Title of Invention	STABLE PHARMACEUTICAL COMPOSITIONS OF CALCITRIOL AND MINERAL SUPPLEMENTS
Abstract	The invention relates to a stable pharmaceutical compositions and a process for the preparation of the same, which is used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of a therapeutically effective amount of Calcitriol; a therapeutically effective amount of elemental Calcium; a therapeutically effective amount of elemental Zinc; along with suitable pharmaceutically acceptable excipients; wherein Calcitriol is present in a dosage unit that physically separates it from other therapeutic components.

Title of Invention

STABLE PHARMACEUTICAL COMPOSITIONS OF CALCITRIOL AND MINERAL SUPPLEMENTS

Abstract

The invention relates to a stable pharmaceutical compositions and a process for the preparation of the same, which is used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of a therapeutically effective amount of Calcitriol; a therapeutically effective amount of elemental Calcium; a therapeutically effective amount of elemental Zinc; along with suitable pharmaceutically acceptable excipients; wherein Calcitriol is present in a dosage unit that physically separates it from other therapeutic components.

Full Text	Form 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULE 2003 PROVISIONAL SPECIFICATION [See section 10 and rule 13] 1. TITLE OF THE INVENTION "Stable pharmaceutical compositions of Calcitriol and mineral supplements" 2. APPLICANT (a) NAME: USV LIMITED (b) NATIONALITY: Indian Company incorporated under the Companies ACT 1956 (c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088, Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention. Technical field of the invention: The present invention relates to stable pharmaceutical compositions used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of: (a) a therapeutically effective amount of Calcitriol; (b) a therapeutically effective amount of elemental Calcium; (c) a therapeutically effective amount of elemental Zinc; along with suitable pharmaceutically acceptable excipients; wherein Calcitriol is present in a dosage unit that physically separates it from other therapeutic components. Further, the invention relates to a novel process for preparation of said stable compositions. Background and Prior art: Osteoporosis is a disorder characterized by porous, fragile bones. Osteoporosis is a concern as it is associated with fractures of the hip, vertebrae, wrist, pelvis, ribs, and other bones. Millions of men and women in India suffer from Osteoporosis every year. In Osteoporosis, the bone becomes weak and is likely to fracture. As Osteoporosis is characterized by low bone mass and deterioration of bone tissue, a bone mineral density (BMD) test helps to diagnose osteoporosis. Factors which cause Osteoporosis include low calcium intake, low vitamin D intake, poor calcium absorption and excess calcium excretion. When calcium intake is low or calcium is poorly absorbed, bone breakdown occurs as the body makes use of the calcium stored in bones to maintain normal biological functions such as nerve and muscle function. Bone loss also occurs as a part of the aging process. Some medications, such as glucocorticoids or some anti-convulsants may also have a negative effect on bone density and increase the chances for osteoporosis. Osteoarthritis, also known as degenerative arthritis is a type of arthritis that is caused by the breakdown and eventual loss of the cartilage of one or more joints. Cartilage provides a cushion and helps the bone to glide over one another and also absorbs the shock generated during physical movements. As the cartilage breaks down and wears out, the bones get rubbed together and causes pain and swelling. Osteoarthritis commonly affects the hands, feet, spine, and large weight-bearing joints, such as the hips and knees. Calcium is one of the most abundant minerals in the human body, the bones and teeth and plays a significant role in several functions such as muscle contraction, clotting of blood, blood vessel contraction and expansion, the secretion of hormones and enzymes, and sending messages through the nervous system. A constant level of calcium is maintained in body fluid and tissues so that these vital body processes function efficiently. Consumption of adequate dietary calcium reduces the risk of osteoporosis. Elemental calcium may be obtained from various forms of calcium such as calcium carbonate, calcium citrate, calcium gluconate, oyster shell calcium, scallop shell calcium, eggshell calcium, milk products and coral calcium. Another source of Calcium is Active Absorbable Algal Calcium (AAA Ca) also known as Triple A Cal. Active Absorbable Algal Calcium is a mixture of Active Absorbable calcium (AA Ca) and heated algal seaweed Cystophyllum fusiforme. Triple A cal is a highly absorbable form of calcium and research has shown that it increases the bone density even in the elderly persons. Calcitriol is a white, crystalline compound which occurs naturally in humans. Calcitriol is chemically (5Z,7E)-9,10-secocholesta-5,7,10(19)- triene-la, 3b,25 -triol and has a molecular weight of 416.65. Calcitriol is soluble in organic solvents and fatty oils, but relatively insoluble in water. Calcitriol is a synthetic vitamin D analog. Vitamin D is a fat-soluble vitamin which acts like a hormone, regulating the formation of bone and the absorption of calcium and phosphorus from the intestine and re-absorption of calcium in the kidneys. Vitamin D is essential for the development of strong skeleton as it promotes bone formation and mineralization. Vitamin D3 is produced photochemically in the skin from 7-dehydrocholesterol on exposure to sunlight, specifically ultraviolet B radiation or may also be consumed as a supplement. Vitamin D3 (cholecalciferol) gets hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3 or calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes. 25-hydroxycholecalciferol is further hydroxylated in the kidneys by the enzyme la-hydroxylase, into two dihydroxylated metabolites, the main biologically active hormone 1,25-dihydroxycholecalciferol (l,25(OH)2D3 or calcitriol). Vitamin D deficiency can result from inadequate intake and by inadequate sunlight exposure. Combined Calcium (500 mg of elemental Calcium as carbonate) and vitamin D (400 IU) daily supplementation was found to significantly increase bone mineral density in elderly women with vitamin D deficiency. Zinc plays a role in the preservation of bone mass and Zinc deficiency causes bone growth retardation. On aging, the bone zinc content gets decreased. Zinc has been demonstrated to have stimulatory effect on bone formation and mineralization. Several single ingredient compositions or stand alone products are commercially available. Major drawbacks associated with such single ingredient compositions include patient non-compliance due to multiple dosing. There are various commercially available soft gelatin capsule preparations containing combination of Calcitriol, Calcium and Zinc such as Calcom, Calzem, Calnet. However, these products contain calcium carbonate which is a poorly absorbed form of Calcium. Compositions containing Calcitriol in close contact with Calcium derived from Active Absorbable Algal Calcium show slow degradation due to the chemical interaction between calcitriol and highly alkaline AAA Calcium. US7067154 discloses a pharmaceutical composition containing Vitamin D and calcium, comprising a binding agent chosen from among the group consisting of: propylene glycol, a polyethylene glycol presenting a molecular weight comprised between 300 and 1500, liquid paraffin or silicone oil, useful for the treatment of nutritional deficiency of calcium and Vitamin D in the elderly. WO03055500 discloses a stable oral pharmaceutical composition used for the treatment or prevention of osteoporosis and other bone diseases which are characterised by a loss of bone mass. Compositions are in the form of chewable tablets, effervescent granules or effervescent tablets and contains a fluoride ion salt, vitamin D and elemental calcium in the form of salt as well as sufficient quantities of pharmaceutically-acceptable excipients. CN1729995 discloses a medicinal composition and its use in treating osteoporosis or bone fracture caused by osteoporosis, wherein the composition comprises alendronate, vitamin D and calcium salt. Although there are various compositions available there still exists a need for stable compositions which are effective and possess good shelf life stability and do not degrade on long term storage. Object of the Invention: The main object of the invention is to provide stable pharmaceutical compositions used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of therapeutically effective amount of Calcitriol, elemental Calcium and elemental Zinc. Another object of the invention is to provide combination of Active Absorbable Algal Calcium, Zinc Sulphate and Calcitriol where Calcitriol is stabilized in the presence of both Active Absorbable Algal Calcium and Zinc Sulphate. Another object of the invention is to provide a novel process for preparation of stable compositions wherein Calcitriol is formulated into a dosage unit which physically separates it from Active Absorbable Algal Calcium and zinc sulphate. Yet another object of the invention is to provide a fixed dose combination of Calcitriol, Calcium and Zinc for ease of administration and better patient compliance. Another object of the invention is to provide an Alu-Alu cold formed blister pack for the compositions which acts as an excellent moisture barrier with negligible moisture vapour transmission rates. Summary of the invention: The present invention discloses stable pharmaceutical compositions used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of: (a) a therapeutically effective amount of Calcitriol; (b) a therapeutically effective amount of elemental Calcium; (c) a therapeutically effective amount of elemental Zinc; along with suitable pharmaceutically acceptable excipients; wherein Calcitriol is present in a dosage unit that physically separates it from other therapeutic components. Further, the present invention discloses a novel process for preparation of said stable compositions comprising the steps of: (i) preparing granules of Active Absorbable Algal Calcium and Zinc sulphate using suitable pharmaceutical excipients; (ii) preparing Calcitriol solution using suitable pharmaceutical excipients; (iii)preparing Calcitriol soft gelatin capsules by encapsulation of Calcitriol solution of step(ii); (iv) filling the soft gelatin capsules of step (iii) into hard gelatin or hard cellulose capsules of appropriate size; (v) further filling the granules of Active Absorbable Algal Calcium and Zinc sulphate of step(i) into hard gelatin or hard cellulose capsules. Detailed Description of the invention: The present invention describes stable pharmaceutical compositions used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of: (a) a therapeutically effective amount of Calcitriol; (b) a therapeutically effective amount of elemental Calcium; (c) a therapeutically effective amount of elemental Zinc; along with suitable pharmaceutically acceptable excipients; wherein Calcitriol is present in a dosage unit that physically separates it from other therapeutic components. The present invention further describes a novel process for preparation of said stable compositions. Calcium is an essential component which prevents osteoporosis. Calcium requires the presence of vitamin D for maximum absorption. Calcium deficiency may be caused due to various reasons such as increased loss of calcium, low dietary calcium intake, medications that inhibit calcium absorption, decreased gastrointestinal tract absorption due to gastric or intestinal problems etc. Various forms of calcium are available in the market such as calcium carbonate, calcium gluconate, and calcium citrate. In the practice of the present invention, the source of elemental calcium is Active Absorbable Algal Calcium (AAA Ca) also known as Triple A cal. Active Absorbable Algal Calcium (AAA Ca) is a mixture of Active Absorbable calcium (AA Ca) and heated algal ingredient produced by heating cleaned oyster shell and seaweed Cystophyllum fusiforme submaximally under reduced pressure. Oyster shells contain abundant calcium and serves as the calcium supplement. These shells found near the sea coast are cleaned to remove the adhering materials and are heated submaximally to about 800°C under reduced pressure avoiding complete ashing to obtain active absorbable calcium (AA Ca) which mainly consists of calcium oxide. AA Ca is less irritable to the gastro-intestinal tract in comparison to the chemically synthesized calcium oxide. Cystophyllum fusiforme, a seaweed which grows along the sea coast is heated and added to AACa to produce AAA Ca. AAA Ca is better absorbed from the intestine than AA Ca. AAA Ca has been reported to be absorbed from the intestine more efficiently than calcium carbonate or any other calcium preparations. Calcitriol is a white, crystalline compound which occurs naturally in humans. Calcitriol is chemically (5Z,7E)-9,10-secocholesta-5,7,10(19)- triene-la, 3b,25 -triol. It has a calculated molecular weight of 416.65 and is soluble in organic solvents but relatively insoluble in water. Calcitriol improves the absorption of calcium from the gut, as calcium cannot be absorbed without vitamin D. Calcitriol is prone for chemical degradation in solid form. Another drawback associated with Calcitriol is that it is unstable in the presence of acidic or alkaline environment. Solid state Calcitriol is sensitive to pH, mechanical force and environment factors such as light, temperature, moisture and atmospheric oxygen. Zinc is an essential element in the preservation of bone mass and its deficiency causes bone growth retardation. On aging, the bone zinc content gets decreased. Zinc may be given as a supplement in treatment of osteoporosis and osteoarthritis. Zinc sulphate is the commonly used source of zinc. Although there are various combinations available for treatment of osteoporosis, it is found that long term stability of such combinations may not be guaranteed. Fixed dose combinations of the present invention are particularly in the form of solid dosage forms such as hard gelatin capsules or hard cellulose capsules wherein Calcitriol is formulated into soft gelatin capsules and Triple A cal, the source of elemental Calcium and Zinc sulphate, the source of elemental Zinc are formulated into granules. According to one embodiment of the invention, the stable pharmaceutical composition comprises Calcitriol formulated into a soft gelatin capsule and filled along with granules of Active Absorbable Algal Calcium and Zinc sulphate into hard gelatin capsules. Calcitriol is protected from degradation as it is encapsulated into soft gelatin capsule which separates it from the other two active components and in particular from the highly alkaline Active Absorbable Algal Calcium. Soft gelatin capsules serve the dual purpose of providing a barrier between Calcitriol and elemental metals and thus ensures accuracy in the dosage administered. In the practice of the present invention, as the soft gelatin capsule acts as a barrier between the Calcitriol and Calcium and Zinc components shelf-life stability of Calcitriol is ensured. Zinc Sulphate and Active Absorbable Algal Calcium are provided as combination blend and Calcitriol is in the form of a solution which is encapsulated into soft gelatin capsule along with antioxidants. According to another embodiment, the present invention provides fixed dose combinations containing Calcitriol, elemental Calcium and elemental Zinc. Fixed dose combination of the present invention ensures ease of administration and patient compliance. According to one embodiment of the invention, the stable composition comprises about 0.0001 wt % to about 0.2 wt % of Calcitriol; about 30.0wt % to about 50.0 wt % of Active Absorbable Algal Calcium and about 0.5 wt% to about 6.0 wt % of zinc sulphate or suitable pharmaceutically acceptable salt of zinc. Calcitriol soft gelatin capsules may preferably be used in an amount from about 5.0% to 15.0% by weight of the total composition preferably 10.0% to 15.0 % by weight of the total composition. According to the present invention, the stable composition contains elemental Calcium in an amount from 150mg to 300mg; preferably as 150mg or 300mg dose and elemental Zinc is present in the composition in an amount from 5.0mg to 7.5mg; preferably as 7.5mg dose. In the practice of the present invention, 150mg of elemental Calcium may be derived from about 300mg of Active Absorbable Algal Calcium and 7.5 mg of elemental Zinc may be derived from 20.58mg of Zinc sulphate monohydrate. As the total quantity of Active Absorbable Algal Calcium and Zinc sulphate monohydrate amounts to a very bulky preparation, formulating it into soft gelatin capsule would result in a bigger size soft gelatin capsule which may be difficult to swallow. According to one aspect of the invention, the fixed dose combination contains AAA Calcium equivalent to 150mg of elemental Calcium, Zinc sulphate equivalent to 7.5 mg of elemental Zinc and 0.25 microgram of Calcitriol. According to another aspect, the fixed dose combination contains AAA Calcium equivalent to 300mg of elemental Calcium, Zinc sulphate equivalent to 7.5 mg of elemental Zinc and 0.25 microgram of Calcitriol. Although the sensitive nature of calcitriol and alkaline nature of Active Absorbable Algal Calcium pose various problems during formulation, the inventors of the present invention have successfully developed a process for preparation of stable pharmaceutical compositions in the form of a unit dosage form wherein said compositions are stabilized by virtue of physical separation of the unstable components from the other active components. The inventors of the present invention also attempted formulating Calcitriol by dissolving it in absolute alcohol and further adding vitamin E and butylated hydroxy anisole into it to form a clear solution. This solution was then adsorbed over mannitol and the resultant mass was mixed with a mixture of zinc sulphate and colloidal anhydrous silica. The final blend was then mixed with Calcium and filled into hard gelatin capsules. In another approach, cetyl alcohol was dissolved in ethanol and vitamin E. Butylated hydroxy anisole was added to the solution followed by Calcitriol. The solution was then adsorbed over maize starch and the contents were dried and mixed initially with colloidal anhydrous silica and finally with Zinc granules and then with Calcium granules. Similar approach was initiated excluding cetyl alcohol in the same process. Another approach was made by dissolving Calcitriol in the solution of vitamin E and butylated hydroxy anisole in ethanol. Povidone was seperately dissolved in ethanol. Calcitriol solution was added to the povidone solution. Zinc sulphate was granulated with this solution and the granules thus obtained were blended with Calcium granules. However, all the three approaches attempted above were not considered successful with due consideration to Calcitriol stability. According to one embodiment of the present invention, the process of preparation of stable composition comprises the steps of: (i) preparing granules of Active Absorbable Algal Calcium and zinc sulphate using suitable pharmaceutical excipients; (ii) preparing calcitriol solution using suitable pharmaceutical excipients; (iii)preparing calcitriol soft gelatin capsules by encapsulation of Calcitriol solution of step(ii); (iv) filling the soft gelatin capsules of step (iii) into hard gelatin or hard cellulose capsules of appropriate size; (v) further filling the granules of Active Absorbable Algal Calcium and zinc sulphate of step(i) into hard gelatin or hard cellulose capsules. The process of preparation of AAA Calcium and Zinc Sulphate granules comprises the steps of: (a) mixing together AAA Calcium, Zinc Sulphate and suitable pharmaceutical excipients in a suitable equipment for a suitable period of time; (b) preparing the aqueous binder solution by dissolving the binder in purified water at 55 ± 5°C; (c) cooling the binder solution of step(b) to room temperature; (d) granulating the mixture of step(a) using the binder solution of step(c) to form a wet mass; (e) drying the wet mass of step (d) in a suitable equipment at about 60 - 65°C for sufficient time till loss on drying value in the range of 3.5% to 5.5% is achieved; (f) sizing and milling the dried mass to produce granules of required size; (g) mixing the sized granules of step(f) with suitable pharmaceutical excipients to form ready-to-fill granules. In the practice of the present invention, AAA calcium and zinc sulphate may be previously co-sifted prior to the mixing stage. Dry mixing may be carried out in any conventional mixing equipment such as rapid mixer granulator or fluid bed processor for about 10 minutes. The process of preparation of wet mass may be carried out in a conventional rapid mixer granulator and further the wet mass may be dried using fluid bed processor or fluid bed drier. However, in a conventional fluid bed processor both the steps of granulation and drying can be carried out in the same equipment thereby simplifying the process and saving the processing time. Dried mass may be sized using 20# sieve on vibratory sifter and further milling the oversized granules through 1.5 mm screen on the Multi-mill and then sifting through 20 # on Vibratory sifter. Suitable pharmaceutically acceptable excipients that may be used according to the invention include, but are not limited to, for example, diluents/fillers, acidifying agents, binders, wetting agents, glidants, lubricants, antiadherants and the like. Diluents, which may be used for preparation of AAA Calcium and zinc sulphate granules as per the invention, include, but are not limited to maize starch, lactose anhydrous, microcrystalline cellulose, pregelatinised starch or mixtures thereof. Diluents may be used in the range of about 1% to 60% by weight of the total composition. Preferred diluent being microcrystalline cellulose in an amount from 1% to 60% by weight of the total composition ; preferably from 5% to 60% by weight of the total composition. Acidifying agents which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to citric acid, tartaric acid, ascorbic acid and the like and may be used in the range of about 5.0% to about 15.0% by weight of the total composition; preferably about 7.0% to 10.0% by weight of the total composition. Binders which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to hydroxy propyl cellulose, povidone, hydroxy propyl methyl cellulose, sodium carboxy methylcellulose, xanthan gum, pregelatinised starch, maize starch and the like or mixtures thereof in an amount from 1% to 7% by weight of the total composition. The preferred binder is povidone alone or in combination with maize starch preferably in an amount from 1% to 7% by weight of the total composition most preferably from 2% to 6% by weight of the total composition. Wetting agents which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to sodium lauryl sulphate, docusate sodium and the like and may be used in an amount from 0.1% to 5% and preferably from 0.2% to 2.0% by weight of the total composition. Lubricants which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to calcium stearate, magnesium stearate, stearic acid, silicon dioxide, purified talc, sodium stearyl fumarate. Preferred lubricant being magnesium stearate, used in an amount from 0.1% to 1.5% and preferably from 0.2% to 1.0% by weight of the total composition. Glidants which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to colloidal silicon dioxide, purified talc. Colloidal silicon dioxide may be used in an amount from 0.1% to 1.5% by weight of the total composition; preferably from 0.2% to 1.0% and purified talc may be used in an amount from 0.5% to 2.5% by weight of the total composition; preferably from 0.7% to 1.5% by weight of the total composition. The process of preparation of Calcitriol soft gelatin capsules comprises the steps of: (a) dissolving the antioxidants in an edible fixed oil to form a solution; (b) dissolving the Calcitriol in the solution of step (a); (c) encapsulation of the Calcitriol solution of step(b) to form soft gelatin capsules using suitable capsule filling machine with 2 minims fill volume providing a fill weight between 70 to 100 mg. Antioxidants which may be used for preparation of Calcitriol soft gelatin capsules as per the invention include, but are not limited to butylated hydroxy anisole, butylated hydroxy toluene, sodium metabisulphite, ascorbic acid, sodium ascorbate, vitamin E and the like. Preferred antioxidants are butylated hydroxy toluene and butylated hydroxy anisole and may be present in an amount of not more than 0.5% weight of the soft gelatin capsule. Edible fixed oils which may be used for preparation of Calcitriol soft gelatin capsules as per the invention include, but are not limited to sesame oil, refined sunflower oil, refined corn oil, palm oil, olive oil, medium chain triglyceride oil(MCT Oil). Preferred edible fixed oils are MCT Oil and refined sunflower oil and are be used in an amount from 90% to 99%. Most preferred edible fixed oil is MCT oil and is used in the range from 95% to 99%. Medium chain triglyceride oil is most preferred as it is readily digested than long chain triglycerides and also possesses good stability against oxidation. Soft gelatin capsule of Calcitriol may be filled into the empty hard gelatin or empty hard cellulose capsule on automatic capsule filling machine with suitable change parts for filling of soft gelatin capsule into a hard gelatin capsule. Empty hard gelatin capsule or empty hard cellulose capsule of size '00' to '000' may be used. Capsules of size '00' may be preferred. Blend weight of AAA Calcium and Zinc Sulphate granules may be preferably from about 500mg to about 600mg and fill weight of soft gelatin capsules may be from 70mg to 100mg. Pharmaceutical compositions prepared by the process according to the present invention exhibits excellent chemical stability of Calcitriol and also maintains the potency and accuracy of Calcitriol dose. Stable compositions of the present invention may be packed in aluminium strips or by cold formed blister pack which is a cold process of blister packing which acts as an excellent moisture barrier with negligible moisture vapour transmission rate and provides protection from external environment. The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the disclosure. Examples Example 1 Step I : Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc sulphate granules: (a) Triple A cal (286.5gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer. (b) Zinc sulphate (20.58 gm) was mixed in geometric proportion with the mixture of Triple A Cal and anhydrous citric acid. (c) Binder solution was prepared by dissolving povidone (5gm) in water (lOOgm). Maize starch (15gm) was added to the hot binder solution to obtain a translucent starch paste. (d) Mixture of Triple A cal, citric acid anhydrous and zinc sulphate was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size. (e) Maize starch (15gm), microcrystalline cellulose (150gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend. (f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes. (g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate. Step II: Preparation of Calcitriol soft gelatin capsules: (a) Butylated hydroxy toluene (0.035 gm) and butylated hydroxy anisole (0.035 gm) was dissolved in medium chain triglyceride oil (65.0 gm). (b) Calcitriol (0.325mg) was added to the mixture of step(a) and further about 4.93 gm Medium Chain Triglyceride Oil was added to it to obtain Calcitriol solution. (c) Calcitriol solution of step(b) was encapsulated into soft gelatin capsules using 2 minims fill volume providing a fill weight of 70 mg. Step III: Preparation of hard gelatin capsule composition. (a) One calcitriol soft gelatin capsule prepared by step II procedure was filled into the hard gelatin/hard cellulose capsule of suitable size (size 00) using a suitable capsule filling machine with attachment for filling of Soft gelatin Capsules. (b) Ready-to-fill granules of step I was further filled into the hard gelatin/hard cellulose capsule of step(a). (c) Hard gelatin/hard cellulose capsules were packed in cold form Alu-Alu blisters. Example 2 Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc sulphate granules: (a) Triple A cal (286.5gm) and microcrystalline cellulose (150 gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer. (b) Zinc sulphate (20.58 gm) was mixed in geometric proportion with the mixture of Triple A Cal, microcrystalline cellulose and anhydrous citric acid. (c) Binder solution was prepared by dissolving povidone (5gm) in water (lOOgm). Maize starch (15gm) was added to the hot binder solution to obtain a translucent starch paste. (d) Mixture of Triple A cal, microcrystalline cellulose, anhydrous citric acid and zinc sulphate was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size. (e) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend. (f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes. (g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate. Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin/cellulose capsule composition was prepared according to the procedure described in step III of example 1. Example 3 Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc sulphate granules: (a) Triple A cal (286.5gm), microcrystalline cellulose (150 gm) and povidone (5gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer. (b) Zinc sulphate (20.58 gm) was mixed in geometric proportion with the mixture of Triple A Cal, microcrystalline cellulose, povidone and anhydrous citric acid. (c) Binder solution was prepared by dissolving maize starch (15gm) in water (lOOgm) to obtain a translucent starch paste. (d) Mixture of Triple A cal, microcrystalline cellulose, povidone, anhydrous citric acid and zinc sulphate was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size. (e) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend. (f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes. (g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate. Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin capsule composition was prepared according to the procedure described in step III of example 1. Example 4 Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc sulphate granules: (a) Triple A cal (286.5gm) and microcrystalline cellulose (150 gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer. (b) Zinc sulphate (20.58 gm) was dissolved in hot water (lOOgm) and further povidone (5.0 gm) and maize starch (15gm) was added to it to obtain a translucent starch paste. (c) Mixture of Triple A cal, microcrystalline cellulose and anhydrous citric acid was granulated with binder of step (b) to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size. (d) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend. (e) The blend of step(d) was mixed with granules of step(c) in a suitable blender for about 15 minutes. (f) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (e) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate. Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin capsule composition was prepared according to the procedure described in step III of example 1. Example 5 Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc sulphate granules: (a) Triple A cal (286.5gm) and microcrystalline cellulose (75 gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer. (b) Zinc sulphate (20.58 gm) was mixed with microcrystalline cellulose (75 gm) and further mixed with the mixture of Triple A Cal, microcrystalline cellulose and anhydrous citric acid in geometric proportion. (c) Binder solution was prepared by dissolving povidone (5gm) in water (lOOgm). Maize starch (15gm) was added to the hot binder solution to obtain a translucent starch paste. (d) Mixture of Triple A cal, microcrystalline cellulose, anhydrous citric acid and zinc sulphate was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size. (e) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend. (f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes. (g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate. Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin capsule composition was prepared according to the procedure described in step III of example 1. Example 6 Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc sulphate granules: (a) Triple A cal (286.5gm) and microcrystalline cellulose (150 gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer. (b) Binder solution was prepared by dissolving povidone (5gm) in water (100gm). Maize starch (15gm) was added to the hot binder solution to obtain a translucent starch paste. (c) Mixture of Triple A cal, microcrystalline cellulose and anhydrous citric acid was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size. (d) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend. (e) Zinc sulphate (20.58 gm) was mixed in geometric proportion with the blend of step(d). (f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes. (g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate. Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin capsule composition was prepared according to the procedure described in step III of example 1. While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.

Full Text

Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"Stable pharmaceutical compositions of Calcitriol and mineral supplements"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field of the invention:
The present invention relates to stable pharmaceutical compositions used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of:
(a) a therapeutically effective amount of Calcitriol;
(b) a therapeutically effective amount of elemental Calcium;
(c) a therapeutically effective amount of elemental Zinc;
along with suitable pharmaceutically acceptable excipients; wherein Calcitriol is present in a dosage unit that physically separates it from other therapeutic components.
Further, the invention relates to a novel process for preparation of said stable compositions.
Background and Prior art:
Osteoporosis is a disorder characterized by porous, fragile bones. Osteoporosis is a concern as it is associated with fractures of the hip, vertebrae, wrist, pelvis, ribs, and other bones. Millions of men and women in India suffer from Osteoporosis every year. In Osteoporosis, the bone becomes weak and is likely to fracture. As Osteoporosis is characterized by low bone mass and deterioration of bone tissue, a bone mineral density (BMD) test helps to diagnose osteoporosis.
Factors which cause Osteoporosis include low calcium intake, low vitamin D intake, poor calcium absorption and excess calcium excretion. When calcium intake is low or calcium is poorly absorbed, bone breakdown occurs as the body makes use of the calcium stored in bones to maintain normal biological functions such as nerve and muscle function. Bone loss also occurs as a part of the aging process. Some medications, such as glucocorticoids or some anti-convulsants may also have a negative effect on bone density and increase the chances for osteoporosis.

Osteoarthritis, also known as degenerative arthritis is a type of arthritis that is caused by the breakdown and eventual loss of the cartilage of one or more joints. Cartilage provides a cushion and helps the bone to glide over one another and also absorbs the shock generated during physical movements. As the cartilage breaks down and wears out, the bones get rubbed together and causes pain and swelling. Osteoarthritis commonly affects the hands, feet, spine, and large weight-bearing joints, such as the hips and knees.
Calcium is one of the most abundant minerals in the human body, the bones and teeth and plays a significant role in several functions such as muscle contraction, clotting of blood, blood vessel contraction and expansion, the secretion of hormones and enzymes, and sending messages through the nervous system. A constant level of calcium is maintained in body fluid and tissues so that these vital body processes function efficiently.
Consumption of adequate dietary calcium reduces the risk of osteoporosis. Elemental calcium may be obtained from various forms of calcium such as calcium carbonate, calcium citrate, calcium gluconate, oyster shell calcium, scallop shell calcium, eggshell calcium, milk products and coral calcium.
Another source of Calcium is Active Absorbable Algal Calcium (AAA Ca) also known as Triple A Cal. Active Absorbable Algal Calcium is a mixture of Active Absorbable calcium (AA Ca) and heated algal seaweed Cystophyllum fusiforme. Triple A cal is a highly absorbable form of calcium and research has shown that it increases the bone density even in the elderly persons.
Calcitriol is a white, crystalline compound which occurs naturally in humans. Calcitriol is chemically (5Z,7E)-9,10-secocholesta-5,7,10(19)- triene-la, 3b,25 -triol and has a molecular weight of 416.65. Calcitriol is soluble in organic solvents and fatty oils, but relatively insoluble in water. Calcitriol is a synthetic

vitamin D analog.
Vitamin D is a fat-soluble vitamin which acts like a hormone, regulating the formation of bone and the absorption of calcium and phosphorus from the intestine and re-absorption of calcium in the kidneys. Vitamin D is essential for the development of strong skeleton as it promotes bone formation and mineralization. Vitamin D3 is produced photochemically in the skin from 7-dehydrocholesterol on exposure to sunlight, specifically ultraviolet B radiation or may also be consumed as a supplement. Vitamin D3 (cholecalciferol) gets hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3 or calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes. 25-hydroxycholecalciferol is further hydroxylated in the kidneys by the enzyme la-hydroxylase, into two dihydroxylated metabolites, the main biologically active hormone 1,25-dihydroxycholecalciferol (l,25(OH)2D3 or calcitriol). Vitamin D deficiency can result from inadequate intake and by inadequate sunlight exposure.
Combined Calcium (500 mg of elemental Calcium as carbonate) and vitamin D (400 IU) daily supplementation was found to significantly increase bone mineral density in elderly women with vitamin D deficiency.
Zinc plays a role in the preservation of bone mass and Zinc deficiency causes bone growth retardation. On aging, the bone zinc content gets decreased. Zinc has been demonstrated to have stimulatory effect on bone formation and mineralization.
Several single ingredient compositions or stand alone products are commercially available. Major drawbacks associated with such single ingredient compositions include patient non-compliance due to multiple dosing.

There are various commercially available soft gelatin capsule preparations containing combination of Calcitriol, Calcium and Zinc such as Calcom, Calzem, Calnet. However, these products contain calcium carbonate which is a poorly absorbed form of Calcium.
Compositions containing Calcitriol in close contact with Calcium derived from Active Absorbable Algal Calcium show slow degradation due to the chemical interaction between calcitriol and highly alkaline AAA Calcium.
US7067154 discloses a pharmaceutical composition containing Vitamin D and calcium, comprising a binding agent chosen from among the group consisting of: propylene glycol, a polyethylene glycol presenting a molecular weight comprised between 300 and 1500, liquid paraffin or silicone oil, useful for the treatment of nutritional deficiency of calcium and Vitamin D in the elderly.
WO03055500 discloses a stable oral pharmaceutical composition used for the treatment or prevention of osteoporosis and other bone diseases which are characterised by a loss of bone mass. Compositions are in the form of chewable tablets, effervescent granules or effervescent tablets and contains a fluoride ion salt, vitamin D and elemental calcium in the form of salt as well as sufficient quantities of pharmaceutically-acceptable excipients.
CN1729995 discloses a medicinal composition and its use in treating osteoporosis or bone fracture caused by osteoporosis, wherein the composition comprises alendronate, vitamin D and calcium salt.
Although there are various compositions available there still exists a need for stable compositions which are effective and possess good shelf life stability and do not degrade on long term storage.

Object of the Invention:
The main object of the invention is to provide stable pharmaceutical compositions used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of therapeutically effective amount of Calcitriol, elemental Calcium and elemental Zinc.
Another object of the invention is to provide combination of Active Absorbable Algal Calcium, Zinc Sulphate and Calcitriol where Calcitriol is stabilized in the presence of both Active Absorbable Algal Calcium and Zinc Sulphate.
Another object of the invention is to provide a novel process for preparation of stable compositions wherein Calcitriol is formulated into a dosage unit which physically separates it from Active Absorbable Algal Calcium and zinc sulphate.
Yet another object of the invention is to provide a fixed dose combination of Calcitriol, Calcium and Zinc for ease of administration and better patient compliance.
Another object of the invention is to provide an Alu-Alu cold formed blister pack for the compositions which acts as an excellent moisture barrier with negligible moisture vapour transmission rates.
Summary of the invention:
The present invention discloses stable pharmaceutical compositions used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of:
(a) a therapeutically effective amount of Calcitriol;
(b) a therapeutically effective amount of elemental Calcium;
(c) a therapeutically effective amount of elemental Zinc;
along with suitable pharmaceutically acceptable excipients; wherein Calcitriol is

present in a dosage unit that physically separates it from other therapeutic components.
Further, the present invention discloses a novel process for preparation of said stable compositions comprising the steps of:
(i) preparing granules of Active Absorbable Algal Calcium and Zinc sulphate
using suitable pharmaceutical excipients;
(ii) preparing Calcitriol solution using suitable pharmaceutical excipients; (iii)preparing Calcitriol soft gelatin capsules by encapsulation of Calcitriol
solution of step(ii);
(iv) filling the soft gelatin capsules of step (iii) into hard gelatin or hard
cellulose capsules of appropriate size;
(v) further filling the granules of Active Absorbable Algal Calcium and Zinc
sulphate of step(i) into hard gelatin or hard cellulose capsules.
Detailed Description of the invention:
The present invention describes stable pharmaceutical compositions used for the prevention and treatment of osteoporosis and osteoarthritis comprising a combination of:
(a) a therapeutically effective amount of Calcitriol;
(b) a therapeutically effective amount of elemental Calcium;
(c) a therapeutically effective amount of elemental Zinc;
along with suitable pharmaceutically acceptable excipients; wherein Calcitriol is present in a dosage unit that physically separates it from other therapeutic components.
The present invention further describes a novel process for preparation of said stable compositions.
Calcium is an essential component which prevents osteoporosis. Calcium requires

the presence of vitamin D for maximum absorption. Calcium deficiency may be caused due to various reasons such as increased loss of calcium, low dietary calcium intake, medications that inhibit calcium absorption, decreased gastrointestinal tract absorption due to gastric or intestinal problems etc. Various forms of calcium are available in the market such as calcium carbonate, calcium gluconate, and calcium citrate.
In the practice of the present invention, the source of elemental calcium is Active Absorbable Algal Calcium (AAA Ca) also known as Triple A cal. Active Absorbable Algal Calcium (AAA Ca) is a mixture of Active Absorbable calcium (AA Ca) and heated algal ingredient produced by heating cleaned oyster shell and seaweed Cystophyllum fusiforme submaximally under reduced pressure.
Oyster shells contain abundant calcium and serves as the calcium supplement. These shells found near the sea coast are cleaned to remove the adhering materials and are heated submaximally to about 800°C under reduced pressure avoiding complete ashing to obtain active absorbable calcium (AA Ca) which mainly consists of calcium oxide. AA Ca is less irritable to the gastro-intestinal tract in comparison to the chemically synthesized calcium oxide. Cystophyllum fusiforme, a seaweed which grows along the sea coast is heated and added to AACa to produce AAA Ca.
AAA Ca is better absorbed from the intestine than AA Ca. AAA Ca has been reported to be absorbed from the intestine more efficiently than calcium carbonate or any other calcium preparations.
Calcitriol is a white, crystalline compound which occurs naturally in humans. Calcitriol is chemically (5Z,7E)-9,10-secocholesta-5,7,10(19)- triene-la, 3b,25 -triol. It has a calculated molecular weight of 416.65 and is soluble in organic solvents but relatively insoluble in water. Calcitriol improves the absorption of

calcium from the gut, as calcium cannot be absorbed without vitamin D.
Calcitriol is prone for chemical degradation in solid form. Another drawback associated with Calcitriol is that it is unstable in the presence of acidic or alkaline environment. Solid state Calcitriol is sensitive to pH, mechanical force and environment factors such as light, temperature, moisture and atmospheric oxygen.
Zinc is an essential element in the preservation of bone mass and its deficiency causes bone growth retardation. On aging, the bone zinc content gets decreased. Zinc may be given as a supplement in treatment of osteoporosis and osteoarthritis. Zinc sulphate is the commonly used source of zinc.
Although there are various combinations available for treatment of osteoporosis, it is found that long term stability of such combinations may not be guaranteed.
Fixed dose combinations of the present invention are particularly in the form of solid dosage forms such as hard gelatin capsules or hard cellulose capsules wherein Calcitriol is formulated into soft gelatin capsules and Triple A cal, the source of elemental Calcium and Zinc sulphate, the source of elemental Zinc are formulated into granules.
According to one embodiment of the invention, the stable pharmaceutical composition comprises Calcitriol formulated into a soft gelatin capsule and filled along with granules of Active Absorbable Algal Calcium and Zinc sulphate into hard gelatin capsules. Calcitriol is protected from degradation as it is encapsulated into soft gelatin capsule which separates it from the other two active components and in particular from the highly alkaline Active Absorbable Algal Calcium. Soft gelatin capsules serve the dual purpose of providing a barrier between Calcitriol and elemental metals and thus ensures accuracy in the dosage administered.

In the practice of the present invention, as the soft gelatin capsule acts as a barrier between the Calcitriol and Calcium and Zinc components shelf-life stability of Calcitriol is ensured. Zinc Sulphate and Active Absorbable Algal Calcium are provided as combination blend and Calcitriol is in the form of a solution which is encapsulated into soft gelatin capsule along with antioxidants.
According to another embodiment, the present invention provides fixed dose combinations containing Calcitriol, elemental Calcium and elemental Zinc. Fixed dose combination of the present invention ensures ease of administration and patient compliance.
According to one embodiment of the invention, the stable composition comprises about 0.0001 wt % to about 0.2 wt % of Calcitriol; about 30.0wt % to about 50.0 wt % of Active Absorbable Algal Calcium and about 0.5 wt% to about 6.0 wt % of zinc sulphate or suitable pharmaceutically acceptable salt of zinc. Calcitriol soft gelatin capsules may preferably be used in an amount from about 5.0% to 15.0% by weight of the total composition preferably 10.0% to 15.0 % by weight of the total composition.
According to the present invention, the stable composition contains elemental Calcium in an amount from 150mg to 300mg; preferably as 150mg or 300mg dose and elemental Zinc is present in the composition in an amount from 5.0mg to 7.5mg; preferably as 7.5mg dose.
In the practice of the present invention, 150mg of elemental Calcium may be derived from about 300mg of Active Absorbable Algal Calcium and 7.5 mg of elemental Zinc may be derived from 20.58mg of Zinc sulphate monohydrate.
As the total quantity of Active Absorbable Algal Calcium and Zinc sulphate monohydrate amounts to a very bulky preparation, formulating it into soft gelatin

capsule would result in a bigger size soft gelatin capsule which may be difficult to
swallow.
According to one aspect of the invention, the fixed dose combination contains
AAA Calcium equivalent to 150mg of elemental Calcium, Zinc sulphate
equivalent to 7.5 mg of elemental Zinc and 0.25 microgram of Calcitriol.
According to another aspect, the fixed dose combination contains AAA Calcium equivalent to 300mg of elemental Calcium, Zinc sulphate equivalent to 7.5 mg of elemental Zinc and 0.25 microgram of Calcitriol.
Although the sensitive nature of calcitriol and alkaline nature of Active Absorbable Algal Calcium pose various problems during formulation, the inventors of the present invention have successfully developed a process for preparation of stable pharmaceutical compositions in the form of a unit dosage form wherein said compositions are stabilized by virtue of physical separation of the unstable components from the other active components.
The inventors of the present invention also attempted formulating Calcitriol by dissolving it in absolute alcohol and further adding vitamin E and butylated hydroxy anisole into it to form a clear solution. This solution was then adsorbed over mannitol and the resultant mass was mixed with a mixture of zinc sulphate and colloidal anhydrous silica. The final blend was then mixed with Calcium and filled into hard gelatin capsules.
In another approach, cetyl alcohol was dissolved in ethanol and vitamin E. Butylated hydroxy anisole was added to the solution followed by Calcitriol. The solution was then adsorbed over maize starch and the contents were dried and mixed initially with colloidal anhydrous silica and finally with Zinc granules and then with Calcium granules. Similar approach was initiated excluding cetyl alcohol in the same process.

Another approach was made by dissolving Calcitriol in the solution of vitamin E and butylated hydroxy anisole in ethanol. Povidone was seperately dissolved in ethanol. Calcitriol solution was added to the povidone solution. Zinc sulphate was granulated with this solution and the granules thus obtained were blended with Calcium granules. However, all the three approaches attempted above were not considered successful with due consideration to Calcitriol stability.
According to one embodiment of the present invention, the process of preparation of stable composition comprises the steps of:
(i) preparing granules of Active Absorbable Algal Calcium and zinc sulphate
using suitable pharmaceutical excipients;
(ii) preparing calcitriol solution using suitable pharmaceutical excipients; (iii)preparing calcitriol soft gelatin capsules by encapsulation of Calcitriol
solution of step(ii);
(iv) filling the soft gelatin capsules of step (iii) into hard gelatin or hard
cellulose capsules of appropriate size;
(v) further filling the granules of Active Absorbable Algal Calcium and zinc sulphate of step(i) into hard gelatin or hard cellulose capsules.
The process of preparation of AAA Calcium and Zinc Sulphate granules comprises the steps of:
(a) mixing together AAA Calcium, Zinc Sulphate and suitable pharmaceutical excipients in a suitable equipment for a suitable period of time;
(b) preparing the aqueous binder solution by dissolving the binder in purified water at 55 ± 5°C;
(c) cooling the binder solution of step(b) to room temperature;
(d) granulating the mixture of step(a) using the binder solution of step(c) to form a wet mass;
(e) drying the wet mass of step (d) in a suitable equipment at about 60 - 65°C

for sufficient time till loss on drying value in the range of 3.5% to 5.5% is achieved;
(f) sizing and milling the dried mass to produce granules of required size;
(g) mixing the sized granules of step(f) with suitable pharmaceutical excipients to form ready-to-fill granules.
In the practice of the present invention, AAA calcium and zinc sulphate may be previously co-sifted prior to the mixing stage. Dry mixing may be carried out in any conventional mixing equipment such as rapid mixer granulator or fluid bed processor for about 10 minutes. The process of preparation of wet mass may be carried out in a conventional rapid mixer granulator and further the wet mass may be dried using fluid bed processor or fluid bed drier. However, in a conventional fluid bed processor both the steps of granulation and drying can be carried out in the same equipment thereby simplifying the process and saving the processing time. Dried mass may be sized using 20# sieve on vibratory sifter and further milling the oversized granules through 1.5 mm screen on the Multi-mill and then sifting through 20 # on Vibratory sifter.
Suitable pharmaceutically acceptable excipients that may be used according to the invention include, but are not limited to, for example, diluents/fillers, acidifying agents, binders, wetting agents, glidants, lubricants, antiadherants and the like.
Diluents, which may be used for preparation of AAA Calcium and zinc sulphate granules as per the invention, include, but are not limited to maize starch, lactose anhydrous, microcrystalline cellulose, pregelatinised starch or mixtures thereof. Diluents may be used in the range of about 1% to 60% by weight of the total composition. Preferred diluent being microcrystalline cellulose in an amount from 1% to 60% by weight of the total composition ; preferably from 5% to 60% by weight of the total composition.

Acidifying agents which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to citric acid, tartaric acid, ascorbic acid and the like and may be used in the range of about 5.0% to about 15.0% by weight of the total composition; preferably about 7.0% to 10.0% by weight of the total composition.
Binders which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to hydroxy propyl cellulose, povidone, hydroxy propyl methyl cellulose, sodium carboxy methylcellulose, xanthan gum, pregelatinised starch, maize starch and the like or mixtures thereof in an amount from 1% to 7% by weight of the total composition. The preferred binder is povidone alone or in combination with maize starch preferably in an amount from 1% to 7% by weight of the total composition most preferably from 2% to 6% by weight of the total composition.
Wetting agents which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to sodium lauryl sulphate, docusate sodium and the like and may be used in an amount from 0.1% to 5% and preferably from 0.2% to 2.0% by weight of the total composition.
Lubricants which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to calcium stearate, magnesium stearate, stearic acid, silicon dioxide, purified talc, sodium stearyl fumarate. Preferred lubricant being magnesium stearate, used in an amount from 0.1% to 1.5% and preferably from 0.2% to 1.0% by weight of the total composition.
Glidants which may be used for preparation of AAA Calcium-zinc sulphate granules as per the invention include, but are not limited to colloidal silicon dioxide, purified talc. Colloidal silicon dioxide may be used in an amount from

0.1% to 1.5% by weight of the total composition; preferably from 0.2% to 1.0% and purified talc may be used in an amount from 0.5% to 2.5% by weight of the total composition; preferably from 0.7% to 1.5% by weight of the total composition.
The process of preparation of Calcitriol soft gelatin capsules comprises the steps of:
(a) dissolving the antioxidants in an edible fixed oil to form a solution;
(b) dissolving the Calcitriol in the solution of step (a);
(c) encapsulation of the Calcitriol solution of step(b) to form soft gelatin capsules using suitable capsule filling machine with 2 minims fill volume providing a fill weight between 70 to 100 mg.
Antioxidants which may be used for preparation of Calcitriol soft gelatin capsules as per the invention include, but are not limited to butylated hydroxy anisole, butylated hydroxy toluene, sodium metabisulphite, ascorbic acid, sodium ascorbate, vitamin E and the like. Preferred antioxidants are butylated hydroxy toluene and butylated hydroxy anisole and may be present in an amount of not more than 0.5% weight of the soft gelatin capsule.
Edible fixed oils which may be used for preparation of Calcitriol soft gelatin capsules as per the invention include, but are not limited to sesame oil, refined sunflower oil, refined corn oil, palm oil, olive oil, medium chain triglyceride oil(MCT Oil). Preferred edible fixed oils are MCT Oil and refined sunflower oil and are be used in an amount from 90% to 99%. Most preferred edible fixed oil is MCT oil and is used in the range from 95% to 99%. Medium chain triglyceride oil is most preferred as it is readily digested than long chain triglycerides and also possesses good stability against oxidation.

Soft gelatin capsule of Calcitriol may be filled into the empty hard gelatin or empty hard cellulose capsule on automatic capsule filling machine with suitable change parts for filling of soft gelatin capsule into a hard gelatin capsule. Empty hard gelatin capsule or empty hard cellulose capsule of size '00' to '000' may be used. Capsules of size '00' may be preferred. Blend weight of AAA Calcium and Zinc Sulphate granules may be preferably from about 500mg to about 600mg and fill weight of soft gelatin capsules may be from 70mg to 100mg.
Pharmaceutical compositions prepared by the process according to the present invention exhibits excellent chemical stability of Calcitriol and also maintains the potency and accuracy of Calcitriol dose.
Stable compositions of the present invention may be packed in aluminium strips or by cold formed blister pack which is a cold process of blister packing which acts as an excellent moisture barrier with negligible moisture vapour transmission rate and provides protection from external environment.
The present invention is further illustrated by reference to the following examples which does not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, can be practiced without departing from the purpose and scope of the disclosure.

Examples
Example 1
Step I : Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc
sulphate granules:
(a) Triple A cal (286.5gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer.
(b) Zinc sulphate (20.58 gm) was mixed in geometric proportion with the mixture of Triple A Cal and anhydrous citric acid.
(c) Binder solution was prepared by dissolving povidone (5gm) in water (lOOgm). Maize starch (15gm) was added to the hot binder solution to obtain a translucent starch paste.
(d) Mixture of Triple A cal, citric acid anhydrous and zinc sulphate was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size.
(e) Maize starch (15gm), microcrystalline cellulose (150gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend.
(f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes.
(g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate.

Step II: Preparation of Calcitriol soft gelatin capsules:
(a) Butylated hydroxy toluene (0.035 gm) and butylated hydroxy anisole (0.035 gm) was dissolved in medium chain triglyceride oil (65.0 gm).
(b) Calcitriol (0.325mg) was added to the mixture of step(a) and further about 4.93 gm Medium Chain Triglyceride Oil was added to it to obtain Calcitriol solution.
(c) Calcitriol solution of step(b) was encapsulated into soft gelatin capsules using 2 minims fill volume providing a fill weight of 70 mg.
Step III: Preparation of hard gelatin capsule composition.
(a) One calcitriol soft gelatin capsule prepared by step II procedure was filled into the hard gelatin/hard cellulose capsule of suitable size (size 00) using a suitable capsule filling machine with attachment for filling of Soft gelatin Capsules.
(b) Ready-to-fill granules of step I was further filled into the hard gelatin/hard cellulose capsule of step(a).
(c) Hard gelatin/hard cellulose capsules were packed in cold form Alu-Alu blisters.

Example 2
Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc
sulphate granules:
(a) Triple A cal (286.5gm) and microcrystalline cellulose (150 gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer.
(b) Zinc sulphate (20.58 gm) was mixed in geometric proportion with the mixture of Triple A Cal, microcrystalline cellulose and anhydrous citric acid.
(c) Binder solution was prepared by dissolving povidone (5gm) in water (lOOgm). Maize starch (15gm) was added to the hot binder solution to obtain a translucent starch paste.
(d) Mixture of Triple A cal, microcrystalline cellulose, anhydrous citric acid and zinc sulphate was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size.
(e) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend.
(f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes.
(g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate.
Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin/cellulose capsule composition was prepared according to the procedure described in step III of example 1.

Example 3
Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc
sulphate granules:
(a) Triple A cal (286.5gm), microcrystalline cellulose (150 gm) and povidone (5gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer.
(b) Zinc sulphate (20.58 gm) was mixed in geometric proportion with the mixture of Triple A Cal, microcrystalline cellulose, povidone and anhydrous citric acid.
(c) Binder solution was prepared by dissolving maize starch (15gm) in water (lOOgm) to obtain a translucent starch paste.
(d) Mixture of Triple A cal, microcrystalline cellulose, povidone, anhydrous citric acid and zinc sulphate was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size.
(e) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend.
(f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes.
(g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate.
Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin capsule composition was prepared according to the procedure described in step III of example 1.

Example 4
Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc
sulphate granules:
(a) Triple A cal (286.5gm) and microcrystalline cellulose (150 gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer.
(b) Zinc sulphate (20.58 gm) was dissolved in hot water (lOOgm) and further povidone (5.0 gm) and maize starch (15gm) was added to it to obtain a translucent starch paste.
(c) Mixture of Triple A cal, microcrystalline cellulose and anhydrous citric acid was granulated with binder of step (b) to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size.
(d) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend.
(e) The blend of step(d) was mixed with granules of step(c) in a suitable blender for about 15 minutes.
(f) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (e) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate.
Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin capsule composition was prepared according to the procedure described in step III of example 1.

Example 5
Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc
sulphate granules:
(a) Triple A cal (286.5gm) and microcrystalline cellulose (75 gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer.
(b) Zinc sulphate (20.58 gm) was mixed with microcrystalline cellulose (75 gm) and further mixed with the mixture of Triple A Cal, microcrystalline cellulose and anhydrous citric acid in geometric proportion.
(c) Binder solution was prepared by dissolving povidone (5gm) in water (lOOgm). Maize starch (15gm) was added to the hot binder solution to obtain a translucent starch paste.
(d) Mixture of Triple A cal, microcrystalline cellulose, anhydrous citric acid and zinc sulphate was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size.
(e) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend.
(f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes.
(g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate.
Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin capsule composition was prepared according to the procedure described in step III of example 1.

Example 6
Step I: Preparation of Active Absorbable Algal Calcium (Triple A cal) and zinc
sulphate granules:
(a) Triple A cal (286.5gm) and microcrystalline cellulose (150 gm) was mixed with pre-milled anhydrous citric acid (50gm) in a suitable mixer.
(b) Binder solution was prepared by dissolving povidone (5gm) in water (100gm). Maize starch (15gm) was added to the hot binder solution to obtain a translucent starch paste.
(c) Mixture of Triple A cal, microcrystalline cellulose and anhydrous citric acid was granulated with binder to obtain granules of suitable consistency. The granules were dried in fluid bed drier at 60°C for sufficient time till loss on drying value of about 3.5% to 5.5% was achieved. Dried granules were sized to obtain granules of desired size.
(d) Maize starch (15gm), sodium lauryl sulphate (5.0gm), colloidal silicon dioxide (1.5 gm) and talc (5.0 gm) was co-sifted through #40 mesh stainless steel sieve and mixed for 5 minutes in a suitable blender to form a blend.
(e) Zinc sulphate (20.58 gm) was mixed in geometric proportion with the blend of step(d).
(f) The blend of step(e) was mixed with granules of step(d) in a suitable blender for about 15 minutes.
(g) Magnesium stearate (2.0 gm) was sifted through 60 mesh S.S.Sieve and added to granules of step (f) and further mixed for 3 minutes to obtain ready-to-fill granules of Triple A cal and zinc sulphate.
Calcitriol soft gelatin capsules were prepared according to the procedure described in step II of example 1 and hard gelatin capsule composition was prepared according to the procedure described in step III of example 1.

While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.

Documents:

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Patent Number

272821

Indian Patent Application Number

2078/MUM/2007

PG Journal Number

18/2016

Publication Date

29-Apr-2016

Grant Date

28-Apr-2016

Date of Filing

19-Oct-2007

Name of Patentee

USV LIMITED

Applicant Address

B.S.D. MARG, GOVANDI, MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	OMRAY ASHOK	C-501, REDWOODS, B/H VEENA NAGAR, OFF L.B.S. ROAD, MULUND (W), MUMBAI 400080
2	BHIDE YOGESH SHARAD	BLOCK NO.4, SAYALI APARTMENTS, 878/2 SADASHIV PETH, OPPOSITE RAJWADE MANGAL KARYALAYA, PUNE 411030
3	CHOUDHARY VARSHA SHAHANK	29/A-303, MANISH ROSE CO-OP HSG SOCIETY, MANISH NAGAR, ANDHERI (W), MUMBAI 400053

PCT International Classification Number

A61K31/59

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA