Patent Application
20160128962
The present invention provides a low dose oral pharmaceutical composition of isotretinoin having reduced food effect. 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. Further, isotretinoin is known to have a “food effect”, i.e., its absorption is dependent on the presence of food in the stomach. Therefore, there is a need to develop a composition of isotretinoin which has a lower dose and reduced food effect. The present inventors have developed an oral pharmaceutical composition of isotretinoin wherein said composition has enhanced bioavailability, lower dose and reduced food effect in comparison to the marketed formulations of isotretinoin, i.e., Roaccutane® and Absorica®. These advantages would lead to better patient compliance.
The present invention provides a low dose oral pharmaceutical composition of isotretinoin having reduced food effect. The oral pharmaceutical composition of the present invention comprises isotretinoin and a pharmaceutically acceptable excipient. The present composition is in the form of a dispersion which is further filled into capsules. The present invention further provides a process for preparing the oral pharmaceutical composition of the present invention. It also provides a method of treating acne by administering the oral pharmaceutical composition of the present invention.
In one aspect, the present invention provides a low dose oral pharmaceutical composition comprising isotretinoin and a pharmaceutically acceptable excipient.
In another aspect, the present invention provides a low dose oral pharmaceutical composition comprising isotretinoin and a pharmaceutically acceptable excipient, wherein said composition, when administered orally, provides an equivalent efficacy at a lower dose of isotretinoin in comparison to the marketed Absorica® capsules, wherein said dose is at least 10% lower.
In another aspect, the present invention provides a low dose oral pharmaceutical composition comprising isotretinoin and a pharmaceutically acceptable excipient, wherein said composition, when administered orally, provides an equivalent efficacy at a lower dose of isotretinoin in comparison to the marketed Absorica® capsules, wherein said dose is at least 20% lower.
In another aspect, the present invention provides a low dose oral pharmaceutical composition comprising isotretinoin and a pharmaceutically acceptable excipient, wherein said composition exhibits reduced food effect as indicated by comparable Cmax and AUC in fasting and fed states.
In an embodiment of the above aspect, the composition exhibits a mean Cmax of about 451.38 ng/mL under fed condition and a mean Cmax of about 454.92 ng/mL under fasting condition.
In another embodiment of the above aspect, the composition exhibits a mean AUC of about 6514.86 ng·h/mL under fed condition and a mean AUC of about 5566.90 ng·h/mL under fasting condition.
In another embodiment of the above aspect, the composition, when administered orally, has a mean fed/fasted ratio of AUC of about 1.17 and a mean fed/fasted ratio of Cmax of about 0.99.
In another aspect, the present invention provides a low dose oral pharmaceutical composition comprising:
(a) isotretinoin; and
(b) an oily vehicle.
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 16 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 8 mg, 16 mg, 20 mg, 24 mg, 28 mg, or 32 mg.
In another embodiment of the above aspect, said composition is in the form of a dispersion which is further filled into capsules.
In another embodiment of the above aspect, the oily vehicle includes, but is not limited to, groundnut oil, olive oil, soybean oil, kernel oil, almond oil, safflower oil, sunflower oil, palm oil, sesame oil, canola oil, corn oil, castor oil, coconut oil, cotton seed oil, grape seed oil, and mixtures thereof.
In another embodiment of the above aspect, the oily vehicle is present in an amount of about 1% w/w to about 99% w/w by the total weight of the composition; preferably in an amount of about 10% w/w to about 95% w/w by the total weight of the composition.
In another embodiment of the above aspect, the oily vehicle is present in an amount of about 71% w/w to about 95% w/w by the total weight of the composition.
In another embodiment of the above aspect, the ratio of isotretinoin to the oily vehicle ranges from about 1:99 to about 99:1.
In another embodiment of the above aspect, the composition further comprises a surfactant.
In another embodiment of the above aspect, the surfactant includes, but is not limited to, anionic, cationic, or non-ionic surfactants; sorbitan fatty acid esters; polysorbates prepared from lauric, palmitic, stearic, and oleic acids; mononylphenyl ethers of polyethylene glycols such as nanoxynols; polyoxyethylene monoesters such as polyoxyethylethylene monostearate, polyoxyethylene monolaurate, and polyoxyethylene monooleate; dioctyl sodium sulfosuccinate; sodium lauryl sulphate; lecithin; fatty acid esters of propylene glycol; fatty acid esters of glycerol; poloxamers; and mixtures thereof.
In another embodiment of the above aspect, the surfactant is present in an amount of about 0.05% w/w to about 10.0% w/w by the total weight of the composition.
In yet another embodiment of the above aspect, the composition further comprises other excipients like antioxidants, preservatives, and alkaline stabilizers.
In yet another embodiment of the above aspect, the composition is free of wax.
In yet another embodiment of the above aspect, the composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D90 is less than 60 μm, less than 55 μm, less than 50 μm, less than 45 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.
In yet another embodiment of the above aspect, the composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D90 is less than 30 μm.
In another embodiment of the above aspect, the composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D50 is less than 40 μm, less than 35 μm, less than 30 μm, less than 25 μm, less than 20 μm, less than 15 μm, less than 10 μm, or less than 5 μm.
In yet another embodiment of the above aspect, the composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D50 is less than 15 μm.
In another embodiment of the above aspect, the composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D10 is less than 20 μm, less than 18 μm, less than 17 μm, less than 15 μm, less than 12 μm, less than 10 μm, less than 8 μm, less than 7 μm, less than 5 μm, or less than 2 μm.
In yet another embodiment of the above aspect, the composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D10 is less than 7 μm.
In yet another embodiment of the above aspect, the composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D90 is less than 60 μm and the D50 is less than 40 μm.
In yet another embodiment of the above aspect, the composition comprises isotretinoin wherein the particle size distribution of isotretinoin is such that the D90 is less than 60 μm, D50 is less than 40 μm, and D10 is less than 20 μm.
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, there is provided a process for the preparation of a low dose oral pharmaceutical composition comprising isotretinoin and an oily vehicle wherein the process comprises:
(a) dispersing isotretinoin in an oily carrier;
(b) milling the dispersion to get the desired particle size;
(c) adding one or more excipients to the above dispersion;
(d) optionally adding an oily carrier to the dispersion of step (c); and
(e) filling the dispersion into capsules.
In one embodiment of the above aspect, the oily carrier used in step (a) is present in an amount which is at least 25% w/w of the total amount of the oily carrier.
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, a low dose 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, a low dose oral pharmaceutical composition of the present invention.
The term “isotretinoin” refers to isotretinoin in its crystalline or amorphous form, as well as its esters, salts, or derivatives thereof.
The term “low dose,” as used herein, refers to the dose of isotretinoin wherein said dose is at least 10% lower than the presently approved dose.
The bioequivalence is established by comparing pharmacokinetic parameters, for example, AUC and Cmax of the pharmaceutical composition of the present invention with Absorica® formulation 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 the same values when the same formulation is administered in a fasted state or without food. Isotretinoin shows a food effect, i.e., its absorption is dependent on the presence of food in the stomach.
The term “D10” refers to the particle size of isotretinoin where 10% (w/v) of the particles have a size less than the defined D10 value; “D50” refers to the particle size of isotretinoin where 50% (w/v) of the particles have a size less than the defined D50 value; “D90” refers to the particle size of isotretinoin where 90% (w/v) of the particles have a size less than the defined D90 value.
“Defined D10 value/D50 value/D90 value” refers to the values defined in the embodiments.
Examples of suitable 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. The antioxidant is present in an amount of about 0.002% w/w to about 2% w/w of the total composition.
Examples of alkaline stabilizers include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate or bicarbonate, potassium carbonate or bicarbonate, lithium hydroxide, triethylamine, meglumine, methylamine, 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 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 size reduction of isotretinoin is achieved by wet milling the dispersion of isotretinoin in an oily vehicle using mechanical means such as a jet mill, ball mill, or media mills such as a sand mill, DYNO®-mill, or a bead mill. The grinding media in these mills can comprise spherical particles such as stainless steel beads or zirconium oxide balls.
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 1 (containing 16 mg of isotretinoin) was compared with the marketed formulation of isotretinoin (20 mg Absorica® capsules) for the release profile in an FDA recommended dissolution medium as given in the following tables:
Reference (R): Absorica® 20 mg capsules
Test (T): Isotretinoin 16 mg capsules (Example 1)
The pharmaceutical composition of Example 1 (containing 16 mg of isotretinoin) was compared with the marketed formulation of isotretinoin (20 mg Absorica® capsules) under fed conditions on 15 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.
Reference (R): Absorica® 20 mg capsules
Test (T): Isotretinoin 16 mg capsules (Example 1)
The pharmaceutical composition of Example 1 (16 mg Test capsule) was compared in fed and fasting conditions on 15 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 1) under fasting conditions
Test (B): Isotretinoin 16 mg capsules (Example 1) under fed conditions
| Number | Date | Country | Kind |
|---|---|---|---|
| 2827/DEL/2014 | Oct 2014 | IN | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/IB2015/054080 | May 2015 | US |
| Child | 14958467 | US |
