Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2003-06-02
2004-11-02
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S055200, C536S121000, C536S122000, C536S055300
Reexamination Certificate
active
06812223
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel crystalline glucosamine sulphate metal salts for use in the treatment of acute and chronic forms of rheumatic and arthritic diseases and of all the pathological conditions originating from metabolic disorders of the osteo-articular tissues. More particularly, the present invention relates to novel crystalline glucosamine sulphate metal salts having low metal content wherein the metal may be either sodium or potassium. The present invention further relates to a solution-based and a solvent-free process for the preparation of the novel crystalline glucosamine sulphate metal salts having low metal content and to pharmaceutical compositions comprising the novel crystalline glucosamine sulphate metal salts having low metal content.
BACKGROUND OF THE INVENTION
Both acute and chronic forms of rheumatic and arthritic diseases are associated with joint pain and inflammation and hence cause a lot of distress to patients suffering from such a disease. Osteoarthritis, a degenerative joint disease, is the most common form of arthritis. This disease is mostly prevalent in older people. The standard therapy for the treatment of osteoarthritis mostly includes the use of aspirin, corticosteroids, non-steroidal anti-inflammatory drugs (NSAID's) e.g. ibuprofen, naproxen etc. and the most recent COX-2 inhibitors e.g. rofecoxib, celecoxib. However, all these drugs are associated with one or more side effects which may also be long term in some cases. An ideal treatment of osteoarthritis must effectively control pain as well as slow down or reverse the degeneration of joints and also cause fewer side effects. In the early 1970's it was discovered that a naturally occurring substance namely glucosamine can slow down the progression of osteoarthritis and also alleviate the pain associated with this disease [Kurtz J. F. et. al.:
Z. Allgemeinmed
46(21): 1090-1095 (1970); Vinel P. et. al.:
Therapeutique
, 47(10): 839-843 (1971)].
Glucosamine (an amino saccharide) helps in strengthening the joint structure thereby improving mobility. So far four main sources of glucosamine are reported namely glucosamine hydrochloride, glucosamine hydroiodide, glucosamine sulphate and N-acetyl glucosamine. Of these, glucosamine sulphate is the most preferred form of glucosamine and is widely used in the treatment of osteoarthritis and other acute and chronic forms of rheumatic and arthritic diseases. The benefits of using glucosamine sulphate in the treatment of osteoarthritis and other arthritic diseases as well as the safety and efficacy of this drug are well proven [Dormant A. et. al.:
Clin. Ther.
3(4): 260-272 (1980); Vaz. A. L.:
Curr. Med. Res. Opin
.; 8(3): 142-149 (1982); Tapadinhas M. J.:
Pharmaceutica
3: 157-168(1982); Reichelt A. et. al.:
Arzneim Forschung
44: 75-80 (1994)].
Although highly effective, glucosamine sulphate is unstable in its free form due to its highly hygroscopic nature and also the amino group gets oxidised readily. Hence, oral formulations such as capsules, tablets of this drug contain anti-oxidants. However, this does not solve the problem of its hygroscopic nature. To overcome this problem glucosamine sulphate is usually combined with metal salts preferably sodium or potassium salts. Mixed salts of glucosamine hydrochloride with alkali metals or alkaline earth metal sulphates such as sodium or potassium sulphates are well known in the literature. Usually glucosamine sulphate metal salts are prepared starting from either glucosamine hydrochloride or the glucosamine free base.
Preparation of glucosamine sulphate is described in GB Patent No. 1056331, U.S. Pat. No. 3,683,076 and Swiss Patent No. 525861.
Preparation of mixed salt of glucosamine sulphate and sodium chloride is described in U.S. Pat. No. 4,642,340 wherein previously prepared glucosamine sulphate is treated with sodium chloride solution followed by addition of liquid precipitant to precipitate the mixed salt. This process involves direct use of glucosamine sulphate which has to be strictly maintained in an environment with a relative humidity not greater than 30% and a temperature not more than 15° C., thus one has to take proper precautions in this case.
EP 214642 describes a process for the preparation of mixed salt of glucose sulphate and potassium chloride starting from glucosamine free base wherein solution of the glucosamine free base in water is treated with concentrated sulphuric acid and to the resulting solution potassium chloride is added. The metal salt is precipitated out from the solution by adding liquid precipitant. This is a lengthy process since it first involves liberation of free glucosamine base from glucosamine hydrochloride followed by the subsequent reaction steps. Also this process results in low yield.
U.S. Pat. No. 5,847,107 teaches a process for preparing crystalline form of mixed glucosamine sulphate salts wherein glucosamine hydrochloride is treated with a metal sulphate e.g. sodium sulphate in an aqueous solvent and the stable crystalline form of glucosamine sulphate is precipitated from the solution by adding a liquid precipitant.
U.S. Pat. Nos. 5,843,923 and 5,902,801 follow the same method for the preparation of glucosamine sulphate metal salts, however, in these cases the process avoids addition of liquid precipitating agent but involves freeze drying of the solution resulted from the reaction of glucosamine hydrochloride and metal sulphate.
Although, the mixed glucosamine sulphate metal salts, the products described in U.S. Pat. Nos. 5,847,107 and 5,902,801, are suitable for treatment of rheumatic and arthritic diseases, they have proportionately high metal content e.g. sodium or potassium. Rheumatic and arthritic diseases are mostly prevalent in older people who are also at higher risk of other diseases such as hypertension and cardiovascular diseases. Hyperkalemia (high potassium level) is also a serious electrolyte disorder which appears to develop more commonly in the aged patients. In such cases the patients are advised a restricted sodium or potassium intake depending on the case history. Also people suffering from renal dysfunction require low sodium intake. Therefore, administration of glucosamine sulphate mixed salts having proportionately high sodium or potassium content may not be advisable to those rheumatic or arthritic patients who are also having history of hypertension, cardiovascular diseases, renal dysfunction, hyperkalemia and other diseases which require restricted sodium or potassium intake. Taking into account the proven safety and efficacy of glucosamine sulphate over other conventional drugs for arthritic diseases, there is a need to develop a specific form of glucosamine sulphate which can also be safely administered to sodium or potassium sensitive patients.
The present inventors have now found novel crystalline glucosamine sulphate metal salts having low metal content, wherein the metal may be either sodium or potassium. The use of the crystalline glucosamine sulphate sodium or potassium salt of the present invention, is not only an efficacious treatment for all arthritic patients but also a safer remedy for those patients who are also having history of diseases which require restricted sodium or potassium intake.
OBJECTS OF THE INVENTION
The primary object of the invention aims at providing novel crystalline glucosamine sulphate metal salts having low metal content, useful in the treatment of acute and chronic forms of rheumatic and arthritic diseases and of all the pathological conditions originating from metabolic disorders of the osteo-articular tissues.
Another object of the present invention is to provide novel crystalline glucosamine sulphate metal salts having low metal content, wherein the metal may be either sodium or potassium, as efficacious and safer remedy to sodium or potassium sensitive arthritic patients.
Yet another object of the invention is to provide a solution-based process and a solvent-free process for the preparation of the crystalline glucosa
Bhat Ravi Gajanan
Mukhopadhyay Triptikumar
Sreekumar E. S.
Henry Michael C.
Nicholas Piramal India Limited
Pendorf & Cutliff
Wilson James O.
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