DESC:AN AQUEOUS PARENTERAL COMPOSITION OF VITAMIN D3

FILED OF THE INVENTION
The present invention provides a clear 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. 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 leads 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 the 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.
Another approach is to prepare parenteral formulation of containing alcohol as disclosed in US 20060183722. US ‘722 discloses pharmaceutical formulations of lipophilic therapeutic agents in which such agents are solubilized in largely aqueous vehicles along with alcohol, and processes for preparing and using the same. However, alcohol containing injection can cause pain on injection and tissue necrosis and is not popular.
IN 431119 provides an aqueous parenteral composition comprising 300000 to 600000 IU 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 of Vitamin D3 can be prepared using less than 5% w/v of a surfactant in a judiciously selected solvent.

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 less than 5% w/v of a surfactant.
Another object of the invention is to provide the said clear 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 the said clear aqueous parenteral composition of Vitamin D3.

SUMMARY OF THE INVENTION

It has been surprisingly found that a clear aqueous parenteral composition comprising 300000 to 600000 IU of Vitamin D3 can be prepared using less than 5% w/v of a surfactant in a judicially selected solvent such as alcohol, or transcutol, or glycofurol, or mixture thereof.
In another aspect, the present invention provides a process for the preparation of the clear aqueous parenteral composition comprising 300000 to 600000 IU of Vitamin D3.
DETAILED DESCRIPTION

As used herein, the term “vitamin D3” means cholecalciferol, (i.e. the pro-hormone form of vitamin D3) as opposed to the metabolically active form, calcitriol.
Vitamin D3 (Cholecalciferol), known as (3ß,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol and is represented by the following structural of formula (I):

Formula (I)
The preferred range of concentration of the vitamin D3 in the clear aqueous parenteral composition is in the range 300000 IU to 600000 IU.
The clear aqueous composition of the present invention is transparent, and has the desirable viscosity for parenteral administration.
The clear aqueous parenteral composition comprising 300000 to 600000 IU of Vitamin D3 can be prepared using less than 5% w/v and more than 0.5% w/v of surfactant in a judiciously selected solvent.
It has surprisingly been found that an aqueous parenteral composition comprising Vitamin D3, less than 5% w/v and more than 0.5% w/v of surfactant and a solvent, wherein the solvent is selected from alcohol, or transcutol, or glycofurol, or mixture thereof.
The clear aqueous parenteral compositions may contain suitable pharmaceutically acceptable excipients.
The pharmaceutically acceptable excipients include ß-cyclodextrin.
The ß-cyclodextrin as an excipient is selected from derivatives of cyclodextrin including hydroxy-propyl betacyclodextrin, sulfo-butyl ether cyclodextrin and salt thereof.
The pharmaceutically acceptable excipients include chelating agents, anti-oxidant, buffer.
The chelating agent as an excipient is selected from disodium EDTA, edetic acid, citric acid, trisodium citrate, potassium citrate and like.
The antioxidant as an excipient is selected from citric acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium hydrogen sulfite, sodium metabisulfite, sodium pyrosulfite and like.
The buffer as an excipient is selected from alanine, glycine, lysine, phosphate, monobasic sodium phosphate and like.
Alcohol in the parenteral aqueous composition is up to 10% w/v.
Transcutol in the parenteral aqueous composition is up to 40 % w/v.
Glycofurol in the parenteral aqueous composition is up to 80 % w/v.
ß-cyclodextrin in the parenteral aqueous composition is up to 50 % w/v.
The ratio of surfactant to solvent is more than 0.005.
The clear aqueous parenteral composition comprising Vitamin D3 in amount of 300000 to 600000 IU facilitates the administration of high concentration of Vitamin D3 in a single dose by eliminating the side effects associated with oil-based Vitamin D3 containing parenteral formulations.
In one embodiment, the composition comprises a surfactant and transcutol.
In another embodiment, the composition comprises a surfactant and glycofurol.
In another embodiment, the composition comprises a surfactant and alcohol.
In yet another embodiment, the composition comprises a surfactant transcutol, and glycofurol.
In yet another embodiment, the composition comprises a surfactant, an alcohol, and transcutol or glycofurol.
In yet another embodiment, the composition comprises a surfactant, an alcohol, transcutol, and glycofurol.
The process of the preparation of the composition comprises dissolving Vitamin D3 in a solvent followed by addition of a surfactant. Water for injection is added to make up final volume.
In another embodiment of the process, Vitamin D3 is dissolved in a surfactant and solvent, optionally containing pharmaceutically acceptable excipients. Water for injection containing pharmaceutically acceptable excipients, is added to make up final volume.
In yet another embodiment of the process, Vitamin D3 is added to solution containing a surfactant and solvent. Further a solvent is added, to solubilize Vitamin D3. Optionally adding a solution of pharmaceutically acceptable excipients. Water for injection is added to make up final volume.
The surfactant is selected from anionic and/or non-ionic surfactant. The non-ionic surfactants include but are not limited to polyoxyethylenated ester of fatty acid e.g. polysorbate 80, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrol ether; polyethylene glycol stearate such as, polyoxyethylenated castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide such, and the like.
The commonly used and commercially available surfactants are Tween®80, Solutol®, Cremophor®, and Poloxamer®.
As per present invention, clear solutions are those compositions which do not develop particulates.
The invention is now illustrated with non-limiting examples.
The following Examples provides composition of aqueous Vitamin D3 as per the present invention:
Example 1: Composition using the surfactant along with transcutol.
S. No Ingredients Example 1
Qty. (gm) %
1 Vitamin D3 0.375 0.75
2 Tween 80 2.2 4.4
3 Transcutol 2.4 4.8
4 Propyl gallate 0.025 0.05
5 Sodium meta bisulphite 0.25 0.5
6 Tri sodium citrate 0.05 0.1
7 Na2HPO4 0.2 0.4
8 Na H2PO4 2H2O 0.1 0.2
9 Water for injection Q.s to 50ml 100
Observation Clear solution

Example 2, 3 & 4: Composition using the surfactant along with transcutol.
S. No Ingredients Example 2 Example 3 Example 4
Qty. (gm) % Qty. (gm) % Qty. (gm) %
1 Vitamin D3 0.375 0.75 0.375 0.75 0.375 0.75
2 Tween 80 0.375 0.75 0.5 1 0.25 0.5
3 Transcutol 20 40 20 40 20 40
4 Water for injection Q.s to 50ml 100 Q.s to 50ml 100 Q.s to 50ml 100
observation Clear solution Clear solution Particulates

Example 5, 6, 7, 8, 9, 10 & 11: Composition using the surfactant along with glycofurol.
S. No Ingredients Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11
Qty. (gm) % Qty. (gm) % Qty. (gm) % Qty. (gm) % Qty. (gm) % Qty. (gm) % Qty. (gm) %
1 Vitamin D3 0.075 0.75 0.075 0.75 0.075 0.75 0.375 0.75 0.375 0.75 0.075 0.75 0.075 0.75
2 Tween 80 0.05 0.5 0.075 0.75 0.075 0.75 0.25 0.5 0.20 0.40 0.1 1 0.1 1
3 Glycofurol 8 80 8 80 3.5 35 20 40 20 40 8 80 3.5 35
4 Water for injection Q.s to 10ml 100 Q.s to 10ml 100 Q.s to 10ml 100 Q.s to 50ml 100 Q.s to 50ml 100 Q.s to 10ml 100 Q.s to 10ml 100
observation Particulates Clear solution Clear solution Particulates Particulates Clear solution Clear solution

Example 12 & 13: Composition using the surfactant, transcutol and glycofurol.
S. No Ingredients Example 12 Example 13
Qty. (gm) % Qty. (gm) %
1 Vitamin D3 0.375 0.75 0.375 0.75
2 Tween 80 2.2 4.4 2.2 4.4
3 Glycofurol 1.25 2.5 1 2
4 Transcutol 1.25 2.5 1 2
5 Propyl gallate 0.025 0.05 0.025 0.05
6 Sodium meta-bisulphite 0.25 0.5 0.25 0.5
7 Tri sodium citrate 0.05 0.1 0.05 0.1
8 Na2HPO4 0.2 0.4 0.2 0.4
9 Na H2PO4 2H2O 0.1 0.2 0.1 0.2
10 Water for injection Q.s to 50ml 100 Q.s to 50ml 100
Observation Clear solution Clear solution

Example 14, 15 & 16: Composition using the surfactant, alcohol, transcutol and/or glycofurol.
S. No Ingredients Example 14 Example 15 Example 16
Qty (gm) % Qty (gm) % Qty (gm) %
1 Vitamin D3 0.375 0.75 0.375 0.75 0.375 0.75
2 Tween 80 1.25 2.5 1.25 2.5 1.25 2.5
3 Glycofurol 1.25 2.5 x x 1.25 2.5
4 Transcutol x x 1.25 2.5 1.25 2.5
5 Alcohol 1.25 2.5 1.25 2.5 1.25 2.5
6 Water for injection Q.s to 50ml 100 Q.s to 50ml 100 Q.s to 50ml 100
OBSERVATION Clear Solution Clear Solution Clear Solution

Example 17, 18, 19 & 20: Composition using the surfactant, alcohol, transcutol and/or glycofurol.
S. No Ingredients Example 17 Example 18 Example 19 Example 20
Qty (gm) % Qty (gm) % Qty (gm) % Qty (gm) %
1 Vitamin D3 0.375 0.75 0.375 0.75 0.375 0.75 0.375 0.75
2 Tween 80 0.375 0.75 0.375 0.75 0.375 0.75 0.375 0.75
3 Glycofurol x x 1.25 2.5 x x 0.25 0.5
4 Transcutol 0.25 0.5 x x 0.25 0.5 x x
5 Alcohol 0.125 0.25 0.125 0.25 2.5 5 2.5 5
6 Water for injection q.s 50 ml 100 q.s 50 ml 100 q.s 50 ml 100 q.s 50 ml 100
OBSERVATION Particulates Particulates Particulates Particulates

Example 21 & 22: Composition using the surfactant, alcohol and/or transcutol.
S. No Ingredients Example 21 Example 22
Qty (gm) % Qty (gm) %
1 Vitamin D3 0.1875 0.375 0.1875 0.375
2 Tween 80 0.375 0.75 0.5 1
3 Transcutol 0.25 0.5 0.25 0.5
4 Alcohol 0.125 0.25 2.5 5
5 Water for injection q.s 50 ml 100 q.s 50 ml 100
OBSERVATION Particulates Clear solution

Example 23: Composition using the surfactant, transcutol and Hydroxy propyl beta cyclodextrin.
S. No
Ingredients
Example 23
Qty (gm) %
1 Vitamin D3 0.375 0.75
2 Tween 80 1.25 2.5
3 Transcutol 1.25 2.5
4 Hydroxy propyl beta cyclodextrin 20 40
5 Water for injection Q.s to 50ml 100
OBSERVATION Clear solution

Example 24, 25 & 26: Composition using the surfactant and Glucoferol.
S. No Ingredients Example 24 Example 25 Example 25
Qty (mg) % Qty (mg) % Qty (mg) %
1 Vitamin D3 37.5 0.375 37.5 0.375 76.8 0.768
2 Tween 80 75 0.75 75 0.75 50 0.5
3 Glucoferol 8000 80 3500 35 8000 80
4 Water for injection q.s 10 ml 100 q.s 10 ml 100 q.s 10 ml 100
OBSERVATION Clear solution Clear solution Clear solution

The present invention provides compositions and process of preparing aqueous parenteral composition comprising, 300000 to 600000 IU of Vitamin D3 with less than 5% w/v and more than 0.5% w/v of a surfactant in a judiciously selected solvent.
,CLAIMS:We Claim:

1. A clear aqueous parenteral composition comprising
a. 300000 to 600000 IU of Vitamin D3,
b. a surfactant less than 5% w/v and more than 0.5% w/v,
c. a solvent selected from transcutol, or glycofurol, or alcohol, or a mixture thereof, and
d. optionally pharmaceutically acceptable excipients.
2. The clear aqueous parenteral composition as claimed in claim 1, wherein the surfactant is selected from polyoxyethylenated, polyoxyethylenated alkyl ethers; polyoxypropylated fatty alcohols; polyethylene glycol stearate, polyoxyethylenated castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide.
3. The clear aqueous parenteral composition as claimed in claim 1 and claim 2, wherein the surfactant is preferably selected from polysorbate 80, Solutol® and Poloxamer®.
4. A clear aqueous parenteral composition as claimed in claim 1, wherein transcutol is in the range of 0.1% w/v to 40% w/v.
5. A clear aqueous parenteral composition as claimed in claim 1, wherein glycofurol is in the range of 0.1% to 80% w/v.
6. A clear aqueous parenteral composition as claimed in claim 1, wherein alcohol is in the range of 0.5% to 10% w/v.
7. A clear aqueous parenteral composition as claimed in claim 1, wherein ratio of Surfactant to solvent is more than 0.005.
8. The clear aqueous parenteral composition as claimed in any preceding claims, wherein the pharmaceutically acceptable excipients include ß-cyclodextrin.
9. A clear aqueous parenteral composition as claimed in any preceding claims, wherein ß-cyclodextrin is up to 50 % w/v.
10. The clear aqueous parenteral composition as claimed in any preceding claims, wherein the ß-cyclodextrin is selected from derivatives of cyclodextrin including hydroxy-propyl betacyclodextrin, sulfo-butyl ether cyclodextrin and salt thereof.