Patent Application
20160081965
The present invention provides an oral pharmaceutical composition of isotretinoin with a reduced dose. The present invention further relates to a process for preparing the oral pharmaceutical composition of the present invention.
Isotretinoin is a retinoid (also known as 13-cis retinoic acid). Owing to its low water solubility, the oral bioavailability of isotretinoin is low. PCT Publication No. WO 00/25772 discloses that the presently marketed formulation of isotretinoin, i.e., Accutane®, contains isotretinoin at a mean particle size of about 100 μm resulting in only 20% oral bioavailability. Therefore, this application discloses a formulation of isotretinoin having a reduced particle size, thereby enhancing the oral bioavailability.
U.S. Pat. Nos. 7,435,427 and 8,367,102 cover the marketed formulation of Absorica®. These patents disclose capsules comprising a semi-solid suspension of isotretinoin containing at least two lipidic excipients, one having an HLB value equal to or greater than 10 and the other being an oily vehicle. These patents are based on the use of the “Lidose technology” to provide a formulation of isotretinoin with enhanced bioavailability.
Isotretinoin has a very high teratogenic potential. This drug may be prescribed only by or under the supervision of a consultant dermatologist. Therefore, reduction of dose in case of such a teratogenic drug is highly beneficial. The present inventors have developed an oral pharmaceutical composition of isotretinoin which has a reduced but effective dose in comparison to the already marketed formulations of isotretinoin, i.e., Roaccutane® and Absorica®/Epuris™.
The present invention provides an oral pharmaceutical composition of isotretinoin with a reduced dose. The oral pharmaceutical composition of the present invention comprises isotretinoin and a solvent selected from the group comprising:
The composition is in the form of a solution which is further filled into capsules. The present invention further provides a process for preparing said oral pharmaceutical composition. It also provides a method of treating acne by administering said oral pharmaceutical composition.
In one aspect, the present invention provides an oral pharmaceutical composition comprising isotretinoin and a solvent selected from the group comprising:
In one embodiment of the above aspect, the solvent is present in an amount of about 1% to about 99% by total weight of the composition; preferably in an amount of about 10% w/w to about 90% w/w by total weight of the composition.
In one embodiment of the above aspect, said composition, when administered orally to a patient in need thereof, provides an equivalent efficacy at a lower dose of isotretinoin in comparison to the marketed Epuris™ formulation.
In one embodiment of the above aspect, the dose of isotretinoin is reduced by at least 10% in comparison to the marketed Epuris™ formulation.
In one embodiment of the above aspect, the dose of isotretinoin is reduced by at least 20% in comparison to the marketed Epuris™ formulation.
In one embodiment of the above aspect said composition exhibits improved pharmacokinetic profile as compared to Epuris™ formulation under fed as well as fasting conditions, wherein the pharmacokinetic profile is defined by Cmax and AUC.
In another embodiment of the above aspect, said monoalkyl ether of diethylene glycol having a general formula C4H9O3(CnH2n+1), wherein n is 1-4 includes, but is not limited to, include diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, and mixtures thereof.
In another embodiment of the above aspect, said oily vehicle includes, but is not limited to, fatty acids, fatty acid esters, and vegetable oils.
The fatty acids include, but are not limited to, saturated-, mono-, or di-unsaturated acids, for example, oleic acid, linoleic acid, caprylic acid, caproic acid, and mixtures thereof.
The fatty acid esters include, but are not limited to, polyol esters of medium chain fatty acids selected from esters and mixed esters of glycerol, propylene glycol, polyglycerol, and polyethylene glycol with medium chain fatty acids, phosphatidyl choline with medium chain glycerides, for example caprylic and capric mono-diglyceride esters such as Capmul® MCM, Capmul® MCM C8, glycerol caprylate caprate (Captex® 355), propylene glycol monocaprylate (Capmul® PG-8), ethyl oleate, and mixtures thereof.
The vegetable oils include, but are not limited to, groundnut oil, olive oil, soybean oil, safflower oil, sunflower oil, palm oil, sesame oil, canola oil, corn oil, and mixtures thereof.
In one embodiment of the above aspect, said composition further comprises a surfactant, a co-surfactant or a co-solvent, a hydrophilic polymer, a basic substance, a preservative, and/or an antioxidant.
The surfactants include, but are not limited to, lecithin; sorbitan esters; polysorbates prepared from lauric, palmitic, stearic, and oleic acids; dioctyl sodium sulfosuccinate (DOSS); docusate sodium; sodium lauryl sulfate; Span® 20 and 80; macrogol ethers such as cetomacrogol 1000; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters such as Tween®; polyoxyethylene stearates; poloxamers such as Pluronic® F-68 and Pluronic® F.108; macrogolglycerol esters such as Cremophor® EL or Kolliphor® EL; glycerides esters such as lauroyl polyoxyl-32 glycerides (Gelucire®); and mixtures thereof.
The co-surfactants/co-solvents include, but are not limited to, short chain mono-, di-, and polyhydric alcohols, such as ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, polyethylene glycol with an average molecular weight of about 200 to about 10,000, polyethylene glycol esters such as Labrafil® M1944CS, polyglyceryl-3 dioleate, diethylene glycol monoethyl ether such as Transcutol® HP, and mixtures thereof.
The hydrophilic polymers include, but are not limited to, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidone, polysaccharides, gums, alginates, acrylic acid derivatives, and mixtures thereof.
The basic substances include, but are not limited to, inorganic or organic bases, including sodium hydroxide, potassium hydroxide, sodium carbonate or bicarbonate, potassium carbonate or bicarbonate, lithium hydroxide, triethylamine, meglumine, methylamine, and mixtures thereof.
The 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 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.
In one embodiment of the above aspect, the oral pharmaceutical composition comprises:
In another embodiment of the above aspect, the oral pharmaceutical composition comprises:
In one embodiment of the above aspect, said composition comprises isotretinoin in an amount of about 1 mg to 100 mg, 5 mg to 50 mg, 10 mg to 40 mg, 9 mg to 36 mg, or 8 mg to 32 mg.
In another embodiment of the above aspect, said composition comprises isotretinoin in an amount of about 40 mg.
In another embodiment of the above aspect, said composition comprises isotretinoin in an amount of about 36 mg.
In another embodiment of the above aspect, said composition comprises isotretinoin in an amount of about 32 mg.
In another embodiment of the above aspect, said composition comprises isotretinoin in an amount of about 16 mg.
In yet another embodiment of the above aspect, said composition is in the form of a solution which is further filled into capsules.
In yet another embodiment of the above aspect, said composition is in the form of a self nano-emulsifying drug delivery system (SNEDDS) or self micro-emulsifying drug delivery system (SMEDDS).
In yet another embodiment of the above aspect, said composition is in the form of a self nano-emulsifying drug delivery system (SNEDDS) comprising:
In yet another embodiment of the above aspect, said SNEDDS is a nano-emulsion with globule size less than 1 μm, preferably less than 200 nm, more preferably less than 100 nm.
The ratio of isotretinoin to the oily phase in the said SNEDDS ranges from about 0.04 to about 0.35.
The amount of oily phase in the said SNEDDS ranges from about 10% w/w to about 25% w/w by total weight of the composition.
The amount of surfactant in the said SNEDDS ranges from about 5% w/w to about 55% w/w by total weight of the composition.
The amount of co-surfactant or co-solvent in the said SNEDDS ranges from about 15% w/w to about 75% w/w by total weight of the composition.
In yet another embodiment of the above aspect, 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, wherein said process comprises:
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, or cutaneous photoaging, by administering to the individual in need thereof the oral pharmaceutical composition of the present invention.
In one embodiment of the above aspect, the present invention provides a method of treating acne by administering to the individual in need thereof the oral pharmaceutical composition of the present invention.
The term “isotretinoin” refers to isotretinoin in its crystalline or amorphous form, its esters, salts, or derivatives thereof.
The bioequivalence is established by comparing pharmacokinetic parameters for example, AUC and Cmax of the pharmaceutical composition of the present invention with Epuris™ in healthy human subjects in fed as well as fasting conditions.
The term “AUC” refers to the area under the time/plasma concentration curve after administration of the pharmaceutical composition. AUC0-infinity denotes the area under the plasma concentration versus time curve from time 0 to infinity; AUC0-t denotes the area under the plasma concentration versus time curve from time 0 to time t.
The term “Cmax” refers to the maximum concentration of isotretinoin in the blood following administration of the pharmaceutical composition.
The term “tmax” refers to the time in hours when Cmax is achieved following administration of the pharmaceutical composition.
The term “food effect” as used herein means food-drug interactions which either decrease or increase the extent of drug absorption. It refers to a relative difference in AUC, Cmax, and/or tmax of a drug, when said drug or a formulation thereof is administered orally to a human, concomitantly with food or in a fed state as compared to when administered in a fasted state or without food.
In certain embodiments, the pharmaceutical composition of the present invention has a reduced food effect, in that when the composition is administered orally to a human concomitantly with food or in a fed state, it has about the same in AUC, Cmax, and/or tmax as compared to the same values when the same composition is administered in a fasted state or without food.
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 invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
The pharmaceutical composition of Example 3 (Test, 16 mg of isotretinoin) was compared with the marketed formulation of isotretinoin (Reference, 20 mg Epuris™ capsules) for the release profile in FDA recommended dissolution medium as given below:
The pharmaceutical composition of Example 3 (Test, 16 mg of isotretinoin) was compared with the marketed formulation of isotretinoin (Reference; 20 mg Epuris™ capsules) under fed conditions in 12 healthy adult male subjects.
Values for various pharmacokinetic parameters, including observed Cmax, AUC0-t and AUC0-inf, were calculated and are provided in Table 1 below.
The pharmaceutical composition of Example 3 (16 mg Test capsule) was compared in fed and fasting conditions in 12 healthy adult male subjects.
Values for various pharmacokinetic parameters, including observed Cmax, AUC0-t, and AUC0-inf were calculated and are provided in Table 2 below.
Test (A): Isotretinoin 16 mg capsules (Example 3) under fasting conditions
Test (B): Isotretinoin 16 mg capsules (Example 3) under fed conditions
| Number | Date | Country | Kind |
|---|---|---|---|
| 1456/DEL/2014 | Jun 2014 | IN | national |
| 1737/DEL/2014 | Jun 2014 | IN | national |
| 4002/DEL/2014 | Dec 2014 | IN | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/IB2015/054088 | May 2015 | US |
| Child | 14958337 | US |
