SUSTAINED RELEASE DOSAGE FORM OF GLUCOSAMINE FIELD OF THE INVENTION

The present invention relates sustained release dosage form of nutraceutical. More particularly the present invention relates to sustained release dosage form of Glucosamine and its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Glucosamine (C6Hi3NOs) is an amino sugar and a prominent precursor in the biochemical synthesis of glycosylated proteins and lipids. A type of glucosamine forms chitosan and chitin, which composes the exoskeletons of crustaceans and other arthropods, cell walls in fungi and many higher organisms. Glucosamine is one of the most abundant monosaccharides. It is produced commercially by the hydrolysis of crustacean exoskeletons, or less commonly and more expensive to the consumer, by fermentation of a grain such as corn or wheat. Glucosamine is commonly used as a treatment for osteoarthritis, although its acceptance as a medical therapy varies.

Natural ingredients, including Ayurvedic formulations, have been used to treat bone and joint inflammation, especially in eastern countries, and, increasingly, in western countries. Such natural ingredients include, for example, cartilage, chondroitin, glucosamine, proteolytic and other enzymes, and herbs, such as the gummy extract of B. serrata, Ashwagandha root and ginseng root. Although such natural ingredients generally do not lead to the kind of side effects observed with the steroidal and nonsteroidal anti-inflammatory drugs (NSAIDS), many of these natural ingredients do not always provide sufficient relief of pain or restoration of significant function and use of inflamed tissue, e.g., joints. However, glucosamine and chondroitin have been found to contribute to restoring such function and use. Although glucosamine generally does not provide the same rapid temporary relief of inflammation and pain as aspirin or nonsteroidal anti-inflammatory drugs (NSAIDS), it plays several key roles in the preservation and rebuilding of joint tissues. Namely, it stimulates the cartilage cells to produce glycosaminoglycans and proteoglycans, which maintain healthy joints and contribute to rebuilding connective tissue, and it, is one of the main ingredients of the synovial fluid that lubricates and provides nutrients for the joint structure. By participating in the preservation and rebuilding of joint tissues, it is believed that glucosamine can contribute to long term relief of a wide range of degenerative and inflammatory conditions such as rheumatoid arthritis, osteoarthritis, degenerative spinal disc disease, tendonitis, bursitis, and trauma to joints, tendons and ligaments, and may actually reverse the underlying disease process, in many cases.

Chondroitin, e.g., chondroitin sulfate, have also been found to play a role in the preservation and rebuilding of joint tissues. In a similar fashion to glucosamine, chondroitin have been found to stimulate cartilage cells to produce the needed proteoglycans and to inhibit the enzymes that break down proteoglycans. Chondroitin sulfate in particular also functions to draw fluid into the proteoglycans molecules. This fluid acts as a shock absorber for the joint tissue and also carries nutrients into the cartilage.

Although the administration of glucosamine appears to be an effective treatment for many conditions having an inflammatory component, it is not free of side effects. In that regard, it has been found that high blood serum levels of glucosamine can interfere with glucose regulation in both normal individuals and individuals with diabetes mellitus. The high .levels of glucosamine can induce an insulin resistance response, resulting in reduced rates of insulin-mediated glucose uptake by the liver, skeletal muscle, and adipose tissue (fat cells). If uncontrolled, insulin-resistance can lead to hyperglycemia and possibly glucose toxicity. In normal (i.e., non-diabetic) individuals, hyperglycemia can interfere with cellular metabolism and the mechanics for insulin- induced glucose disposal. The hyperglycemia itself can worsen insulin resistance, thus contributing to a vicious cycle that makes glycemic regulation more difficult. Moreover, hyperglycemia and insulin resistance are major contributing factors in the pathogenesis of non-insulin dependent diabetes mellitus (NIDDM).

The effects of high glucosamine levels on patients with NIDDM are typically more pronounced, since such patients generally affect glycemic regulation with dietary control. Thus, in such patients the cause and effect of insulin resistance and hyperglycemia on each other result in worsening the diabetic state and making glycemic regulation more difficult. Moreover, clinical studies have shown that hyperglycemia is the cause of most if not all of the chronic complications of diabetes. Insulin resistance induced by high levels of glucosamine can also have dramatic effects on patients with insulin dependent diabetes mellitus (IDDM) by again initiating a vicious cycle that worsens the diabetic state and makes glycemic regulation more difficult, possibly leading to glucose toxicity.

Drawbacks of glucosamine conventional tablets and capsules:

■ Glucosamine can be a stomach irritant in certain individuals, when glucosamine contacts the stomach lining.

■ Glucosamine capsule dissolves very quickly and leads to stomach irritation because of the sudden release of the glucosamine.

■ Glucosamine tablets sudden dissolution provides high local concentrations and cause causes stomach lining irritation.

■ Significant fraction of the ingested glucosamine is catabolized by first-pass metabolism in the liver.

The bioavailability of oral glucosamine sulfate is only 26% of that seen with intravenous injection. The half life of glucosamine is short and is less than one hour Irritation mechanisms that depend on the fast release into the stomach of the active substance contained in a tablet should be significantly off-set if the active substance is released slowly.

Currently Glucosamine hydrochloride is available as 500, 750, 1000 & 1500mg immediate release tablets/capsules. It is also available in sustained release dosage forms of 1500mg strength.

There is limited literature available for sustained release technology for Glucosamine. Following are few prior arts which describes about sustained/ controlled release technology of Glucosamine.

U.S 6,767,899 patent describes a controlled-release glucosamine composition comprising a therapeutically effective amount of a glucosamine component dispersed in a controlled-release matrix system, said matrix system comprising a continuum of material and controlled-release component finely dispersed throughout said matrix system capable of releasing said glucosamine in an amount and at a rate sufficient to maintain an effective glucosamine blood serum level over a designated time period, said controlled-release component comprising at least one water soluble high molecular weight cellulose polymer.

U.S 7,056,531 patent describes a sustained release composition comprising powdered cellulose and maltodextrin and a compound selected from the group consisting of glucosamine sulfate, glucosamine hydrochloride and mixtures thereof.

WO 2008/136016 application describes a stable controlled release oral solid dosage form composition for management of arthritis and related disorders, said composition comprising glucosamine and/ or salt (s) of glucosamine at a concentration ranging from 50% to 98%, Eudragit RL 100 at a concentration ranging from 0.1 % to 5 %, and Eudragit RS 100 at a concentration ranging from 0.1 % to 5 %,

CN1634087 patent describes a sustained release formulation of a glucosamine salt, its preparation and usage. The sustained formulation includes the actives along with slow release materials.

The above prior arts describe about controlled/sustained release dosage forms of Glucosamine and its salts. However, still there is need to develop sustained release dosage forms of Glucosamine and its salts. The '899 patent describes hydroxylpropyl menthylcellulose molecular weight maximum of 85,000 for Glucosamine release upto 12 hours at a concentration of 8-12% and there is no disclosure for use of hydroxylpropyl menthylcellulose molecular weight more than of 85,000. The inventors of the present invention developed sustained release composition of Glucosamine and its salts using water soluble release polymer of hydroxypropyl methylcellulose having molecular weight of 100,000 to 200,000 using matrix based technology.

SUMMARY OF THE INVENTION

The main embodiment of the present invention provides sustained release dosage form of Glucosamine and its salts comprising hydroxypropyl methylcellulose having molecular weight of 100,000 to 200,000.

In another embodiment of the present invention provides process for preparing sustained release dosage form of Glucosamine and its salts comprising hydroxypropyl methylcellulose having molecular weight of 100,000 to 200,000.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides sustained release dosage form of Glucosamine and its salts comprising hydroxypropyl methylcellulose having molecular weight of 100,000 to 200,000.

Sustained release dosage form of the present invention further contains diluent, disintegrant, binder, lubricant, glidant and combinations thereof.

Suitable diluents used according to the present invention may be selected from microcrystalline cellulose, mannitol, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, dicalcium phosphate and combinations thereof.

Suitable binders used according to the present invention may be selected from povidone, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof.

Suitable disintegrants used according to the present invention may be selected from sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, polacraillin potassium, starch, and combinations thereof.

Suitable lubricants used according to the present invention may be selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and combinations thereof.

Suitable Glidants used according to the present invention may be selected from starch, talc, magnesium and calcium stearate, zinc stearate, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, colloidal anhydrous silica and combinations thereof..

Glucosamine component is selected from the group consisting of N-acetyl-D-glucosamine, and salts may be selected from glucosamine hydrochloride, glucosamine sulfate, phosphate, potassium chloride, sodium chloride and mixtures thereof. A typical dosage according to the invention ranges from about 2 mg to about 45 mg of glucosamine per kilogram of body weight per 24 hour period. Preferably, the daily dosage is from about 14 mg to about 29 mg and more preferably about 21 mg per kilogram of body weight.

Hydroxypropyl methylcellulose (HPMC) having molecular weight of 100,000 to 200,000 may be used in alone or combination of two different molecular weights of HPMC. Preferably combination of HPMC K 100 and K 200 were used.

In another embodiment of the present invention provides process for preparing sustained release dosage form of Glucosamine and its salts comprising hydroxypropyl methylcellulose (HPMC) having molecular weight of 100,000 to 200,000.

Sustained release dosage form of the present invention may be prepared by wet granulation, dry granulation or direct compression. Preferably wet granulation process.

Suitable solvents used in wet granulation may be selected from water, ethanol, isopropyl alcohol, and combinations thereof.

Sustained release dosage form of the present invention may be tablet, capsule, granule or suspension. The tablet may be film coated or uncoated.

Suitable film forming agents used according to the present invention may be selected from ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, shellac, gelatin and combinations thereof.

The sustained release dosage form of the present invention releases glucosamine in an amount and at a rate sufficient to maintain an effective glucosamine blood serum level
over a designated time period. Preferably, the sustained release dosage form is capable of releasing the glucosamine at a substantially constant rate over a designated time period selected from about 6, 8, 12 and 24 hours. More preferably the designated time period is about 12 hours.

"substanfially constant rate" refers to maintaining a release rate of the active ingredient, i.e., glucosamine, within a desired range over at least about 75% of the designated time period for release, preferably over at least about 80% and more preferably over at least about 90% of the designated time period.

The invention is illustrated by the following non limiting examples: Examples 1:



Brief manufacturing process:

1. Sifted Glucosamine HC1 through # 30 mesh, Calcium hydrogen phosphate anhydrous, Hypromellose K200M, Hypromellose K100M, Microcrystalline Cellulose PH 102, Colloidal anhydrous silica and Stearic acid (50) through # 40 mesh separately and Collected into double lined poly bag.

2. Dissolved the Povidone K90F in Purified water under stirring and continued the stirring to form a clear solution.

3. Mixed sifted intragraular Glucosamine HC1, Hypromellose K200M and Calcium Hydrogen phosphate anhydrous in rapid mix granulator for 5 minutes, slowly added povidone solution to the mixture for 1-5 minutes and continued mixing till to form consistent granules.

4. Dried the granules in fluid bed dryer and sifted the dried granules through 20# screen.

5. Blended sifted granules of step (4) with sifted extragranular Glucosamine Hydrochloride, Hypromellose 100M, Microcrystalline Cellulose PHI02 and Colloidal anhydrous silica for 10 minutes and lubricatec the blend with Stearic acid and blend for 5 minutes.

6. Compressed the lubricated blend into tablets.

Coating:

Layer I:

a) Dispersed HPMC E5 in Isopropyl alcohol under stirring.

b) Dissolved Macrogol (PEG 6000) in Purified water and added to step a) dispersion under stirring and continued the stirring till to form clear solution.

c) coated step b) dispersion on core tablets and dried the tablets

Layer II:

a) Purified water was taken into SS vessel with stirrer and form vortex under stirring. Added Macrogol (PEG 6000) under stirring and continued the stirring to form clear solution.

b) Added and dispersed HPMC E5 and Opadry White OY-58900 to the above a) step under stirring. Continued the stirring for 45 minutes.

c) Coated step b) dispersion on layer I film coated tablets.

We Claim:

1. Sustained release dosage form of Glucosamine and its salts comprising hydroxypropyl methylcellulose having molecular weight of 100,000 to 200,000 as sustained releasing agent and one or more pharmaceutically acceptable excipients.

2. Sustained release dosage form of Claim 1, wherein Glucosamine salts are selected from hydrochloride, sulfate, phosphate, potassium chloride, sodium chloride and mixtures thereof.

3. Sustained release dosage form of Claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluent, binder, disintegrant, lubricant, glidant and combinations thereof.

4. Sustained release dosage form of Claim 3, wherein diluent is selected from microcrystalline cellulose, mannitol, lactose, starch, calcium hydrogen phosphate, sorbitol, sucrose, dicalcium phosphate and combinations thereof.

5. Sustained release dosage form of Claim 3, wherein binder is selected from povidone, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof.

6. Sustained release dosage form of Claim 3, wherein disintegrant is selected from sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, polacraillin potassium, starch, and combinations thereof.

7. Sustained release dosage form of Claim 3, wherein lubricant is selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and combinations thereof.

8. Sustained release dosage form of Claim 3, wherein glidant is selected from starch, talc, magnesium and calcium stearate, zinc stearate, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, colloidal anhydrous silica and combinations thereof.

9. Sustained release dosage form of Claim 1, maybe be prepared by wet granulation, dry granulation or direct compression.