FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
ORAL PHARMACEUTICAL COMPOSITION COMPRISING VANCOMYCIN AND A NOVEL PROCESS FOR PREPARATION OF THE SAME
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides oral composition of vancomycin or
pharmaceutically acceptable salts thereof in the form of hard gelatin capsule.
The invention further provides a novel process for the preparation of said
composition.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides oral composition of vancomycin or pharmaceutically acceptable salts thereof, in the form of hard gelatin capsule. The invention further provides a novel process for the preparation of said composition.
Vancomycin hydrochloride, a tricyclic vancomycin is derived from Amycolatopsis orientalis (formerly Nocardia orientalis), which has the chemical formula C66H75Cl2N9024'HCI. The molecular weight of vancomycin hydrochloride is 1485.73; 500 mg of the base is equivalent to 0.34 mmol. Vancomycin hydrochloride capsules are indicated for treatment of staphylococcal enterocolitis and antibiotic-associated pseudo-membranous colitis caused by Clostridium difficile.

FORMULA 1
British Patent GB 1,596,008 discloses a locking capsule filled with liquid or other viscous material and having a body part and a cap part telescoped thereon.
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British Patent GB 1,590,864 discloses a method of filling a hard gelatin capsule with a pharmaceutically active substance which is liquid, semi-solid or paste like, and comprises formulating said active substance into a thixotropic mixture with a pharmaceutically inert carrier and filling the capsule with said thixotropic mixture.
U. S. Patent No. 6,709,675 discloses liquid or pasty thixotropic compositions containing an active substance for filling capsules at room temperature.
U. S. Patent No. 6,171,615 discloses sustained release theophylline composition in capsule unit dosage form comprising a gelatin capsule containing a semi-solid matrix, said semi-solid matrix consisting essentially of polyglycolized glycerides, a nucleation enhancer composition consisting essentially of glyceryl mono stearate and PEG, and a therapeutically effective amount of theophylline.
U. S. Patent Application No. 20030039956 discloses pharmaceutical composition for oral delivery of an antimicrobial agent comprising a biopolymer; an antimicrobial agent entrained within or ionically bound to the biopolymer; and a cationic binding agent entrained within or tonically bound to the biopolymer or the antimicrobial agent.
Filling of conventional hard gelatin capsules with liquid or semi-solid pharmaceutical preparations is relatively complex. Also problems are encountered during sealing, because the liquid/semi-solid pharmaceutical preparation penetrates into the space between the external surface of the body part and the internal surface of the cap part and is necessary to protect against such leaking by providing a band around the capsule.
For liquid filled hard gelatin capsules viscosity and temperature of the fill material are two important parameters, which must be monitored through out the capsule filling process. Further the process is time and money consuming and requires sophisticated machineries.
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Vancomycin hydrochloride is highly hygroscopic and must be handled in a vial as a lyophilized powder, which is reconstituted with water before use. The increasing recognition of the antibiotic's importance in treating pseudomembranous colitis as well as issues of solution stability and patient acceptability led to a demand for the antibiotic in a stable oral dosage form that had a low level of moisture uptake and that offered a great convenience to patients.
The present invention now provides an oral pharmaceutical composition comprising of vancomycin or pharmaceutically acceptable salts thereof and polyethylene glycol (hereafter referred to as PEG). The said composition is in the form of hard gelatin capsule and is prepared by a novel process, which is easy, fast and economical. The said process comprises of filling of a blend of vancomycin or pharmaceutically acceptable salts thereof and PEG in the powder form, without the necessity of temperature monitoring. Further, the filled capsules are heated to obtain the desired product. The product of the instant invention provides the same dissolution pattern in line with the innovator's product marketed under the tradename of VANCOCIN® HCI.
In one general aspect there is provided a pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and PEG.
In one of the embodiments vancomycin can be present in the form of vancomycin hydrochloride and PEG may be selected from high molecular weight (greater than 4000) grades such as PEG 6000, PEG 8000, PEG 10000 and the like. The high molecular weight PEG offers acceptable moisture up-take properties and thus protects hygroscopic vancomycin from absorbing moisture. The ratio of vancomycin or pharmaceutically acceptable salts thereof to PEG in the composition can be varied from about 0.1:1 to about 1:0.1 parts by weight. The composition may be in the form of hard gelatin capsules.
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In one of the embodiments the ratio of vancomycin or pharmaceutically acceptable salts thereof to PEG in the composition can be varied from about 1:1 to about 1:2 parts by weight.
Further, in one of the embodiments, combination of two or more grades of PEGs may also be used for the purpose of release modulation.
In one of the embodiments, high molecular weight (greater than 4000) PEG selected from the group comprising of PEG 6000, 8000, 10000 and the like, can be combined with low molecular weight PEG (less than 4000) selected from the group comprising of PEG 200, 300, 400, 600 and the like, in suitable proportion.
In another general aspect there is provided a pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and PEG prepared by a novel process wherein the process comprises the steps of:
1) blending vancomycin or pharmaceutically acceptable salts thereof and PEG
2) filling blend of step 1 in capsule
3) heating the capsule of step 2 at suitable temperature above 40° C.
Embodiments of the process may include one or more of the following features. For example, the blending of vancomycin or pharmaceutically acceptable salts thereof and PEG may be carried out in suitable blender like double cone blender, v-blender, ribbon blender, zig-zag blender, and plow blender. The filled capsules may be heated in tray dryer or by rolling in coating pan at suitable temperature above 40°C.
Further, in one of the embodiment of the present invention the heating of filled hard gelatin capsules may be carried out at temperature of about 60°C to about 65°C.
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In yet another general aspect of the present invention there is provided a pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients characterized by the fact that at least one excipient has melting point below 100°C.
Excipients with melting point below 100°C provide favorable condition for hard gelatin capsules while rolling into the coating pan, as hard gelatin capsule shells cannot withstand the higher temperature.
Embodiments of the composition may include one or more of the following features. For example, excipients having melting point below 100°C comprises one or more of polyethylene glycols, polyvinyl acetate, beeswax, lanolin/wool wax, camauba wax, castor wax, carbowax and the like.
In one of the embodiments of the present invention pharmaceutically acceptable excipients comprises one or more of lubricants, disintegrants, glidants and the like.
The lubricants comprises one or more of magnesium stearate, calcium stearate, stearic acid, talc and the like.
The disintegrants comprises one or more of sodium starch glycolate, croscarmellose sodium, pregelatinised starch and the like.
The glidants comprises one or more of talc, silicon dioxide and the like.
In yet another general aspect of the present invention there is provided a solid filled capsule dosage form comprising vancomycin or pharmaceutically acceptable salts thereof, wherein the capsule is essentially free of glycerides and mixtures of fatty acid esters of glycerol and PEG.
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The term "essentially free of glycerides and mixtures of fatty acid esters of glycerol and PEG" refers to the amount of the glycerides and mixtures of fatty acid esters of glycerol and PEG, which is not sufficient to provide any functional aid such as protection from moisture or release modulation.
In one of the embodiments of the present invention glycerides include one or more of monoglycerides, diglycerides, triglycerides, polyoxyethylene glycerides, lactic acid derivatives of mono- and diglycerides, propylene glycol diglycerides, mono-acetylated tartaric acid esters of mono- and diglycerides, diacetylated tartaric acid esters of mono- and diglycerides, succinylated monoglycerides, citric acid esters of mono- and diglycerides, sucroglycerides and mixtures thereof.
Further, in one of the embodiments of the present invention mixtures of fatty acid esters of glycerol and PEG comprise various grades of Gelucire® such as 44/14, 50/13, 53/10, 55/18 and the like.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present Invention.
Examples: The composition of the batches is provided in Table 1 and 2.
Table 1 - Composition of the present invention.

Sr. No. Ingredients 125 mg (mg/Cap) 250 mg (mg/Cap)
1 Vancomycin hydrochloride 128.125 256.25
2 PEG 6000 221.875 443.75
3 Total Fill Weight 350 700
Procedure - Vancomycin hydrochloride & PEG 6000 were sifted through mesh and mixed well for few minutes in double cone blender. This blend was filled in
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empty hard gelatin capsules. Further the capsules were rolled in coating pan at 60-65°C for 45-60 min or till the blend in capsule shell melt.
Table 2 - Composition of the present invention.

Sr. No. Ingredients 125 mg (mg/Cap) 250 mg (mg/Cap)
1 Vancomycin hydrochloride 128.125 256.25
2 PEG 6000 121.875 243.75
3 Total Fill Weight 250 500
Procedure - Vancomycin hydrochloride & PEG 6000 were sifted through mesh and mixed well for few minutes in double cone blender. This blend was filled in empty hard gelatin capsules. Further the capsules were rolled in coating pan at 60-65°C for 45-60 min or till the blend in capsule shell melt.
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WE CLAIM:
1) A pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and PEG.
2) The pharmaceutical composition according to claim 1, wherein the PEG comprises PEG with molecular weight greater than 4000.
3) The pharmaceutical composition according to claim 2, wherein the PEG is PEG 6000.
4) The pharmaceutical composition according to claim 1, wherein the vancomycin or pharmaceutically acceptable salts thereof and PEG are mixed in the ratio from about 1:1 to about 1:2 parts by weight.
5) The pharmaceutical composition according to claim 1, wherein the composition comprises combination of two or more PEGs.
6) The pharmaceutical composition according to claim 1, wherein the composition is in the form of hard gelatin capsule.
7) A pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and PEG prepared by a novel process wherein the process comprises the steps of:

1) blending vancomycin or pharmaceutically acceptable salts thereof and PEG;
2) filling blend of step 1 in capsule;
3) heating the capsule of step 2 at suitable temperature above 40°C.
8) The pharmaceutical composition according to claim 6, wherein the heating
of capsule is carried out at the temperature of about 60°C to about 65°C.
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9) A pharmaceutical composition comprising vancomycin or pharmaceutical^ acceptable salts thereof and pharmaceutical^ acceptable excipients characterized by the fact that at least one excipient has melting point below 100°C.
10) A solid filled capsule dosage form comprising vancomycin or pharmaceutically acceptable salts thereof, wherein the capsule is essentially free of glycerides and mixtures of fatty acid esters of glycerol and PEG (GELUCIRE).

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Abstract
The present invention provides oral composition of vancomycin or pharmaceutically acceptable salts thereof, in the form of hard gelatin capsule. The invention further provides a novel process for the preparation of said composition.