Specification
FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
& THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10)
A STABLE, ORAL SOLID DOSAGE FORM
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERl (E). MUMBAI-400059, MAHARASHTRA, INDIA
ORIGINAL
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
The present invention relates to a stable, oral, solid dosage form comprising rosiglitazone acid addition salt and biguanide (s).
BACKGROUND OF THE INVENTION
The literature reveals prior arts related to the formulations comprising a combination of rosiglitazone acid addition salt and metformin or its pharmaceutically acceptable salt. An important consideration in the preparation of formulations containing combination of active agents is the stability of the active agents with each other as well with the pharmaceutically acceptable excipients that are used in formulations.
United States Patent 5,741,803 (hereinafter referred to as '803) disclosed acid addition salt of rosiglitazone base to be particularly stable. Useful acids included mineral acids such as hydrochloride and mineral acids and organic acids such as tartaric acid and maleic acid. United States patent application number US2006/0089387 further disclosed that a stable composition can be prepared from rosiglitazone base without the need to particularly convert it into an acid addition salt simply by incorporating into the mixture of rosiglitazone and pharmaceutical excipients, a suitable quantity of the acid. However, when preparing a composition of rosiglitazone acid addition salt and a biguanide, the problem of instability arises in spite of use of acid addition salt rosiglitazone as is discussed below.
Metformin hydrochloride, the commonly administered salt, is known to have poor compressibility. This lack of compressibility combined with the large unit dosage requirements, results in significant formulation problems, especially in compressed dosage forms. United States Patent Number 5,955,106 (herein after referred to as '106 patent) enumerates several formulation problems associated with metformin such as for example, capping. The '106 patent provides solution to these problems by using a hydrocolloid-forming agent as a retardant and maintaining a residua] moisture content of the composition of 0.45 to 3 % by weight. The '106 patent further states that it was surprisingly found that the use of hydrocolloid-forming retarding agent enabled for the first time the known poor compressibility of metformin to be brought under control in a technically satisfactory manner. The '106 patent therefore teaches use of a hydrocolloid forming agents such as polyvinyl pyrrolidone, hydroxypropyl methyl cellulose in the formulations of metformin to avoid the compressibility problems.
Another prior art namely, WO2001035941 (hereafter referred to as PCT publication '941) says that although polyvinyl pyrrolidone is particularly effective as a binder with metformin hydrochloride providing excellent flow and compressibility properties, it is indicated that its use in the formulation destabilizes rosiglitazone maleate. The PCT publication '941 solves this problem by separating the two drugs in separate carrier. The '941 publication therefore teaches that the two drugs are located in discrete zones with respect to each other, wherein
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each zone comprises the active agent. The two drugs along with its carrier are in different phases and the two phases do not come in physical contact with each other.
PCT publication WO200135940 (hereafter referred to as patent publication '940) discloses a pharmaceutical composition wherein rosiglitazone maleate composition is deposited on the surface of a core containing metformin hydrochloride. The '940 publication states that the instability of rosiglitazone maleate is prevented by avoiding the mutual interaction between the two drugs by physically separating them, for example, by coating the thiazolidinedione on the surface of metformin or making multilayer compositions.
PCT publication WO2005065663 (hereafter referred to as patent publication '663) discloses fast dissolving dosage form comprising microparticles of rosiglitazone and/or metformin together with a protective material substantially shielding rosiglitazone and/ or metformin from coming in contact with the environment outside of the microparticle. It discloses use of an effervescent couple for example, acids such as citric acid, tartaric acid, malic acid and an alkali metal carbonate. The '663 patent publication teaches to provide a taste masking coating on the rosiglitazone maleate and/or metformin and further mixing these coated particles with effervescent couple to make the chewable tablets.
Thus, it may be concluded that the prior arts suggest that certain excipients which are compatible with metformin or its pharmaceutically acceptable salt may not be compatible with rosiglitazone acid addition salt. Therefore making a dosage form using excipients that are suitable for both active ingredients, i.e, rosiglitazone acid addition salt and metformin or its pharmaceutically acceptable salt is a task to formulators. Moreover, high dose of metformin salts for example, hydrochloride salt and its poor compressibility adds to the problem in terms of achieving optimum physical characteristics when the dosage form is a compressed dosage form, such as tablets. Therefore, there lies a need to provide a balance between achieving the optimum physical characteristics while maintaining a desirable chemical stability, for the dosage form of rosiglitazone acid addition salt and metformin or its pharmaceutically acceptable salts.
We have surprisingly found that the addition of citric acid to the uncoated rosiglitazone acid addition salt and uncoated biguanide solves the stability problems associated with rosiglitazone acid addition salt while providing a formulator the flexibility to choose the excipients that are recommended for the metformin which are otherwise not compatible with rosiglitazone acid addition salt. Further, even more surprisingly, it was found that citric acid provides the required solution to the problem which was otherwise not solved by the addition of another acid, namely maleic acid.
OBJECTS OF THE INVENTION
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It is the object of the present invention to provide a dosage form of rosiglitazone acid addition salt and metformin or its pharmaceutically acceptable salt in a single dosage form.
It is also the object of the present invention to provide an easy method to prevent destabilization of rosiglitazone acid addition salt when formulated with metformin or its pharmaceutically acceptable salt, in a single dosage form.
It is another object of the present invention to find means which allow the use of the excipients that are incompatible with rosiglitazone acid addition salt but are essential for metformin or its pharmaceutically acceptable salt portion.
It is also the object of the present invention to provide a dosage form to get satisfactory physical parameters such as hardness, capping etc. of the solid dosage forrri.
SUMMARY OF THE INVENTION
The present invention provides a stable, oral, solid dosage form comprising uncoated rosiglitazone acid addition salt, uncoated biguanide (s), citric acid and other Ipharmaceutically acceptable excipients.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a stable, oral, solid dosage form comprising uncoated rosiglitazone acid addition salt, uncoated biguanide (s), citric acid and other jpharmaceutically acceptable excipients.
The term 'stable' as used herein means that when the solid dosage form is stored at a temperature of 40°C ± 2°C and 75 % ± 5 % relative humidity for a period; of three months, the total impurities are less than 1 % of the labeled amount of rosiglitazone acid addition sali
The term 'uncoated' as used herein means thatj the rosiglitazone acid addition salt and the biguanide are not coated with any protective coating substantially! encompassing the particles and is not isolated from coming in contact with the other pharmaceutically acceptable excipients.
The acid addition salts of rosiglitazone used in me solid dosage form of the present invention, includes, but are not limited to, salts with the mineral acids suchjas hydrobromic acid, hydrochloric acid, sulfuric acids, or salts with organic acids such as methanesulphonic,' tartaric and maleic acid and the like. In preferred embodiment of rhe nresent invention msiplitazone maleate is used.
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The oral solid dosage form of the present invention comprises biguanide (s). Biguanide used in the oral, solid dosage form of the present invention include, but are not limited to, metformin, phenformin, buformin, their pharmaceutically acceptable salts, hydrates, solvates and the like. Preferably a hydrochloride salt of metformin is used. The amount of metformin hydrochloride used in the oral solid, dosage form of the present invention, may range from about 100 mg to about 2000 mg, preferably from about 200 mg to about 1500 mg by weight of the solid dosage form.
In one embodiment of the present invention, maleate salt of rosiglitazone is used. Impurities arising from the degradation of the rosiglitazone maleate were identified by their chemical structures. Amongst them, Structure I was identified as 5-[4-{2-(N-methyl, N-(2-pyridyl))amino}ethoxy benzaldehyde and was termed as impurity B. This impurity B was monitored as the known impurity along with the other unknown impurities.
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Documents
Application Documents
| # |
Name |
Date |
| 1 |
1104-mum-2008-abstract.doc |
2018-08-09 |
| 1 |
1104-mum-2008-form 5.pdf |
2018-08-09 |
| 2 |
1104-mum-2008-form 3.pdf |
2018-08-09 |
| 2 |
1104-mum-2008-abstract.pdf |
2018-08-09 |
| 3 |
1104-mum-2008-form 2.pdf |
2018-08-09 |
| 4 |
1104-mum-2008-claims.pdf |
2018-08-09 |
| 5 |
1104-mum-2008-correspondence.pdf |
2018-08-09 |
| 5 |
1104-mum-2008-form 2(title page).pdf |
2018-08-09 |
| 6 |
1104-mum-2008-form 1.pdf |
2018-08-09 |
| 7 |
1104-mum-2008-description(complete).pdf |
2018-08-09 |
| 8 |
1104-mum-2008-form 1.pdf |
2018-08-09 |
| 9 |
1104-mum-2008-correspondence.pdf |
2018-08-09 |
| 9 |
1104-mum-2008-form 2(title page).pdf |
2018-08-09 |
| 10 |
1104-mum-2008-claims.pdf |
2018-08-09 |
| 11 |
1104-mum-2008-form 2.pdf |
2018-08-09 |
| 12 |
1104-mum-2008-form 3.pdf |
2018-08-09 |
| 12 |
1104-mum-2008-abstract.pdf |
2018-08-09 |
| 13 |
1104-mum-2008-form 5.pdf |
2018-08-09 |