Title of Invention

STABLE SOLID ORAL PHARMACEUTICAL COMPOSITIONS OF ISOTRETINOIN AND PROCESS THEREOF

Abstract Disclosed herein are stable pharmaceutical compositions of drug with low water solubility. Specifically, the present invention discloses stable pharmaceutical compositions of Isotretinois and process threof.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"Stable solid oral pharmaceutical compositions of Isotretinoin and process
thereof
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LIMITED
(b)NATIONALITY: An Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West) Mumbai - 400 067, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical Field of the invention:
The present invention relates to stable solid oral pharmaceutical compositions of poorly water soluble drug Isotretinoin and process thereof. The present invention particularly relates stable compositions useful for the treatment of severe acne and skin disorders like hypertrophic lupus erythematosus and keratinization disorders.
Background and prior art:
Isotretinoin (13-cis retinoic acid or 13-cis vitamin A), its isomers and some of its analogs are widely known to have a therapeutic activity in the treatment of several severe skin disorders like cystic acne, hypertrophic lupus erythematosus, and keratinization disorders. Some evidences have also been brought about the activity of Isotretinoin in basal cell carcinoma and squamous cell carcinoma.
The cis-derivative of Isotretinoin is known to be less toxic than all trans vitamin A derivatives, side effects resulting from its use are headache, vomiting, irrigation of mucosa and liver toxicity, occur frequently.
In order to well understand the interest of this invention, it is important to briefly summarize the physicochemical pharmacokinetic properties. Isotretinoin is a reddish-orange powder. It is decomposed in presence of light and atmospheric oxygen. Isotretinoin is very poorly soluble in water which makes its bioavailability quite low after an oral intake (25% in fasting conditions and 40% in fed conditions). The maximum concentration (Cmax) is reached after 2-4 hours, while the (Cmax) of the active metabolite, 4-oxo- Isotretinoin is reached after 6 hours. The elimination half-life of Isotretinoin is of 7 to 37 hours while the half life (ti/2) of the active metabolite is of 11 to 50 hours. The steady-state concentrations of Isotretinoin are reached after 1 week of treatment.
There are various publications and/or patents about the pharmaceutical formulation of Isotretinoin are available. The drug is available in most markets in the form of a soft gelatin capsule containing a fatty liquid formulation of Isotretinoin.
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The U.S. Patent No. 4464394 describes the therapeutic use of Isotretinoin also describes briefly some compositions including it. The invention does not disclose a process for preparation of tablet formulation of Isotretinoin.
The EP 0184942 describes more specific compositions of Isotretinoin involving the use of one antioxidant, one chelating agent, one pharmaceutical carrier and one suspending agent. The composition contains not more than 22% wax. Higher wax content tends to diminish the bioavailability. The median particle size of the drug is also reduced to about 12(0. with a decade particle ratio of less than25(x. An increase in the bioavailability is of only about 1.6 -1. 9 times that of commercially available 'Accutane S' formulation.
The U.S. Patent No. 4545977 relates to improved compositions of Isotretinoin wherein taurine is associated with Isotretinoin to reduce the side effects thereof.
WO 00/25772 discloses the currently marketed as Accutane. RTM. Formulation of Isotretinoin has a mean particle size of lOOum and has a bioavailability of only about 20%. In this patent application the inventors describe a process for the micronization of Isotretinoin to a mean particle size in the range from about 5um about 30um suspended in an oily or other pharmaceutically acceptable vehicle.
US application No. 2004/0009225 Al relates to an oral semi-solid pharmaceutical composition of Isotretinoin containing at least two lipidic excipients, one of them being hydrophilic (i.e. having an HLB value superior or equal to 10), the other being an oily vehicle.
The U.S. Patent No. 5716928 describes a method for increasing bioavailability and for reducing inter and intra individual variability of an orally administered hydrophobic pharmaceutical compound, which comprises orally administering the pharmaceutical compound with an essential oil or essential oil component in an amount sufficient to provide greater bioavailability of the active ingredient.
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US Patent No. 6740337 B2, WO 01/95886 Al, 596/DEL/00 of Pant, Abha et.al discloses a bioavailable capsule formulation of 13-cis Vitamin A acid particles. The formulation comprising: (a) a medicament paste of 13-cis Vitamin A acid particles and a carrier, wherein 90% of said particles have a size of less than 240 .mu.m and 50% of said acid particles have a size of less than 118.mu.m, and wherein the surface area of said acid particles is between 0.05-0.3sq.m/g. (b) a suspending agent comprising more than 30 percent by weight of the formulation, and other pharmaceutically acceptable excipients. The suspending agent is a wax mixture comprising 1 part hydrogenated soyabean oil, 1.2 parts white wax and 4.2 parts hydrogenated vegetable oil.
The U.S. Patent No. 5993858 describes a self micro-emulsifying excipient formulation for increasing the bioavailability of a drug which includes an emulsion including oil or other lipid material, a surfactant and an hydrophilic co-surfactant.
In another PCT application WO 99/52504, a process for the manufacture of (sub) micron sized particles by dissolving in compressed gas and surfactants is described. Isotretinoin is listed as one of the several drugs whose particle size can be reduced by the process disclosed in this application. No specific data on the critical particle size or its effect on bioavailability has, however, been given in this application. Of course, if the dramatic increase in bioavailability as a function of its particle size was known, the specifics of the critical particle sizes and their effect on the increase in bioavailability would likely been described.
Isotretinoin decomposes in presence of light and atmospheric oxygen making it a highly unstable drug. Additionally Isotretinoin is very poorly soluble in water which makes its bioavailability very low after an oral intake. None of the above patents deal with a stable tablet composition of Isotretinoin with at least one antioxidant is present and a process for its preparation.
Object of the invention:
The main object of the present invention is to provide stable solid oral compositions of Isotretinoin and process for their preparation.
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Summary of the invention:
The present invention discloses stable pharmaceutical compositions of poorly water soluble drug and process thereof. Specifically, the present invention discloses stable, oral solid dosage pharmaceutical formulation of Isotretinoin and process for their preparation, wherein the solid dosage form is tablet or a capsule. Further, the said solid oral dosage compositions of Isotretinoin are used for the treatment of severe acne and skin disorders like hypertrophic lupus erythematosus and keratinization disorders.
Detailed description of the invention:
The present invention describes stable, oral solid dosage pharmaceutical compositions of Isotretinoin and process for preparation thereof. The process of preparation of the said composition comprises active ingredient dispersed in diluent and disintegrants with atleast one antioxidant.
The present invention further describes the process of preparation of solid oral dosage formulation, wherein the solid dosage form is tablet or a capsule.
One embodiment of the present invention describes pharmaceutically acceptable solid oral dosage composition; the said process comprises wet granulation method and then direct compression with or without coating.
In a further embodiment of this invention describes pharmaceutically acceptable solid oral dosage composition, the process comprises; wet granulation method with polymer matrix and then compression with or without coating.
In a further embodiment the invention describes pharmaceutically acceptable solid oral dosage composition of the present invention, the said process comprises; direct compression known in art with tablet-in-tablet approach with or without coating.
In a preferred embodiment the present invention describes lOmg Isotretinoin along with pharmaceutically acceptable excipients and antioxidant such as fumaric acid formulated
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as a stable tablet dosage form. The process comprises sifting Isotretinoin through mesh 60 and lactose monohydrate, cross carmellose sodium and fumaric acid through mesh 40 and then mixing geometrically. The blend is then mixed with lubricant which is sifted through mesh 40. The blend is then compressed using direct compression and coating said tablets using manual coater with inlet temperature 45 °C at optimum spray rate with 2% weight gain by coating. The preferred coating composition comprises dispersing hydroxy propyl methyl cellulose 5cps, purified talc, titanium dioxide, polyethylene glycol 6000 and iron oxide yellow in isopropyl alcohol. To this blend adding methylene chloride which is homogenized and filtered through mesh 100 nylon cloth.
As per the present invention, the carefully screened pharmaceutically acceptable excipients are selected from diluents, binders, disintegrants, emulsifiers, lubricants, glidants, flavors, alkalizing agents, preservatives, sweeteners, film formers, antioxidant and plasticizers either alone or in combination thereof.
Diluents are selected from the group consisting of microcrystalline cellulose, lactose monohydrate, maize starch and mannitol or their modified forms and preferably in the range of 5% to 95% of tablet weight.
Binders are selected from the group consisting of maize starch, polyvinylpyrrolidone with K value 30 and pregelatinzed starch. The said polyvinylpyrrolidone is in the range of 3% to 15% and maize starch is in the range of 2% tol0% wherein pregelatinzed starch is in the range of 5% to 20%
Disintegrants are selected from the group consisting of starch, derivative of starch, preferably sodium starch glycolate and crosscarmellose sodium. The preferred disintegrant is sodium starch glycolate, used in the range of l%-6% and crosscarmellose sodium, used in range of 2%-6%.
Lubricants and glidants are selected from the group consisting of magnesium stearate, preferably in the range of 0.25% to 5.0%, colloidal silicon dioxide is used in the range of 0.1% to 0.5% and purified talc used in range of 0.1% to 1.92%
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Film formers are selected from the group consisting of polymers such as hydroxy propyl methyl cellulose, in the range of 0.45% to 2.0% and ethyl cellulose, used in range of 0.1% to 3%
Plasticizers are selected from the group consisting of polyethylene glycol with molecular weight 400 and 6000 in the range of 5%-15%.
Surfactant or emulsifying agents are selected from the group consisting of sodium lauryl sulphate, is used in range of 0.5 to 2.5%.
Antioxidant selected from group consisting of butylated hydroxy toluene, used in range of 0.01% to 1%, butylated hydroxyanisole, used in range not exceeding 0.01%, sodium metabisulfate is used in range of 0.01% to 1%, fumaric acid is used in range not exceeding 0.37% and propyl gallate is used in range not exceeding 0.01%.
Colourants like sunset yellow lake, quinoline yellow lake and iron oxide yellow are used in range not exceeding 2% and an opacifier viz. titanium dioxide is used in range of 0.1% to2.7%.
Solvents selected from group containing isopropyl alcohol, methylene chloride and acetone are used in range of 0.5 to 2%.
Purified water used as a granulating fluid in the manufacture of granulating agent.
Other miscellaneous auxiliaries required for processing the product and maintaining stability can also used.
The in-vitro dissolution profile of the tablets of the present invention when tested in a USP type 2 (Paddle) apparatus at 50rpm in 900ml of 0.1 N sodium hydroxide solution, each film coated tablet containing Isotretinoin USP lOmg at 37°C shows not less than 70% dissolution in 30mins.
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The invention is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes the following examples and further can be modified and altered within the technical concept of the present invention.
Examples
Example 1:
Isotretinoin granules: Contains lOmg Isotretinoin along with the following excipients. Isotretinoin, microcrystalline cellulose, polyethylene glycol 6000 and maize starch were mixed geometrically. This blend was granulated with mixture of isopropyl alcohol, butylated hydroxy toluene, and polyvinylpyrrolidone-30 using wet granulation. Granules were milled through mesh 10. Granules are dried at 50°C in oven. Dried granules were sifted through mesh 20. It was then lubricated with cross carmellose sodium and magnesium stearate. This bend is then compressed using (punch size 6.5mm).

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 10.09%
2 Microcrystalline cellulose 40%
3 Butylated hydroxy toluene 0.4%
4 Polyvinylpyrrolidone 30 10%
5 Polyethylene glycol 6000 10%
6 Cross carmellose sodium 10%
7 Maize starch 15%
8 Magnesium stearate 10%
9 Isopropyl alcohol qs
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Example 2:
Isotretinoin granules: Contains lOmg Isotretinoin along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 10.09%
2 Hydroxypropyl methyl cellulose 50cps 30%
3 Microcrystalline cellulose 0.09%
4 Butylated hydroxy toluene 0.40%
5 Polyethylene glycol 6000 25%
6 Manitol 5%
7 Croscarmellose sodium 8%
8 Maize starch 5%
9 Magnesium stearate 4%
10 Isopropyl alcohol qs
11 Purified water qs
Isotretinoin is sifted through mesh 60 and microcrystalline cellulose, manitol, maize starch and polyethylene glycol 6000 were sifted through mesh 40 and then mixed geometrically. This blend was granulated with mixture of purified water, butylated hydroxy toluene and hydroxypropyl methyl cellulose 50cps using wet granulation. These granules are compressed by direct compression.
Example 3:
Isotretinoin granules: Contains lOmg Isotretinoin along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 10%
2 Mannitol 75.5%
3 Polyethylene glycol 6000 5%
4 Sodium lauryl sulphate 1%
5 Cross carmellose sodium 3%
6 Hydroxypropyl methyl cellulose 50cps 3.09%
7 Butylated hydroxy toluene 0.02%
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8 colloidal silicon dioxide 0.6%
9 sodium starch glycolate 2%
10 Purified water qs
11 Purified talc 3%
Isotretinoin, manitol, sodium lauryl sulphate, polyethylene glycol 400 and colloidal silicon dioxide were mixed geometrically after sifting through mesh 40. Hydroxypropyl methyl cellulose 50cps, sodium starch glycolate and butylated hydroxy toluene disperse in purified water and stirred continuously. This blend was granulated with above mixture using wet granulation. Granules are dried at 40°C in tray drier. Dried granules were sifted through mesh 20. It was then lubricated with cross carmellose sodium and magnesium stearate which were sifted through mesh 40. These granules then compress by direct compression.
Coating:
The coating solution has following composition:

1 Hydroxypropyl methyl cellulose 50cps 8.2%
2 Ethyl cellulose 0.16%
3 Polyethylene glycol 400 0.6%
4 Sunset yellow lake 0.2%
5 quinoline yellow lake 0.7%
6 Titanium dioxide 1.5%
7 Isopropyl alcohol qs
8 Methylene chloride qs
There is a 1.64 % weight gain by coating.
Preparation of coating solution:
Disperse hydroxy propyl methyl cellulose 5cps, titanium dioxide, polyethylene glycol 400, ethyl cellulose, sunset yellow lake, quinoline yellow lake and titanium dioxide in
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isopropyl alcohol. To this blend add methylene chloride and homogenized for 30min. After filtering this blend through mesh 100 nylon cloth, used as coating solution. Process of coating: The coating was done using manual coater with inlet temperature 45°C at optimum spray rate.
Example 4:
Isotretinoin granules: Contains lOmg Isotretinoin along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 10.9%
2 Manitol 69.5%
3 Sodium lauryl sulphate 1.1%
4 Cross carmellose sodium 3%
5 Hydroxypropyl methyl cellulose 50cps 2%
6 Butylated hydroxy toluene 0.01%
7 Butylated hydroxyanisole 0.01%
8 Methylene chloride qs
9 Acetone qs
10 Isopropyl alcohol qs
11 Colloidal silicon dioxide 0.5%
12 Sodium starch glycolate 3.1%
13 Pregelatinized starch 10.1%
14 Magnesium stearate 1.1%
Isotretinoin, manitol, sodium lauryl Sulphate and colloidal silicon dioxide were mixed geometrically after sifting through mesh 40. Hydroxypropyl methyl cellulose 50cps, sodium starch glycolate, pregelatinized starch, butylated hydroxy toluene and butylated hydroxyanisole disperse in isopropyl alcohol, acetone and methylene chloride, this blend was granulated with above mixture. Dried granules were sifted through mesh 20. It was then lubricated with cross carmellose sodium and magnesium stearate which were sifted through mesh 40. These granules then compressed.
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Example 5:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 Lactose monohydrate 86.16%
3 Cross carmellose sodium 4.83%
4 Sodium metabisulfate 0.69%
5 Magnesium stearate 1.03%
Isotretinoin and lactose monohydrate were mixed geometrically for 10 min. after sifting through mesh 40. Cross carmellose sodium and sodium metabisulfate sifting through mesh 40 and geometrically mixed with above mixture. This blend is then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. These blends then compressed using direct compression
Example 6:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 Lactose monohydrate 86.48%
3 Cross carmellose sodium 4.83%
4 Fumaric acid 0.37%
5 Magnesium stearate 1.03%
Isotretinoin sifted through mesh 60 and lactose monohydrate, cross carmellose sodium and fumaric acid were sifted through mesh 40 and then mixed geometrically for 10 min. This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. These blends then pressed using direct compression.
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Example 7:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients:

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 Lactose monohydrate 86.84%
3 Cross carmellose sodium 4.83%
4 Propyl gallate 0.01%
5 Magnesium stearate 1.03%
Isotretinoin sifted through mesh 60 and lactose monohydrate, cross carmellose sodium and propyl gallate were sifted through mesh 40 and then mixed geometrically for 10 min. This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. These blends then compressed using direct compression.
Example 8:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 Lactose monohydrate 86.16%
3 Cross carmellose sodium 4.83%
4 Sodium metabisulfate 0.69%
5 Magnesium stearate 1.03%
Isotretinoin and lactose monohydrate were mixed geometrically for 10 min. after sifting through mesh 40. Cross carmellose sodium and sodium metabisulfate sifting through mesh 40 and geometrically mixed with above mixture. This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. These blends then compressed using direct compression.
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Example 9:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 lactose monohydrate 86.16%
3 crosscarmellose sodium 4.83%
4 sodium metabisulphate 0.69%
5 magnesium stearate 1.03%
Isotretinoin and lactose monohydrate were mixed geometrically for 10 min. after sifting through mesh 40. Cross carmellose sodium and sodium metabisulfate sifting through mesh 40 and geometrically mixed with above mixture. This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. This blend then compressed using direct compression.
Coating:
The coating solution has following composition

Sr. No. Ingredient Qty % w/w of total weight
1 hydroxy propyl methyl cellulose 5cps 1.21%
2 purified talc 0.51%
3 titanium dioxide 0.22%
4 Polyethylene glycol 6000 0.10%
5 iron oxide yellow 0.04%
6 * isopropyl alcohol qs
7 methylene chloride qs
There is a 2% weight gain by coating.
Preparation of coating solution:
Disperse hydroxy propyl methyl cellulose 5cps, purified talc, titanium dioxide, polyethylene glycol 6000 and iron oxide yellow in isopropyl alcohol. To this blend add
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methylene chloride and homogenized for 30min. After filtering this blend through mesh 100 nylon cloth, used as coating solution. The coating is done using manual coater with inlet temperature 45°C at optimum spray rate.
Example 10:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 lactose monohydrate 86.48%
3 crosscarmellose sodium 4.83%
4 fumaric acid 0.37%
5 magnesium stearate 1.03%
Isotretinoin sifted through mesh 60 and lactose monohydrate, cross carmellose sodium and fumaric acid were sifted through mesh 40 and then mixed geometrically for 10 min. This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. The blend is then compressed using direct compression.
Coating:
The coating solution has following composition

Sr. No. Ingredient Qty % w/w of total weight
1 hydroxy propyl methyl cellulose 5cps 1.21%
2 purified talc 0.51%
3 titanium dioxide 0.22%
4 Polyethylene glycol 6000 0.10%
5 iron oxide yellow 0.04%
6 isopropyl alcohol qs
7 methylene chloride qs
There is a 2% weight gain by coating.
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Preparation of coating solution:
Disperse hydroxy propyl methyl cellulose 5cps, purified talc, titanium dioxide, polyethylene glycol 6000 and iron oxide yellow in isopropyl alcohol. To this blend add methylene chloride and homogenized for 30min. After filtering this blend through mesh 100 nylon cloth, used as coating solution. The coating is done using manual coater with inlet temperature 45°C at optimum spray rate.
Example 11:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 lactose monohydrate 86.83%
3 Cross carmellose sodium 4.83%
4 Propyl gallate 0.0103%
5 magnesium stearate 1.03%
Isotretinoin sifted through mesh 60 and lactose monohydrate, cross carmellose sodium and propyl gallate were sifted through mesh 40 and then mixed geometrically for 10 min. This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. The blend is then compressed using direct compression.
Coating:
The coating solution has following composition

Sr. No. Ingredient Qty % w/w of total weight
1 hydroxy propyl methyl cellulose 5cps 1.21%
2 purified talc 0.51%
3 titanium dioxide 0.22%
4 Polyethylene glycol 6000 0.10%
5 iron oxide yellow 0.04%
6 isopropyl alcohol qs
7 methylene chloride qs
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There is a 2% weight gain by coating. Preparation of coating solution:
Disperse hydroxy propyl methyl cellulose 5cps, purified talc, titanium dioxide, polyethylene glycol 6000 and iron oxide yellow in isopropyl alcohol. To this blend add methylene chloride and homogenized for 30min. After filtering this blend through mesh 100 nylon cloth, used as coating solution. The coating is done using manual coater with inlet temperature 45°C at optimum spray rate.
Example 12:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 lactose monohydrate 86.83%
3 crosscarmellose sodium 4.83%
4 Propyl gallate 0.0103%
5 magnesium stearate 1.03%
Isotretinoin sifted through mesh 60 and lactose monohydrate, cross carmellose sodium
and propyl gallate were sifted through mesh 40 and then mixed geometrically for 10 min.
This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh
40. The blend is then compressed using direct compression.
Coating:
The coating solution has following composition:

Sr. No. Ingredient Qty % w/w of total weight
1 hydroxy propyl methyl cellulose 5cps 1.75%
2 purified talc 0.74%
3 titanium dioxide 0.32%
4 Polyethylene glycol 6000 0.14%
5 iron oxide yellow 0.06%
6 isopropyl alcohol qs
7 methylene chloride qs
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There is a 2% weight gain by coating. Preparation of coating solution:
Disperse hydroxy propyl methyl cellulose 5cps, purified talc, titanium dioxide, polyethylene glycol 6000 and iron oxide yellow in isopropyl alcohol. To this blend add methylene chloride and homogenized for 30min. After filtering this blend through mesh 100 nylon cloth, used as coating solution. The coating is done using manual coater with inlet temperature 45°C at optimum spray rate.
Tablet- in tablet approach:

Sr. No. Ingredient Qty % w/w of total weight
1 lactose monohydrate 0.04%
2. magnesium stearate 0.125%
(Lactose monohydrate and magnesium stearate sifted through mesh size 40 and were dry
mixed. The product is prepared by incorporating the coated tablet and the uncoated tablet
of Isotretinoin into the core of inactive blend to form a tablet - in - tablet using a suitable
tablet press.)
The above mentioned coated or uncoated tablets pressed using compression with punch
size 7mm s/c were used as inner core or inner tablets.
Lactose monohydrate and magnesium stearate sifted through mesh size 40 and were dry
mixed. This inactive blend used as outer core or tablet with punch size 9mm s/c and
compressed using compression.
Example 13:
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 lactose monohydrate 86.48%
3 crosscarmellose sodium 4.83%
4 Fumaric acid 0.37%
5 magnesium stearate 1.03%
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Isotretinoin sifted through mesh 60 and lactose monohydrate, cross carmellose sodium and fumaric acid were sifted through mesh 40 and then mixed geometrically for 10 min. This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. The blend is then compressed using direct compression.
Coating
The coating solution has following composition:

Sr. No. Ingredient Qty % w/w of total weight
1 hydroxy propyl methyl cellulose 5cps 1.75%
2 purified talc 0.74%
3 titanium dioxide 0.32%
4 Polyethylene glycol 6000 0.14%
5 iron oxide yellow 0.06%
6 isopropyl alcohol qs
7 methylene chloride qs
There is a 2% weight gain by coating.
Preparation of coating solution:
Disperse hydroxy propyl methyl cellulose 5cps, purified talc, titanium dioxide, polyethylene glycol 6000 and iron oxide yellow in isopropyl alcohol. To this blend add methylene chloride and homogenized for 30min. After filtering this blend through mesh 100 nylon cloth, used as coating solution. The coating is done using manual coater with inlet temperature 45°C at optimum spray rate.
Tablet- in-tablet approach:

Sr. No. Ingredient Qty % w/w of total weight
1 lactose monohydrate 68.5%
2. magnesium stearate 0.25%
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The above mentioned coated or uncoated tablets pressed using compression method known in art with punch size 7mm s/c were used as inner core or inner tablets. Lactose monohydrate and magnesium stearate sifted through mesh size 40 and were dry mixed. This inactive blend used as outer core or tablet with punch size 9mm s/c and compressed using compression.
Example 14
Isotretinoin: Contains lOmg Isotretinoin along with the following excipients.

Sr. No. Ingredient Qty % w/w of total weight
1 Isotretinoin 7.29%
2 lactose monohydrate 86.48%
3 crosscarmellose sodium 4.83%
4 fumaric acid 0.37%
5 magnesium stearate 1.03%
Isotretinoin sifted through mesh 60 and lactose monohydrate, cross carmellose sodium and fumaric acid were sifted through mesh 40 and then mixed geometrically for 10 min. This blend then mixed with magnesium stearate for 2 min. which was sifted through mesh 40. The blend is then compressed using direct compression.
Coating:
The coating solution has following composition

Sr. No. Ingredient Qty % w/w of total weight
1 hydroxy propyl methyl cellulose 5cps 1.75%
2 purified talc 0.74%
3 titanium dioxide 0.32%
4 Polyethylene glycol 6000 0.14%
5 iron oxide yellow 0.06%
6 isopropyl alcohol qs
7 methylene chloride qs
There is a 2% weight gain by coating.
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Preparation of coating solution:
Disperse hydroxy propyl methyl cellulose 5cps, purified talc, titanium dioxide, polyethylene glycol 6000 and iron oxide yellow in isopropyl alcohol. To this blend add methylene chloride and homogenized for 30min. After filtering this blend through mesh 100 nylon cloth, used as coating solution. The coating is done using manual coater with inlet temperature 45°C at optimum spray rate.
The present invention provides a stable formulation shown by the following stability and dissolution data. The sample comprising Isotretinoin lOmg, each film coated tablet contains Isotretinoin USP lOmg is stored at: 30 ± 2°C & 65 ± 5% RH.
The in-vitro dissolution profile when tested in a USP type 2 (Paddle) apparatus at 50rpm in 900ml of 0.1 N sodium hydroxide solution, each film coated tablet contains Isotretinoin USP lOmg and at 37°C is not less than 70%.

TEST SPECIFICATION BATCH NO. INITIAL AFTER 03 MONTHS AFTER 06 MONTHS
Appearance Yellow coloured, circular, biconvex, both side plain tablets IN/IST (10)22/06 Complies Complies Complies
Dissolution Profile Isotretinoin 30min NLT 70% IN/IST (10)22/06 99.48-107.79% 77.59 -77.95% 79.60-79.72%
Assay Isotretinoin: 95.0%-110.0% IN/IST (10122/06 105.95 101.76 97.47
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We Claim;
1. Stable pharmaceutical solid oral compositions of 13-cis retinoic acid or 13-cis vitamin or Isotretinoin and atleast one antioxidant formulated with pharmaceutically acceptable excipients and process of preparation thereof, wherein the said 13-cis vitamin or Isotretinoin is in the range of lOmg to 40mg and the said antioxidant preferably Fumaric acid is in the range of about 0.01 % to about 0.4%.
2. Stable pharmaceutical compositions as claimed in claim 1, wherein the amount of said 13-cis vitamin or Isotretinoin is preferably lOmg.
3. Stable pharmaceutical compositions as claimed in claim 1, wherein the compositions are tablet or capsule, preferably tablet and optionally film coated.
4. Stable pharmaceutical compositions as claimed in claim 1, wherein the diluents are selected from the group consisting lactose monohydrate or their modified forms, used in the range of 5% to 95% of tablet weight.
5. Stable pharmaceutical compositions as claimed in claim 1, wherein disintegrants are selected from the group consisting of starch, derivative of starch, preferably cross carmellose sodium preferably cross carmellose sodium, used in range of 2%-6%.
6. Stable pharmaceutical compositions as claimed in claim 1, wherein lubricants and glidants are selected from the group consisting of magnesium stearate, used in the range of 0.25% to 5.0%, and purified talc used in range of 0.1% to 1.92%.
7. Stable pharmaceutical compositions as claimed in claim 1, wherein film formers are selected from the group consisting of polymers such as hydroxy propyl methyl cellulose, used in the range of 0.45% to 2.0%.
8. Stable pharmaceutical compositions as claimed in claim 1, wherein plasticizers are selected from the group consisting of polyethylene glycol with molecular weight 6000 in the range of 5% to 15%.
9. Stable pharmaceutical compositions as claimed in claim 1, wherein colorant such as iron oxide yellow is used in range not exceeding 2% and opacifier such as titanium dioxide is used in range of 0.1% to 2.7%.
22

10. Stable pharmaceutical compositions as claimed in claim 1, wherein solvents selected from group containing isopropyl alcohol, methylene chloride is used in rangeof0.5to2%.
11. Stable pharmaceutical compositions as claimed in claim 1, wherein the process comprises the following step:
a. Sifting Isotretinoin through mesh 60, and lactose monohydrate,
cross carmellose sodium and fumaric acid through mesh 40,
b. mixing geometrically for 10 min and blending the above mixture
with magnesium stearate for 2 min. ( previously sifted through
mesh 40),
c. directly compressing the above blend into tablets (dry granulation)
and
d. optionally coating with hydroxy propyl methyl cellulose alongwith
pharmaceutically acceptable excipients, using manual coater with
inlet temperature 45°C at optimum spray rate.
12. Stable pharmaceutical compositions as claimed in any of the preceding claims 1 to
11, their process of preparation as substantially described herein with reference to
the foregoing examples 1 to 14.

Dr. Gopakumar G. Nair Agent for the Applicant
Dated this 5th day of September 2007
23

Abstract:
Disclosed herein are stable pharmaceutical compositions of drug with low water solubility. Specifically, the present invention discloses stable pharmaceutical compositions of Isotretinoin and process thereof.
24

Documents:

1698-MUM-2007-ABSTRACT(GRANTED)-(10-10-2011).pdf

1698-mum-2007-abstract.doc

1698-mum-2007-abstract.pdf

1698-MUM-2007-CANCELLED PAGES(15-9-2011).pdf

1698-MUM-2007-CLAIMS(AMENDED)-(15-9-2011).pdf

1698-MUM-2007-CLAIMS(AMENDED)-(26-3-2010).pdf

1698-MUM-2007-CLAIMS(GRANTED)-(10-10-2011).pdf

1698-MUM-2007-CLAIMS(MARKED COPY)-(15-9-2011).pdf

1698-MUM-2007-CLAIMS(MARKED COPY)-(26-3-2010).pdf

1698-mum-2007-claims.doc

1698-mum-2007-claims.pdf

1698-MUM-2007-CORRESPONDENCE(26-2-2008).pdf

1698-MUM-2007-CORRESPONDENCE(5-10-2007).pdf

1698-MUM-2007-CORRESPONDENCE(IPO)-(10-10-2011).pdf

1698-mum-2007-correspondence-received.pdf

1698-mum-2007-description (complete).pdf

1698-MUM-2007-DESCRIPTION(GRANTED)-(10-10-2011).pdf

1698-MUM-2007-FORM 1(5-10-2007).pdf

1698-MUM-2007-FORM 1(5-9-2007).pdf

1698-mum-2007-form 18(26-2-2008).pdf

1698-MUM-2007-FORM 2(GRANTED)-(10-10-2011).pdf

1698-MUM-2007-FORM 2(TITLE PAGE)-(5-9-2007).pdf

1698-MUM-2007-FORM 2(TITLE PAGE)-(GRANTED)-(10-10-2011).pdf

1698-MUM-2007-FORM 3(26-3-2010).pdf

1698-MUM-2007-FORM 3(5-9-2007).pdf

1698-mum-2007-form-1.pdf

1698-mum-2007-form-2.doc

1698-mum-2007-form-2.pdf

1698-mum-2007-form-26.pdf

1698-mum-2007-form-3.pdf

1698-MUM-2007-REPLY TO EXAMINATION REPORT(26-3-2010).pdf

1698-MUM-2007-REPLY TO HEARING(15-9-2011).pdf


Patent Number 249181
Indian Patent Application Number 1698/MUM/2007
PG Journal Number 42/2011
Publication Date 21-Oct-2011
Grant Date 10-Oct-2011
Date of Filing 05-Sep-2007
Name of Patentee IPCA LABORATORIES LIMITED
Applicant Address 48, KANDIVLI INDUSTRIAL ESTATE, CHARKOP, KANDIVLI(WEST), MUMBAI-400607,
Inventors:
# Inventor's Name Inventor's Address
1 GODHA PREMCHAND HOUSE NO.20, RUIA PARK, JUHU, MUMBAI-400049
2 BANSAL YATISH KUMAR FLAT NO.5, SIRAS VILLA, PLOT NO.40, SAI BABA PARK, EVERSHINE NAGAR, MALAD (W), MUMBAI-400064
3 SENGUPTA SUBHRANGSHU B-401, GANGA VASANT NAGAR, THAKUR VILLAGE, KANDIVLI(E), MUMBAI-400101
4 KADAM SONAL 1, NILKANTHA SADAN, PERU BAUG, AAREY ROAD, GOREGAON(E), MUMBAI-400063
PCT International Classification Number A61K9/48,A61K9/107,A61K31/203
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA