LT5148B - Crystalline glucosamine sulphate metal salts and process for preparing the same - Google Patents

Abstract

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.

Description

Field of the Invention

The present invention relates to novel crystalline glucosamine sulfate metal salts for the treatment of acute and chronic forms of rheumatic and arthritic diseases and all pathological conditions resulting from the metabolic disorder of bone and joint tissues. More particularly, the present invention relates to novel crystalline glucosamine sulfate metal salts having a low metal content in which the metal may be sodium or potassium. The present invention also relates to novel crystalline glucosamine sulfate metal salts having low metal content, processes for preparing solvents without using solvents and pharmaceutical compositions comprising novel crystalline glucosamine sulfate metal salts having low metal content.

Origin of the Invention

Both acute and chronic forms of rheumatic and arthritic diseases are associated with joint pain and inflammation and therefore cause a great deal of suffering to patients with these conditions. The predominant form of arthritis is osteoarthritis, a degenerative joint disease. This disease is most prevalent among the elderly. As a standard treatment for osteoarthritis, aspirin, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used, e.g. ibuprofen, naproxen, etc., and more commonly COX-2 inhibitors e.g. rofecoxib, celecoxib. However, all of these drugs are associated with one or more side effects, which in some cases can be long lasting. The ideal treatment for osteoarthritis should be effective pain control and slowing or stopping joint degeneration with fewer side effects. In the early 1970s, a natural substance, glucosamine, was discovered to slow the progression of osteoarthritis and reduce the pain associated with it [Kurtz J.F. et al .: Z. Algemeinmed

46 (21): 1090-1095 (1970); Vinel P. et al., Therapeutique, 47 (10): 839-843 (1971)].

Glucosamine (an aminosaccharide) helps to strengthen the structure of the joint, thus improving mobility. To date, 4 major sources of glucosamine have been described, namely glucosamine hydrochloride, glucosamine hydroiodide, glucosamine sulfate, and N-acetylglucosamine. The preferred form of glucosamine is glucosamine sulfate and is most widely used in the treatment of osteoarthritis and other acute and chronic forms of rheumatic and arthritic diseases. The benefits of glucosamine sulfate in the treatment of osteoarthritis and other arthritic diseases and the safety and efficacy of this drug have been sufficiently well established [Dormant A. et al. Ther.

3 (4): 260-272 (1980); Vaz A.L .: Curr. Med. Res. I learned. 8 (3): 142-149 (1982); Tapadinhas M.J .: Pharmaceutica 3: 157-168 (1982); Reichelt A. et al .: Arzneim. Forschung 44: 75-80 (1994)].

Although glucosamine sulfate is highly effective, due to its high hygroscopicity in free form, it is unstable and its amino group is easily oxidized. Thus, oral forms of the drug, such as capsules, tablets, contain antioxidants. However, this does not solve his hygroscopicity problem. To solve this problem, glucosamine sulfate is usually mixed with metal salts, preferably sodium or potassium salts. Mixed glucosamine hydrochloride salts with alkali metal or alkaline earth metal sulfates such as sodium or potassium sulfates are well known in the literature. Typically, the metal salts of glucosamine sulfate are prepared from either glucosamine hydrochloride or glucosamine free base.

The preparation of glucosamine sulfate is described in British patent no. 1056331, U.S. Pat. 3683076; 525861.

The preparation of glucosamine sulfate and sodium chloride mixed salts is described in U.S. Pat. 4642340, wherein the glucosamine sulfate prepared initially is treated with a sodium chloride solution and then a liquid precipitant is added to precipitate the mixed salt. This process involves the direct application of glucosamine sulfate, which must be strictly stored in an environment having a humidity of not more than 30% and a temperature of not more than 15 ° C; so proper precautions must be taken in this case.

EP 214642 describes a process for preparing a mixed salt of glucosamine succinate and potassium chloride by leaving the glucosamine free base, wherein the free base of glucosamine in water is treated with concentrated sulfuric acid and potassium chloride is added to the resulting solution. The metal salt is precipitated from the solution by adding a liquid precipitant. This is a lengthy process since it involves first isolating the glucosamine free base from glucosamine hydrochloride and then proceeding to the next steps. In addition, this method yields low yields.

U.S. Pat. No. 5,847,107 discloses a process for preparing crystalline forms of mixed glucosamine sulfate salts wherein the glucosamine hydrochloride is treated with a metal sulfate, e.g. sodium sulfate, in an aqueous solvent, and a stable crystalline form of glucosamine sulfate is precipitated from the solution by adding a liquid precipitant.

U.S. Pat. Nos. 5843923 and 5902801 use the same process to obtain metal salts of glucosamine sulfate, but do not add a liquid precipitating agent, but involve the lyophilization of the solution obtained by the glucosamine hydrochloride-metal sulfate reaction.

Although mixed glucosamine sulfate metal salts are disclosed in U.S. Pat. 5847107 and 5902801 are suitable for the treatment of rheumatic and arthritic diseases and have a relatively high amount of metal, e.g. sodium or potassium. Rheumatic and arthritic diseases are most prevalent among older people who have a high risk of developing other diseases such as hypertension and cardiovascular disease. Hyperkalaemia (high levels of potassium in the blood) is also a serious electrolyte disorder that usually develops in the elderly. In such cases, patients are advised to limit their sodium or potassium intake, as appropriate. In addition, people with kidney problems should have low sodium levels. Therefore, administration of glucosamine sulphate mixed salts with proportionally high sodium or potassium intake to patients with hypertensive cardiovascular disease, renal impairment hyperkalaemia, and other conditions requiring sodium and potassium restriction may not be recommended. Given the proven safety and efficacy of glucosamine sulfate compared to other conventional arthritic drugs, there is a need to develop a specific form of glucosamine sulfate that can be safely administered to patients who are sodium or potassium sensitive.

These inventors have now found novel crystalline glucosamine sulfate metal salts having a low metal content, where the metal can be either sodium or potassium. The use of the crystalline sodium or potassium salts of glucosamine sulfate of the present invention not only effectively cures all arthritic patients, but is also a safe drug for patients who have had or have been associated with conditions requiring sodium or potassium restriction.

Objectives of the Invention

The main object of the present invention is to provide novel crystalline glucosamine sulfate metal salts having a low metal content suitable for the treatment of acute and chronic forms of rheumatic and arthritic diseases and all pathological conditions resulting from metabolic disorders of bone-joint tissues.

Another object of the present invention is to provide novel crystalline glucosamine sulfate metal salts having a low metal content which may contain either sodium or potassium as an effective and safe drug for sodium or potassium-sensitive arthritic patients.

It is a further object of the present invention to provide methods for preparing crystalline glucosamine sulfate metal salts having low metal content using solvents and without the use of solvents.

Yet another object of the present invention is to provide a pharmaceutical composition comprising novel crystalline metal salts of glucosamine sulfate with a low metal content.

Summary of the Invention

Thus, it is an object of the present invention to provide novel crystalline glucosamine sulfate metal salts having a low metal content which are represented by the following formula I:

ch ₂ oh

H /

O

HO

H NH ₂

OH

MHSO4-2CI wherein M represents Na or K (hereinafter referred to as Compound I).

Compound I (M = Na) has a sodium content of only 4.22% compared to 8% sodium in mixed glucosamine sulfate sodium, a product described previously (U.S. Patent Nos. 5,847,107 and 5,902,801). In addition, the potassium content of compound I (M = K) is only 7.16% compared to 12.9% of the potassium contained in the product described in U.S. Pat. 5847107 and 5902801.

Thus, the compounds of formula I of the present invention are far superior to the compounds described above in terms of their utility in the specific treatment of arthritic patients who are sodium and potassium sensitive.

According to another aspect of the present invention there is provided a process for the preparation of compounds of formula I using solutions comprising the steps of:

i. interaction of glucosamine hydrochloride and stoichiometric amounts of metal bisulfate selected from sodium bisulfate and potassium bisulfate in a solvent;

ii. precipitating the resulting glucosamine sulfate metal salt in the presence of a water-miscible organic solvent;

iii. filtering the reaction mass to give a compound of formula I.

In this process (i), the solvent used in the reaction step may be water.

In addition, said steps of precipitating the resulting glucosamine sulfate metal salt may be either pouring the resulting solution of step (i) into a water-miscible organic solvent or pouring the water-miscible organic solvent into the resulting solution of step (i) and subsequently mixing the resulting solution set time. This well-stirred reaction mass is then filtered to give the desired compound of formula I.

According to another aspect of the present invention, the reaction mass is allowed to cool for a predetermined period of time prior to filtration of the reaction mass in step (iii) and then filtered to give a compound of formula I.

The term "stoichiometric amounts" in a solvent-based method refers to a 2: 1 ratio of glucosamine hydrochloride to metal bisulfate.

Water-miscible organic solvents may be selected from ethanol, propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide and the like. The preferred solvent is isopropanol.

The water-miscible organic solvent is taken in a ratio of four to ten parts by volume based on the volume of the solution of step (i). It is best to add the solution of step (i) to 6 times the volume of the water miscible solvent.

The time required for the solutions to pour can vary from 5 minutes to 4 hours, preferably 1 hour.

The resulting solution of step (i) is added to a water-miscible organic solvent, or the water-miscible organic solvent is added to the resultant solution of step (i) at room temperature ranging from 17 ° C to 35 ° C, preferably 20 to 25 ° C.

The resulting precipitated mixture is stirred for about 2 to 6 hours, preferably for 4 hours, at room temperature ranging from 17 ° C to 35 ° C, preferably 20 to 25 ° C. This well-stirred reaction mass is then filtered under vacuum. The product is washed to give glucosamine sulfate salt as a white solid and dried at 25 ° C in vacuo.

In another aspect of the present invention, this well-mixed mass may be cooled to 0-20 ° C, preferably to 0-10 ° C, more preferably to 0-5 ° C, and maintained at this temperature for 1-24 hours, preferably 1-20 hours. preferably 1-16 hours. The product is washed to give glucosamine sulfate salt as a white solid and dried at 25 ° C in vacuo.

According to another aspect of the present invention there is provided a process for the preparation of compounds of Formula I without the use of a solvent comprising rubbing stoichiometric amounts of a mixture of glucosamine hydrochloride and metal bisulfate at room temperature for a defined period of time.

The term "stoichiometric amounts in a solvent-free process" refers to a 2: 1 ratio of glucosamine hydrochloride to metal bisulfate.

The term "room temperature" in a solvent-free mode refers to temperatures ranging from 17 ° C to 35 ° C, preferably 20 to 25 ° C.

The mixture is pulverized using suitable equipment such as a ball mill, a multi-purpose mill, a hammer mill, and the like; or Pest and mortar It is best to use a mortar and pestle for powdering.

Rub into powder for about 0.2 to 2 hours, preferably 0.5 to 1 hour.

the compounds of formula I of the present invention are stable at room temperature and humidity. The yield of the product is 75-85% when using a solvent-based process. The yield of the product is 97 - 99.5% when using a solvent-free process.

The compounds of the formula I of the present invention are useful in the treatment of both acute and chronic forms of rheumatic and arthritic diseases, in particular osteoarthritis, and in general, all pathological conditions resulting from metabolic disorders of bone-joint tissues.

Preferably, the compounds of the present invention are administered orally in dosage form, such as tablets or capsules, or by injection. The present invention also encompasses other dosage forms containing the compounds of the present invention.

Thus, another aspect of the present invention is to provide a pharmaceutical composition comprising a compound of formula I of the present invention. The pharmaceutical composition of the present invention may be prepared according to standard procedures by mixing a compound of Formula I with one or more pharmacologically acceptable excipients and / or excipients such as fillers, emulsifiers, ointments, taste masking, coloring or buffering agents, and converting the mixture into a suitable dosage form. such as tablets, coated tablets, capsules, or suspensions or solutions for parenteral administration.

The scope and objects of the present invention will be further illustrated by the following examples which are not to be construed as limiting the invention in any way:

Preparation of glucosamine sulphate sodium (low sodium content)

Glucosamine hydrochloride (6.45 g, 0.03 mol) and sodium bisulfate (1.8 g, 0.015 mol) were added to the flask and dissolved in water (25 mL). The resulting solution was added dropwise to vigorously stirred isopropanol (150 mL) at room temperature over 1 hour. Stir the contents of the flask for 4 hours, then store at 0-5 ° C for 16 hours. The precipitate was filtered off with suction (150 mm Hg). The product is washed twice (each time with 25 ml isopropanol). Glucosamine sulphate salt is obtained in the form of a white solid which is dried at 25 ° C in vacuo (2 mm Hg).

6.6 g> 300 ° C + 59 ° (c 2, water)

4.22%.

Yield:

Lyd. temp. Wd ^25: sodium content:

example:

Glucosamine sulphate potassium production (low potassium content)

Glucosamine hydrochloride (6.45 g, 0.03 mol) and potassium bisulfate (2.040 g, 0.015 mol) are added to the flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol (150 mL) at room temperature over 1 hour. Stir the contents of the flask for 4 hours, then store at 0-5 ° C for 16 hours. The precipitate was filtered off with suction (150 mm Hg). The product is washed twice (each time with 25 ml isopropanol). Glucosamine sulphate salt is obtained in the form of a white solid which is dried at 25 ° C in vacuo (2 mm Hg).

Yield:

Lyd. temp.

[a] o ^25:

6.94 g> 300 ° C + 58.5 ° (c 2, water) potassium content: 7.16%.

example:

Preparation of glucosamine sulphate sodium (low sodium content)

Glucosamine hydrochloride (6.45 g, 0.03 mol) and sodium bisulfate (1.8 g, 0.015 mol) are added to the flask and dissolved in water (25 ml). The resulting solution was stirred vigorously and isopropanol (150 mL) was added dropwise over 1 hour at 25 ° C (room temperature). Stir the contents of the flask for 4 hours, then store at 0-5 ° C for 16 hours. The precipitate was filtered off with suction (150 mm Hg). The product is washed twice (each time with 25 ml isopropanol). Glucosamine sulphate salt is obtained in the form of a white solid which is dried at 25 ° C in vacuo (2 mm Hg).

Yield: 6.34 g

Lyd. temp. > 300 ° C [a] o ^25: + 60 ° (c 2, water) Example:

Preparation of glucosamine sulphate sodium (low sodium content)

Glucosamine hydrochloride (6.45 g, 0.03 mol) and sodium bisulfate (1.8 g, 0.015 mol) are added to the flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol (150 mL) at room temperature over 1 hour. The contents of the flask are stirred for another 4 hours and the precipitate is filtered off under vacuum (150 mm Hg). The product is washed twice (each time with 25 ml isopropanol). Glucosamine sulphate salt is obtained in the form of a white solid which is dried at 25 ° C in vacuo (2 mm Hg).

Yield: 6.35 g

Lyd. temp. > 300 ° C [α] _D ^25: + 60.6 ° (c 2, water) v

^{, u} LT 5148 Example B:

Preparation of glucosamine sulphate sodium (low sodium content)

Glucosamine hydrochloride (6.45 g, 0.03 mol) and sodium bisulfate (1.8 g, 0.015 mol) are added to the flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol (150 mL) at room temperature over 1 hour. Stir the contents of the flask for 4 hours, then store at 0-5 ° C for 2 hours. The precipitate was filtered off with suction (150 mm Hg). The product is washed twice (each time with 25 ml isopropanol). Glucosamine sulphate salt is obtained in the form of a white solid which is dried at 25 ° C in vacuo (2 mm Hg).

Yield: 6.86 g

Lyd. temp. > 300 ° C [a] o ^2S + 60.4 ° (c 2, water) Example:

Preparation of glucosamine sulphate sodium (low sodium content)

Add to the flask glucosamine hydrochloride (6.45 g, 0.03 mol) and sodium bisulfate (1.8 g, 0.015 mol) and dissolve in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol (150 mL) at room temperature over 1 hour. Stir the contents of the flask for another 4 hours, then store at 0-5 ° C for 4 hours. The precipitate was filtered off with suction (150 mm Hg). The product is washed twice (each time with 25 ml isopropanol). Glucosamine sulphate salt is obtained in the form of a white solid which is dried at 25 ° C in vacuo (2 mm Hg).

Yield:

Lyd. temp.

[<x] d ^25:

6.9 g> 300 ° C + 59.5 ° (c 2, water).

example:

Preparation of glucosamine sulphate sodium (low sodium content)

Glucosamine hydrochloride (6.45 g, 0.03 mol) and sodium bisulfate (1.8 g, 0.015 mol) are added to the flask and dissolved in water (25 ml). The resulting solution was poured into vigorously stirred isopropanol (150 mL) at room temperature over 5 minutes. Stir the contents of the flask for 4 hours, then store at 0-5 ° C for 16 hours. The precipitate was filtered off with suction (150 mm Hg). The product is washed twice (each time with 25 ml isopropanol). Glucosamine sulphate salt is obtained in the form of a white solid which is dried at 25 ° C in vacuo (2 mm Hg).

yield: 6.68 g

Lyd. temp. > 300 ° C [α] ^25: + 60.0 ° (c 2, water) Example:

Glucosamine hydrochloride (12.9 g, 0.06 mol) is added to sodium bisulfate (3.6 g, 0.03 mol) and the mixture is pulverized with a mortar and pestle to give the glucosamine sulfate salt.

Yield: 16.1 g

Lyd. temp. > 300 ° C [<x] d ^25: + 51 ° (c 2, water)

Determination of metal content in mixed glucosamine sulphate metal salt

Sodium in mixed glucosamine sulfate sodium or potassium in mixed glucosamine sulfate potassium, respectively, was determined using the induced plasma method. Sodium content was measured at 589,592 nm and potassium content was measured at 766,491 nm.

Instrument: Induced plasma spectrometer

Model: Spectrofiame Modula Type FSM A 81 A.

Claims (20)

1. The novel crystalline metal salts of glucosamine sulphate with a low metal content are represented by the following formula I: CH ₂ OH ί ⁺ ? ^H MHSO ₄ - 2Cl Wherein M represents a metal selected from Na or K. Compound of formula 2.1 according to claim 1 wherein M is Na (sodium). Compound of formula 3.1 according to claim 1 wherein M is K (potassium). 4. A process for the preparation of a compound of the formula according to claim 1, characterized in that it comprises the following steps: (i) glucosamine hydrochloride and metal bisulfate of the formula MHSO ₄ , wherein M is as described in formula I above, in an aqueous solvent interaction of stoichiometric amounts to yield the glucosamine sulfate metal salt of (ii) in the resulting solution of step (i) using a water-miscible organic a solvent; (iii) filtering the reaction mass obtained in step (ii) to give a metal salt of glucosamine sulfate of formula I. 5. A process according to claim 4 wherein said aqueous solvent used in step (i) is water. 6. The process of claim 4, wherein said step of precipitating the resulting glucosamine sulfate metal salt comprises either pouring the solution obtained in step (i) into a water-miscible organic solvent or pouring the water-miscible organic solvent into a solution of step (i) at a suitable temperature. and stirring the resulting reaction mixture for a defined period of time 7. A process according to claim 6, wherein the addition is carried out at a temperature of 17 ° C to 35 ° C. 8. The method of claim 6, wherein the addition is carried out over a period of time ranging from 5 minutes to 4 hours. 9. A process according to claim 4 or 6 wherein the ratio of the solution obtained in step (i) to the water-miscible organic solvent is from 1: 4 to 1:10. 10. A process according to claim 4 or 6 wherein the water miscible organic solvent can be selected from ethanol, propanol, isopropanol, acetone, acetonitrile, tetrahydrofuran, dioxane, dimethylformamide and the like. 11. A process according to claim 6, wherein the resulting reaction mixture is stirred at a suitable temperature for a defined period of time. 12. A process according to claim 11, wherein the resulting reaction mixture is stirred for 2 to 6 hours. 13. A process according to claim 11, wherein the reaction mixture is stirred at a temperature of 17 to 35 ° C. 14. The process of claim 4, wherein said reaction mass filtration step (iii) is cooled to a suitable temperature and maintained at said temperature for a defined period of time prior to said filtration step. 15. A process according to claim 14, wherein said reaction mass is cooled to 0-20 ° C. 16. A process according to claim 14, wherein said reaction mass is maintained at said temperature for 1-24 hours. Process for the preparation of a compound of formula 17.1 according to claim 1, characterized in that it comprises glucosamine hydrochloride and metal bisulfate of the formula MHSO ₄ , wherein M represents a powder of a mixture of stoichiometric quantities of a metal selected from Na or K, using an appropriate device at room temperature over a defined period of time. 18. The method of claim 17, wherein the process is powdered within 0.2-2.0 hours. 19. A pharmaceutical composition comprising an effective amount of a compound of formula I according to claim 1. A compound according to claim 1 for use in the treatment of both acute and chronic forms of rheumatic and arthritic diseases and of any pathological condition resulting from metabolic disorders of bone and joint tissues.