DESC:FILED OF THE INVENTION
The present invention provides an aqueous parenteral composition comprising Vitamin D3.
BACKGROUND OF THE INVENTION
Vitamin D is a group of fat-soluble secosteroids responsible for increasing absorption of calcium, magnesium, and phosphate from intestine and kidney, and multiple other biological effects. In humans, the most important compounds in this group are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol).
Vitamin D3 controls the incorporation of calcium and phosphorus in the skeleton.
Vitamin D3 is synthesized by humans in the skin when it is exposed to ultraviolet-B (UVB) rays from sunlight. Foods may be fortified with vitamin D3.
Although the synthesis of Vitamin D3 occurs naturally in the skin with adequate sunlight exposure, Vitamin D3 is not active and needs to be converted to 25(OH) D3 in the liver. From the liver, 25(OH) D3 is transported to the kidney and hydroxylated by 25-hydroxyvitamin D31-hydroxylase to form the active hormone calcitriol. The said active form binds to vitamin D receptors (VDRs) that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of Vitamin D is diminished, resulting in a rise of parathyroid hormone, subsequently leading to secondary parathyroidism and disturbances in the calcium and phosphorus homeostasis.
Inadequate Vitamin D supply often develops in individuals who are infrequently exposed to sunlight without protective sunscreens, have chronically inadequate intakes of Vitamin D, or suffer from conditions that reduce the intestinal absorption of fat soluble vitamins (such as Vitamin D). Inadequate Vitamin D supply can lead to numerous diseases and physical ailments. Rickets and osteomalacia are classic Vitamin D deficiency diseases. In children, Vitamin D deficiency causes rickets, which results in skeletal deformities. In adults, Vitamin D deficiency can lead to osteomalacia, which results in muscular weakness in addition to weak bones.
Nutrients. 2014 Feb; 6(2): 729–775 discloses widespread prevalence of Vitamin D deficiency in India. Factually, sun exposure is an untenable solution, for most individuals in India, towards attaining Vitamin D sufficiency. Low calcium intake in conjunction with Vitamin D deficiency makes matters worse. Therefore, the need for improvement in vitamin status of the Indian population is both important and urgent.
Vitamin D3 can be taken either orally or by intramuscular injection. Intramuscular injection is useful in severe Vitamin D deficiency disease with intestinal malabsorption. It also avoids repeated oral intake of Vitamin D.
Vitamin D3 is fat soluble vitamin. Therefore, first approach is to prepare oil based parenteral formulation for complete solubilization & stabilization of Vitamin D3. Vitamin D3 injection according to IP (Indian pharmacopoeia) & BP (British Pharmacopoeia) is oil-based formulation available as 300000 and 600000 IU/ml of Vitamin D3. However, oil containing injectable formulation can cause pain, erythema, swelling nodule formation at the site of injection and delay release of active ingredient. The oil-based preparation is also known to provide slow release of drug and it is found to be equivalent to oral Vitamin D3 up to 6 weeks (Indian J Endocrinol Metab. 2017 Jan-Feb;21(1):131-136).
To avoid problems associated with oil-based formulations, various attempts have been made in the prior art.
One of them is to prepare emulsion as disclosed in US 2832721, US 3032468, WO 2011063952 and WO 2017115316.
IN 431119 provides an aqueous parenteral composition comprising 300000 to 600000 IU/ml of Vitamin D3, glycofurol is in the range of 5% w/v to 30% w/v, and a surfactant is in the range of 5% w/v to 30% w/v, and optionally pharmaceutically acceptable excipients selected from chelating agent, antioxidant and buffer.
Surprisingly, it has been found that a clear aqueous parenteral composition comprising 300000 to 600000 IU/ml of Vitamin D3 can be prepared using more than 5%w/v of a surfactant and optionally less than 5%w/v of transcutol or less than 5% w/v glycofurol, or mixture thereof.

OBJECT OF THE INVENTION

The object of present invention is to provide a clear aqueous parenteral composition comprising 300000 to 600000 IU of Vitamin D3, and more than 5%w/v of a surfactant and optionally transcutol or glycofurol, or mixture thereof.
Another object of the invention is to provide use of the aqueous parenteral composition of Vitamin D3 for treatment and prevention of vitamin D deficiency and insufficiency.
Another object of the invention is to provide a process for the preparation of an aqueous parenteral composition of Vitamin D3 as discussed in above objects.

SUMMARY OF THE INVENTION
It has been surprisingly found that, an aqueous parenteral composition comprising 300000 to 600000 IU/ml of Vitamin D3 can be prepared using more than 5%w/v of a surfactant, preferably in the range of 5% to 50% w/v and optionally less than 5 % w/v of transcutol or less than 5% w/v of glycofurol, or mixture thereof.

In another aspect, the present invention also provides a process for the preparation of the aqueous parenteral composition of Vitamin D3.

DETAILED DESCRIPTION

It has been surprisingly found that, a clear aqueous parenteral composition comprising 300000 to 600000 IU/ml of Vitamin D3 can be prepared using more than 5%w/v of a surfactant, preferably in the range of 5% w/v to 50% w/v and optionally less than 5 %w/v of transcutol or less than 5% w/v of glycofurol, or mixture thereof.
The aqueous parenteral composition provides a clear solution with desirable viscosity.
The clear aqueous parenteral composition of the present invention of 300000 to 600000 IU/ml of Vitamin D3 can be administered as a single dose without side effects associated with oil-based Vitamin D3 containing parenteral formulations.
The surfactant may be selected from anionic and/or non-ionic surfactant. The non-ionic surfactants include but are not limited to polyoxyethylene sorbitan monolaurate (e.g. polysorbate 80 (Tween® 80)), polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate such as Solutol®, polyoxyethylenated derivatives of castor oil (Cremophor®), polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide such Poloxamer®, and the like. Preferable surfactant is Tween® 80, which is interchangeable with Solutol® and Poloxamer®.
The anionic surfactants include but are not limited to alkaline stearates, sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates (e.g. sodium lauryl sulphate and sodium cetyl sulphate); sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, and the like.
In one embodiment, a clear aqueous parenteral composition comprising Vitamin D3, and solvent system comprising more than 5% w/v surfactant, preferably in the range of 5% w/v to 50% w/v and optionally less than 5% w/v of transcutol or less than 5% w/v of glycofurol, or mixture thereof is used with water.
In one embodiment, the process for the preparation of a clear aqueous parenteral composition comprising 300000 to 600000 IU/ml of Vitamin D3 in the following steps:
i. solubilizing vitamin D3 in a solvent system comprising alcohol or diethyl ether, or mixture thereof
ii. adding a surfactant in the range of 5% w/v to 50% w/v
iii. adding water
iv. evaporating the alcohol or diethyl ether, or mixture of thereof.
v. optionally, adding pharmaceutically acceptable excipients selected from chelating agent, antioxidant and buffer and
vi. adding water to make up final volume.
In another embodiment, the process for the preparation of a clear aqueous parenteral compositions comprising 300000 to 600000 IU/ml of Vitamin D3 in the following steps:
i. solubilizing vitamin D3 in a solvent comprising less than 5% w/v transcutol or less than 5% w/v glycofurol, or mixture thereof;
ii. adding a surfactant in the range of 5% w/v to 50% w/v;
iii. adding water
iv. optionally, adding pharmaceutically acceptable excipients selected from chelating agent, antioxidant and buffer; and
v. adding water to make up final volume

The invention is illustrated with non-limiting examples.
Example 1: Preparation of Vitamin D3 injection using surfactant and glycofurol.
Sr. No. Ingredients Example 1
Qty. (gm) %
1 Vitamin D3 0.75 0.75
2 Tween 80 6 6
3 Glycofurol 4.8 4.8
4 Water for injection Q.s. to 100 ml 100
Process for the preparation:
(a) Vitamin D3 was dissolved in mixture of Glycofurol and Tween 80;
(b) water for injection was added to above solution and mixed;
(c) volume was made up to 100 ml with water for injection.
Observation: The composition prepared as per example 1 was clear.
Example 2: Preparation of Vitamin D3 injection using surfactant and transcutol.
Sr. No. Ingredients Example 2
Qty. (gm) %
1 Vitamin D3 0.75 0.75
2 Tween 80 6 6
3 Transcutol 4.8 4.8
4 Water for injection Q.s. to 100 ml 100
Process for the preparation:
(a) Vitamin D3 was dissolved in Transcutol;
(b) Tween 80 was added to above solution;
(c) water for injection was added to above solution and mixed;
(d) volume was made up to 100 ml with water for injection.
Observation: The composition prepared as per example 2 was clear.

Example 3: Preparation of Vitamin D3 injection using surfactant, glycofurol and transcutol.
Sr. No. Ingredients Example 3
Qty. (gm) %
1 Vitamin D3 0.75 0.75
2 Tween 80 6 6
3 Glycofurol 2.4 2.4
4 Transcutol 2.4 2.4
5 Water for injection Q.s. to 100 ml 100
Process for the preparation:
(a) Vitamin D3 was dissolved in a mixture of Transcutol and glycofurol;
(b) Tween 80 was added to above solution;
(c) water for injection was added to above solution and mixed;
(d) volume was made up to 100 ml with water for injection.
Observation: The composition prepared as per example 3 was clear.
Example 4 & 5: Preparation of Vitamin D3 injection without use of glycofurol or transcutol.
Sr. No Ingredients Example 4 Example 5
Qty. (gm) % Qty. (gm) %
1 Vitamin D3 0.75 0.75 0.75 0.75
2 Tween 80 9 9 9 9
3 Alcohol 10 10 - -
4 Diethyl ether - - 15 15
5 Water for injection Q.s to 100 ml 100 Q.s to 100 ml 100
Process for the preparation:
(a) Vitamin D3 was dissolved in mixture of alcohol / Diethyl ether and Tween 80;
(b) water for injection was added to above solution and mixed, was added and dissolved by mixing;
(c) alcohol / Diethyl ether was evaporated;
(d) volume was made up to 100 ml with water for injection.
Observation: The compositions prepared as per example 4 and example 5 were clear.
Example 6: Preparation of Vitamin D3 injection using surfactant, glycofurol and transcutol.
Sr. No. Ingredients Example 6
Qty. (gm) %
1 Vitamin D3 0.375 0.75
2 Tween 80 3 6
3 Glycofurol 2.4 4.8
4 Transcutol 2.4 4.8
5 Water for injection Q.s. to 50ml 100
Process for the preparation:
(a) Vitamin D3 was dissolved in a mixture of Transcutol and glycofurol;
(b) Tween 80 was added to above solution;
(c) water for injection was added to above solution and mixed;
(d) volume was made up to 50 ml with water for injection.
Observation: The composition prepared as per example 6 was clear.

Example 7 & 8: Preparation of Vitamin D3 injection using surfactant, glycofurol or transcutol.
Sr. No. Ingredients Example 7 Example 8
Qty. (gm) % Qty. (gm) %
1 Vitamin D3 0.375 0.75 0.375 0.75
2 Tween 80 30 60 30 60
3 Glycofurol 2.4 4.8 - -
4 Transcutol - - 2.4 4.8
5 Water for injection Q.s. to 50 ml 100 Q.s. to 50 ml 100
Process for the preparation:
(a) Vitamin D3 was dissolved in Transcutol or glycofurol;
(b) Tween 80 was added to above solution;
(c) water for injection was added to above solution and mixed;
(d) volume was made up to 50 ml with water for injection.
Observation: The compositions prepared as per example 7 and example 8 were clear Gel.

Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Moreover, it will be understood that the illustrations are for the purpose of describing exemplary embodiments of the invention and the same do not limit the scope of the present invention. ,CLAIMS:We Claim:
1. A clear aqueous parenteral composition comprising 300000 to 600000 IU/ml of Vitamin D3 and 5 – 50 %w/v surfactant, and optionally less than 5% w/v of transcutol or less than 5% w/v of glycofurol, or mixture thereof, and optionally pharmaceutically acceptable excipients.

2. A process for the preparation of a clear aqueous parenteral composition comprising 300000 to 600000 IU/ml of Vitamin D3 in the following steps:
i. solubilizing vitamin D3 in a solvent system comprising alcohol or diethyl ether, or mixture thereof;
ii. adding a surfactant;
iii. adding water;
iv. evaporating alcohol or diethyl ether;
v. optionally, adding pharmaceutically acceptable excipients selected from chelating agent, antioxidant and buffer; and
vi. adding water to make up final volume.

3. A process for the preparation of a clear aqueous parenteral composition comprising 300000 to 600000 IU/ml of Vitamin D3 in the following steps:
i. solubilizing vitamin D3 in a solvent system comprising transcutol or glycofurol, or mixture thereof;
ii. adding a surfactant;
iii. adding water;
iv. optionally, adding pharmaceutically acceptable excipients selected from chelating agent, antioxidant and buffer; and
v. adding water to make up final volume

4. The process for the preparation of a clear aqueous parenteral composition claimed in claim 2, wherein the surfactant in the range of 5 – 50 %w/v.

5. The process for the preparation of a clear aqueous parenteral composition claimed in claim 3, wherein the solvent system comprises less than 5% w/v transcutol or less than 5% w/v glycofurol, or mixture thereof and the surfactant is in the range of 5 – 50 %w/v.

6. The clear aqueous parenteral composition as claimed in any preceding claims, wherein the surfactant can be selected from anionic, non-ionic surfactant and mixture of thereof, wherein the anionic surfactants selected to alkaline stearates, sodium, potassium or ammonium stearates; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, and the like. wherein the non-ionic surfactants include but are not limited to polyoxyethylene sorbitan monolaurate, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate such as Solutol®, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide such Poloxamer®, and the like.
7. The clear aqueous parenteral composition as claimed in any preceding claims, wherein the surfactant is preferably selected from the group consisting of polyoxyethylene sorbitan monolaurate.