Pharmaceutical compositions containing isotretinoin, processes for their preparation and uses

Abstract

The present invention provides high drug load and high dose oral pharmaceutical compositions of isotretinoin with low fill weights and smaller capsules. The present invention further provides processes for the preparation of the disclosed oral pharmaceutical compositions, and methods for treating diseases and conditions such as skin disorders, including acne, by orally administering the disclosed oral pharmaceutical compositions to a patient in need thereof.

Description

[Technical Field]

[0001] Cross-reference to related applications 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.

[0002] Technical Field The present disclosure relates to pharmaceutical compositions comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof as an active agent at high doses and high drug loads, processes for their preparation, and methods of their use. [Background technology]

[0003] Isotretinoin (13-cis retinoic acid or 13-cis vitamin A) is a retinoid that occurs naturally in the body in small amounts. Isotretinoin, its isomers, and some of its analogs are widely known for their therapeutic efficacy in treating severe skin diseases such as acne (such as nodular or conglobate acne, or acne at risk of permanent scarring), lupus erythematous, and icthyosis [Peck GL & DiGiovanna (1994) "Synthetic Retinoids in Dermatology" in Sporn, MB, Roberts, AB, and Goodman, DS (eds.), The Retinoids: Biology, Chemistry, and Medicine, 2nd ed., New York: Raven Press, pp. 631-658]. They have also been reported to be used in the treatment of childhood neuroblastoma, cutaneous T-cell lymphoma, and squamous cell skin cancers, and are being investigated for the treatment of a variety of other cancers [Hong, W.K., and T.M., L.M. (1994) "Retinoids and human cancer," in Sporn, M.B., Roberts, A.B., and Goodman, D.S. (eds.), The Retinoids: Biology, Chemistry, and Medicine, 2nd ed., New York: Raven Press, pp. 597-630]. Summary of the Invention [Problem to be solved by the invention]

[0004] In 1982, the U.S. Food and Drug Administration (FDA) approved isotretinoin for the treatment of nodular acne in capsule form (ACCUTANE®) in 10 mg, 20 mg, and 40 mg strengths. Each ACCUTANE® capsule contains beeswax, butylated hydroxyanisole, edetate disodium, hydrogenated soybean oil flakes, hydrogenated vegetable oil, and soybean oil. Isotretinoin is highly lipophilic and has low oral bioavailability. Absorption is enhanced when taken with a high-fat meal. Oral bioavailability, which depends on food intake, can be highly variable, potentially leading to unpredictable toxicity and teratogenicity associated with isotretinoin [Jerry Tan and Sanja Knezevic; "Improved Oral Bioavailability with a Novel Isotretinoin Formulation (Isotretinoin-Liddose)"; Skin Therapy Lett. 2013 September-October; 18(6):1-3]. Approved by the U.S. Food and Drug Administration (FDA) in 2012, ABSORICA® is a hard gelatin capsule formulation of isotretinoin that is said to have reduced food effect. ABSORICA® is available in 10 mg, 20 mg, 25 mg, 30 mg, 35 mg, and 40 mg strengths.

[0005] U.S. Patent No. 4,322,438, assigned to Hoffmann-La Roche, discloses a method for treating nodulocystic and conglobate acne in humans by oral administration of 13-cis-retinoic acid in an amount and for a duration that effectively results in complete relief of symptoms even after administration of the compound is discontinued.

[0006] PCT International Publication WO 00 / 25772, filed by Hoffmann-La Roche, relates to softgel capsules of isotretinoin with improved bioavailability. The application discloses that the currently available ACCUTANE® formulation of isotretinoin has an average particle size of 100 μm, resulting in a bioavailability of only about 20%. It also discloses a process for further reducing the particle size of isotretinoin to a range of about 5 μm to about 30 μm, thereby improving the bioavailability of isotretinoin.

[0007] U.S. Patent No. 7,435,427 and related patents disclose isotretinoin formulations related to the ABSORICA® marketed formulation. These patents disclose capsules containing a semi-solid suspension of isotretinoin containing at least two lipid excipients, one of which has a hydrophilic-lipophilic balance (HLB) value of 10 or greater and the other of which is an oily vehicle. These patents disclose the use of "Lidose technology," which provides formulations of isotretinoin with improved bioavailability by preparing hard gelatin capsules filled with liquid or semi-liquid lipidic contents containing the active agent mixed with molten excipients. The mixture is then filled into hard gelatin capsules and cooled under specific, consistent conditions.

[0008] PCT International Publication WO2015 / 181802 discloses an oral pharmaceutical composition comprising isotretinoin dissolved or dispersed in a liquid vehicle selected from water, a water-miscible solvent, and / or a mixture thereof, and a carrier substrate with improved bioavailability. The improved bioavailability of isotretinoin according to the present invention may directly correlate with a reduced dosage of isotretinoin.

[0009] PCT International Publication No. WO2016 / 051288 discloses a low-dose oral pharmaceutical composition of isotretinoin and pharmaceutically acceptable excipients in the form of a dispersion further packed into capsules that have equivalent efficacy at lower doses of isotretinoin compared to commercially available ABSORICA® capsules.

[0010] PCT International Publication No. 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 cosolvents, and the composition is substantially oil-free.

[0011] PCT International Publication No. WO2016 / 189481 discloses a pharmaceutical composition of isotretinoin for oral administration once daily to improve patient compliance. The oral pharmaceutical composition of the present invention may be a sustained-release composition, an immediate-release composition, or a combination thereof.

[0012] PCT International Publication No. WO2010 / 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 alcoholic carriers, and exhibiting no bitter taste.

[0013] The standard dosage range for isotretinoin is 0.5 to 1 mg / kg / day given in two divided doses for 15 to 20 weeks (ABSORICA® label). However, adult patients with very severe acne and scarring, or acne that occurs primarily on the trunk, may need to have their dose adjusted up to 2 mg / kg / day, depending on tolerability. Therefore, based on body weight, heavier and more severely affected patients may need to receive up to 200 mg of isotretinoin in two divided doses.

[0014] The maximum dose of isotretinoin a patient can take is 40 mg, which is usually provided in large, size 00 capsules that are difficult to swallow. Furthermore, many patients require multiple capsules to adjust the dose to 0.5 to 1 mg / kg / day. Therefore, patients requiring higher doses, such as up to 200 mg per day, require at least three capsules. This increased "pill burden" can lead to decreased patient compliance and recurrence of symptoms within two years, potentially requiring repeated medical interventions. [Amanda Cyrulnik, Aron Gewirtzman, Kate Viola, and Steven Cohen, "High-Dose Isotretinoin (Accutane) Therapy: Good Results for Nodulocystic Acne," American Academy of Dermatology, Peter Sonnenreich, P. T. 2011 May; 36(5):294-296]

[0015] Therefore, there is a need for higher dose and drug loading formulations with lower fill-weights, smaller capsule sizes, and comparable and / or better bioavailability. [Means for solving the problem]

[0016] overview The disclosed formulations allow patients to take fewer capsules and smaller capsule sizes when higher doses are required. Thus, the disclosed compositions and methods include smaller capsule sizes, higher dose formulations, and high drug load formulations, offering dosing flexibility to prescribers while potentially achieving better patient compliance.

[0017] The present invention provides high-dose oral pharmaceutical compositions and high drug loads of isotretinoin or its pharmaceutically acceptable salts or esters in lower fill weights and smaller capsules (such as size 1, size 2, or size 3 or smaller), with comparable and / or better bioavailability, reduced food effect, fewer capsules required, and lower toxicity.

[0018] The disclosed oral pharmaceutical compositions comprise isotretinoin or a pharmaceutically acceptable salt or ester thereof, and other pharmaceutically acceptable excipients or carriers.

[0019] The present disclosure further provides oral pharmaceutical compositions comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof in the form of a liquid or semi-solid medicament filled in a capsule, and methods for the preparation of such compositions.

[0020] The present disclosure further provides processes for preparing the disclosed oral pharmaceutical compositions.

[0021] The present disclosure further provides methods of treating conditions and disorders such as skin diseases, including acne, by, for example, orally administering the disclosed pharmaceutical compositions to a patient in need thereof.

[0022] The disclosure further provides methods that include using the oral pharmaceutical compositions for treating acne conditions, such as severe recalcitrant nodular acne, in patients 12 years of age or older.

[0023] Detailed Description Definition:

[0024] As used herein, the term "about" generally refers to a value within a range of + / - 10% of the specified value. The term "about" refers to within the pharmaceutically acceptable limits for the amount of an active pharmaceutical ingredient as set forth in the 2003 edition of the United States Pharmacopeia (USP-NF 21) or available at www.usp.org. With respect to blood levels, "about" means within the acceptable guidelines of the U.S. Food and Drug Administration (FDA).

[0025] "Administration" or "administering" refers to the step of giving (i.e., administering) a pharmaceutical composition or active ingredient to a subject. The pharmaceutical compositions disclosed herein may be administered via several suitable routes, including oral and intramuscular or subcutaneous routes of administration, such as by injection, topically, or using an implant.

[0026] The term "AUC" refers to the area under the time / plasma concentration curve following administration of a pharmaceutical composition. AUC 0-∞ denotes the area under the plasma concentration versus time curve from time 0 to infinity, AUC 0-t means the area under the plasma concentration versus time curve from time 0 to time t.

[0027] "C max The term "maximum concentration of isotretinoin in the blood after administration of the pharmaceutical composition" refers to the maximum concentration of isotretinoin in the blood after administration of the pharmaceutical composition. The pharmacokinetic and pharmacodynamic parameters of the pharmaceutical composition of the present invention when administered to healthy human subjects in the fed and fasted states include the area under the curve (AUC), maximum concentration (C max ) and maximum concentration time (T max )

[0028] The term "D10" refers to the particle size of isotretinoin where 10% (w / v) of the particles are below the defined D10 value, "D50" refers to the particle size of isotretinoin where 50% (w / v) of the particles are below the defined D50 value, and "D90" refers to the particle size of isotretinoin where 90% (w / v) of the particles are below the defined D90 value.

[0029] The term "food effect" as used herein refers to the interaction between food and a drug that decreases or increases the extent of drug absorption. This refers to the AUC, C, and D of a drug when the drug or its formulation is orally administered to humans with food or in the fed state. max , and / or the relative difference in drug concentration compared to the same value when the same formulation is administered in the fasted state or without food.

[0030] As used herein, the phrase "high dose" refers to a dose of isotretinoin that is at least 45 mg, which is at least 12.5% ​​higher than the maximum dose of 40 mg currently approved for ABSORICA® and ACCUTANE®.

[0031] The term "isotretinoin" refers to crystalline or amorphous forms of isotretinoin, or mixtures thereof.

[0032] As used herein, the phrase "high drug load" refers to the mass ratio of drug / isotretinoin or its pharmaceutically acceptable salt or ester to the drug-loaded composition / isotretinoin or its pharmaceutically acceptable salt or ester and pharmaceutical excipients loaded in the capsule. A high drug-loaded capsule has a high mass ratio of drug loaded in the capsule to the drug-loaded composition, resulting in a smaller capsule size for loading the composition. The disclosed pharmaceutical composition has a ratio of isotretinoin or its pharmaceutically acceptable salt or ester to isotretinoin or its pharmaceutically acceptable salt or ester and pharmaceutically acceptable excipients of 0.20:1 or greater.

[0033] "Patient" means a human or non-human subject receiving medical or veterinary care.

[0034] The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharmaceutically acceptable materials, compositions, or vehicles, such as, for example, liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in carrying or transporting a subject composition from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the subject composition and not injurious to the patient. In certain embodiments, pharmaceutically acceptable carriers are non-pyrogenic. Examples of substances that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; 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 glycerin, 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, ethyl alcohol, phosphate buffer, and other non-toxic, compatible substances used in pharmaceutical formulations.

[0035] "Pharmaceutical composition" refers to a formulation containing an active ingredient. The term "formulation" means that in addition to the active ingredient, at least one additional ingredient is present in the pharmaceutical composition, such as, but not limited to, albumin (such as human serum albumin (HSA) or recombinant human albumin) and / or sodium chloride. A pharmaceutical composition is thus a formulation suitable for diagnostic, therapeutic, or cosmetic administration to a subject, such as a human patient. The pharmaceutical composition may be in a lyophilized or vacuum-dried state, a solution formed after reconstitution of a lyophilized or vacuum-dried pharmaceutical composition, for example, with saline or water, or a solution that does not require reconstitution. As noted above, the pharmaceutical composition can be liquid, semi-solid, or solid. The pharmaceutical composition may be animal protein-free.

[0036] As used herein, the term "stable" refers to chemical stability such that no more than 1.5% w / w of total related substances are formed upon storage under conditions consistent with ICH guidelines, including accelerated conditions (40°C, 75% relative humidity) and long-term stability conditions (25°C, 60% relative humidity) for at least 3 months.

[0037] "T max " refers to the C max This refers to the time (in hours) by which this is achieved.

[0038] "Therapeutically effective amount" means the level, amount, or concentration of an active ingredient required to treat a symptom, disease, disorder, or condition without causing significant adverse or harmful side effects.

[0039] "Treat," "treating," or "treatment" means to achieve a desired therapeutic or cosmetic result, such as by alleviating or relieving (including some relief, significant relief, near complete relief, and complete relief), eliminating or preventing (either temporary or permanent) symptoms, disease, disorder, or condition, healing damaged or injured tissue, or altering, altering, enhancing, improving, ameliorating, and / or beautifying an existing or recognized disease, disorder, or condition. DETAILED DESCRIPTION OF THE INVENTION

[0040] composition

[0041] The present disclosure provides embodiments comprising high-dose oral pharmaceutical compositions comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof. The disclosed compositions may further comprise at least one pharmaceutically acceptable excipient or carrier.

[0042] In embodiments, the present disclosure provides high drug loaded oral pharmaceutical compositions comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof. The disclosed compositions can further comprise at least one pharmaceutically acceptable excipient.

[0043] In embodiments, the present disclosure provides a. at least 45 mg of isotretinoin or a pharmaceutically acceptable salt or ester thereof, wherein the amount is at least 12.5% ​​greater than the 40 mg maximum dose currently approved for ABSORICA® and ACCUTANE®; and b. at least one pharmaceutically acceptable excipient; and The present invention provides a high-dose oral pharmaceutical composition comprising:

[0044] wherein the composition provides equivalent or superior efficacy, equivalent and lower side effect profile when administered orally in higher doses and with a minimal number of capsules.

[0045] In a further embodiment, the present disclosure provides a method for manufacturing a semiconductor device comprising: 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 b. at least one pharmaceutically acceptable excipient filled into a capsule of smaller size compared to approved ABSORICA® and ACCUTANE®; and (c) providing a pharmaceutical composition comprising:

[0046] Here, the composition provides an easy-to-swallow capsule composition for individuals who need to orally administer two or more capsules for dose adjustment up to 2 mg / kg / day for the treatment of acne, which may improve patient compliance.

[0047] In embodiments, the present disclosure provides a. Isotretinoin or a pharmaceutically acceptable salt or ester thereof at a dose that is 12.5% ​​to about 50% higher than the highest dose available in ABSORICA® capsules, i.e., 40 mg; and b. and a pharmaceutically acceptable excipient; and (c) providing a high dose oral pharmaceutical composition comprising:

[0048] wherein the composition provides equivalent or superior efficacy, equivalent and lower side effect profile when administered orally in higher doses and with a minimal number of capsules.

[0049] In embodiments, the present disclosure provides high dose oral pharmaceutical compositions comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, which compositions reduce the food effect, thereby providing increased patient flexibility.

[0050] In embodiments, the present disclosure provides high drug loaded oral pharmaceutical compositions comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient, which compositions reduce the food effect, thereby providing greater patient flexibility.

[0051] In a disclosed embodiment, the present invention comprises: a. Isotretinoin or a pharmaceutically acceptable salt or ester thereof; b. oily / lipid vehicle; c.surfactant, d. co-surfactant, e. antioxidant(s), and / or f. co-solvent, The present invention provides a high dose oral pharmaceutical composition comprising:

[0052] In a disclosed embodiment, the present invention comprises: a. Isotretinoin or a pharmaceutically acceptable salt or ester thereof; b. oily / lipid vehicle; c.surfactant, d. co-surfactant, e. antioxidant(s), and / or f. co-solvent, and (c) providing a pharmaceutical composition comprising:

[0053] 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.

[0054] 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.

[0055] In disclosed embodiments, 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.

[0056] In disclosed embodiments, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof, for example, in an amount of from about 10% w / w to about 90% w / w of the total composition, or from about 10% w / w to about 50% w / w of the total composition, or from about 10% w / w to about 40% w / w of the total composition, preferably from about 20% w / w to about 30% w / w of the total composition.

[0057] The present disclosure provides a high drug loading of isotretinoin or a pharmaceutically acceptable salt or ester thereof at a low fill weight, thereby allowing compositions of isotretinoin or a pharmaceutically acceptable salt or ester thereof to be filled into smaller size capsules, for example, size 1, size 2, size 3, or smaller.

[0058] The present disclosure provides high drug loaded compositions of isotretinoin or pharmaceutically acceptable salts or esters thereof, with isotretinoin dosages of 30 mg to 100 mg, in smaller size capsules, such as size 1, size 2, size 3, or smaller, at low fill weights compared to the currently approved ABSORICA® and ACCUTANE®.

[0059] In one embodiment, the composition is in the form of a liquid, semi-solid, solution, suspension, emulsion, microemulsion, dispersion, self-emulsifying drug delivery systems (SEDDS®), or self-emulsifying microemulsion drug delivery systems (SMEDDS®). The composition is filled into capsules to 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.

[0060] In other embodiments, the composition comprises isotretinoin in crystalline or amorphous form, or a mixture of crystalline and amorphous forms.

[0061] In another embodiment, the composition comprises isotretinoin or a pharmaceutically acceptable salt or ester thereof in milled or unmilled (unmilled) form, and the particle size distribution of the isotretinoin or a pharmaceutically acceptable salt or ester thereof is such that 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, and 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.

[0062] In further embodiments, the disclosed compositions are isotretinoin or a pharmaceutically acceptable salt or ester thereof in milled or unmilled (unmilled) form, and the particle size distribution of the isotretinoin or a pharmaceutically acceptable salt or ester thereof is, for example, D50 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 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.

[0063] In further embodiments, the disclosed compositions are isotretinoin or a pharmaceutically acceptable salt or ester thereof in milled or unmilled (unmilled) form, and the particle size distribution of the isotretinoin or a pharmaceutically acceptable salt or ester thereof is D90 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.

[0064] In a further embodiment, the oral pharmaceutical composition comprises isotretinoin and pharmaceutically acceptable excipients filled in a size 1 or smaller, size 2 or smaller, size 3 or smaller, size 4 or smaller, or size 5 or smaller capsule.

[0065] In further embodiments, the oral pharmaceutical composition comprises isotretinoin and pharmaceutically acceptable excipients filled in a capsule, wherein the capsule has a volume of about 0.50 mL or less, about 0.37 mL or less, about 0.30 mL or less, about 0.21 mL or less, or about 0.13 mL or less.

[0066] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and pharmaceutically acceptable excipients filled into a capsule, wherein the concentration of isotretinoin in the capsule is from about 200 mg / ml to about 300 mg / ml, preferably from about 220 mg / ml to about 280 mg / ml, preferably from about 230 mg / ml to about 270 mg / ml, preferably from about 240 mg / ml to about 260 mg / ml, preferably about 245 mg / ml, preferably about 250 mg / ml, preferably about 255 mg / ml.

[0067] In a further embodiment, the oral pharmaceutical composition comprises isotretinoin and pharmaceutically acceptable excipients contained in a capsule, wherein the concentration of isotretinoin in said capsule is at least 25% w / w or more.

[0068] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, said 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; a. Isotretinoin or a pharmaceutically acceptable salt or ester thereof; b. oily / lipid vehicle; c.surfactant, d. co-surfactant, e. antioxidant(s), and / or f. co-solvent, Includes.

[0069] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, said composition having 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, or about 0.13 mL or less; a. Isotretinoin or a pharmaceutically acceptable salt or ester thereof; b. oily / lipid vehicle; c.surfactant, d. co-surfactant, e. antioxidant(s), and / or f. co-solvent, Includes.

[0070] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, said composition being in suspension dosage form; a. Isotretinoin or a pharmaceutically acceptable salt or ester thereof; b. oily / lipid vehicle; c.surfactant, d. co-surfactant, e. antioxidant(s), and / or f. co-solvent, Including,

[0071] 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, or about 0.13 mL or less; and

[0072] The concentration of isotretinoin in the capsule is from about 200 mg / ml to about 300 mg / ml, preferably from about 220 mg / ml to about 280 mg / ml, preferably from about 230 mg / ml to about 270 mg / ml, preferably from about 240 mg / ml to about 260 mg / ml, preferably about 245 mg / ml, preferably about 250 mg / ml, preferably about 255 mg / ml.

[0073] In another embodiment, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, wherein the composition is in suspension dosage form; a. Isotretinoin or a pharmaceutically acceptable salt or ester thereof; b. oily / lipid vehicle; c.surfactant, d. co-surfactant, e. antioxidant(s), and / or f. co-solvent, Including,

[0074] 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 more, 0.40:1 or more, 0.60:1 or more, 0.80:1 or more, 1:1 or more, etc.

[0075] In another embodiment of the present invention, an oral pharmaceutical composition comprises isotretinoin and a pharmaceutically acceptable excipient, said composition being in suspension dosage form; a. Isotretinoin or a pharmaceutically acceptable salt or ester thereof; b. oily / lipid vehicle; c.surfactant, d. co-surfactant, e. antioxidant(s), and / or f. co-solvent, Including,

[0076] Isotretinoin or a pharmaceutically acceptable salt or ester thereof is present in a concentration of about 25% or greater.

[0077] In a further embodiment, an oral pharmaceutical composition comprises isotretinoin and pharmaceutically acceptable excipients filled into a size 1 or smaller, size 2 or smaller, size 3 or smaller, size 4 or smaller, or size 5 or smaller capsule, wherein the capsule containing the pharmaceutical composition is easier to swallow than currently available oral isotretinoin pharmaceutical compositions, including ABSORICA® and / or ACCUTANE®.

[0078] 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, glyceryl monooleate, polyglycerol-3-oleat, glyceryl monolinoleate, mono & diglycerides, polyglycerol 10-oleate, and mixtures thereof.

[0079] 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 about 5% w / w to about 90% w / w of the total weight of the composition, more preferably about 5% w / w to about 80% w / w of the total weight of the composition, and most preferably about 5% w / w to about 75% w / w of the total weight of the composition.

[0080] In additional embodiments, the ratio of isotretinoin or a pharmaceutically acceptable salt or ester thereof to oily vehicle ranges 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, and more preferably about 1:1.

[0081] In additional embodiments, the ratio of isotretinoin or a pharmaceutically acceptable salt or ester thereof to isotretinoin or a pharmaceutically acceptable salt or ester thereof 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, preferably 0.24:1 or greater.

[0082] In additional embodiments, surfactants include anionic, cationic, or non-ionic surfactants, sorbitan fatty acid esters, polysorbates prepared from lauric acid, palmitic acid, stearic acid, and oleic acid, polyoxyethylene monoesters such as polyoxyethyl ethylene monostearate, polyoxyethylene monolaurate, and polyoxyethylene monooleate, glycerol monostearate, sorbitan esters, polysorbate 80, polyoxyethylene sorbitan monooleate, and the like. monooleate, polyoxyl stearate macrogol ethers, polyoxyethylene, macrogolglycerol esters, caprylocaproyl macrogol-8 glycerides, PEG-8 caprylic / capric glycerides, macrogol glycerol hydroxystearate, polyoxyl 35 castor oil, macrogol glycerol hydroxystearateglycerolhydroxystearate, polyoxyl 40 hydrogenated castor oil, macrogolglycerides such as caprylocaproyl polyoxylglycerides, hydrogenated coconut oil PEG 1500 esters, lauroyl polyoxylglycerides such as Gelucire 44 / 14, stearoyl polyoxylglycerides, PEG-8 beeswax, polyethylene glycol derivatives, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers ethers, polyoxyethylene stearates, a mixture of glycerol monostearate and PEG-75 stearate beeswax, glyceryl monostearate polyoxylethylene stearates, and mixtures thereof.

[0083] In another embodiment, the surfactant is present in an amount of from about 0.01% w / w to about 90% w / w of the total weight of the composition, preferably from about 10% w / w to about 85% w / w of the total weight of the composition, more preferably from about 10% w / w to about 80% w / w of the total weight of the composition, and most preferably from about 10% w / w to about 70% w / w of the total weight of the composition.

[0084] In further embodiments, the co-surfactant may be anionic, cationic, or non-ionic surfactants, hydrophilic or hydrophobic, water dispersible or water soluble surfactants, fatty acid ester derivatives, propylene glycol esters of caprylic acid consisting mainly of monoesters and diesters, propylene glycol monocaprylate, sorbitan fatty acid esters, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monoole ... monostearate, sorbitan sesquiisostearate, sorbitan sesquioleate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate; oleoyl polyoxylglycerides, such as apricot kernel oil PEG 300 esters, Labrafil M1944CSM1944CS, Acconon® AKG-6, macrogolglyceridorum oleates, peglicol-5-oleate, glycerol monocaprylocaprate, glyceryl caprylate / caprate, mono-diglycerides of medium chain fatty acids, glyceryl esters derivatives, propylene glycol esters of caprylic and capric acids, propylene glycol dicaprylocaprate, propylene glycol dicaprylocaprate, propylene glycol dicaprolate / dicaprate dicaprolate / dicaprate), linoleoyl polyoxylglycerides such as macrogolglyceridorum linoleates, corn oil PEG 300 esters, Labrafil® M 2125, lauroyl polyoxylglycerides such as hydrogenated palm / palm kernel oil PEG 300 esters, Labrafil® M 2130 CS, and mixtures thereof.

[0085] In a further embodiment, the co-surfactant is present in an amount of from about 0.01% w / w to about 90% w / w relative to the total weight of the composition, preferably from about 5% w / w to about 85% w / w relative to the total weight of the composition, more preferably from about 5% w / w to about 80% w / w relative to the total weight of the composition, and most preferably from about 5% w / w to about 50% w / w relative to the total weight of the composition.

[0086] In a further embodiment, the surfactant and co-surfactant are present in an amount of from about 0.01% w / w to about 90% w / w of the total weight of the composition, preferably from about 5% w / w to about 85% w / w of the total weight of the composition, more preferably from about 5% w / w to about 80% w / w of the total weight of the composition, and most preferably from about 5% w / w to about 50% w / w of the total weight of the composition.

[0087] In further embodiments, the co-solvent may be ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and their isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives. alcohols and polyols such as tetrahydrofurfuryl alcohol PEG ether or methoxy PEG; polyethylene glycols such as tetrahydrofurfuryl alcohol PEG ether or methoxy PEG;glycol ethers, 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, amides such as dimethylacetamide, dimethylformamide, and polyvinylpyrrolidone; ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, and ethyl oleate. oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, δ-caprolactone and its isomers thereof, δ-valerolactone and its isomers thereof, β-butyrolactone and its isomers thereof, and other esters, as well as dimethyl isosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and the like.Other solubilizers include, but are not limited to, ethanol, dimethyl sulfoxide (DMSO), water, and mixtures thereof.

[0088] In another embodiment, the co-solvent is present in an amount of from about 1% w / w to about 90% w / w of the total weight of the composition, preferably from about 10% w / w to about 90% w / w of the total weight of the composition, more preferably from about 10% w / w to about 80% w / w of the total weight of the composition, and most preferably from about 10% w / w to about 40% w / w of the total weight of the composition.

[0089] In other embodiments, the composition comprises an antioxidant, including, but not limited to, butylated hydroxyl anisole, butylated hydroxyl toluene, 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.

[0090] In further embodiments, the composition comprises a chelating agent, including but not limited to EDTA, disodium EDTA, calcium disodium edetate, tartaric acid, malic acid, citric acid, etc. 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.

[0091] In further embodiments, the composition comprises precipitation inhibitor agents, including, but not limited to, hypromellose (HPMC), hypromellose acetate succinate, hypromellose phthalate, poloxamer and its derivatives, cyclodextrin and its derivatives, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, vinylpyrrolidone-vinyl acetate copolymer, and mixtures thereof. The precipitation inhibitors are present in an amount of about 0.05% w / w to about 60% w / w of the total weight of the composition.

[0092] In further embodiments, the composition includes other excipients, such as permeability enhancers, pH modifiers, and complexation agents. Examples of suitable permeability enhancers include, but are not limited to, phospholipids and their derivatives, phosphatidylcholine, lecithin and its derivatives, and mixtures thereof. Examples of suitable pH modifiers include, but are not limited to, megulamine and its derivatives, sodium hydroxide and its derivatives, sodium bicarbonate and its derivatives, and mixtures thereof. Examples of suitable complexation agents include, but are not limited to, cyclodextrins and their derivatives, phospholipids and their derivatives, and mixtures thereof. In the present invention, these excipients may be present in an amount ranging from about 5% w / w to about 70% w / w of the total weight of the composition.

[0093] Preparation method

[0094] In another aspect, there is provided 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, the method comprising: a. heating a mixture of oil, surfactant and co-surfactant at 40°C to 45°C; b. dissolving antioxidants in the mixture of step (i) at 40°C to 45°C, and then cooling to room temperature; c. dispersing isotretinoin into step (ii) with stirring; d. optionally, adding a co-solvent after step (iii); e. optionally, grinding after step (iii); f. filling the medicament of step (iii) or step (iv) or step (v) into a hard gelatin capsule; g. soaking gelatin in water at room temperature for 6 hours, followed by adding polysorbate 80 at a temperature of 60±10°C to prepare a gelatin banding solution; h. banding the filled capsules of step (vi) with a banding solution of step (vii); Includes:

[0095] 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 3 months or longer.

[0096] 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 6 months or longer.

[0097] 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 12 months or longer.

[0098] In yet another embodiment, the oral pharmaceutical composition has a drug content of about 102% w / w to about 110% w / w during the stability period.

[0099] 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.

[0100] Treatment method

[0101] The present invention provides methods for treating normally treatable diseases using isotretinoin or a pharmaceutically acceptable salt or ester thereof. For example, in disclosed embodiments, a therapeutically effective dose of isotretinoin can be 30 mg or more, 40 mg or more, 50 mg or more, or 60 mg or more. The disclosed methods include, for example, the treatment of cancer, skin diseases, and the like.

[0102] In embodiments, the present disclosure provides methods 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.

[0103] In embodiments, the present disclosure provides methods of treating acne by administering to an individual in need thereof a high drug loaded oral pharmaceutical composition comprising isotretinoin or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable excipient.

[0104] In another embodiment, the composition has a ln-transformed geometric least squares mean C of about 915.3556 ng / mL under fed conditions. maxshowed a natural log-transformed geometric least squares mean C of approximately 302.8420 ng / mL under fasting conditions. max Shows.

[0105] In another embodiment, the composition has a ln-transformed geometric least squares mean AUC 0→t is approximately 15924.4305ng.h / mL, AUC 0→∞ was approximately 16953.5405 ng.h / mL, and under fasting conditions, the ln-transformed geometric least squares mean AUC 0→t is approximately 4911.7465ng.h / mL, AUC 0→∞ represents approximately 5335.7760 ng.h / mL.

[0106] In another embodiment, when orally administered, the composition has an AUC 0→t and AUC 0→∞ The mean fed / fasted ratio of 1.5 was approximately 1.5, and the ln-transformed geometric least squares C max The average fed / fasted ratio is approximately 2.25.

[0107] The present invention is further described by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention. Variations of the examples that are within the scope and spirit of the appended claims and that would be obvious to one of ordinary skill in the art based on the disclosure herein are also deemed to be within the scope of the invention.

[0108] Example Example 1 The weight (wt) of active ingredients and excipients is expressed in milligrams (mg) and the percentages are expressed as % w / w of the composition. The examples are not limiting and can be applied to the full scope of the invention in terms of amounts.

[0109] [Table 1]

[0110] Composition Preparation Procedure: (i) heating a mixture of oil, surfactant, and co-surfactant; (ii) dissolving an antioxidant in the mixture of step (i); (iii) dispersing isotretinoin or a pharmaceutically acceptable salt or ester thereof into step (ii) with stirring; (iv) optionally, after step (iii), adding a co-solvent; (v) optionally, a grinding step after step (iii); (vi) filling the medicament of step (iii) or step (iv) or step (v) into a capsule; (vii) preparing a gelatin banding solution by soaking gelatin in water followed by adding polysorbate; (vii) banding the filled capsules of step (vi) with the banding solution of step (vii).

[0111] Compositions prepared without cosolvents

[0112] [Table 2]

[0113] Compositions prepared with cosolvents

[0114] [Table 3]

[0115] [Table 4]

[0116] [Table 5]

[0117] Procedure for the preparation of the examples in Tables 1, 2, 3, and 4:

[0118] 1. Mix the surfactant and co-surfactant and heat at 40-45°C until a clear solution is formed.

[0119] 2. Melt the BHA and BHT at 40-45°C, let cool to room temperature, then add the oil.

[0120] 3. Disperse the isotretinoin into Step 2 while stirring at room temperature.

[0121] 4. Optionally, milling is performed after step (3): The drug dispersion from step 3 is milled using a dyno mill under optimal processing conditions until a PSD (d(0.9)) of NMT 80 microns is achieved.

[0122] 5. Optionally, add a co-solvent after step (3).

[0123] 6. Fill the drug into hard gelatin capsules.

[0124] 7. Prepare a gelatin banding solution by soaking gelatin in water at room temperature for the specified time, then heat the gelatin mass to 60±10°C, followed by adding polysorbate 80 at 60±5°C.

[0125] 8. Band the filled capsules from step 6 using the banding solution from step 7.

[0126] Example 2

[0127] Ratio Optimization Study: The compositions in Table 3 were prepared with isotretinoin or its pharmaceutically acceptable salts or esters to peppermint oil (oily vehicle) at ratios of 1:10, 1:9, 1:4, 13:1, 9:1, 4:1, and 1:1. The 1:1 isotretinoin or its pharmaceutically acceptable salts or esters to peppermint oil (oily vehicle) composition remains stable under accelerated and long-term stability conditions. Related substances, known impurities, and unknown impurities were measured and reported to be within ICH guideline limits.

[0128] Example 3

[0129] Dissolution Testing: Dissolution testing of the pharmaceutical compositions of Examples A and B was performed using USP Type II apparatus in modified USP and discriminatory dissolution media. The % drug release versus time was studied.

[0130] Example 4

[0131] Stability studies: The stability of the pharmaceutical compositions of Examples A and B in PVC-Aclar blister packaging was studied according to ICH guidelines at accelerated and long-term stability conditions. Related substances, known impurities, and unknown impurities were determined and reported to be within ICH guideline limits.

[0132] Example 5

[0133] Clinical studies: The pharmacokinetic and pharmacodynamic parameters of Isotretinoin Capsules USP 60 mg compositions - Treatment-1 (T1) and Treatment-2 (T2) in human volunteers were studied and compared to the currently approved ABSORICA® (isotretinoin) capsules (one 40 mg capsule and two 10 mg capsules), listed as Treatment R in the table below.

[0134] [Table 6]

[0135] [Table 7]

[0136] [Table 8]

[0137] Finally, while aspects of the present specification have been emphasized by reference to particular embodiments, those skilled in the art should readily understand that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Accordingly, it should be understood that the disclosed subject matter is in no way limited to the particular methodology, protocols, and / or reagents, etc., described herein. Accordingly, various modifications or variations of the disclosed subject matter, or alternative configurations, may be made in accordance with the teachings herein without departing from the spirit of the specification. Finally, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

[0138] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to adopt such variations as necessary, and the inventors intend the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Furthermore, unless otherwise stated herein or clearly contradicted by context, this invention includes any combination of all possible variations of the above-described embodiments.

[0139] The grouping of alternative embodiments, elements, or steps of the invention is not to be construed as limiting. Each group member may be individually referenced and claimed, or may be combined in any manner with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When such inclusion or deletion occurs, the specification is deemed to include the modified group, which may thereby fulfill the recitation of all Markush groups used in the appended claims.

[0140] Unless otherwise noted, all numbers expressing properties, items, quantities, parameters, characteristics, terms, etc. used in the specification and claims can be understood to be modified in all instances by the term "about." As used herein, the term "about" means that the so-qualified property, item, quantity, parameter, characteristic, or term encompasses a range of plus or minus 10 percent of the value of the stated property, item, quantity, parameter, characteristic, or term. Accordingly, unless otherwise noted, the numerical parameters set forth in this specification and the appended claims are approximations and may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical designation should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values ​​setting forth the broad scope of the invention are approximations, the numerical ranges and values ​​set forth in the specific examples are reported as precisely as possible. However, numerical ranges and values ​​inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of numerical ranges herein is merely intended as a shorthand method of individually referencing each individual numerical value falling within the range. Unless otherwise stated herein, each individual value of a numerical range is incorporated herein as if each individual value were individually set forth herein.

[0141] In the context of describing the present invention (particularly in the context of the claims that follow), the terms "a," "an," "the," and similar referents used herein should be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the invention and does not limit the scope of the claimed invention. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0142] Certain embodiments disclosed herein may be further limited in the claims using the phrases "consisting only of" or "consisting essentially of." When used in the claims, whether added at the time of filing or by amendment, the transitional term "consisting only of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics. Thus, the claimed embodiments of the invention are enabled and operable as essentially or explicitly described herein.

[0143] All patents, patent publications, and other publications referenced or identified in this specification are individually and expressly incorporated herein by reference in their entireties for the purpose of describing and disclosing the compositions, methodology, and the like described in the publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or contents of such documents are based on the information available to the applicant and do not constitute an admission as to the accuracy of the dates or contents of such documents.

Claims

1. at least 30 mg of isotretinoin or a pharmaceutically acceptable salt or ester thereof; and and a pharmaceutically acceptable excipient; A capsule dosage form with capsule sizes of 1 to 4.

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

3. 10. The pharmaceutical composition of claim 1, wherein the composition comprises a semi-solid composition.

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

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

6. 4. A pharmaceutical composition according to claim 2 or 3, characterized in that the capsule is size 4.

7. 6. 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. 5. 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 pharmaceutically acceptable excipient is at least 0.20:

1.

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

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

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

12. 10. The pharmaceutical composition of claim 1, comprising about 30 to 60 mg of isotretinoin, about 5 to 70% by weight of peppermint oil, 20 to 80% by weight of polyoxyl 35 castor oil, about 1 to 10% by weight of propylene glycol monocaprylate, and about 0.1 to 5% by weight of butylated hydroxyanisole and butylated hydroxytoluene.

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

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

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

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

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

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

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