[0111] a. isotretinoin or a pharmaceutically acceptable salt or ester thereof;

[0112] b. Oily / lipid vehicles;

[0113] c. Surfactant;

[0114] d. co-surfactant;

[0115] e. Antioxidants; and / or

[0116] f. co-solvent;

[0117] The ratio of isotretinoin or its pharmaceutically acceptable salt or ester to isotretinoin or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable excipient is 0.20:1 or greater; 0.40:1 or greater; 0.60:1 or greater: 0.80:1 or greater: 1:1 or greater, etc.

[0118] In another embodiment of the present invention, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, wherein the composition is in a suspension dosage form comprising:

[0119] a. isotretinoin or a pharmaceutically acceptable salt or ester thereof;

[0120] b. Oily / lipid vehicles;

[0121] c. Surfactant;

[0122] d. co-surfactant;

[0123] e. Antioxidants; and / or

[0124] f. Co-solvent,

[0125] Wherein the isotretinoin or a pharmaceutically acceptable salt or ester thereof is present in a concentration of about 25% or more.

[0126] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient filled into a capsule of size 1 or smaller, size 2 or smaller, size 3 or smaller, size 4 or smaller, or size 5 or smaller, wherein said capsule having said pharmaceutical composition is different from currently available capsules comprising and / or The oral pharmaceutical composition of isotretinoin is easier to swallow.

[0127] In further embodiments, the oily / lipid vehicle includes, but is not limited to, vegetable oils, hydrogenated vegetable oils, essential oils, digestible or non-digestible oils, peanut oil, olive oil, peppermint oil, soybean oil, kernel oil, almond oil, safflower oil, sunflower oil, palm oil, sesame oil, canola oil, corn oil, castor oil, coconut oil, cottonseed oil, grapeseed oil, animal fats, fatty acids, fatty acid esters, fats, waxes, sucrose esters, monoolein, polyglycerol-3-oleate, monolinolein, mono- and diglycerides, polyglycerol 10-oleate, and mixtures thereof.

[0128] In another embodiment, the oily / lipid vehicle is present in an amount of about 1% w / w to about 90% w / w of the total weight of the composition; preferably, it is present in an amount of about 5% w / w to about 90% w / w of the total weight of the composition; more preferably, it is present in an amount of about 5% w / w to about 80% w / w of the total weight of the composition; and most preferably, it is present in an amount of about 5% w / w to about 75% w / w of the total weight of the composition.

[0129] In other embodiments, the ratio of isotretinoin or a pharmaceutically acceptable salt or ester thereof to the oily vehicle is from about 1:10 to about 13:1, preferably from about 1:9 to about 9:1, more preferably from about 1:4 to about 4:1, more preferably about 1:1.

[0130] In other embodiments, the ratio of isotretinoin or a pharmaceutically acceptable salt or ester thereof to isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient is 0.20:1 or greater; 0.40:1 or greater; 0.60:1 or greater:0.80 or greater:1:1 or greater, preferably 0.24:1 or greater.

[0131] In other embodiments, surfactants include, but are not limited to, anionic, cationic, or nonionic surfactants; sorbitan fatty acid esters; polysorbates prepared from lauric acid, palmitic acid, stearic acid, and oleic acid; polyoxyethylene monoesters, such as polyoxyethylene ethyl monostearate, polyoxyethylene monolaurate, and polyoxyethylene monooleate; glyceryl monostearate; sorbitan esters; polysorbate 80; polyoxyethylene sorbitan monooleate; polyoxyl stearate macrogol ether; polyoxyethylene; macrogol glycerides; caprylocaproyl caprylocaproyl macrogol-8-glyceride; macrogol-8glycerides); PEG-8 caprylic / capric glycerides; macrogol glyceryl hydroxystearate; polyoxyl 35 castor oil; macrogol glyceryl hydroxystearate; polyoxyl 40 hydrogenated castor oil; macrogol glycerides, such as caprylocaproylpolyoxylglycerides; lauroyl polyoxyglycerides, such as hydrogenated coconut oil PEG 1500 esters, Gelucire 44 / 14; and stearyl polyoxyglycerides; PEG-8 beeswax; polyethylene glycol derivatives; polyoxyethylene castor oil derivatives; polyoxyethylene alkyl ethers; polyoxyethylene stearate; a mixture of glyceryl monostearate and PEG-75 stearic acid beeswax; glyceryl monostearate polyoxyethylene stearate and mixtures thereof.

[0132] In other embodiments, the surfactant is present in an amount of about 0.01% w / w to about 90% w / w of the total weight of the composition; preferably, it is present in an amount of about 10% w / w to about 85% w / w of the total weight of the composition; more preferably, it is present in an amount of about 10% w / w to about 80% w / w of the total weight of the composition; and most preferably, it is present in an amount of about 10% w / w to about 70% w / w of the total weight of the composition.

[0133] In other embodiments, co-surfactants include, but are not limited to, anionic, cationic or nonionic surfactants; hydrophilic or hydrophobic; water-dispersible or water-soluble surfactants; fatty acid ester derivatives; propylene glycol esters of caprylic acid, mainly composed of monoesters and diesters, propylene glycol monocaprylate; sorbitan fatty acid esters, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate; oleoyl polyoxyglycerol esters, such as almond oil PEG300 esters; Labrafil M1944 CS, AKG-6; oleic acid macrogol glycerides; Peglicol 5-oleate; glycerol monocaprylocaprate, glyceryl caprylate / caprate, mono-diglycerides of medium chain fatty acids, glyceride derivatives; propylene glycol esters of caprylic and capric acid, propylene glycol dicaprylocaprate, propylene glycol dicaprylate / dicaprate; linoleoyl polyoxyglycerides, such as linoleic acid macrogol glycerides, corn oil PEG300 ester, M 2125; Lauroyl polyoxyglycerol esters, such as hydrogenated palm / palm kernel oil PEG 300 esters, M2130CS and mixtures thereof.

[0134] In a further embodiment, the co-surfactant is present in an amount of about 0.01% w / w to about 90% w / w of the total weight of the composition; preferably, it is present in an amount of about 5% w / w to about 85% w / w of the total weight of the composition; more preferably, it is present in an amount of about 5% w / w to about 80% w / w of the total weight of the composition; and most preferably, it is present in an amount of about 5% w / w to about 50% w / w of the total weight of the composition.

[0135] In further embodiments, the surfactant and co-surfactant are present in an amount of about 0.01% w / w to about 90% w / w of the total weight of the composition; preferably, they are present in an amount of about 5% w / w to about 85% w / w of the total weight of the composition; more preferably, they are present in an amount of about 5% w / w to about 80% w / w of the total weight of the composition; and most preferably, they are present in an amount of about 5% w / w to about 50% w / w of the total weight of the composition.

[0136] In further embodiments, co-solvents include, but are not limited to, alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol such as tetrahydrofurfuryl alcohol PEG ether or methoxy PEG; amides such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N- -alkylcaprolactams, dimethylacetamide, dimethylformamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, F-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers; and other solubilizers such as dimethyl isosorbide, N-methylpyrrolidone, monooctanoin, diethylene glycol monoethyl ether, dimethyl sulfoxide (DMSO), water and mixtures thereof.

[0137] In another embodiment, the cosolvent is present in an amount of about 1% w / w to about 90% w / w of the total weight of the composition; preferably, it is present in an amount of about 10% w / w to about 90% w / w of the total weight of the composition; more preferably, it is present in an amount of about 10% w / w to about 80% w / w of the total weight of the composition; and most preferably, it is present in an amount of about 10% w / w to about 40% w / w of the total weight of the composition.

[0138] In other embodiments, the composition comprises an antioxidant, and includes, but is not limited to, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, ascorbyl palmitate, ascorbic acid, sodium ascorbate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, propyl gallate, and mixtures thereof. The antioxidant is present in an amount of about 0.05% w / w to about 1.00% w / w of the total weight of the composition.

[0139] In a further embodiment, the composition comprises a chelating agent and includes but is not limited to EDTA, disodium EDTA, disodium calcium edetate, tartaric acid, malic acid and citric acid. The chelating agent is present in an amount of about 0.05% w / w to about 1.00% w / w of the total weight of the composition.

[0140] In a further embodiment, the composition comprises a precipitation inhibitor, and includes but is not limited to hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, poloxamers and derivatives thereof, cyclodextrins and derivatives thereof, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, vinyl pyrrolidone-vinyl acetate copolymers and mixtures thereof. The precipitation inhibitor is present in an amount of about 0.05% w / w to about 60% w / w of the total weight of the composition.

[0141] In further embodiments, the composition comprises other excipients, such as penetration enhancers, pH regulators and complexing agents. Examples of suitable penetration enhancers include, but are not limited to, phospholipids and their derivatives, phosphatidylcholine, lecithin and its derivatives and mixtures. Examples of suitable pH regulators include, but are not limited to, megulamine and its derivatives, sodium hydroxide and its derivatives, sodium bicarbonate and its derivatives and mixtures. Examples of suitable complexing agents include, but are not limited to, cyclodextrins and derivatives, phospholipids and their derivatives and mixtures. These excipients may be present in the present invention at about 5% w / w to about 70% w / w of the total weight of the composition.

[0142] Preparation method

[0143] In another aspect, a method for preparing a high-dose oral pharmaceutical composition is provided, the pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutical excipient, wherein the method comprises the following steps:

[0144] a. Heat the mixture of oil, surfactant and co-surfactant at 40°C-45°C;

[0145] b. dissolving the antioxidant in the mixture of step (i) at 40 ℃ -45 ℃, and then cooling to room temperature;

[0146] c. dispersing isotretinoin into step (ii) under stirring;

[0147] d. Optionally, adding a co-solvent after step (iii)

[0148] e. Optionally, grinding is performed after step (iii);

[0149] f. filling the drug of step (iii) or step (iv) or step (v) in a hard gelatin capsule;

[0150] g. preparing a gelatin banding solution by soaking gelatin in water at room temperature for 6 hours and then adding polysorbate 80 at a temperature of 60 ± 10 ° C; and

[0151] h. bundling the filled capsules of step (vi) with the bundling solution of step (vii).

[0152] In yet another embodiment, the oral pharmaceutical composition is stable when stored for at least three months or more at a temperature of 40°C and 75% relative humidity, or at a temperature of 30°C and 65% relative humidity, or at a temperature of 25°C and 60% relative humidity.

[0153] In yet another embodiment, the oral pharmaceutical composition is stable when stored for at least six months or longer at a temperature of 40°C and 75% relative humidity, or at a temperature of 30°C and 65% relative humidity, or at a temperature of 25°C and 60% relative humidity.

[0154] In yet another embodiment, the oral pharmaceutical composition is stable when stored at a temperature of 40°C and 75% relative humidity, or at a temperature of 30°C and 65% relative humidity, or at a temperature of 25°C and 60% relative humidity for at least twelve months or more.

[0155] In yet another embodiment, the oral pharmaceutical composition has a drug content of about 102% w / w to about 110% w / w during the stable period.

[0156] In yet another embodiment, the oral pharmaceutical composition has impurities such as tretinoin, impurity G (5,6-epoxy-13-cis retinoic acid) and less than 1.5 unknown impurities.

[0157] Treatment

[0158] The present disclosure provides methods for treating diseases that are typically treated with isotretinoin or a pharmaceutically acceptable salt or ester thereof. For example, in disclosed embodiments, a therapeutically effective dose of isotretinoin may be 30 mg or more; 40 mg or more; 50 mg or more; 60 mg or more. The disclosed methods include treating, for example, cancer, skin disorders, and the like.

[0159] In an embodiment, the present disclosure provides a method of treating acne by administering to an individual in need thereof a high-dose oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.

[0160] In an embodiment, the present disclosure provides a method of treating acne by administering to a subject in need thereof a high drug load oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.

[0161] In another embodiment, the composition exhibits a ln-transformed geometric least mean square C of about 915.3556 ng / mL under fed conditions. max and the ln-transformed geometric least mean square C of approximately 302.8420 ng / mL under fasting conditions max .

[0162] In another embodiment, the composition exhibits a ln-transformed geometric least mean square AUC0→ of about 15924.4305 ng.h / mL under fed conditions. t and AUC0 of about 16953.5405 ng.h / mL→ ∞ , and a ln-transformed geometric least mean square AUC0 of about 4911.7465 ng.h / mL under fasting conditions → t and AUC0 of about 5335.7760 ng.h / mL→ ∞ .

[0163] In another embodiment, when administered orally, the composition has an AUC0→ of about 1.5. t and AUC0→ ∞ The average fed / fasting ratio and the ln-transformed geometric least squares C of about 2.25 max The average fed / fasting ratio.

[0164] The present invention can be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way. Modifications in the examples fall within the scope and spirit of the appended claims, and will be apparent to those skilled in the art based on the disclosure herein and are also considered to be within the scope of the present invention.

[0165] Example

[0166] Example 1

[0167] The weight (wt) of active ingredients and excipients are expressed in milligrams (mg) and the % in the composition is expressed as % w / w. The examples are non-limiting and are quantitatively applicable to the entire scope of the invention.

[0168] Composition:

[0169] Sr.No. Element %w / w range 1 Isotretinoin or its pharmaceutically acceptable salt or ester 10-90 2 Oily or lipid vehicle 1-90 3 Surfactants 0.01-90 4 Co-surfactant 0.01-90 5 Antioxidants 0.05-1 6 Co-solvent 0.01-90 total 100 Hard gelatin capsule shell size 1, 2, 3, 4 or 5

[0170] Procedure for preparing the composition:

[0171] (i) heating a mixture of oil, surfactant and co-surfactant;

[0172] (ii) dissolving an antioxidant in the mixture of step (i);

[0173] (iii) dispersing isotretinoin or a pharmaceutically acceptable salt or ester thereof into step (ii) under stirring;

[0174] (iv) optionally, adding a co-solvent after step (iii);

[0175] (v) optionally, grinding after step (iii);

[0176] (vi) filling the capsule with the drug of step (iii) or step (iv) or step (v);

[0177] (vii) preparing a gelatin bundling solution by soaking gelatin in water and then adding polysorbate;

[0178] (vii) bundling the filled capsules of step (vi) with the bundling solution of step (vii).

[0179] Compositions prepared without co-solvents

[0180] Table 1:

[0181]

[0182]

[0183] Compositions prepared using co-solvents

[0184] Table 2:

[0185]

[0186]

[0187]

[0188] Table 3:

[0189]

[0190] Table 4:

[0191]

[0192]

[0193] Procedure for preparing the Examples in Tables 1, 2, 3 and 4:

[0194] 1. Mix the surfactant and co-surfactant and heat together at 40°C-45°C until a clear solution is formed.

[0195] 2. Dissolve BHA and BHT into the above solution at 40℃-45℃, then cool to room temperature and add oil.

[0196] 3. Disperse isotretinoin into step 2 with stirring at room temperature.

[0197] 4. Optionally, grinding is performed after step (3). The drug dispersion of step 3 is ground by using a dyno grinder under optimal processing conditions until a PSD (d(0.9)) of NMT 80 microns is achieved.

[0198] 5. Optionally, step (3) is followed by the addition of a co-solvent

[0199] 6. Fill the drug into hard gelatin capsules.

[0200] 7. Prepare gelatin bundling solution by soaking gelatin in water at room temperature for specified hours and then heating the gelatin mass to 60 ± 10 °C and then adding polysorbate 80 thereto at 60 ± 5 °C.

[0201] 8. Bundle the filled capsules of step 6 by using the bundling solution of step 7.

[0202] Example 2

[0203] Ratio Optimization Study: The compositions of Table 3 were prepared using ratios of isotretinoin or a pharmaceutically acceptable salt or ester thereof to peppermint oil (oily vehicle) of 1:10, 1:9, 1:4, 13:1, 9:1, 4:1 and 1:1. The composition having a 1:1 ratio of isotretinoin or a pharmaceutically acceptable salt or ester thereof to peppermint oil (oily vehicle) remained stable under accelerated and long-term stability conditions. Related substances, known impurities and unknown impurities were measured and reported to be within the ICH guideline limits.

[0204] Example 3

[0205] Dissolution Studies: Dissolution studies of the pharmaceutical compositions of Examples A and B were studied in modified USP and Identical dissolution media using USPI Type II apparatus. The % drug release with respect to time was studied.

[0206] Example 4

[0207] Stability Study: The stability of the pharmaceutical compositions of Examples A and B in PVC-Aclar blister packs was studied under accelerated and long-term stability conditions according to ICH guidelines. Related substances, known impurities, and unknown impurities were measured and reported to be within the ICH guideline limits.

[0208] Example 5

[0209] Clinical Study: The pharmacokinetic and pharmacodynamic parameters of isotretinoin capsules USP 60 mg composition-treatment group-1 (T1) and treatment group-2 (T2) were studied in human volunteers and compared with the currently approved (isotretinoin) capsules [one 40 mg capsule and two 10 mg capsules] (referred to as treatment group R in the table below) were compared.

[0210] Statistics of pharmacokinetic parameters of isotretinoin capsules USP 60 mg FED BE study

[0211]

[0212] Statistics of pharmacokinetic parameters of isotretinoin capsules USP 60 mg in the FASTING BE study

[0213]

[0214]

[0215] Related substances or impurities data for Isotretinoin Capsules USP 60 mg Composition - Treatment Group-1 (T1) and Treatment Group-2 (T2) under accelerated conditions

[0216]

[0217] Finally, it should be understood that although various aspects of this specification are highlighted by reference to specific embodiments, it will be readily understood by those skilled in the art that these disclosed embodiments only illustrate the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is by no means limited to the specific methods, schemes and / or reagents described herein, etc. Therefore, various modifications, changes or alternative configurations can be made to the disclosed subject matter according to the teachings herein without departing from the spirit of this specification. Finally, the terms used herein are only used for the purpose of describing specific embodiments and are not intended to limit the scope of the present invention, which is limited only by the claims.

[0218] Therefore, the invention is not limited to what has been precisely shown and described.

[0219] Certain embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention.

[0220] Of course, after reading the foregoing description, changes to the embodiments described will become apparent to those of ordinary skill in the art. The inventor expects that the skilled person will appropriately adopt such variations, and the inventor intends to practice the invention in a manner different from that specifically described herein. Therefore, the present invention includes all modifications and equivalents of the subject matter recorded in the appended claims as permitted by applicable law. In addition, unless otherwise specified herein or clearly contradicted by the context, the present invention encompasses any combination of the above-described embodiments in all possible variations thereof.

[0221] The grouping of alternative embodiments, elements or steps of the present invention should not be construed as limiting. Each group member can be cited and claimed individually or in any combination with other group members disclosed herein. It can be expected that, for convenience and / or patentability reasons, one or more members of the group can be included in the group or deleted from the group. When any such inclusion or deletion occurs, this specification is considered to contain the modified group, thereby satisfying the written description of all Markush groups used in the appended claims.

[0222] Unless otherwise stated, all numbers used in this specification and claims to represent characteristics, items, quantities, parameters, properties, terms, etc. should be understood to be modified by the term "about" in all cases. As used herein, the term "about" means that the characteristics, items, quantities, parameters, properties or terms so defined cover a range of plus or minus ten percent above and below the value of the characteristics, items, quantities, parameters, properties or terms. Therefore, unless otherwise indicated, the numerical parameters set forth in the specification and the appended claims are approximate values ​​that can vary. At least, and without attempting to limit the application of the doctrine of equivalents to the scope of the claims, each digital indication should be interpreted at least according to the number of reported significant figures and by applying ordinary rounding techniques. Although the numerical ranges and values ​​setting forth the wide range of the present invention are approximate values, the numerical ranges and values ​​set forth in the specific embodiments are reported as accurately as possible. However, any numerical range or value inherently contains certain errors that must be generated by the standard deviation found in its respective test measurements. Numerical ranges are listed herein only to refer to each independent numerical value within the range in a simple manner. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the specification as if it were individually recited herein.

[0223] Unless otherwise specified herein or clearly contradictory to the context, the terms "one", "the" and similar indicators used in the context of describing the present invention (especially in the context of the following claims) are interpreted to cover both the singular and the plural. Unless otherwise specified herein or clearly contradictory to the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "for example") provided herein is intended only to better illustrate the present invention and does not limit the scope of the present invention claimed in other ways. Any statement in this specification should not be interpreted as implying that any unclaimed element is essential for implementing the present invention.

[0224] The specific embodiments disclosed herein may be further limited in the claims using the expression "consisting of" or "consisting essentially of." When used in a claim, whether as filed or added by amendment, the transition term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transition term "consisting essentially of" limits the scope of a claim to the specified materials or steps, and those materials or steps that do not materially affect the basic and novel characteristics. The various embodiments of the invention so claimed are inherently or expressly described and enabled herein.

[0225] All patents, patent publications, and other publications cited and referred to in this specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, compositions and methods described in these publications that may be used in conjunction with the present invention. These publications are provided only because they were published before the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosures by virtue of prior invention or for any other reason. All statements regarding the dates of these documents or representations of their contents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents.

Claims

1. A capsule dosage form, comprising: A pharmaceutical composition comprising at least 30 mg of isotretinoin or a pharmaceutically acceptable salt or ester thereof; and Pharmaceutically acceptable excipients; The size of the capsules is 1 to 4.

2. The pharmaceutical composition of claim 1, wherein the composition comprises a liquid composition.

3. The pharmaceutical composition of claim 1, wherein the composition comprises a semisolid composition.

4. The pharmaceutical composition of claim 2 or 3, wherein the capsule is size 2 or smaller.

5. The pharmaceutical composition of claim 2 or 3, wherein the capsule is size 3 or smaller.

6. The pharmaceutical composition of claim 2 or 3, wherein the capsule is size 4.

7. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises at least 45 mg of isotretinoin or a pharmaceutically acceptable salt or ester thereof.

8. The pharmaceutical composition of claim 4, wherein the ratio of isotretinoin or a pharmaceutically acceptable salt or ester thereof to isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient is at least 0.20:

1.

9. The composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from one or more oils or lipid vehicles, one or more surfactants, one or more co-surfactants and one or more antioxidants and combinations thereof.

10. The composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from one or more oils or lipid vehicles, one or more surfactants, one or more co-surfactants and one or more antioxidants and combinations thereof.

11. The pharmaceutical composition according to claim 1, wherein The composition comprises about 30-60 mg of isotretinoin, about 5-70 wt % of an oily vehicle, 20-80 wt % of a surfactant, about 1-10 wt % of a co-surfactant and about 0.1-5 wt % of an antioxidant.

12. The pharmaceutical composition of claim 1, wherein the composition comprises about 30-60 mg of isotretinoin, about 5-70 wt% of peppermint oil, 20-80 wt% of polyoxyl 35 castor oil, about 1-10 wt% of propylene glycol monocaprylate, and about 0.1-5 wt% of butylated hydroxyanisole and butylated hydroxytoluene.

13. A method for preparing a high-dose oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutical excipient, wherein the method comprises the following steps: (i) heating a mixture of oil, surfactant and co-surfactant at 40° C.-45° C.; (ii) dissolving an antioxidant in the mixture of step (i) at 40° C.-45° C., and then cooling to room temperature; (iii) dispersing isotretinoin into step (ii) under stirring; (iv) optionally, adding a co-solvent after step (iii); (v) optionally, grinding after step (iii); (vi) filling the mixture of step (iii) or step (iv) or step (v) into a hard gelatin capsule; (vii) preparing a gelatin bundling solution by soaking gelatin in water at room temperature for 6 hours and then adding polysorbate 80 at a temperature of 60±10°C; and (vii) bundling the filled capsules of step (vi) with the bundling solution of step (vii).

14. A method of treating a skin disorder comprising administering to a patient the pharmaceutical composition of claim 1.

15. The method of claim 14, wherein the skin disorder comprises one of acne, lupus erythematosus, and ichthyosis.

16. The method of claim 15, wherein the skin condition comprises acne.

17. The method of claim 16, wherein the acne comprises severe, recalcitrant nodular acne.

18. The method of claim 17, wherein the patient is at least 12 years old.

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