ONCE-DAILY ORAL PHARMACEUTICAL COMPOSITION OF

ISOTRETINOIN

Field of the Invention

The present invention relates to a once-daily oral pharmaceutical composition of isotretinoin and a process for its preparation.

Background of the Invention

Isotretinoin is a retinoid, approved for the treatment of severe recalcitrant nodular acne. Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A). The presently marketed dosage forms of isotretinoin, i.e., Absorica ^® capsules and generic formulations of Accutane ^® , require twice daily administration based on the body weight of the patient.

There is a need to develop a more convenient method of administration which allows once-daily dosing of isotretinoin in order to have better patient compliance. To suffice this unmet need in the art, the present inventors have developed a once-daily oral pharmaceutical composition of isotretinoin.

Summary of the Invention

The present invention relates to a once-daily oral pharmaceutical composition of isotretinoin. The oral pharmaceutical composition of the present invention may be a modified-release composition, or an immediate-release composition, or a combination thereof.

The oral pharmaceutical composition of the present invention is in the form of a solution, suspension, emulsion, nanoemulsion, solid particles adsorbed onto carrier substrate, spray-dried particle dispersion, solid dispersion, powder, granules, pellets, minitablets, microcapsules, spheroids, capsules, tablets, or any other suitable dosage form. This invention also provides a method of treating acne by administering the

pharmaceutical composition once-daily.

Detailed Description of the Invention

As used herein, the word "a" or "plurality" before a noun represents one or more of the particular noun. For the terms "for example" and "such as," and grammatical equivalences thereof, the phrase "and without limitation" is understood to follow unless explicitly stated otherwise. As used herein, the term "about" is meant to account for variations due to experimental error. All measurements reported herein are understood to be modified by the term "about," whether or not the term is explicitly used, unless explicitly stated otherwise. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

In one aspect, the present invention provides an oral pharmaceutical composition of isotretinoin meant for once-daily administration.

In one embodiment of the above aspect, said oral pharmaceutical composition is a modified-release composition.

In a further embodiment, the modified-release composition comprises an extended release component and a delayed-release component.

In another embodiment of the above aspect, said oral pharmaceutical composition is an immediate-release composition.

In another embodiment of the above aspect, said oral pharmaceutical composition is a combination of immediate-release and modified-release compositions.

In another embodiment, the ratio of the immediate-release and modified-release components is about 1 : 99 to about 99: 1.

In another embodiment the ratio of the immediate-release and modified-release components is about 5:95, about 10:90, about 15:85, about 20:80, about 25:75, about 30:70, about 35:65, about 40:60, or 45:55, about 50:50, about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 90: 10, or about 95:5. In another embodiment of the above aspect, said oral pharmaceutical composition comprises an extended release component, a delayed-release component, and an immediate-release component.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises:

(a) 1 mg to 100 mg of isotretinoin or a pharmaceutically acceptable salt, ester or a derivative thereof; and

(b) a release modifying agent.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin in an amount of about 5 mg to about 100 mg, about 10 mg to about 90 mg, about 24 mg to about 96 mg, about 20 mg to about 80 mg, or about 16 mg to about 64 mg.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin in an amount of about 5 mg to about 80 mg, about 10 mg to about 75 mg, about 15 mg to about 70 mg, about 20 mg to about 65 mg, about 25 mg to about 60 mg, about 30 mg to about 55 mg, about 35 mg to about 50 mg, about 40 mg to about 45 mg, about 40 mg to about 50 mg, or about 50 mg to about 80 mg.

In another embodiment of the above aspect, the oral pharmaceutical composition is in the form of matrix type composition, a reservoir type composition, a layered composition, inlay tablets, solid dispersion, multiple unit pellet system, multiple unit particulate systems, an osmotic drug delivery system, a gastro-retentive composition, SEDDS, SMEDDS, SNEDDS, adsorbates, or a combination thereof.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises an inert, hydrophilic or hydrophobic core layered with a coating comprising isotretinoin, and a release modifying agent.

In another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a capsule wherein the capsule shell is coated with a coating of a release modifying agent.

In another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a capsule wherein the capsule fill comprises a release modifying agent. In another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a capsule wherein said capsule provides a gastro-retentive system.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a matrix tablet wherein isotretinoin is distributed uniformly with one or more release modifying agents.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a reservoir type tablet comprising a coating of a release modifying agent over the core comprising isotretinoin.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a gastro-retentive tablet.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a bilayer gastro-retentive tablet having immediate -release and modified-re lease layers.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of an osmotic drug delivery system.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of an osmotic drug delivery system wherein said system is a bilayer system comprising a drug layer having a water swellable polymer or an osmogen and a push layer.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of an osmotic drug delivery system wherein said system is a single layer system.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a nanoemulsion adsorbed on an adsorbant and converted to a suitable dosage form.

In yet another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin in an amount of about 1% w/w to about 90% w/w of the total composition, or in an amount of about 1% w/w to about 50% w/w of the total composition, or in an amount of about 1% w/w to about 30% w/w of the total composition, or in an amount of about 1% w/w to 15% w/w of the total composition. In yet another embodiment of the above aspect, the oral pharmaceutical composition exhibits reduced food effect as indicated by comparable C _max and AUC in fasting and fed states.

In yet another embodiment of the above aspect, the oral pharmaceutical composition provides the same effect at a lower dose in comparison to the already marketed formulations of isotretinoin.

In yet another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D ₉₀ of the particles is less than 60 μιη, less than 55 μιη, less than 50 μιη, or less than 45 μιη.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D ₉₀ of the particles is less than 60 μιη, less than 40 μιη, less than 35 μιη, or less than 25 μιη.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D ₉₀ of the particles is less than 50 μιη, less than 30 μιη, less than 20 μιη, or less than 10 μιη.

In yet another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D50 of the particles is less than 40 μιη, less than 35 μιη, less than 30 μιη, or less than 25 μιη.

In yet another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D ₅₀ of the particles is less than 40 μιη, less than 30 μιη, less than 20 μιη, or less than 15 μιη.

In yet another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D ₅₀ of the particles is less than 20 μιη, less than 15 μιη, less than 10 μιη, or less than 5 μιη. In another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the Dio of the particles is less than 20 μιη, less than 17 μιη, less than 15 μιη, or less than 12 μιη.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the Dio of the particles is less than 18 μιη, less than 15 μιη, less than 10 μιη, or less than 8 μιη.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the Dio of the particles is less than 10 μιη, less than 7 μιη, less than 5 μιη, or less than 2 μιη.

In yet another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D ₉₀ of the particles is less than 60 μιη and the D ₅₀ of the particles is less than 40 μτη.

In yet another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D ₉₀ of the particles is less than 60 μιη, the D ₅₀ of the particles is less than 40 μιη and the Di ₀ of the particles is less than 20 μιη.

In another embodiment of the above aspect, the oral pharmaceutical composition comprises isotretinoin in a dissolved form.

In another embodiment of the above aspect, the release modifying agent comprises a release modifying polymer, a lipidic material, a polysaccharide, and mixtures thereof.

In another embodiment of the above aspect, the release modifying agent is present in amount of about 1% to about 90% by the total weight of the composition, or in an amount of about 1% w/w to about 70% w/w of the total composition, or in an amount of about 1% w/w to about 50% w/w of the total composition, or in an amount of about 1% w/w to about 30% w/w of the total composition.

In yet another embodiment of the above aspect, the oral pharmaceutical composition is in the form of a solution, suspension, emulsion, nanoemulsion, solid particles adsorbed onto carrier substrate, spray-dried particles, dispersion, solid dispersion, powder, granules, pellets, minitablets, microcapsules, spheroids, capsules, or tablets. In yet another embodiment, said oral pharmaceutical composition is stable when stored at 40°C and 75% relative humidity, or at 25 °C and 60% relative humidity, for a period of at least three months or to the extent necessary for the use of the composition.

In another aspect, the present invention provides a process for preparing an oral pharmaceutical composition comprising isotretinoin meant for once-daily administration wherein said process comprises wet or dry granulation using a fluidized bed granulator or high shear mixer granulator; direct compression; extrusion-spheronization; melt granulation/extrusion; spray-drying; spray-congealing; freeze-drying; or any other conventional process known in the art.

In another aspect, the present invention provides a process for preparing an oral pharmaceutical composition comprising:

(a) 1 mg to 100 mg of isotretinoin or a pharmaceutically acceptable salt, ester, or a derivative thereof;

(b) a release modifying agent; and

(c) a pharmaceutically acceptable excipient

wherein said process comprises wet or dry granulation using a fluidized bed granulator or high shear mixer granulator; direct compression; extrusion-spheronization; melt granulation/extrusion; spray-drying; spray-congealing; freeze-drying; or any other conventional process known in the art.

In still another aspect, the present invention provides a method of treating acne, musculoskeletal and connective tissue inflammations, emphysema, ulcerating diseases, cervical tumors in HIV positive women, lung cancer in smokers, skin cancer,

neuroblastoma, recurrent prostate cancer, leukemia, high-grade glioma, head and neck cancers, multiple myeloma, gram-negative folliculitis, recalcitrant rosacea, pyoderma faciale, psoriasis, cutaneous lupus erythematosus, acne fulminans, squamous cell carcinoma, cutaneous photoaging, and other off-label indications of isotretinoin by administering to the individual in need thereof an oral pharmaceutical composition of the present invention once-daily.

In one embodiment of the above aspect, the present invention provides a method of treating acne by administering to the individual in need thereof an oral pharmaceutical composition of the present invention once-daily. In another aspect, the present invention provides a method of treating acne, wherein said method comprises administering to the patient in a need thereof about 0.4mg/kg to about 2.4 mg/kg of isotretinoin in an oral dosage form once-daily, wherein the therapeutic blood plasma levels of isotretinoin are maintained over approximately a twenty-four hour period.

In one embodiment of the above aspect, the present invention provides a method of treating acne, wherein said method comprises administering to the patient in a need thereof about 0.45 mg/kg to about 2.2 mg/kg of isotretinoin in an oral dosage form once- daily, wherein the therapeutic blood plasma levels of isotretinoin are maintained over approximately a twenty-four hour period.

In another embodiment of the above aspect, the present invention provides a method of treating acne, wherein said method comprises administering to the patient in a need thereof about 0.5 mg/kg to about 2 mg/kg of isotretinoin in an oral dosage form once- daily, wherein the therapeutic blood plasma levels of isotretinoin are maintained over approximately a twenty-four hour period.

In another embodiment of the above aspect, the present invention provides a method of treating acne, wherein the dose of isotretinoin is about 16 mg to about 240 mg, or about 18 mg to about 220 mg, or about 20 mg to about 200 mg once-daily.

The phrase "modified-release" as used herein relates to a kind of release pattern wherein the active pharmaceutical ingredient is released from the composition over an extended period of time, and encompasses prolonged, sustained, controlled, chrono- therapeutic, pH-dependent, extended, pulsed, and delayed-release, or combinations thereof.

Matrix-type compositions are those in which the drug is distributed uniformly in the matrix of one or more release modifying agents, and reservoir type compositions utilize coating of release modifying agent over the core comprising the drug.

Multiple unit particulate systems are single-unit formulations that contain the active ingredient within the single tablet or capsule, whereas multiple-unit dosage forms comprise a number of discrete particles that are combined into one dosage unit. These discrete units may be granules, pellets, spheroids, tablets, or beads. These discrete units have individual release patterns. A pH-dependent system may contain four different tablets - one providing immediate-release, a second providing release at pH 5.5, a third providing release at pH 6, and a fourth providing release at pH 7, wherein the tablets are filled into a capsule to provide a single unit system.

A gastro retentive system is a system which is designed to retain in the stomach for a prolonged time and release the active pharmaceutical ingredient, thereby enabling sustained and prolonged availability of the drug to the upper part of the gastrointestinal (GI) tract. Different approaches or systems to prolong the gastric residence time include mucoadhesive or bioadhesive systems, high density systems, expandable or swelling systems, and floating drug delivery systems, including gas generating systems.

An osmotic drug delivery system is a system that uses osmotic pressure as a driving force for controlled delivery of active agents. The osmotic delivery system comprises a homogenous drug core coated with a semi-permeable layer and an aperture created through the wall for the release of contents from the core. When placed in dissolution media/GI fluid, the fluid permeates into the core through the semipermeable wall and dissolves the drug. The osmotic pressure thus built in exerts pressure against the wall and thereby releases out the solution of the drug through the aperture in the wall.

The phrase "release modifying agent" as used herein refers to an agent or material which helps in achieving the desired modified-release of the composition and includes one or more of a release modifying polymer, a lipidic material, a polysaccharide, and mixtures thereof.

A release modifying polymer may be selected from hydrophilic polymers which include both water soluble and water swellable polymers, hydrophobic polymers, enteric polymers, delayed-release polymers, and mixtures thereof.

Examples of hydrophilic polymers include, but are not limited to,

hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, polyvinylpyrrolidone, polyethylene oxide, polyvinyl alcohol, and mixtures thereof.

Examples of hydrophobic polymers include, but are not limited to, methyl cellulose, ethyl cellulose, propyl cellulose, ethylmethyl cellulose, isopropyl cellulose, ethylpropyl cellulose, butyl cellulose, benzyl cellulose; cellulose esters such as cellulose acetate, cellulose butyrate, cellulose propionate, cellulose butyrate, and cellulose acetate propionate; cellulose cyanoalkyl ethers such as cyanoethyl cellulose, cyanomethyl cellulose, cyanoethylmethyl cellulose, cyanopropyl cellulose, methacrylic acid-acrylic acid copolymers (e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE, Eudragit® RSPO, and Eudragit® RLPO) and mixtures thereof.

Examples of enteric polymers or delayed-release polymers include, but are not limited to, methacrylic acid copolymers, ammonio methacrylate copolymer,

Hydroxypropylmethyl cellulosephthalate, Hydroxypropylmethyl celluloseacetate succinate, cellulose acetate phthalate, and mixtures thereof.

Examples of lipidic materials include, but are not limited to, vegetable oils or hydrogenated vegetable oils such as soyabean oil, cottonseed oil, peanut oil, castor oil, sesame oil, and Kolliwax®; waxes such as beeswax, carnauba wax, microcrystalline wax, candelilla wax, lecithin, paraffin wax, shellac wax, and petrolatum; fatty acids such as stearic acid, capric, caproic acid, linoleic acid, linolenic acid, palmitic acid, lauric acid, and eleostearic acid; fatty alcohols such as lauryl alcohol, cetostearyl alcohol, stearyl alcohol, cetyl alcohol, and myristyl alcohol; fatty acid esters such as glycerol monostearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, and cetyl esters glyceryl palmitostearate; glyceryl behenate; medium chain triglycerides such as Neobee® 0 and Neobee® M5, Miglyol® 629, 810, 812, 818 and 829, Captex® 350, 355 and 810D, Labrafac™ lipophile WL 1349, Crodamol™ GTCC, Gelucire®, such as glyceryl palmitostearate (Precirol®), glycerol esters of fatty acids (Gelucire® 43/01 and Gelucire® 39/01), polyethyleneglycol derivatives, and mixtures thereof.

Examples of polysaccharides include, but are not limited to, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, xanthan gum, guar gum, locust bean gum, potassium pectate, potassium pectinate, and derivatives and mixtures thereof.

Examples of oily vehicles include, but are not limited to, fatty acid esters, fatty acids, fatty alcohols, vegetable oils, and mixtures thereof. Examples of suitable fatty acid esters include polyol esters of medium chain fatty acids selected from esters and mixed esters of glycerol, propylene glycol, polyglycerol, polyethylene glycol with medium chain fatty acids, phosphatidyl choline with medium chain glycerides, and mixtures thereof. Examples of suitable fatty acids include C6-C20 saturated or mono- or di-unsaturated acid, for example, oleic acid, linoleic acid, caprylic acid, and caproic acid. Examples of suitable fatty alcohols include C6-C20 saturated or mono- or di-unsaturated alcohols, for example, oleyl alcohol, capryl alcohol and capric alcohol. Examples of suitable vegetable oils include groundnut oil, olive oil, soybean oil, safflower oil, sunflower oil, palm oil, sesame oil, canola oil, and corn oil. The oily vehicle may comprise from about 5% w/w to about 95% w/w of the total composition.

Examples of surfactants or surface stabilizers include, but are not limited to, sorbitan monostearate; polysorbates prepared from lauric, palmitic, stearic, and oleic acid (e.g., polysorbate 80); polyoxyethylene monoesters such as polyoxyethyl ethylene monostearate, polyoxyethylene monolaurate, and polyoxyethylene monooleate; dioctyl sodium sulfosuccinate; sodium lauryl sulfate; and poloxamers. Lecithin, gelatin, casein, gum acacia, stearic acid, calcium stearate, glycerol monostearate, sorbitan esters, macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters such as Tweens, polyoxyethylene stearates, colloidal silicon dioxide (Aerosil®), sodium dodecylsulfate, carboxymethylcellulose calcium,

carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone (PVP), poloxamers such as Pluronics® F68 and F108, dioctyl sodium sulfosuccinate (DOSS), docusate sodium, sodium lauryl sulfate, Span® 20 and 80, and macrogolglycerol esters such as Cremophor® EL, Kolliphor® EL, or Kolliphor® RH.

Examples of alkaline stabilizers include, but are not limited to, primary, secondary, and tertiary amines, cyclic amines, Ν,Ν'-dibenzylethylenediamine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), monosodium glutamate, polacrillin sodium, sodium alginate, and mixtures thereof.

Examples of antioxidants include, but are not limited to, butylated hydroxyl anisole, butylated hydroxyl toluene, tocopherol, ascorbyl palmitate, ascorbic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, propyl gallate, and mixtures thereof.

Examples of carrier substrates used for adsorption of the drug include but are not limited to lactose; microcrystalline cellulose; calcium phosphate; dextrin; dextrose;

sucrose; mannitol; maltodextrin; sodium alumino silicate; clays, including bentonite, kaolin, montmorrillonite, attapulgite, halloysite, laponite, and the like; silica, including colloidal silica, mesoporous silica, and fumed silica; zeolites; talc; cholesteramine; polystyrene sulfonates; mono and polysulfonated resins; activated charcoal; magnesium aluminometasilicate; Neusilin ^® ; and mixtures thereof.

Examples of suitable preservatives include, but are not limited to, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzoic acid, sodium benzoate, benzyl alcohol, sorbic acid, potassium sorbate, and mixtures thereof.

The oral pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipients selected from one or more of fillers, binders, osmogens, disintegrants, lubricants, anti-adherents, glidants, solvents, coloring agents, and flavoring agents.

Examples of fillers or diluents include, but are not limited to, lactose, sorbitol, calcium dihydrogen phosphate dihydrate, calcium phosphate-dibasic, calcium phosphate- tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, starch, pregelatinized starch, and mixtures thereof.

Examples of binders include, but are not limited to, corn starch, pregelatinized starch, microcrystalline cellulose, silicified MCC (e.g., Prosolv ^® HD 90), methyl cellulose, hydroxypropyl cellulose (HPC-L), methylcellulose, carboxymethyl cellulose sodium, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and mixtures thereof.

Examples of osmogens include, but are not limited to, water soluble salts of inorganic acids, such as magnesium chloride or magnesium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; water soluble salts of organic acids, such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; nonionic organic compounds with high water solubility, e.g., carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, and raffinose; water soluble amino acids, such as glycine, leucine, alanine, or methionine; and urea and urea derivatives.

Examples of disintegrants include, but are not limited to, cross-linked polyvinyl pyrrolidone, corn starch, modified starches, agar-agar, calcium carbonate, sodium carbonate, alginic acids, cross-carmellose sodium, sodium starch glycolate,

microcrystalline cellulose, hydroxypropyl cellulose (L-HPC), and mixtures thereof. Examples of anti-adherents include, but are not limited to, magnesium stearate, talc, calcium stearate, glyceryl behenate, stearic acid, and mixtures thereof.

Examples of lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, microcrystalline wax, yellow beeswax, white beeswax, sodium stearyl fumarate, and mixtures thereof.

Solvents include aqueous or non-aqueous solvents.

The coloring agents and flavoring agents may be selected from any FDA approved colors or flavors for oral use.

The coating layer present can further comprise other excipients, such as film forming polymers, solvents, plasticizers (e.g., triethyl citrate, triacetin, Myvacet®), antiadherents, and opacifiers, and optionally colorants and polishing agents.

The term "stable," as used herein, refers to chemical stability, wherein not more than 1.5% w/w of total related substances are formed on storage at accelerated conditions of stability at 40°C and 75% relative humidity or at 25 °C and 60% relative humidity for a period of at least three months or to the extent necessary for use of the composition.

The term "about" as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.

The size reduction of isotretinoin is achieved by wet milling the dispersion of isotretinoin in an oily vehicle or the dispersion of isotretinoin in an aqueous medium using mechanical means such as a ball mill, and media mills such as a sand mill, Dyno®-Mill, or bead mill. The grinding media in these mills can comprise spherical particles, such as stainless steel beads or zirconium oxide balls. The size reduction of isotretinoin can also be achieved by spray drying the solution of isotretinoin in a non-aqueous vehicle.

The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

EXAMPLES

Example 1

S.No. Ingredients Quantity (% w/w)

Core Capsule 1. Isotretinoin 13.92

2. Butylated hydroxy anisole 3.83

3. Polysorbate 80 0.08

4. Soyabean oil 82.17

5. Gelatin q.s.

6. Purified water q.s.

7. FDA approved color q.s.

Capsu e coating

8. Ethyl cellulose 38.15

9. Hydroxypropylmethyl celluloseE5 57.25

10. Triethyl citrate 4.60

11. Isopropyl alcohol q.s

12. Purified water q.s.

Procedure

1. Butylated hydroxy anisole and polysorbate 80 were dissolved in soyabean oil to form clear solution.

2. Isotretinoin was added to the solution of step 1 under stirring to obtain a uniform dispersion.

3. The dispersion of step 2 was milled to get a particle size of isotretinoin such that the D90 was about 21 μπι.

4. The dispersion of step 3 was filled into hard gelatin capsules.

5. Gelatin was soaked in purified water at a temperature of 60°C to 90°C along with color to get a uniform solution.

6. The filled capsules of step 4 were band-sealed using the gelatin solution of step 5.

7. Ethyl cellulose was dissolved in isopropyl alcohol under stirring.

8. Hydroxypropylmethyl cellulose E5 was dissolved in water, and this aqueous solution was added to the solution of step 7 under stirring.

9. Triethyl citrate was added in solution of step 8 and stirring was continued for a few minutes to ensure homogeneity of the coating solution.

10. The filled capsules of step 6 were coated with the coating solution of step 9.

Example 2

S.No. |lngredients Quantity (% w/w) 1. Isotretinoin 6.25

2. Butylated hydroxy anisole 1.72

3. Polysorbate 80 0.04

4. Soyabean oil 85.74

5. Hydroxypropylmethyl celluloseKlOOLV CR 6.25

6. Gelatin q.s.

7. Purified water q.s.

8. Sunset yellow color q.s.

Procedure

1. Butylated hydroxy anisole and polysorbate 80 were dissolved in soyabean oil (43% w/v) to form a clear solution.

2. Isotretinoin was added to the solution of step 1 under stirring to obtain a uniform

dispersion.

3. The dispersion of step 2 was milled to get a particle size of isotretinoin such that the D ₉₀ was about 15 μπι.

4. Hydroxypropylmethyl cellulose was added to the remaining quantity of soyabean oil (57% w/v) under stirring to obtain a uniform dispersion.

5. The dispersion of step 3 was added into the dispersion of step 4 under stirring to obtain a uniform dispersion.

6. The dispersion of step 5 was filled into hard gelatin capsules.

7. Gelatin was soaked in purified water at a temperature of 60°C to 90°C along with idacol sunset yellow color to get a uniform solution.

8. The filled capsules of step 6 were band-sealed using the gelatin solution of step 7.

Example 3

Procedure

1. Butylated hydroxy anisole and polysorbate 80 were dissolved in soyabean oil (43% w/w) to form a clear solution.

2. Isotretinoin was added to the solution of step 1 under stirring to obtain a uniform

dispersion.

3. The dispersion of step 2 was milled to get a particle size of isotretinoin such that the D ₉₀ was about 15 μιη.

4. Gelucire ^® 43/01 was melted at 55°C.

5. The remaining quantity of soaybean oil (57% w/w) was heated at 55°C and mixed with the product of step 4 under stirring,

6. The dispersion of step 3 was added into the mixture of step 5 under stirring to obtain a uniform dispersion.

7. The dispersion of step 6 was filled into hard gelatin capsules.

8. Gelatin was soaked in purified water at a temperature of 60°C to 90°C along with idacol sunset yellow color to get a uniform solution.

9. The filled capsules of step 7 were band-sealed using the gelatin solution of step 8.

Example 4

Procedure

1. Butylated hydroxy anisole and polysorbate 80 were dissolved in soyabean oil (43% w/w) to form a clear solution. Isotretinoin was added to the solution of step 1 under stirring to obtain a uniform dispersion.

The dispersion of step 2 was milled to get a particle size of isotretinoin such that the D ₉₀ was about 15 μιη.

Glycerol monostearate was melted at 65°C.

The remaining quantity of soyabean oil (57% w/w) was heated at 65°C and mixed with the product of step 4 under stirring.

The dispersion of step 3 was added into the mixture of step 5 under stirring to obtain a uniform dispersion.

The dispersion of step 6 was filled into hard gelatin capsules.

Gelatin was soaked in purified water at 60°C to 90°C along with idacol sunset yellow color to obtain a uniform solution.

The filled capsules of step 7 were band-sealed using the gelatin solution of step 8.

Example 5

Procedure

Butylated hydroxy anisole and polysorbate 80 were dissolved in soyabean oil (70% w/v) to form a clear solution.

Isotretinoin was added to the solution of step 1 under stirring to obtain a uniform dispersion.

The dispersion of step 2 was milled to get a particle size of isotretinoin such that the Dgo was about 15 μπι. 4. Eudragir RLPO was added to MiglyoP 829 under stirring.

5. The remaining quantity of soyabean oil (30% w/v) was added to the dispersion of step 4 under stirring.

6. The dispersion of step 3 was added into the dispersion of step 5 under stirring to obtain a uniform dispersion.

7. The dispersion of step 6 was filled into hard gelatin capsules.

8. Gelatin was soaked in purified water at a 60°C to 90°C along with idacol sunset

yellow color to obtain a uniform solution.

9. The filled capsules of step 7 were band-sealed using the gelatin solution of step 8.

Example 6

Procedure

1. Povidone, Kolliphor ^® RH 40 and Hydroxypropylmethyl celluloseK 100M were added to a mixture of dichloromethane and ethanol (in a ratio of 70:30) under stirring to form a clear solution.

2. Butylated hydroxy anisole and isotretinoin were dissolved in the solution of step 1.

3. Lactose and L-hydroxypropyl cellulose were loaded into a fluidized bed processor bowl for granulation.

4. The material of step 3 was granulated in fluidized bed processor by spraying the

solution of step 2 on it.

5. The granules were dried, and then filled into hard gelatin capsules. Example 7

Procedure

1. Povidone, Kolliphor ^® RH 40 and Hydroxypropylmethyl celluloseK 100M were added to a mixture of dichloromethane and ethanol (in a ratio of 70:30) under stirring to form a clear solution.

2. Butylated hydroxy anisole and isotretinoin were dissolved in the solution of step 1.

3. Lactose and L-hydroxy propyl cellulose were loaded into a fluidized bed processor bowl for granulation.

4. The material of step 3 was granulated in fluidized bed processor by spraying the solution of step 2 on it.

5. The granules were dried and filled into hard gelatin capsules.

Example 8

Procedure 1. Povidone and Kolliphor RH 40 were added to a mixture of dichloromethane and ethanol (in a ratio of 70:30) under stirring to form a clear solution.

2. Butylated hydroxy anisole and isotretinoin were dissolved in the solution of step 1.

3. Lactose and L-hydroxypropyl cellulose were loaded into a fluidized bed processor bowl for granulation.

4. The material of step 3 was granulated in fluidized bed processor by spraying the solution of step 2 on it.

5. The granules were dried, then mixed with Hydroxypropylmethyl celluloseKlOOM, and then filled into hard gelatin capsules.

Example 9

Procedure

1. Povidone, Gelucire ^® 50/13 and xanthan gum were dissolved in a mixture of

dichloromethane and ethanol (in a ratio of 70:30) to form a clear solution.

2. Butylated hydroxy anisole and isotretinoin were dissolved in the solution of step 1.

3. Lactose and L-hydroxy propyl cellulose were loaded into a fluidized bed processor bowl for granulation.

4. The material of step 3 was granulated in fluidized bed processor by spraying the solution of step 2 on it.

5. The granules were dried, and then mixed with extra-granular excipients to form a blend.

6. The blend of step 5 was compressed into tablets. Example 10

Procedure

1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxy toluene and propyl gallate were dispersed in the solution of step 1.

3. Isotretinoin was suspended in the dispersion of step 2.

4. The drug suspension of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D90 was about 2 μπι.

5. Kolliphor ^® EL was added to the dispersion of step 4 at the end of the milling process.

6. Lactose and mannitol were loaded into a fluidized bed processor bowl for granulation.

7. The dispersion of step 5 was sprayed over the material of step 6 to form granules.

8. The granules obtained in step 7 were dried, then mixed with Hydroxypropylmethyl celluloseK4M, magnesium stearate, colloidal silicon dioxide, and Kolliwax ^® HCO to form a blend.

9. The blend of step 8 was compressed into tablets.

Example 11 2. Hydroxypropylmethyl celluloseE3 2.87

3. Meglumine 0.71

4. Butylated hydroxy toluene 0.08

5. Propyl gallate 0.05

6. Lactose DCL 21 27.14

7. Mannitol 200 SD 27.43

8. Kolliphor ^® EL 3.43

9. Hydroxypropylmethyl celluloseK4M 14.29

10. Hydroxypropylmethyl celluloseKlOOLV CR 7.14

11. Magnesium stearate 0.71

12. Colloidal silicon dioxide 4.87

13. Kolliwax ^® HCO 5.57

14. Purified water q.s.

Procedure

1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxy toluene and propyl gallate were dispersed in the solution of step 1.

3. Isotretinoin was suspended in the dispersion of step 2.

4. The drug suspension of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D90 was about 2 μπι.

5. Kolliphor ^® EL was added to the dispersion of step 4 at the end of the milling process.

6. Lactose and mannitol were loaded into a fluidized bed processor bowl for granulation.

7. The dispersion of step 5 was sprayed over the material of step 6 to form granules.

8. The granules obtained in step 7 were dried, then mixed with Hydroxypropylmethyl cellulose K4M, Hydroxypropylmethyl celluloseKlOOLV CR, magnesium stearate, colloidal silicon dioxide, and Kolliwax ^® HCO to form a blend.

9. The blend of step 8 was compressed into tablets.

Example 12

S.No. Ingredients Quantity (% w/w)

1. Isotretinoin 5.71

2. Hydroxypropylmethyl celluloseE3 2.87

3. Meglumine 0.71

4. Butylated hydroxy toluene 0.08

5. Propyl gallate 0.05

6. Lactose DCL 21 27.14 7. Mannitol 200 SD 27.43

8. Kolliphor ^® EL 3.43

9. Hydroxypropylmethyl celluloseK4M 14.29

10. Hydroxypropylmethyl celluloseK 100M 7.14

11. Magnesium stearate 0.71

12. Colloidal silicon dioxide 4.87

13. Kolliwax ^® HCO 5.57

14. Purified water q.s.

Procedure

1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxyl toluene and propyl gallate were dispersed in the solution of step 1.

3. Isotretinoin was suspended in the dispersion of step 2.

4. The drug suspension of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D ₉₀ was about 2 μπι.

5. Kolliphor ^® EL was added to the dispersion of step 4 at the end of the milling process.

6. Lactose and mannitol were loaded into a fluidized bed processor bowl for granulation.

7. The dispersion of step 5 was sprayed over the material of step 6 to form granules.

8. The granules obtained in step 7 were dried, then mixed with Hydroxypropylmethyl celluloseK4M, Hydroxypropylmethyl celluloseKlOOM, magnesium stearate, colloidal silicon dioxide, and Kolliwax ^® HCO to form a blend.

9. The blend of step 8 was compressed into tablets.

Example 13

S.No. Ingredients Quantity (% w/w)

1. Isotretinoin 4.00

2. Hydroxypropylmethyl celluloseE3 2.01

3. Meglumine 0.50

4. Butylated hydroxy toluene 0.05

5. Propyl gallate 0.04

6. Lactose DCL 21 19.00

7. Mannitol 200 SD 19.20

8. Kolliphor ^® EL 2.40

9. Crospovidone PPXL 25.00

10. Polyethylene oxide WSR 303 23.90

11. Magnesium stearate 0.50 12. Colloidal silicon dioxide 3.40

13. Purified water q.s.

Procedure

1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxy toluene and propyl gallate were dispersed in the solution of step 1.

3. Isotretinoin was suspended in the dispersion of step 2.

4. The drug suspension of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D90 was about 2 μπι.

5. Kolliphor ^® EL was added to the dispersion of step 4 at the end of the milling process.

6. Lactose and mannitol were loaded into a fluidized bed processor bowl for granulation.

7. The dispersion of step 5 was sprayed over the material of step 6 to form granules.

8. The granules obtained in step 7 were dried, then mixed with polyethylene oxide, crospovidone PPXL, magnesium stearate, and colloidal silicon dioxide to form a blend.

9. The blend of step 8 was compressed into tablets.

Example 14

Procedure 1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxy toluene and propyl gallate were dispersed in the solution of step 1.

3. Isotretinoin was suspended in the dispersion of step 2.

4. The drug suspension of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D90 was about 2 μιη.

5. Kolliphor ^® EL was added to the dispersion of step 4 at the end of the milling process.

6. Lactose and mannitol were loaded into a fluidized bed processor bowl for granulation.

7. The dispersion of step 5 was sprayed over the material of step 6 to form granules.

8. The granules obtained in step 7 were dried, then mixed with extra-granular

Hydroxypropylmethyl celluloseK4M, Hydroxypropylmethyl celluloseKlOOLV CR, crospovidone PPXL, magnesium stearate, and colloidal silicon dioxide to form a blend.

9. The blend of step 8 was compressed into tablets.

Example 15

17. Isopropyl alcohol q.s.

18. Purified water q.s.

Procedure

Core tablets

1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxy toluene and propyl gallate were dispersed in the solution of step 1. 3. Isotretinoin was suspended in the dispersion of step 2.

4. The drug suspension of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D ₉₀ was about 2 μπι.

5. Kolliphor ^® EL was added to the dispersion of step 4 at the end of the milling process.

6. Lactose and mannitol were loaded into a fluidized bed processor bowl for granulation. 7. The dispersion of step 5 was sprayed over the material of step 6 to form granules.

8. The granules obtained in step 7 were dried, then mixed with extra-granular lactose, magnesium stearate, colloidal silicon dioxide, and Kolliwax ^® HCO to form a blend.

9. The blend of step 8 was compressed into tablets.

Coating

10. Ethyl cellulose was dissolved in a mixture of isopropyl alcohol and water in a ratio of

80:20 to make a 6% w/w solution.

11. Hydroxypropylmethyl celluloseand triethyl citrate were added to the solution of step

10.

12. The core tablets were coated with the coating solution of step 11.

Example 16

5 Propyl gallate 0.05

6 Lactose DCL 21 27.14

7 Mannitol 200 SD 27.43

8 Kolliphor ^® EL 3.44

9 Water q.s.

Extra- granular part

10 Lactose DCL 21 21.43

11 Magnesium stearate 0.71

12 Colloidal silicon dioxide 4.87

13 Kolliwax ^® HCO 5.57

Coating solution/dispersion

14 Ethyl cellulose 64.48

15 Hydroxypropylmethyl celluloseE5 25.84

16 Triethyl citrate 9.68

17 Isopropyl alcohol q.s.

18 Purified water q.s.

Procedure

Core tablets

1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxy toluene and propyl gallate were dispersed in the solution of step 1.

3. Isotretinoin was suspended in the dispersion of step 2.

4. The drug suspension of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D ₉₀ was about 2 μπι.

5. Kolliphor ^® EL was added to the dispersion of step 4 at the end of the milling process.

6. Lactose and mannitol were loaded into a fluidized bed processor bowl for granulation.

7. The dispersion of step 5 was sprayed over the material of step 6 to form granules.

8. The granules obtained in step 7 were dried, then mixed with extra-granular lactose, magnesium stearate, colloidal silicon dioxide, and Kolliwax ^® HCO to form a blend.

9. The blend of step 8 was compressed into tablets.

Coating

10. Ethyl cellulose was dissolved in a mixture of isopropyl alcohol and water in a ratio of 80:20 to make a 6% w/w solution.

11. Hydroxypropylmethyl celluloseand triethyl citrate were added to the solution of step 10. 12. The core tablets were coated with coating solution of step 11.

Example 17

Procedure:

1. Capmul ^® PG8, Transcutol ^® HP, and Kolliphor ^® EL were mixed to form a solution under stirring.

2. Butylated hydroxy toluene and propyl gallate were dissolved in the solution of step 1.

3. Isotretinoin was dissolved in the solution of step 2 with stirring.

4. The solution of step 3 was adsorbed onto Neusilin ^® to form a powder.

5. The powder obtained in step 5 was filled into capsules.

Example 18

15. Sodium stearyl fumarate 0.87

Procedure:

1. Isotretinoin, hydroxypropylmethyl cellulose, meglumine, poloxamer, butylated hydroxy anisole, and propyl gallate were added to a mixture of dichloromethane and ethanol under stirring to form a clear solution.

2. The solution of step 1 was processed into dry form.

Compression - Part A

3. The dried blend (25%) of step 2 was mixed with anhydrous lactose, colloidal silicon dioxide, and sodium stearyl fumarate to form a blend.

4. The blend of step 3 was compressed into tablets.

Compression - Part B

5. The dried blend (75%) of step 2 was mixed with anhydrous lactose, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate to form a blend.

6. The blend of step 5 was compressed into tablets.

Filling of Capsules

7. One tablet each of part A and part B were filled into a hard gelatin capsule.

Example 19

14 Colloidal silicon dioxide 1.00

15 Sodium stearyl fumarate 1.25

Procedure:

1. Isotretinoin, hydroxypropyl methylcellulose, meglumine, poloxamer, butylated hydroxy anisole, and propyl gallate were added in a mixture of dichloromethane and ethanol under stirring to form a clear solution.

2. The solution of step 1 was processed into dry form.

3. The dried blend of step 2 was mixed with anhydrous lactose, hydroxypropyl

methylcellulose, xanthan gum, sodium alginate, sodium bicarbonate, colloidal silicon dioxide, and sodium stearyl fumarate to form a blend.

4. The blend of step 3 was compressed into tablets.

5. One tablet was filled into a hard gelatin capsule.

Example 20

Procedure:

I. Isotretinoin, Hydroxypropylmethyl celluloseE3, meglumine, poloxamer, butylated hydroxy anisole, and propyl gallate were added to a mixture of dichloromethane and ethanol (in a ratio of 70:30) under stirring to form a clear solution.

2. The solution of step 1 was processed into dry form.

Compression - Part A

3. The dried blend (25%) of step 2 was mixed with anhydrous lactose, colloidal silicon dioxide, and sodium stearyl fumarate to form a blend.

4. The blend of step 3 was compressed into tablets.

Compression - Part B

5. The dried blend (75%) of step 2 was mixed with anhydrous lactose, hydroxypropyl methylcellulose, colloidal silicon dioxide, and sodium stearyl fumarate to form a blend.

6. The blend of step 1 was compressed into tablets.

Coating - Part B

7. Isopropyl alcohol and acetone were mixed under stirring.

8. Eudragit ^® LI 00 was dissolved into half of the solvent mixture of step 7 under stirring to obtain a clear solution.

9. Talc was dispersed into the other half of the solvent mixture of step 7 under stirring. 10. The dispersion of step 9 was added into solution of step 8 under stirring, followed by the addition oftriethyl citrate.

I I . The dispersion of step 10 was stirred, and then the core tablets of Part B were coated using the dispersion.

Filling of Capsules

12. One tablet each of part A and part B were filled into a hard gelatin capsule.

Example 21 Quantity (%w/w)

1 Isotretinoin 8.62 8.62

2 Butylated hydroxy anisole 0.09 0.09

3 Oleic acid 46.98 46.98

4 Polysorbate 80 2.16 2.16

5 Ethyl cellulose 7.67 7.67

6 Soybean oil 34.48 34.48

7 Gelatin q.s. q.s.

8 Purified water q.s. q.s.

9 FDA approved color q.s. q.s.

Coating ingredients Coat composition (mg/capsule)

Seal coating (3%w/w)

10 Hydroxypropyl methylcellulose 9.00 9.00

11 Isopropyl alcohol q. s. q. s.

12 Dichloromethane q. s. q. s.

Functional Coating

7%w/w 9%w/w

13 Ethyl cellulose 8.83 11.35

14 Hydroxypropylmethyl cellulose 10.59 13.62

15 Triethyl citrate 2.21 2.84

16 Isopropyl alcohol q.s. q.s.

17 Dichloromethane q.s. q.s.

Procedure

1. Butylated hydroxy anisole and polysorbate 80 were dissolved in soyabean oil to form a clear solution.

2. Isotretinoin was added to the solution of step 1 under stirring to obtain a uniform

suspension.

3. The suspension of step 2 was milled to get a particle size of isotretinoin such that the D ₉₀ was about 19 μπι.

4. The suspension of step 3 was filled into hard gelatin capsules.

5. Gelatin was soaked in purified water at 60°C to 90°C along with color to get a uniform solution.

6. The filled capsules of step 4 were band-sealed using the gelatin solution of step 5.

7. Hydroxypropylmethyl cellulosewas dissolved in dichloromethane, and then isopropyl alcohol was added into the mixture to form a clear solution.

8. The band-sealed capsules of step 6 were seal -coated using the solution of step 7.

9. Ethyl cellulose was dissolved in isopropyl alcohol. 10. Hydroxypropylmethyl cellulosewas dissolved in dichloromethane, and then isopropyl alcohol was added to the mixture to obtain a clear solution.

11. The solutions of step 9 and step 10 were mixed under stirring while adding triethyl citrate.

12. The seal-coated capsules of step 8 were coated with the solution of step 11.

Example 22

Procedure

Butylated hydroxy anisole was dissolved in oleic acid to form a clear solution.

Isotretinoin was added to the solution of step 1 under stirring to obtain a uniform suspension.

The suspension of step 2 was milled to get a particle size of isotretinoin such that the D ₉₀ was about 7 μιη.

Ammonio methacrylate copolymer and triethyl citrate were dissolved in soybean oil under stirring, to obtain a uniform suspension.

The suspension of step 4 was added into the suspension of step 3 under stirring to obtain a uniform suspension.

The suspension of step 5 was filled into hard gelatin capsules.

Example 23

Triethyl citrate 1.29

Procedure

1. Butylated hydroxy anisole and polysorbate 80 were dissolved in oleic acid to form a clear solution.

2. Isotretinoin was added to the solution of step 1 under stirring to obtain a uniform suspension.

3. The suspension of step 2 was milled to get a particle size of isotretinoin such that the D ₉₀ was about 26 μιη.

4. Ethyl cellulose and triethyl citrate were added to diethylene glycol monoethyl ether under stirring to form a solution.

5. The solution of step 4 was added into the suspension of step 3, under stirring, to get a uniform suspension.

6. The suspension of step 5 was filled into hard gelatin capsules.

Exam le 24

18 Water qs

Functional coat

19 Cellulose acetate CA-398-10 3.90

20 Polyethylene glycol 3350 1.16

21 Acetone qs

22 Water qs

Film-coating

23 Opadry ^® Brown 03F565089 2.91

24 Water qs

Procedure:

Dvno-milled dispersion

1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxyl toluene and propyl gallate were dispersed in the solution of step 1. 3. Isotretinoin was added to the dispersion of step 2.

4. The drug dispersion of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D ₉₀ was about 2 μιη.

Granulation

5. Mannitol was sifted through a sieve and loaded into a fluidized bed granulator.

6. Kolliphor ^® EL was added to the Dyno-milled dispersion of step 4 under stirring.

7. The dispersion of step 6 was sprayed over the loaded mannitol of step 5 to form

granules.

Drug layer

8. The granules obtained in step 7 were mixed with previously sifted polyethylene oxide, sodium chloride, and magnesium stearate to form a drug blend.

Polymer layer

9. Polyethylene oxide, sodium chloride and magnesium stearate were sifted through a sieve and blended together to form a push layer blend.

Compression

10. The blends of the drug layer and the push layer were loaded into respective hoppers of a bilayer compression machine and compressed into bilayered tablets.

Seal Coating 11. Hydroxypropylmethyl cellulose and polyethylene glycol were dissolved in water to form a coating solution.

12. The tablets of step 10 were coated with the solution of step 11.

Functional coating

13. Cellulose acetate was dispersed in acetone to form a clear solution.

14. Polyethylene glycol was dissolved in purified water to form a clear solution.

15. The solutions of step 13 and step 14 were mixed together to form a clear solution.

16. The seal coated tablets of step 12 were coated with the solution of step 15.

Film-coating

17. The tablets were film-coated with a 10% dispersion of Opadry ^® Brown 03F565089 in purified water.

Example 25

Procedure:

Dyno-milled dispersion 1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxyl toluene and propyl gallate were dispersed in the solution of step 1.

3. Isotretinoin was added to the dispersion of step 2.

4. The drug dispersion of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve the particle size of isotretinoin such that D90 was about 2μιη.

Granulation

5. Mannitol and lactose were sifted through a sieve and loaded into a fluidized bed

granulator.

6. Kolliphor ^® EL was added to the Dyno-milled dispersion of step 4 under stirring.

7. The dispersion of step 6 was sprayed over loaded material of step 5 to form granules. Compression

8. Granules obtained in step 7 were mixed with previously sifted anhydrous lactose, crospovidone PPXL, polyethylene Oxide N80, polyethylene Oxide WSR 303, sodium chloride, magnesium stearate and colloidal silicon dioxide to form the drug blend.

9. The blend of step 8 was compressed into tablets.

Film-coating

10. The tablets were film-coated with 10% dispersion of Opadry ^® Brown 03F565089 in purified water.

Example 26

11 Magnesium stearate 0.4

12 Colloidal silicon dioxide 0.37

13 Polyethylene oxide WSR 303 11.22

14 Polyethylene oxide N80 7.48

IR layer blend

15 Anhydrous lactose 7.01

16 Crospovidone PPXL 0.85

17 Magnesium stearate 0.19

18 Colloidal silicon dioxide 0.09

19 Ferric oxide red 0.07

Film-coating

20 Opadry ^® Brown 03F565089 3.21

21 Water qs

Procedure:

Dyno-milled dispersion

1. Hydroxypropylmethyl celluloseand meglumine were dissolved in water.

2. Butylated hydroxyl toluene and propyl gallate were dispersed in the solution of step 1. 3. Isotretinoin was added to the dispersion of step 2.

4. The drug dispersion of step 3 was milled in a Dyno ^® -Mill containing zirconium beads to achieve a particle size of isotretinoin such that the D90 was about 2 μιη.

Granulation

5. Mannitol and lactose were sifted through a sieve and loaded into a fluidized bed

granulator.

6. Kolliphor ^® EL was added to the Dyno-milled dispersion of step 4 under stirring.

7. The dispersion of step 6 was sprayed over the loaded material of step 5 to form

granules.

MR layer blend

8. 75% of the granules obtained in step 7 were mixed with previously sifted crospovidone PPXL, polyethylene oxide N80, polyethylene oxide WSR 303, magnesium stearate, and colloidal silicon dioxide to form the MR layer blend.

IR layer blend 9. 25% of the granules obtained in step 7 were mixed with previously sifted anhydrous lactose, crospovidone PPXL, ferric oxide red, magnesium stearate, and colloidal silicon dioxide to form the IR layer blend.

Compression

10. The blends of the MR drug layer and the IR drug layer were loaded into respective hoppers of bilayer compression machines, and compressed into bi-layered tablets.

Film-coating

11. The tablets were film-coated with a 10% dispersion of Opadry ^® Brown 03F565089 in purified water.