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Title:
VANCOMYCIN COMPOSITIONS
Document Type and Number:
WIPO Patent Application WO/2009/004592
Kind Code:
A1
Abstract:
The present invention relates to oral compositions of vancomycin or pharmaceutically acceptable salts thereof. The oral composition is in the form of hard gelatin capsules. The invention also relates to processes for the preparation of such compositions.

Inventors:
DABRE, RAHUL (15 A, Ujjwal SocietyNarendra Nagar, Nagpur 5, 44001, IN)
SANDAL, ROSHANLAL (Grain Market Talwandi Bhai, Ferozpur 0, 14205, IN)
THAKKAR, VIKRANT (S/o Smt.savitri Rani, H. No.5 4-mazla, Shanti Nagar, Sampat 1, 13100, IN)
JAIN, GIRISH KUMAR (4 Sharada Niketan, Teacher's Colony Pitam Pura, Delhi 4, 11003, IN)
Application Number:
IB2008/052675
Publication Date:
January 08, 2009
Filing Date:
July 03, 2008
Export Citation:
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Assignee:
WOCKHARDT RESEARCH CENTRE (D-4 Midc Industrial Area, Chikalthana, Aurangabad 0, 43121, IN)
DABRE, RAHUL (15 A, Ujjwal SocietyNarendra Nagar, Nagpur 5, 44001, IN)
SANDAL, ROSHANLAL (Grain Market Talwandi Bhai, Ferozpur 0, 14205, IN)
THAKKAR, VIKRANT (S/o Smt.savitri Rani, H. No.5 4-mazla, Shanti Nagar, Sampat 1, 13100, IN)
JAIN, GIRISH KUMAR (4 Sharada Niketan, Teacher's Colony Pitam Pura, Delhi 4, 11003, IN)
International Classes:
A61K9/48
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Claims:

Claims

[I] A pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and one or more polyethylene glycols.

[2] The pharmaceutical composition of claim 1, wherein the polyethylene glycol comprises one or more of polyethylene glycols with a molecular weight more than 4000.

[3] The pharmaceutical composition of claim 2, wherein the polyethylene glycol is polyethylene glycol 6000.

[4] The pharmaceutical composition of claim 1, wherein the vancomycin and polyethylene glycol are mixed in a ratio from about 1:1 to about 1:2.

[5] The pharmaceutical composition of claim 1, further comprising one or more pharmaceutically acceptable excipients.

[6] The pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, fillers, binders, lubricants, and glidants.

[7] The pharmaceutical composition of claim 1, wherein the composition is in the form of a hard gelatin capsule.

[8] A pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and one or more polyethylene glycols, wherein rate of dissolution of vancomycin is equal to or greater than that obtained by a vancomycin hydrochloride capsule marketed under the trade name Vancocin hydrochloride ® , as measured in water using USP Type I apparatus at 100 rpm.

[9] A process for preparing a pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof, the process comprising:

(a) mixing and blending vancomycin or pharmaceutically acceptable salts thereof and one or more polyethylene glycols;

(b) filling the blend into a capsule; and

(c) heating the capsule at a temperature above 4O 0 C.

[10] The process of claim 9, wherein the heating of capsule is carried out at a temperature of from about 6O 0 C to about 65 0 C.

[I I] The process of claim 9, wherein the polyethylene glycol comprises one or more of polyethylene glycols with a molecular weight more than 4000.

[12] The process of claim 11, wherein the polyethylene glycol is polyethylene glycol 6000. [13] The process of claim 9, wherein the vancomycin and polyethylene glycol

are mixed in a ratio from about 1 : 1 to about 1 :2.

[14] The process of claim 9, further comprising one or more pharmaceutically acceptable excipients.

[15] The process of claim 14, wherein the pharmaceutically acceptable excipients comprises one or more of diluents, fillers, binders, lubricants, and glidants.

[16] A pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, characterized by the fact that at least one excipient has a melting point below 100 0 C.

[17] The pharmaceutical composition of claim 16, wherein the excipients comprise one or more of polyethylene glycols having a molecular weight greater than 4000.

[18] The pharmaceutical composition of claim 17, wherein the polyethylene glycol is polyethylene glycol 6000.

[19] The pharmaceutical composition of claim 16, wherein the pharmaceutically acceptable excipients comprise one or more of diluents, fillers, binders, lubricants, and glidants.

[20] A solid filled capsule dosage form comprising vancomycin or pharmaceutically acceptable salts thereof and one or more of polyethylene glycols.

[21] The dosage form of claim 20, wherein the polyethylene glycol comprises one or more of polyethylene glycols with a molecular weight more than 4000.

[22] The dosage form of claim 21, wherein the polyethylene glycol is polyethylene glycol 6000.

[23] The dosage form of claim 20, wherein the vancomycin and polyethylene glycol are mixed in a ratio from about 1:1 to about 1:2.

[24] The dosage form of claim 20, further comprising one or more pharmaceutically acceptable excipients.

[25] The dosage form of claim 24, wherein the pharmaceutically acceptable excipients comprises one or more of diluents, fillers, binders, lubricants, and glidants.

[26] A stable pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and one or more polyethylene glycols, and having less than about 3.5% concentration (w/w) of monodechloro vancomycin impurity after three months at 4O 0 C and 75% relative humidity.

Description:

Description VANCOMYCIN COMPOSITIONS

[1] Field of the Invention [2] The present invention relates to oral compositions of vancomycin or pharmaceutically acceptable salts thereof. The oral compositions are in the form of hard gelatin capsules. The invention also relates to processes for the preparation of such compositions.

[3] Background of the Invention [4] Vancomycin hydrochloride, a tricyclic vancomycin is derived from Amycolatopsis orientalis (formerly Nocardia orientalis), having the structural Formula I. Vancomycin hydrochloride capsules are indicated for the treatment of staphylococcal entero-colitis and antibiotic-associated pseudo-membranous colitis caused by Clostridium difficile.

[6] FORMULA I [7] British Patent GB 1,596,008 discloses a locking capsule filled with a liquid or other viscous material and having a body part and a cap part telescoped thereon.

[8] British Patent GB 1,590,864 discloses a method of filling hard gelatin capsules with a pharmaceutically active substance which is liquid, semi-solid or a paste like, and includes formulating the active substance into a thixotropic mixture with a pharmaceutically inert carrier and filling the capsule with said thixotropic mixture.

[9] U.S. Patent No. 6,709,675 disclose liquid or pasty thixotropic compositions containing an active substance for filling capsules at room temperature. These compositions are mainly in the form of dispersions supporting amphiphilic excipients. The compositions become fluid by the effect of shearing when they pass through the filling nozzle, and then recover their consistency with sufficient intensity and rapidity to

prevent, after filling any leak between the two capsule parts.

[10] U.S. Patent No. 6,171,615 discloses a sustained release theophylline composition in a capsule unit dosage form that includes 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 polyethylene glycol, and a therapeutically effective amount of theophylline.

[11] U. S. Application No. 20030039956 discloses a 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.

[12] The filling of conventional hard gelatin capsules with liquid or semi-solid pharmaceutical preparations is relatively complex. Further, during sealing problems are encountered 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 of the capsule, which necessitates protection against such leaking by providing a band around the capsule.

[13] For liquid filled hard gelatin capsules, viscosity of the fill material and temperature are two important parameters which must be monitored throughout the capsule filling process. Further, the process is time consuming and requires cost intensive and sophisticated equipment.

[14] Therefore, there exists a need in the art to develop compositions for vancomycin which are easy to handle and are more economical.

[15] Summary of the Invention

[16] In one general aspect there is provided a pharmaceutical composition that includes vancomycin or pharmaceutically acceptable salts thereof and one or more polyethylene glycols.

[17] Embodiments of the compositions may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of diluents, fillers, binders, lubricants, glidants, and the like.

[18] In another general aspect there is provided a pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and one or more polyethylene glycols, wherein rate of dissolution of vancomycin is equal to or greater than that obtained by a vancomycin hydrochloride capsule marketed under the trade name Vancocin hydrochloride ® , as measured in water using USP Type I apparatus at 100 rpm.

[19] In another general aspect there are provided processes for preparing pharmaceutical compositions that include vancomycin or pharmaceutically acceptable salts thereof.

The process includes: a) mixing vancomycin or pharmaceutically acceptable salts thereof with one or more polyethylene glycols and forming a blend; b) filling the blend into capsules; and (c) heating the capsules at a suitable temperature above 40° C.

[20] In another general aspect there is provided a pharmaceutical composition that includes vancomycin or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients characterized by the fact that at least one of the ex- cipients has a melting point below 100 0 C.

[21] Embodiments of the compositions may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of diluents, fillers, binders, lubricants, glidants, and the like.

[22] In another general aspect there is provided a solid filled capsule dosage form that includes vancomycin or pharmaceutically acceptable salts thereof and one or more of polyethylene glycols.

[23] Embodiments of the dosage form may include one or more of the following features.

For example, the dosage form may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of diluents, fillers, binders, lubricants, glidants, and the like.

[24] In another general aspect there is provided a stable pharmaceutical composition comprising vancomycin or pharmaceutically acceptable salts thereof and one or more polyethylene glycols, and having less than about 3.5% concentration (w/w) of mono- dechloro vancomycin impurity after three months at 4O 0 C and 75% relative humidity.

[25] Embodiments of the dosage form may include one or more of the following features.

For example, the dosage form may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of diluents, fillers, binders, lubricants, glidants, and the like.

[26] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

[27] Detailed Description of the Invention

[28] We have now discovered that pharmaceutical compositions of vancomycin or pharmaceutically acceptable salts thereof can be prepared in the form of a solid dispersion with one or more polyethylene glycols. Further, such compositions can be prepared by a process which is easy and fast as the powder can be filled easily in capsules after proper blending and does not require any temperature monitoring. The product of the instant invention provides a similar dissolution pattern as exhibited by the innovator's product marketed under the trade name Vancocin hydrochloride ® .

[29] Vancomycin can be present in the form of vancomycin hydrochloride. The poly-

ethylene glycols can be selected from one or more of polyethylene glycols with a molecular weight greater than 4000. The ratio of vancomycin to polyethylene glycol in the composition can be varied from about 1:1 to about 1:2. The composition may be in the form of hard gelatin capsules, which are intended predominantly for oral administration.

[30] In general, the pharmaceutical compositions of the invention can be prepared by simple mixing, blending and filling into capsules. T he blending of vancomycin and polyethylene glycol may be carried out in a double cone blender. The filled capsules may be heated using a coating pan at a suitable temperature above 4O 0 C.

[31] Further embodiment of the present invention includes heating of filled hard gelatin capsule shells at a temperature from about 6O 0 C to about 65 0 C.

[32] Suitable excipients having a melting point below 100 0 C may include one or more of polyethylene glycols having a molecular weight greater than 4000.

[33] Suitable binders may include one or more of starch, sugars, gums, low molecular weight hydroxypropylmethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose, and the like.

[34] Suitable lubricants may include one or more talc, magnesium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, glyceryl behenate, sodium benzoate, and the like.

[35] Suitable glidants may include one or both of colloidal silicon dioxide and talc or magnesium stearate, and the like.

[36] The capsule dosage form developed as a part of invention has been tested for the stability by subjecting the dosage form packaged in HDPE containers and/or Aluminium/ Aluminium pack (hereinafter referred to as AIu/ AIu Pack) at 40°C/75%RH and at 25°C/60%RH for 3 months and is found to be stable after multiple testing.

[37] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.

[38] Examples: The composition of the batches is provided in Table 1, 2. and 3.

Following formulations are representatives of the preferred compositions of the invention. The preparation of examples 1 to 3 is detailed below.

[39] The analytical data/stability data of initial, one-month, two-month and three-month stability for both 125mg and 250mg strength composition (packaged in HDPE and Alu/Alu container) at 40°C/75%RH and at 25°C/60%RH is provided in Table 4 to 7.

[40] Example 1

[41] Table 1 - Composition of Vancomycin capsules.

[Table 1] [Table ]

[43] Procedure - Vancomycin Hydrochloride & PEG 6000 were sifted through a mesh and mixed well for few minutes in a double cone blender. This blend was filled in empty hard gelatin capsules. Further, the capsules were rolled in a coating pan at 60-65 0 C for 45-60 min or till the blend in the capsule shell melts.

[44] Example 2 [45] Table 2 - Composition of Vancomycin capsules. [46] [Table 2] [Table ]

[47] Procedure - Vancomycin Hydrochloride & PEG 6000 were sifted through a mesh and mixed well for few minutes in a double cone blender. This blend was filled in empty hard gelatin capsules. Further, the capsules were rolled in a coating pan at 60-65 0 C for 45-60 min or till the blend in the capsule shell melts.

[48] Example 3 [49] Table 3 - Composition of Vancomycin capsules

[Table 3] [Table ]

[51] Procedure - Vancomycin hydrochloride, polyethylene glycol 6000 and glyceryl behenate were sifted using a suitable mesh and mixed properly. This blend was filled in empty hard gelatin capsules. Filled capsules were rolled in a coating pan at 60-65 0 C for 45-60 min or till the blend in the capsule shell melts. The capsules were cooled to room temperature.

[52] Stability Data - [53] Table 4 - [54] 125mg Vancomycin Composition packaged in HDPE containers - [55]

[Table 4] [Table ]

[56] Table 5 - [57] 250mg Vancomycin Composition packaged in HDPE containers - [58]

[Table 5] [Table ]

[59] Table 6 - [60] 125mg Vancomycin Composition packaged in HDPE AIu/ AIu Pack [61]

[Table 6] [Table ]

[62] Table 7 - [63] 250mg Vancomycin Composition packaged in AIu/ AIu Pack - [64]

[Table 7] [Table ]

[65] While the 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 invention.