DESC:Field of Invention:
The present invention provides a parenteral pharmaceutical composition comprising a novel solubilizing mixture for the solubilization of poorly water soluble pharmaceutically active agents and preparation of pharmaceutical composition 5 comprising the same.
Background of the invention:
Vitamin D is an important nutrient for absorption of intestinal calcium and phosphorus, cellular proliferation and differentiation, muscle function, and immunity. Intestinal absorption of vitamin D occurs primarily in the jejunum and ileum. Vitamin D 10 deficiency is recognized as the most prevalent nutrient deficiency in patients with intestinal failure. Enteral supplementation of vitamin D was inefficient in patients with vitamin D deficiency caused by intestinal malabsorption, such as cystic fibrosis, short bowel syndrome, inflammatory bowel disease, and intestinal accessory organ dysfunction. In these cases, parenteral supplementation of vitamin D is a promising 15 alternative strategy. Vitamin D compounds are hydrophobic or lipophilic and are only sparingly or negligibly water-soluble. The poor water solubility of these active agents often results in major difficulties in formulation particularly in preparing aqueous solution of the
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same. Also the poor water solubility of these active agent raises concerns of stability upon storage and especially throughout the shelf-life of the product. Multiple approaches to overcoming these solubility problems have been disclosed. U.S. Patent No. 2006/0183722 discloses a formulation comprising a vitamin D compound, a non-ionic solubilizer and a lipophilic antioxidant. 5 U.S. Pat. No. 6,136,799 discloses an aqueous pharmaceutical self-preserved composition for parenteral administration having paricalcitol, about 50% (v/v) of an organic solvent and about 50% (v/v) water. US Patent no. 20140187520 B disclosed the use of non-ionic solubilizer Solutol HS 15 with ethanol and surfactan for preparing a parenteral composition of Vitamin D3 10 US Patent no. 20100075933A1 describes the use of a glycol and alcohol to prepare an aqueous parenteral composition of vitamin D. Indian patent application no Indian patent application no. 201821004137 describes the preparation of Vitamin D3 parenteral composition with glycofurol and a surfactant. Glycofurol has been reported to have high viscosity and can impact the flow and handling properties of formulation. 15 Glycofurol can also cause skin irritation or sensitization. Thus, there is a need for pharmaceutical injectable formulations of vitamin D compounds that overcome the limitations of the prior art compositions. One approach has been to incorporate water, water-miscible co-solvents, and surfactants into the compositions. The present invention provides a novel mixture of 20
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solubilizing agents for the solubilization of vitamin D in an aqueous vehicle and preparation of pharmaceutical composition comprising the same.
Objective:
An objective of the present invention is to provide an aqueous parenteral composition of vitamin D compounds. 5
Another objective of the present invention is to provide an aqueous parenteral composition of vitamin D compounds wherein a novel solubilizing mixture is used to prepare the aqueous parenteral composition.
An objective of the present invention is to provide a novel mixture of solubilizing agents for solubilizing poorly water soluble active agents, wherein the active agents are 10 vitamin D compounds.
Another objective of the present invention is to provide a pharmaceutical composition comprising a novel mixture of solubilizing agent for the solubilization of poorly water soluble active agents, wherein the solubilizing mixture is free of Glycofurol.
Description 15
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated
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in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions 5 should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles gah, ganh and gtheh are used to refer to one or to more than one (i.e., to at 10 least one) of the grammatical object of the article.
The terms gcompriseh and gcomprisingh are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as gconsists of onlyh.
Throughout this specification, unless the context requires otherwise the word 15 gcompriseh, and variations such as gcomprisesh and gcomprisingh, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term gincludingh is used to mean gincluding but not limited toh. gIncludingh and gincluding but not limited toh are used interchangeably. 20
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Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are 5 incorporated herein by reference.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein. 10
The term gpharmaceutical compositionh refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
The term gpharmaceutically acceptable excipienth refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products. 15
The term gparenteralh refers to drug delivery system in which the active agent(s) are directly administered into blood stream in form of injection surpassing first pass metabolism.
The term gexcipientsh as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a 20 pharmaceutical composition are generally safe and non-toxic.
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The term gmixtureh as used herein refers to the mixture of ingredients present in the final compositions.
The term vitamin D herein refers to any known vitamin D compound including is pro-drug, metabolites and precursors.
The term aqueous herein refers to water based solvent system. 5
In an embodiment the present invention provides a pharmaceutical composition comprising vitamin D and a novel solubilizing agent mixture, wherein the pharmaceutical composition is in the form of aqueous parenteral composition.
In an embodiment, the present invention provides injectable compositions comprising a therapeutically effective amount of a vitamin D compound and at least one alcohol 10 based co-solubiliser, atleast one organic compound as co-solubiliser and atleast one hydrogenated castor oil based solubiliser and a vehicle comprising aqueous solvents, hydro-alcoholic solvents, or mixtures thereof; and optionally one or more pharmaceutically acceptable excipients.
In another embodiment the present invention provides an aqueous injectable 15 composition comprising a therapeutically effective amount of vitamin D compound, wherein the vitamin D compound is Cholecalciferol, and a novel solubilizing agent mixture, wherein the novel mixture of solubilizing agents comprises of hydrogenated castor oil as a solubilizer, an alcohol and an organic compound as co-solubilizers and a surfactant and atleast two or more antioxidants. 20
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In an embodiment the present invention provides a novel solubilizing mixture for the solubilization of poorly soluble active agent. In another embodiment the present invention provides a stable parenteral formulation comprising a poorly soluble active agent wherein the active agent is solubilized by using a novel solubilizing mixture, wherein the novel solubilizing mixture comprises of a solubiliser, atleast one or more 5 co-solubiliser, and a surfactant and at least two or more antioxidants, preferably three antioxidants. The stable parenteral composition provides rapid onset of action, improved bioavailability and patient compliance for those who are unable to swallow tablet or patient who is suffering from nausea and vomiting.
In an embodiment the present invention provides a pharmaceutical composition 10 comprising a poorly soluble active agent and a solubiliser, atleast one or more co-solubiliser, a surfactant and three antioxidants, wherein the pharmaceutical composition may further optionally comprise pharmaceutically acceptable excipients.
In an embodiment the present invention provides a pharmaceutical composition comprising a poorly water soluble active agent and novel mixture of solubilizing agent 15 mixture and an aqueous solvent-vehicle, wherein solubilizing agent mixture comprises of a solubiliser, atleast one or more co-solubiliser, and a surfactant and atleast two or more antioxidant.
In an embodiment the solubiliser is Polyxoyl 50 Hydrogenated Castor Oil.
In an embodiment the alcohol based co-solubiliser is Ethanol 20
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In an embodiment the organic compound as co-solubiliser is propylene glycol or the likes thereof.
In an embodiment the surfactant is polysorbates, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, 5 cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamers. In a preferred embodiment the surfactant is polysorbate
In an embodiment the antioxidants are selected from Propyl gallate, Butylated hydroxyl toluene and Butylated hydroxyl anisole.
In an another embodiment, the present invention provides a stable parenteral 10 formulation comprising vitamin D3 and novel mixture of solubilizing agent, wherein the novel mixture of solubilizing agents comprises of an solubiliser, atleast one or more co-solubiliser, and a surfactant, and three antioxidant agents, wherein the solubiliser is Polyoxyl 50 Hydrogenated Castor Oil, co-solubilisers are Propylene glycol and Ethanol, surfactant is Polysorbate 80, and the three antioxidant agents are Propyl 15 gallate, Butylated hydroxyl toluene and butylated hydroxyl anisole.
In an embodiment, the present invention is directed to pharmaceutical composition for parenteral administration of active agent or a pharmaceutically acceptable salt thereof in the range of 6% to 40% wt./vol of the composition.
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In an embodiment the solubilizer present in the range of 2% to 50% wt./vol of the the total volume of composition.
In a preferred embodiment the solubilizer is present in an amount of 20% wt./vol.
In an embodiment the co-solubilizer are present in the range of 1% to 20% wt./vol of the total volume of composition. 5
In an embodiment the co-solubiliser propylene glycol and ethanol are present in the amount of 5% w/v and 3% w/v respectively.
In an embodiment the surfactant is present in the range of 0.1% to 10% wt./vol of the total volume of composition.
In an embodiment the surfactant is polysorbate 80 and is present in the amount of 5% 10 w/v.
In an embodiment the antioxidants are present in the range of 0.001% to 5% wt./vol of the total volume of composition.
In a preferred the antioxidants are Propyl gallate, Butylated hydroxy toluene and Butylated Hydroxy Anisole are present in the amount of 0.05% w/v, 0.005% w/v and 15 0.5% w/v respectively
In an embodiment the solubiliser and co-solubiliser are present in the ratio of 5:2.
In an another embodiment parenteral formulation are suitable in form of intravenous, intramuscular, subcutaneous, intradermal, intra-arterial administration.
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In an embodiment, the present invention provides a method of producing a pharmaceutical composition for parenteral administration.
In an embodiment the present invention provides a process of manufacturing parenteral solution comprising following steps:
Step 1- Mix polysorbate 80 and poloxyl 50 hydrogeneted solution and stir the 5 solution for 10 minutes at 250 RPM.
Step 2- Add and dissolve Propyl gallate into the solution obtained from the aforementioned step and stir the solution
Step 3- Add and dissolve Butylated Hydroxy Anisole into Step-02 and stir the solution for 10 min and then add and dissolve butylated hydroxyl toluene and 10 stir the solution
Step 4- Add and dissolve Propylene glycol into step 3 and stir the solution
Step 5- Add and dissolve Ethanol into step 4 and stir the solution
Step 6-Add and dissolve cholecalciferol into step 5 and stir the solution and check the clarity of the solution. If solution is not clear, then stir the solution 15 till complete dissolution
Step 7- Make up the 95% volume with help of water for injections under continuous stirring. Check the pH of the bulk solution (6.0 to 8.0)
Step 8 . Make up the final volume 100 ltr by using water for injection under continuous stirring. Purge 0.2ƒÊ filtered nitrogen gas continuously till analysis 20 report of bulk solution received.
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Examples
Example 1: Formula for Vitamin D3 aqueous parenteral Injection:
Table 1: Formulation details:
Ingredients
Amount
Cholecalciferol (Vitamin D3)
0.75%
Polyoxyl 50 Hydrogenated Castor Oil
20%
Propylene glycol
5%
Ethanol
3%
Polysorbate 80
5%
Propyl gallate
0.05%
Butylated Hydroxy Toluene
0.005%
Butylated Hydroxy Anisole
0.5%
Example 2 . Process of Preparation 5
Step 1- Take dispensed quantity of Poloxyl 50 Hydrogeneted Castor Oil, warm up to 35o C- 40oC in a stainless steel container and purged 0.2ƒÊ filter Nitrogen gas throught manufacturing process. Add and mix polysorbate 80IP (35oC-40oC) into the poloxyl 50 hydrogeneted solution and stir the solution for 10 minutes at 250 RPM.
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Step 2- Then add and dissolve Propyl gallate (40oC-45oC) into the solution obtained from the aforementioned step and stir the solution for 15 minute at 250 RM. Increase the temperature of bulk up to 50oC-60oC.
Step 3- Add and dissolve Butylated Hydroxy Anisole (50oC-60oC) into Step-02 and stir the solution for 10min at 250 RPM. Then Add and dissolve butylated hydroxyl toluene 5 (50oC-60oC) and stir the solution for 10 min at 250 RPM.
Step 4- Add and dissolve Propylene glycol (25oC-27oC) into step 3 and stir the solution for 10min at 250 RPM
Step 5- Add and dissolve Ethanol (25oC-27oC) into step 4 and stir the solution for 10 min at 250 RPM 10
Step 6-Add and dissolve cholecalciferol (25oC-27oC) into step 5 and stir the solution for 40-45 min at 300 RPM and check the clarity of the solution. If solution is not clear, then stir the solution till complete dissolution
Step 7- Make up the 95% volume with help of water for injections (25oC-27oC) under continuous stirring at 300RPM for 10 minutes. Check the pH of the bulk solution (6.0 15 to 8.0)
Step 8 . Make up the final volume 100 ltr by using water for injection (25oC-27oC) under continuous stirring at 300 ROM for 10 minutes. Purge 0.2ƒÊ filtered nitrogen gas continuously till analysis report of bulk solution received.
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EXAMPLE-3: Stability study
i. Cholecalciferol injection prepared from example-2 was subjected to stability study under temperature 30‹C } 2‹C/75% RH } 5% RH
Table 2: Stability Study Data summary report
Test
Acceptance criteria
Initial testing
After 3 months
After 6 months
After 9 months
After 12 months
After 18 months
Description
Pale yellow to clear aqueous liquid, free from visible particles and fibers filled in amber coloured glass ampoule having a white ring on neck
Pale yellow to clear aqueous liquid, free from visible particles and fibers filled in amber coloured glass ampoule having a white ring on neck
Pale yellow to clear aqueous liquid, free from visible particles and fibers filled in amber coloured glass ampoule having a white ring on neck
Pale yellow to clear aqueous liquid, free from visible particles and fibers filled in amber coloured glass ampoule having a white ring on neck
Pale yellow to clear aqueous liquid, free from visible particles and fibers filled in amber coloured glass ampoule having a
Pale yellow to clear aqueous liquid, free from visible particles and fibers filled in amber coloured glass ampoule having a white ring on neck
Pale yellow to clear aqueous liquid, free from visible particles and fibers filled in amber coloured glass ampoule having a white ring on neck
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white ring on neck
pH
Between 6.00 to 8.00
6.89
6.33
6.27
6.23
6.35
6.40
Particulate matter (Visible Particles)
Solution should be clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Particulate matter (Sub Visible Particles
Equal to or greater than 10 micron
Not more than 6000 particles per container
116
NA
NA
NA
NA
723
Equal to or greater than 25 micron
Not more than 600 particles per container
4
NA
NA
NA
NA
35
Bacterial endotoxins
Not more than 23.36 EU/mg of Cholecalciferol
Less than 23.36 EU/mg of Cholecalciferol
NA
NA
NA
NA
Less than 23.36 EU/mg of Cholecalciferol
Sterility
No microbial growth should be overserved
No microbial growth be overserved
NA
NA
NA
No microbial growth be overserved
No microbial growth be overserved
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Assay: Each 2ml contains
Cholecalciferol (Vitamin D3) 600000 IU
Not less than 90.00% of label claimed
108.6%
105.10%
101.43%
100.03%
98.33%
100.39%
Propyl Gallate
Not less than 50.00% of label claimed
96.0%
82.40%
74.00%
74.60%
72.80%
70.00%
The cholecalciferol injection prepared from example-2 was found to be stable when placed under temperature 30‹C } 2‹C/75% RH } 5% RH for 18 months.
i. Cholecalciferol injection prepared from example-2 was subjected to stability study under temperature 25‹C } 2‹C/ 5 60% RH } 5% RH
Table 3: Stability Study Data summary report
Test
Acceptance criteria
Initial testing
After 3 months
After 6 months
After 9 months
After 12 months
After 18 months
Description
Pale yellow to clear aqueous liquid, free from visible particles and
Pale yellow to clear aqueous liquid, free from visible particles and
Pale yellow to clear aqueous liquid, free from visible particles and
Pale yellow to clear aqueous liquid, free from
Pale yellow to clear aqueous liquid, free
Pale yellow to clear aqueous liquid, free from visible particles and
Pale yellow to clear aqueous liquid, free from visible particles and
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fibers filled in amber coloured glass ampoule having a white ring on neck
fibers filled in amber coloured glass ampoule having a white ring on neck
fibers filled in amber coloured glass ampoule having a white ring on neck
visible particles and fibers filled in amber coloured glass ampoule having a white ring on neck
from visible particles and fibers filled in amber coloured glass ampoule having a white ring on neck
fibers filled in amber coloured glass ampoule having a white ring on neck
fibers filled in amber coloured glass ampoule having a white ring on neck
pH
Between 6.00 to 8.00
6.89
6.30
6.28
6.24
6.41
6.41
Particulate matter (Visible Particles)
Solution should be clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Solution is clear and free from foreign particles
Particulate matter (Sub Visible Particles
Equal to or greater than 10 micron
Not more than 6000 particles per container
116
NA
NA
NA
NA
433
18
Equal to or greater than 25 micron
Not more than 600 particles per container
4
NA
NA
NA
NA
20
Bacterial endotoxins
Not more than 23.36 EU/mg of Cholecalciferol
Less than 23.36 EU/mg of Cholecalciferol
NA
NA
NA
NA
Less than 23.36 EU/mg of Cholecalciferol
Sterility
No microbial growth should be overserved
No microbial growth be overserved
NA
NA
NA
No microbial growth be overserved
No microbial growth be overserved
Assay: Each 2ml contains
Cholecalciferol (Vitamin D3) 600000 IU
Not less than 90.00% of label claimed
108.6%
104.76 %
103.23 %
101.81 %
98.24%
97.32 %
Propyl Gallate
Not less than 50.00% of label claimed
96.0%
82.00%
76.80%
73.40%
70.00 %
70.60 %
The cholecalciferol injection prepared from example-2 was found to be stable when placed under temperature 30‹C } 2‹C/75% RH } 5% RH for 18 months. ,CLAIMS:We Claim
1. A parenteral solution comprising Cholecalciferol, a solubilizing agent, one or more co-solubilizing agent, wherein the solubiliser is Polyoxyl 50 Hydrogenated Castor Oil, and the co-solubiliser are Propylene glycol and Ethanol 5
2. The parenteral solution according to claim 1 wherein cholecalciferol is present in the amount of 0.75% w/v.
3. The parenteral solution according to claim 1, wherein the solubiliser is present in the amount of 20% w/v.
4. The parenteral solution according to claim 1, wherein the co-solubiliser 10 propylene glycol and ethanol are present in the amount of 5% w/v and 3% w/v respectively
5. The parenteral solution according to claim 1-4, further comprises a surfactant, and antioxidant.
6. The parenteral solution according to claim 5, wherein the surfactant is 15 polysorbate 80 and is present in the amount of 5% w/v.
7. The parenteral solution according to claim 5, wherein the antioxidants are Propyl gallate, Butylated hydroxy toluene and Butylated Hydroxy Anisole are present in the amount of 0.05% w/v, 0.005% w/v and 0.5% w/v respectively.
8. The parenteral solution according to claim 1 wherein the solubiliser and co-20 solubiliser are present in the ration of 5:2.
9. A process for preparation of the parenteral composition according claim 1 comprising the steps of,
Step 1- Mix polysorbate 80 and poloxyl 50 hydrogeneted solution and stir the solution for 10 minutes at 250 RPM. 25
Step 2- Add and dissolve Propyl gallate into the solution obtained from the aforementioned step and stir the solution
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Step 3- Add and dissolve Butylated Hydroxy Anisole into Step-02 and stir the solution for 10 min and then add and dissolve butylated hydroxyl toluene and stir the solution
Step 4- Add and dissolve Propylene glycol into step 3 and stir the solution
Step 5- Add and dissolve Ethanol into step 4 and stir the solution 5
Step 6-Add and dissolve cholecalciferol into step 5 and stir the solution and check the clarity of the solution. If solution is not clear, then stir the solution till complete dissolution
Step 7- Make up the 95% volume with help of water for injections under continuous stirring. Check the pH of the bulk solution (6.0 to 8.0) 10
Step 8 . Make up the final volume 100 ltr by using water for injection under continuous stirring. Purge 0.2ƒÊ filtered nitrogen gas continuously till analysis report of bulk solution received.