DESC:FORM 2

THE PATENTS ACT,
(39 OF 1970)
THE PATENT RULES, 2003.

COMPLETE SPECIFICATION
(SECTION 10 AND RULE 13)

TRANSDERMAL COMPOSITION COMPRISING ONDANSETRON

INM Technologies Private Limited
(Innovative Nano & Micro Technologies Private Limited)
An Indian Company having its address at
#4 T.M. Industrial Estate, 12th KM, Mysore Road
Bangalore-59, Karnataka State, India

&
Shilpa Medicare Limited
An Indian Company having its address at
#12-6-214/A1,
Hyderabad Road,
Raichur – 584 135,
Karnataka, India.

The following specification particularly describes the invention and the manner in which it is performed.

FIELD OF THE INVENTION

The present invention relates to a transdermal composition comprising ondansetron or a pharmaceutically acceptable salt thereof and a preparation containing the same which is capable of delivering the ondansetron efficiently over a period of a day or more without skin irritation.

BACKGROUND OF THE INVENTION

Ondansetron is a selective antagonist of 5-hydroxytryptamine (5HT, or serotonin) at 5-HT3 receptors. Ondansetron has been described in U.S. Pat. No. 4,695,578 and U.S. Pat. No. 4,753,789.

Ondansetron is highly effective for the treatment and prevention of nausea and/or vomiting. Ondansetron is currently available as oral release dosage forms (conventional tablet, orally disintegrating tablet or orally disintegrating film/strips). The oral administration of ondansetron is not adequate for treating serious vomiting. Intravenous and injection dosage form of ondansetron is painful is painful and limited to a hospital practice. Therefore, there existed a need to develop an improved method for administering ondansetron for treatment of vomiting.

Therefore, the inventors of EP Publication No. 1150675B1 developed a transdermal patch comprising a hydrophilic organic solvent, a mixture of N, N,-diethyl-m-toluamide, glycerol monolaureate as skin penetration enhancer, water and antivomiting agent or pharmaceutically acceptable salts thereof. The antivomiting agents as disclosed in the EP ‘675 are selected from group consisting of tropisetron, ondansetron, granisetron and pharmaceutically acceptable salts thereof. The percentage amount of ondansetron base present in transdermal patch composition as disclosed in the EP ‘675 patent (Table 1) is about 3% to 6% based on total weight of the transdermal patch composition.

Gwak etal., (Drug Development and Industrial pharmacy, Vol.30, No.2, pp.187-194,2004) discloses the transdermal patches comprising ondansetron or pharmaceutically acceptable salts thereof, penetration enhancers selected from oleic acid, linoleic acid, or oleyl alcohol with PG, or PGMC-DGME (60:40) cosolvent or combinations thereof.

US Patent No. 9,186,352 discloses the transdermal patch comprising the ondansetron, a first fatty acid or derivative or congener thereof, a second fatty acid, or derivative thereof, and ondansetron as a therapeutic agent, wherein the first therapeutic agent comprises about 14 or more carbon atoms and the second fatty acid comprises about 12 or less carbon atoms. The amount of the ondansetron present in the composition as disclosed in US ‘352 Patent is about 0.3% to about 1% of the composition as disclosed in Composition 6 to 11 of Example-7.

However, there exists a need to develop a transdermal composition system comprising ondansetron or a pharmaceutically acceptable salt thereof and a preparation containing the same which is capable of delivering the ondansetron efficiently over a period of a day or more without skin irritation.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition for transdermal administration of ondansetron or a pharmaceutically acceptable salt thereof which is capable of delivering ondansetron efficiently to the blood over an extended period without skin irritation.

The present invention further provides a transdermal composition comprising (a) a matrix containing (i) hydrophilic organic solvent, and (ii) a fatty acid and (b) ondansetron or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention provides a transdermal composition comprising (a) a matrix containing (i) hydrophilic organic solvent selected from the group consisting of benzyl alcohol and/or diethylene glycol monoethyl ether or combinations thereof, and (ii) a fatty acid selected from the group consisting of oleic acid and/or undecylenic acid or combinations thereof; and (b) ondansetron or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention provides a transdermal composition comprising (a) a matrix consisting of (i) hydrophilic organic solvent, wherein hydrophilic organic solvent is a mixture of benzyl alcohol and diethylene glycol monoethyl ether, and (ii) a fatty acid, wherein the fatty acid is oleic acid; and (b) ondansetron or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention provides a transdermal composition comprising (a) a matrix consisting of (i) hydrophilic organic solvent, wherein hydrophilic organic solvent is diethylene glycol monoethyl ether, and (ii) a fatty acid, wherein the fatty acid is a mixture of oleic acid and undecylenic acid; and (b) ondansetron or a pharmaceutically acceptable salt thereof.

BRIEF DESCRIPTION OF DRAWINGS

Fig.1 illustrates average cumulative amount of ondansetron base that is permeated through pork ear skin over a period of 24 hours with the composition as disclosed in comparative example A.

Fig.2 illustrates average cumulative amount of ondansetron base that is permeated through pork ear skin over a period of 24 hours with the composition of present invention as disclosed in Example-1.

Fig.3. illustrates average cumulative amount of ondansetron base that is permeated through pork ear skin over a period of 24 hours with the composition of present invention as disclosed in Example-2.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition for transdermal administration of ondansetron or a pharmaceutically acceptable salt thereof which is capable of delivering ondansetron efficiently to the blood over an extended period without skin irritation.

The present invention generally provides a transdermal composition comprising (a) a matrix containing (i) hydrophilic organic solvent, and (ii) a fatty acid; and (b) ondansetron or a pharmaceutically acceptable salt thereof.

In the embodiments of the present invention, ondansetron base is preferably used for the preparation of the pharmaceutical matrix composition for transdermal administration. The ondansetron base may be used in an amount ranging from 1% to 15% by weight, preferably from 5% to 10% by weight, based on the weight of the matrix.

The hydrophilic organic solvent which may be used in the present invention is a low molecular weight alcohol such as ethanol, isopropanol, butanol, benzyl alcohol, propylene glycol, glycerin, polyethylene glycol having a molecular weight of 600 or less, diethylene glycol monoethyl ether, triacetin, N-methylpyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, decylmethyl sulfoxide, dioxane, lactone and a mixture thereof. Among these, preferred are a mixture of benzyl alcohol and a mixture of benzyl alcohol and diethylene glycol monoethyl ether. The hydrophilic organic solvent may be used in an amount ranging from 15 to 70 % by weight, preferably from 25 to 60 % by weight, based on the weight of the matrix. In one embodiment of the invention the use of a mixture of 25 to 30 % by weight of benzyl alcohol and 25 to 30 % by weight of diethylene glycol monoethyl ether based on the weight of the matrix is still more preferred.

In embodiments of the present invention the term “fatty acid” has its ordinary meaning as would be understood by a person of ordinary skill in the art and includes a molecule having a carboxylic group and a hydrocarbon chain. Descriptions of the number of carbon atoms in a fatty acid herein refer to the number of carbon atoms in the hydrocarbon chain of the fatty acid, irrespective of whether the hydrocarbon chain is straight or branched.

In embodiments of the invention the “fatty acid” includes saturated fatty acids, which do not contain any double or triple bonds in the hydrocarbon chain. Saturated fatty acids include, but are not limited to propionic acid (C3) (by way of example, C3 indicates propionic acid has 3 carbon atoms in its hydrocarbon chain; the number of carbon atoms in the hydrocarbon chain of other example fatty acids is denoted in analogous fashion herein), butyric acid (C4), valeric acid (C5), caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16), margaric acid (C17), stearic acid (C18), isostearic acid (C18), nonadecylic acid (C19), arachidic acid (C20), heneicosylic acid (C21), behenic acid (C22), tricosylic acid (C23), lignoceric acid (C24), pentacosylic acid (C25), cerotic acid (C26), heptacosylic acid (C27), montanic acid (C28), nonacocylic acid (C29), melissic acid (C30), henatriacontylic acid (C31), lacceroic acid (C32), psyllic acid (C33), geddic acid (C34), ceroplastic acid (C35) and hexatriacontylic acid (C36).

In further embodiments of the invention, the term “fatty acid” also includes monounsaturated fatty acids, which contain one double or triple bond in the hydrocarbon chain, and polyunsaturated fatty acids, which contain more than one double and/or triple bond in the hydrocarbon chain. Such acids include, but are not limited to the omega 3, omega 6, omega 9 fatty acids, other fatty acids such as myristoleic and palmitoleic acid and conjugated fatty acids. Examples of monounsaturated and polyunsaturated fatty acids include but are not limited to, (a) omega 3 fatty acids, such as hexadecatrienoic acid (C16:3); (by way of example, C16:3 indicates hexadecatrienoic acid has 16 carbon atoms in its hydrocarbon chain and 3 double bonds; the number of carbon atoms and double bonds in the hydrocarbon chain of other example unsaturated fatty acids is denoted in analogous fashion herein), alpha linolenic acid (C18:3) and eicosapentanoic acid (20:5), (b) omega 6 fatty acids, such as linoleic acid (18:2), docosadienoic acid (C22:2), arachidonic acid (C20:4) and tetracosatetraenoic acid (C24:5), (c) omega 9 fatty acids, such as oleic acid (C18:1), eicosenoic acid (C20:1) and nevronic acid (C24:1), and (d) conjugated fatty acids such as rumenic acid (C18:2), eleostatic acid (C18:3), and rumelenic acid (C18:3).

In embodiments of the invention the saturated fatty acid may be used in an amount ranging from 15 to 80 % by weight, preferably from 30 to 70 % by weight, based on the weight of the matrix. In one embodiment of the invention the use of a mixture of 30 to 40 % by weight of Oleic acid and 25 to 30 % by weight of undecylenic acid based on the weight of the matrix is still more preferred.

The composition of the present invention may further comprise a thickener. Representative thickeners include Representative thickeners include polyvinylpyrrolidone, colloidal silicon dioxide, polyvinyl alcohol, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbopol and polyoxyethylene-polyoxypropylene block copolymer and preferred is hydroxypropylcellulose.

The composition of the present invention may be formulated into a preparation for the transdermal administration, e.g., a patch. Examples of the patch which may be used in the present invention include a reservoir patch and a monolithic matrix patch.

The present invention also encompasses methods of treating a patient in need thereof by administering to a patient with the present inventive composition for the treatment of vomiting.

Examples

The following examples, while illustrative individual embodiments are not intended to limit the scope of the described invention, and the reader should not interpret them in this way.

Comparative Example A: Preparation of Transdermal Composition

48.5% of diethylene glycol monoethyl ether and 48.5% of oleic acid were mixed and then 3% of ondansetron base was added there to obtain a transdermal composition.

Example 1: Preparation of Transdermal Composition according to the invention.

30 to 40 % of oleic acid, 25 to 30% of diethylene glycol monoethyl ether and 25 to 30% of benzyl alcohol were mixed and then 5 to 10% of ondansetron base were added there to obtain a transdermal composition.

Example 2: Preparation of Transdermal Composition according to the invention.

25 to 35 % of oleic acid, 25 to 30% of diethylene glycol monoethyl ether and 25 to 30% of undecylenic acid were mixed and then 5 to 10% of ondansetron base were added there to obtain a transdermal composition.

Example 3: Skin Permeation studies using the transdermal compositions of Comparative Example A, Example 1 and Example 2.

Skin permeation studies were performed for the transdermal compositions of Comparative Example A, Example 1 and Example 2 using Franz diffusion cells for the duration of the experiment. Pork ear skin was used and all tests were performed in triplicate. The results for cumulative amount permeated through the pork ear skin was calculated for a period of 24 hours, and are shown in Table 1 below:

Table 1

Cumulative amount of Ondansetron Base permeated through Pork ear Skin µg/cm2
Time Comparative Example A Example 1 Example 2
1 0.5 3.5 2.0
2 1.8 10.9 8.9
3 4.8 19.0 18.4
6 20.9 47.8 49.4
9 36.5 76.6 78.7
12 48.5 99.9 101.2
18 62.2 131.3 128.5
24 73.4 153.8 147.3

Example 4: Patch Preparation.

Patches incorporating the compositions of the invention can be readily prepared using methods known to those in the art. For example, the transdermal composition of the present invention comprising ondansetron base, hydrophilic organic solvent and fatty acid, are added to a pressure sensitive adhesive solution such as, for example, Durotak™ 87-2677 (Henkel Corporation, Rocky Hill, Conn.).

The pressure sensitive adhesive (PSA) mass is spread onto, for example, an aluminum polyester backing film to the desired thickness. One suitable backing is Scotchpak™ 9736 (3M, St. Paul, Minn.). The thickness of the mass that will be applied to the backing film can be controlled using, for example, a pilot coater such as those available from Werner Mathis USA (Concord, N.C.). The coated product is allowed to dry at, for example, 75° C. all volatile solvents are volatilized away, approximately 15 to 20 minutes. A release liner such as Scotchpak™ 9741 (3M, St. Paul, Minn.) is then applied on the PSA side of the coated mass. The resulting product is cut into individual patches of the desired size and pouched using a pouching film, for example Barex™ containing film T-1601 (American Packaging Corporation, Rochester, N.Y.).

The disclosures of each patent, patent application, and publication cited or described in this document are hereby incorporated herein by reference, in its entirety.

Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention.
,CLAIMS:We Claim

1. A transdermal composition comprising (a) a matrix containing (i) hydrophilic organic solvent, and (ii) a fatty acid and (b) ondansetron or a pharmaceutically acceptable salt thereof.

2. The transdermal composition according to claim 1, wherein ondansetron is used in an amount from about 5% to about 10% by weight, based on the weight of the matrix.

3. The transdermal composition according to claim 1, wherein hydrophilic organic solvent is a mixture of benzyl alcohol and diethylene glycol monoethyl ether.

4. The transdermal composition according to claim 2, wherein benzyl alcohol is used in an amount from about 25% to about 30% by weight, based on the weight of the matrix.

5. The transdermal composition according to claim 2, wherein diethylene glycol monoethyl ether is used in an amount from about 25% to about 30%, based on the weight of the matrix.

6. The transdermal composition according to claim 1, wherein fatty acid is oleic acid.

7. The transdermal composition according to claim 6, wherein oleic acid is used in an amount from about 30% to about 40%, based on the weight of the matrix.

8. A transdermal composition comprising (a) a matrix consisting of (i) hydrophilic organic solvent, wherein hydrophilic organic solvent is a mixture of benzyl alcohol and diethylene glycol monoethyl ether, and (ii) a fatty acid, wherein the fatty acid is oleic acid; and (b) ondansetron or a pharmaceutically acceptable salt thereof.

9. A transdermal composition comprising (a) a matrix consisting of (i) hydrophilic organic solvent, wherein hydrophilic organic solvent is diethylene glycol monoethyl ether, and (ii) a fatty acid, wherein the fatty acid is a mixture of oleic acid and undecylenic acid; and (b) ondansetron or a pharmaceutically acceptable salt thereof.