GASTRO RETENTIVE DRUG DELIVERY SYSTEM OF CALCIUM AND ITS SALTS

FIELD OF THE INVENTION

The present invention relates to gastro retentive dosage form of calcium and its salts. The present invention also relates to process for preparing gastro retentive dosage form calcium and its salts.

BACKGROUND OF THE INVENTION

Vitamin and mineral supplements for human and veterinary use are commonplace. Some diets, heavy physical exercise and disease conditions may require the intake of considerable quantities of minerals and vitamins apart from those generally obtained through what otherwise would be considered a normal diet. Calcium and vitamin supplementation is important primarily for those who have inadequate diets, including growing children. Older adults have an additional need for calcium to help prevent the bone loss which occurs as a normal consequence of the aging process. In particular, postmenopausal women need additional calcium due to hormonal changes which can accelerate the bone loss rate leading to a further diminishment in bone mass.

There are well-recognized problems associated with adding both calcium and vitamin D to foods and beverages. Some of these are taste; calcium tends to be chalky in flavor. In addition, the solubility of many calcium sources prevents them from being added to many beverages. Interactions of calcium with the food or beverage affect the stability and/or the bio availability of the product. This invention provides a means for making such product.

Calcium is the fifth most abundant element in the human body. It plays an important role in many physiological processes, including nerve and muscle functions. Not surprisingly, nutritional and metabolic deficiencies of calcium can have broad-ranging adverse effects. Since about 90% of the body's calcium is found in bone tissues, many of these adverse effects are manifested through deficiencies in the structure, function and integrity of the skeletal system.

The most common metabolic bone disorder is osteoporosis. Osteoporosis can be generally defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue. In general, there are two types of osteoporosis: primary and secondary. "Secondary osteoporosis" is the result of an identifiable disease process or agent. However, approximately 90% of all osteoporosis cases is idiopathic "primary osteoporosis". Such primary osteoporosis includes postmenopausal osteoporosis, age-associated osteoporosis (affecting a majority of individuals over the age of 70 to 80), and idiopathic osteoporosis affecting middle-aged and younger men and women.

For some osteoporotic individuals the loss of bone tissue is sufficiently great so as to cause mechanical failure of the bone structure. Bone fractures often occur, for example, in the wrist and spine of women suffering from postmenopausal osteoporosis. Kyphosis (abnormally increased curvature of the thoracic spine) may also result.

The mechanism of bone loss in osteoporotics is believed to involve an imbalance in the process of "bone remodeling". Bone remodeling occurs throughout life, renewing the skeleton and maintaining the strength of bone. This remodeling occurs in a series of discrete pockets of activity in the bone, called "osteoclasts" and "osteoblasts". Osteoclasts (bone dissolving or resorbing cells) are responsible for the resorption of a portion of bone within the bone matrix, during the resorption process. After resorption, the osteoclasts are followed by the appearance of osteoblasts (bone forming cells), which then refill the resorbed portion with new bone.

In a healthy adult, the rate at which the osteoclasts and osteoblasts are formed maintains a balance of bone resorption and bone formation. However, in osteoporotics an imbalance in this remodeling process develops, resulting in loss of bone at a rate faster than the accretion of bone. This imbalance is much more severe, and occurs at a younger age, in osteoporotics as compared to healthy adults.

Calcium is a mineral that is helpful for building and maintaining strong bones and preventing bone diseases such as osteoporosis. Therefore, it can be important for individuals to consume a calcium-rich diet. While a variety of dairy products provide good sources of calcium, many individuals still find it difficult to get the calcium they need. One reason for this is that individuals often find it difficult to consume the amount of such foods needed to satisfy their recommended daily allowance of calcium. With milk in particular, many individuals enjoy consuming a glass of milk from time to time, but may find it challenging to consume the roughly three full glasses they need to satisfy their recommended daily allowance of calcium. This task can be made even more difficult if the individual suffers from one of a variety of dairy or lactose-related conditions, such as, for example, lactose intolerance.

Many compositions and methods are described in the medical literature for the "treatment" of osteoporosis. See, for example, R. C. Haynes, Jr. et al., "Agents affecting Calcification", The Pharmacological Basis of Therapeutics, 7th Edition (A. G. Gilman, L. S. Goodman et al., Editors, 1985); and G. D. Whedon et al., "An Analysis of Current Concepts and Research Interest in Osteoporosis", Current Advances in Skeletogenesis (A. Ornoy et al., Editors, 1985). Estrogen is often used to affect the metabolism of calcium by influencing the osteoblast cells. Treatments using fluoride have also been described. However, the utility of such agents may be limited, because of possible adverse side effects. See W. A. Peck, et al., Physician's Resource Manual on Osteoporosis (1987), published by the National

Osteoporosis Foundation.

Nutritional therapies for osteoporosis have also been proposed. Many calcium-containing compounds and vitamins compositions have been described for use as nutritional supplements. Many commercial preparations are also available, typically containing calcium carbonate or calcium phosphate. Other calcium salts have also been described for use in calcium supplements, including calcium lactate, calcium citrate and calcium gluconate.

U.S. 3,949,098 patent describes a nutritious orange drink concentrate that contains whey protein. The patent suggests the addition of minor amounts of vitamins, including vitamin D, and other nutrients which include various minerals, such as calcium salts.

U.S. 4,497,800 patent describes a nutritionally complete ready-to-use liquid diet for providing total patient nourishment. The diet contains free amino acids and small peptides, a carbohydrate source, and nutritionally significant amounts of all essential vitamins and minerals, and stabilizers. Most of these minerals are given as the gluconate salt Cholecalciferol (D.sub.3) is included.

"Effects of calcium carbonate in hydroxyapatite on zinc and iron retention in postmenopausal women", Dawson-Hughes, Seligson and Hughes, American Journal of Clinical Nutrition, 44, 83-88 (1986) describes the effect of calcium carbonate on whole-body retention of zinc and iron in thirteen healthy post menopausal women. The test meal, including both dry food and a formulated beverage, included iron, calcium, copper and zinc at a level of one-third the usual daily requirement. These are levels normally found in human diets.

U.S. 3,992,555 patent describes food supplements prepared by mixing assimilable iron compounds, vitamins and minerals with a heated edible fat carrier. Calcium and vitamin D are among the minerals in the supplement.

U.S. 3,950,547 patent describes a dietary composition containing peptides and/or amino acids, lipids and carbohydrates in an aqueous emulsion. Vitamins, including D, are added. Calcium citrate is also used.
U.S. 4,070,488 patent discloses a highly stabilized balanced nutritive composition useful in supplementing the diet of humans and/or animals. This composition contains gelatin. The patent discloses that the sulfhydryl groups of the gelatin can render copper inactive toward ascorbic acid.

U.S. 4,214,996 patent issued to Buddemeyer et al (R.G.B. Laboratories, 1980) discloses mineral compositions which are very soluble. These compositions contain calcium, ether minerals and vitamins.

U.S. 5,128,374 patent discloses use of Calcium citrate malate for the treatment of osteoporosis.

U.S. 5,186,965 patent discloses process for preparation of calcium citrate malate

U.S. 5,314,919 Calcium citrate malate, having a molar ratio of calcium:citrate:malate of about 6:2:3.

U.S. 7,504,536 patent discloses process for producing a calcium citrate malate composition comprising the steps of: combining a calcium source, a citrate source, a malate source, and water to form a calcium citrate malate mixture; reacting the calcium citrate malate mixture until reaching a peak temperature of from about 45°C to about 70°C; cooling the calcium citrate malate mixture at a rate of from about l°C/minute to about 4°C/minute to reach a final temperature of between about 10°C. and about 40°C, forming a calcium citrate malate precipitate; and drying the calcium citrate malate precipitate to obtain the calcium citrate malate composition.

There are numerous forms of calcium supplements available to today's consumers including calcium tablets, capsules and powders.

Calcium tablets and capsules often come in various dosage strengths which can provide consumers with flexibility in their dosage regimen. However, the calcium within such supplements is often not as bioavailable as thought to be by the consumer, thereby resulting in the consumer absorbing less calcium than anticipated.

Gastric hydrochloric acid helps calcium absorption. The duodenum is the main location for absorption of calcium because further down the small intestine the local environment becomes too alkaline. A fast-moving intestinal tract can also reduce calcium absorption.

All the current marketed formulations are immediate release dosage forms where the drug is immediately released and requires multiple administrations. Hence, there is need to develop more bio-available and less frequency of administration formulations of Calcium containing formulations. The present inventors have developed gastric floating drug delivery system (GFDDS) to facilitate absorption of calcium that is primarily bioavailable from the duodenum and upper jejunum segments. The GFDDS is able to prolong the retention time of a dosage form in the GI tract, thereby improving the oral bioavailability of the drug. The gastric residence time of a calcium-containing formulation was prolonged to permit calcium to reach the site of active absorption in a controlled manner and to increase oral bioavailability of calcium.

SUMMARY OF THE INVENTION

The present invention provides gastro retentive dosage form of Calcium and its salts.

The present invention also provides process for preparing gastro retentive dosage form of Calcium and its satis.

DETAILED DESCRIPTION OF THE INVENTION

The main embodiment of the present invention is gastro retentive dosage form of Calcium and its salts.

In another embodiment of the present invention is process for preparing gastro retentive dosage form of Calcium and its salts.

Calcium and its salts as defined in this patent are selected from Calcium citrate maleate, calcium citrate, calcium lactate, calcium carbonate, calcium gluconate, calcium phosphate.
Gastro retentive dosage form of the present wherein the dosage from may be tablets, capsules, minitablets filled in capsules and the kind.

In an another embodiment of the present invention, gastro retentive dosage fonn of Calcium and its salts comprising calclium salt and one or more pharmaceutically acceptable excipients.

One or more pharmaceutically acceptable excipients are selected from absorption enhancing agents, diluents, binders, disintegrants, floating/gas generating agents, polymers, glidants, lubricants, anti adherents, preservatives and combinations there of.

Suitable absorption enhancing agents used according to the present invention may be selected from Vitamin D3.

Suitable diluents used according to the present invention may be selected from microcrystalline cellulose, lactose, starch, 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 and combinations thereof.

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

Suitable floating/gas generating agents used according to the present invention may be selected from sodium bicarbonate, potassium bicarbonate, citric acid and combinations thereof.

Suitable polymers used according to the present invention may be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene glycol, polymethacrylates, acrylic polymers, methacrylic acid, methacylic acid copolymers, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene-polypropylene glycol copolymers, locust bean gum, tragacanth gum, guar gum, gum arabic, tamarind gum, tara gum, carrageenan, water-soluble alginates, pullulan and synthetic polymers such as polyethyleneoxides, polyoxyethylene-polyoxypropylene copolymers, and combinations thereof.
Suitable lubricants used according to the present invention may be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and the like.

Suitable glidants used according to the present invention may be selected from calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc and combinations thereof.

Suitable preservatives used according to the present invention may be selected from methyl paraben, propyl paraben, benzalkonium chloride, butylated hydroxy anisole and combinations thereof.
In another embodiment of the present invention, the gastro retentive dosage from of calcium and its salts may be prepared by direct compression, wet granulation or dry granulation.

In another embodiment of the present invention, the gastro retentive dosage from of calcium and its salts tablets may be coated tablets or uncoated tablets.

Suitable solvents used for wet granulation according to the present invention may be selected from water, isopropyl alcohol, ethanol, methylene chloride and combinations thereof.

In another embodiment of the present invention, the gastro retentive dosage from calcium and its salts may be used to treat conditions caused by low calcium levels such as bone loss (osteoporosis), weak bones (osteomalacia/rickets), decreased activity of the parathyroid gland (hypoparathyroidism), and a certain muscle disease (latent tetany). It may also be used in certain patients to make sure they are getting enough calcium (e.g., women who are pregnant, nursing, or postmenopausal, people taking certain medications such as phenytoin, phenobarbital, or prednisone).

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

Process:
i) Sifted Calcium Citrate maleate through, # 20 mesh (ASTM) and collected into double lined poly bag. Sifted Methyl Paraben Sodium, Propyl Paraben Sodium, Sodium Bicarbonate, Methocel K4M, Methocel K100M through # 40 mesh (ASTM) and collected them separately, ii) Loaded Vitamine D3, sifted Methyl Paraben Sodium, Propyl Paraben Sodium, Sodium Bicarbonate, Methocel K4M, Methocel K100M in octagonal blender and blended for 10 minutes, iii) Added Magnesium stearate & Colloidal Silicondioxide to the blender of step ii) and blend for 5 minutes, iv) Compressed the blend of step iii) into tablets v) Disperse Opadry in purified water with constant stirring. Continue the stirring to get
uniform coating dispersion. Filter the suspension through # 85 mesh or nylon cloth, vi) finally coated the tablets of step iv) using coating solution of step v)

We Claim:

1. Gastro retentive dosage form of calcium and its salts.

2. Gastro retentive dosage form as claimed in claim 1, wherein calcium salts are selected from Calcium citrate maleate, calcium citrate, calcium lactate, calcium carbonate, calcium gluconate, calcium phosphate.

3. Gastro retentive dosage form as claimed in claim 1, wherein the dosage form comprises absorption enhancing agents, diluents, binders, disintegrants, floating agents, polymers, lubricants, anti adherents, preservatives and combinations thereof.

4. Diluents as claimed in claim 3, wherein diluents are selected from microcrystalline cellulose, lactose, starch, sorbitol, sucrose, dicalcium phosphate or combinations thereof.

5. Binders as claimed in claim 3, wherein binders are selected from povidone, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose or combinations thereof.

6. Disintegrants as claimed in claim 3, wherein disintegratns are selected from sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, starch, and combinations thereof.

7. Floating agents as claimed in claim 3, wherein floating/gas generating agents are selected from sodium bicarbonate, potassium bicarbonate, citric acid and combinations thereof.

8. Polymers as claimed in claim 3, wherein polymers are selected from hydroxypropyl methylcellulose, hydroxy-propyl cellulose, ethyl cellulose, polyethylene glycol, polymethacrylates, acrylic polymers, methacrylic acid, methacylic acid copolymers, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene-polypropylene glycol copolymers, locust bean gum, tragacanth gum, guar gum, gum arabic, tamarind gum, tara gum, carrageenan, water-soluble alginates, pullulan and synthetic polymers such as polyethyleneoxides, polyoxyethylene-polyoxypropylene copolymers, and combinations thereof.

9. Lubricants as claimed in claim 3, wherein lubricants are selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and combinations thereof.

10. Preservatives as claimed in claim 3, wherein preservatives are selected from methyl paraben, propyl paraben, benzalkonium chloride, butylated hydroxy anisole and combinations thereof.