Title of Invention

AN INJECTABLE ANTISPASMODIC AND A METHOD OF MAKING THE SAME

Abstract A stable injectable antispasmodic and analgesic formulation comprising [a] 10 to 30 mg of camylofin dihydrochloride per ml of the injection; [b] 15 to 30 mg of Diclofenac sodium per ml of the injection; [c] at least one adjuvant glycolic co-solvent from 20 % to 65 % of the total volume of the injectable formulation; [d] at least one pH-adjusting/buffering agent for maintaining the pH of the formulation between 5.4 to 7.5 throughout its shelf life; [e] at least one antioxidant from 0.1 wt% to 5 wt% of the total volume of the formulation; [f] at least one surfactant from 1% to 10 % of the total volume of the formulation; and [g] optionally, at least one preservative from 0.01% to 5 wt % of the total volume of the formulation.
Full Text FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE



(See section 10 and rule 13)
A STABLE INJECTABLE ANTISPASMODIC AND ANALGESIC FORMULATION AND PROCESS FOR PREPARING THE SAME
SANJEEV KHANDELWAL
an Indian National
of Prem Nivas, 13, Altamount Road, Mumbai 400026,
Maharashtra, India,
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.


1 SEP 2006

This invention relates to a synergistic combination of an antispasmodic and an analgesic formulation in stable injectable form and to a method of making the same particularly for the treatment of colicky pain.
Colicky abdominal pain may be caused by spasm of smooth muscles of various internal abdominal organs such as intestinal colic, biliary colic, renal colic and dysmenorrhoea.
In the prior art it was not possible to obtain a stable camyfofin dihydrochloride and diclofenac in injectable form having a useful extended shelf life. Camylofin dihydrochloride hydrolyzes in water and loses its potency quickly in solution with increasing pH more than 4.5. Similarly the diclofenac sodium loses its potency quickly in solution with lower pH that is less than 8.0. This has acted as a deterrent in making both combination of camylofin dihydrochloride and diclofenac sodium in an injectable form. The loss of potency is nearly ten percent within a month of manufacture.
Also it has been studied that combination of the said active ingredients in a single solution causes precipitate formation which is insoluble and can not be re-dispersible thereby making a solution containing a combination of both physically as well as chemically incompatible.
An object of this invention is to provide a formulation comprising of a combination of a strongly acidic molecule, Camylofin dihydrochloride ( pH 1.5 to 3.5 ) and a strongly alkaline molecule, Diclofenac sodium ( pH 8.0 to 9.1) in a stable injectable form, the pH of the formulation being maintained between 5.4 to 7.5 throughout its shelf life.
Another object of this invention is to provide a formulation as described above which is administrated into the human body either by slow intravenous infusion, or by intramuscular route.
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Yet another object of this invention is to provide a formulation containing the above ingredients along with excipients, having a stable pH and in which occurrence of any precipitation reaction is inhibited.
The formulation in accordance with this invention mainly comprises at least one adjuvant solvent, at least one antioxidant(s), optionally one chelating agent, at least one preservative(s), at least one surfactant, a pH adjusting/ buffering agent and a carrier aqueous base (water for injection).
According to this invention there is provided a stable injectable antispasmodic and analgesic formulation comprising
[a] 10 to 30 mg of camylofin dihydrochloride per ml of the injection;
[b] 15 to 30 mg of Diclofenac sodium per ml of the injection;
[c] at least one adjuvant glycolic co-solvent from 20 % to 65 % of the total volume of the injectable formulation;
[d] at least one pH-adjusting/buffering agent for maintaining the pH of the formulation between 5.4 to 7.5 throughout its shelf life;
[e] at least one antioxidant from 0.1 wt% to 5 wt% of the total volume of the formulation;
[f] at least one surfactant from 1% to 10 % of the total volume of the formulation; and
[g] optionally, at least one preservative from 0.01% to 5 wt % of the total volume of the formulation.
The glycolic co-solvents along with the water for injection, which may be one or in combination of solvents selected from a group of glycols consisting of propylene glycol, polyethylene glycols - 300, polyethylene glycols - 400 glycerin and other oil based solvents suitable for parenteral.
Unexpectedly and surprisingly, it is found that the co solvents prevent the hydrolysis of camylofin and therefore the camylofin remains stable and potent throughout the period of the shelf life of the product.
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The injectable formulation contains antioxidants that mainly prevent the oxidation of the active drug and to stabilize the formulation throughout the shelf life of the formulation. The anti-oxidant used in the formulation is selected from a group consisting of sodium metabisulfide, sodium sulfide, and sodium disulfide.
The formulation contains at least one chelating agent that forms a complex with the oxidizing agent and thus prevents oxidation of the active drug and also potentiates the stabilizing action of the other antioxidants used thus stabilizing the formulation throughout the shelf life of the formulation. The chelating agent used in the formulation is preferably sodium salt of EDTA (ethylene diamino tetra acetic acid) is optionally included.
The formulation contains at least one surfactant that mainly solubilizes the drug in the medium and thus prevents the precipitation of drug that may occur during the storage of the formulation. The surfactant used in the formulation is selected from the group of polysorbates. The formulation preferably contains polysorbate 80.
Another aspect of the invention comprises the incorporation of ingredients or excipients for adjusting the pH. The pH of the injection is the single most crucial parameter for stability of the drug in the formulation. The formulation of this invention comprises pH-adjusting agent in its dilute solution that may be preferably sodium hydroxide, hydrochloric acid, citric acid, ammonium acetate, glacial acetic acid, ammonium acetate, sodium acetate and phosphates. The pH of the formulation is kept within the range of 5.4 to 7.5 throughout its shelf life.
The formulation contains preservatives that mainly prevent the deterioration of the formulation from microbial contamination. The preservative used in the formulation is a pharmaceutically acceptable material and is preferably selected from the group consisting of benzyl alcohol, methyl paraben, propyl paraben. The preservative may be used optionally in the formulation where the quantity of the said adjuvant solvents is more than 40 % of the total volume. The adjuvant solvent itself acting as a preservative. A preferred
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content of added preservative is from 0.001 % to 5% of the total volume of the formulation.
According to another aspect of this invention there is provided a process for making a stable injectable antispasmodic and analgesic formulation comprising camylofin dihydrochloride and diclofenac sodium which comprises the steps carried out throughout in an inert atmospehere,
[a] dissolving dispensed quantity of camylofin dihydrochloride in fresh water for injection to obtain a clear solution;
[b] transferring the clear solution to a stainless steel reaction vessel containing a dispensed quantity of an adjuvant co solvent;
[c] stirring the clear solution and co solvent for 10 to 30 minutes to obtain a homogenous solution;

[d] mixing together dispensed quantities of an antioxidant and a chelating agent in fresh water for injection to form an antioxidant-chelating agent solution and adding the antioxidant-chelating agent solution to the homogenous solution of step(c) and stirring for 10 to 30 minutes to obtain an active ingredient- antioxidant-chelating agent solution;
[e] adding an alkaline pH adjusting agent to the active ingredient-antioxidant-chelating agent solution to raise the pH of the said solution up to 4.0;
[f] adding diclofenac sodium to co-solvent and slowly adding fresh water for injection with stirring to get a clear diclofenac sodium solution;
[g] slowly adding the diclofenac sodium solution to the pH adjusted active ingredient- antioxidant-chelating agent solution of camylofin dihydrochloride to form a solution of active agents;
[h] adding dispensed quantity of a surfactant dissolved in fresh water for injection to the solution of active ingredients;
[i] optionally adding a preservative to the solution of active agents;
0] checking the pH of the solution of active agents;
[k] adjusting the pH of the solution of the active agents to provide a pH adjusted stable injectable formulation having pH adjusted to lie between pH 5.4 to 7; and
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[i] filtering the injectable formulation through a sterile membrane filter assembly using nitrogen pressure and collecting the filtered injectable solution to form the stable injectable antispasmodic and analgesic formuation for filing in sterile nitrogen flushed ampules.
The invention will now be described with reference to the accompanying examples, which are by no means limiting
EXAMPLES".
Example -1
Fill-2 ml ampoule
Each ml of the formulation contain
Camylofin Dihydrochloride .... 25 mg
Diclofenac Sodium 25 mg
Water for injection q.s
Manufacturing process: (Batch Size: 100 liters)
1. Washing and sterilization:
After completion of the process of washing and sterilization of ampoules, these were transferred to a filling area though a double door chamber.
2. Preparation of the solution:
The mixing of injection solution under nitrogen was carried out throughout the manufacturing operation. 40 liters of Propylene Glycol were transferred to a 100 lits capacity s.s. Vessel (no1) and 2.5 kg of diclofenac sodium was added to this and mixed with medium speed to obtain a clear solution. 2.00 kgs of Benzyl Alcohol was added to the s.s. Vessel (no 1) slowly and gradually under continuous stirring. Meanwhile, 2.500 kgs of camylofin dihydrochloride was dissolved in 10.00 lits of fresh water for injection in another s.s vessel (no 2). 0.250 kgs of sodium metabisulphite was dissolved in 1,00 lits. of fresh water for injection and the solution was added to the s.s Vessel ( no 2). and stirred for 10 minutes. Add sufficient quantity of 5 % sodium hydroxide soiution to obtain a pH ot about 3.6. After the addition was cornpieted the resultant solution was stirred for 10 minutes. 15 liters of propylene glycol was added to this solution and stirred for 10 minutes. This solution was then
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transfer slowly with stirring to the diclofenac sodium injection. Then
polysorbate 80, 4 kg was added slowly under constant stirring for about 10
minutes. Then sufficient quantity of the fresh water for injection was added to
make up the volume to about 90.00 lits and mixed by stirring for 30 minutes.
The pH value of solution was checked and found to be between 5.2. 5 % of
sodium hydroxide solution was added under continuous stirring to adjust the
pH Value of injection solution between 5.4 and 7.5. Sufficient fresh water for
injection was added to make up the final volume of the batch to 100.0 lits and
Mixed by stirring for 30 minutes. Actual pH recorded was 6.4.
Filtration:
The Injection solution was filtered through sterile membrane filter assembly
(0.22 micron) using nitrogen pressure and collected in four sterilized 50 lits.
s.s. pressure vessels with aspirators (vent).
Filling of Ampoules
The hopper of the fiiling machine was loaded with sterile ampoules.
Example-2
Fill-10 ml vial
Each ml of the formulation contain
Camylofin Dihydrochloride .... 25 mg
Diclofenac Sodium 25 mg
Water for injection q.s
Manufacturing process: (Batch Size: 100 liters)
3. Washing and sterilization:
After completion of the process of washing and sterilization of vial, these were transferred to a filling area though a double door chamber.
4. Preparation of the solution:
The mixing of injection solution under nitrogen was carried out throughout the manufacturing operation. 40 liters of Propylene Glycol were transferred to a 100 lits capacity s.s. Vessel (no1) and Add 2.5 kg of diclofenac sodium to this and mixed with medium speed to obtain a clear solution. 2.00 kgs of Benzyl Alcohol was added to the s.s. Vessel (no 1) slowly and gradually under continuous stirring. Meanwhile, 2.500 kgs of camylofin dihydrochloride was dissolved in 10.00 lits of fresh water for injection in another s.s vessel (no 2).
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0.250 kgs of sodium metabisulphite was dissolved in 1.00 lits. of fresh water for injection and the solution was added to the s.s Vessel ( no 2). and stirred for 10 minutes. Sufficient quantity of 5 % sodium hydroxide solution was added to obtain a pH of about 3.4. After the addition was completed the resultant solution was stirred for 10 minutes. Add 15 liters of propylene glycol to this solution and stirred for 10 minutes. This solution is then transfer slowly with stirring to the diclofenac sodium injection. Then polysorbate 80, 4 kg was added slowly under constant stirring for about 10 minutes. Then sufficient quantity of the fresh water for injection was added to make up the volume to about 90.00 lits and mixed by stirring for 30 minutes. The pH value of solution was checked and found to be between 4.68. Add 5 % of sodium hydroxide solution under continuous stirring to adjust the pH Value of injection solution between 5.4 and 7.5. Sufficient fresh water for injection was added to make up the final volume of the batch to 100.0 lits and Mixed by stirring for 30 minutes. Actual pH recorded was 6.38. Filtration:
The Injection solution was filtered through sterile membrane filter assembly (0.22 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent). Filling of vial
The hopper of the filling machine was loaded with sterile vial and filled aseptically with nitrogen gas.
Example - 3
Fill-2 ml ampoule
Each ml of the formulation contain
Camylofin Dihydrochloride .... 25 mg
Diclofenac Sodium 25 mg
Water for injection q.s
Manufacturing process: (Batch Size: 100 liters)
5. Washing and sterilization:
After completion of the process of washing and sterilization of ampoules, these were transferred to a filling area though a double door chamber.
6. Preparation of the solution:
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The mixing of injection solution under nitrogen was carried out throughout the manufacturing operation. 35 liters of Propylene Glycol were transferred to a 100 lits capacity s.s. Vessel (no1) and 2.5 kg of diclofenac sodium was added to this and mixed with medium speed to obtain a clear solution. 2.50 kgs of Benzyl Alcohol was added to the s.s. Vessel (no 1) slowly and gradually under continuous stirring. Meanwhile, 2.500 kgs of camylofin dihydrochloride was dissolved in 10.00 lits of fresh water for injection in another s.s vessel (no 2). 0.250 kgs of sodium bisulphite was dissolved in 1.00 lits. of fresh water for injection and the solution was added to the s.s Vessel ( no 2). and stirred for 10 minutes. Sufficient quantity of 5 % sodium hydroxide solution was added to obtain a pH of about 3.35. After the addition was completed the resultant solution was stirred for 10 minutes. Add 15 liters of polyethyl glycol -300 to this solution and stir for 10 minutes. This solution was then transfer slowly with stirring to the diclofenac sodium injection. Then polysorbate 80 4.50 kg was added slowly under constant stirring for about 10 minutes. Then sufficient quantity of the fresh water for injection was added to make up the volume to about 90.00 lits and mixed by stirring for 30 minutes. The pH value of solution was checked and found to be between 4.8. Add 5 % of sodium hydroxide solution under continuous stirring to adjust the pH Value of injection solution between 5.4 and 7.5. Sufficient fresh water for injection was added to make up the final volume of the batch to 100.0 lits and Mixed by stirring for 30 minutes. Actual pH recorded was 6.2. Filtration:
The Injection solution was filtered through sterile membrane filter assembly (0.22 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent). Filling of Ampules The hopper of the fiiling machine was loaded with sterile ampules.
Example - 4
Fill - 3 ml ampoule
Each ml of the formulation contain
Camylofin Dihydrochloride .... 8.5 mg
Diclofenac Sodium . 8.5 mg
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Water for injection q.s
Manufacturing process: (Batch Size: 100 liters)
7. Washing and sterilization:
After completion of the process of washing and sterilization of ampoules, these were transferred to a filling area though a double door chamber.
8. Preparation of the solution:
The mixing of injection solution under nitrogen was carried out throughout the manufacturing operation. 30 liters of Propylene Glycol were transferred to a 100 lits capacity s.s. Vessel (no1) and 0.850 kg of diclofenac sodium was to this and mixed with medium speed to obtain a clear solution. 1.00 kgs of Benzyl Alcohol was added to the s.s. Vessel (no 1) slowly and gradually under continuous stirring. Meanwhile, 2.500 kgs of camylofin dihydrochloride was dissolved in 10.00 lits of fresh water for injection in another s.s vessel (no 2). 0.200 kgs of sodium metabisulphite was dissolved in 1.00 lits. of fresh water for injection and the solution was added to the s.s Vessel ( no 2). and stirred for 10 minutes. Sufficient quantity of 20 % ammonium acetate solution was added to obtain a pH of about 3.28. After the addition was completed the resultant solution was stirred for 10 minutes. Add 20 liters of propylene glycol to this solution and stir for 10 minutes. This solution is then transfer slowly with stirring to the diclofenac sodium injection. Then polysorbate 80 3.50 kg was added slowly under constant stirring for about 10 minutes. Then sufficient quantity of the fresh water for injection was added to make up the volume to about 90.00 lits and mixed by stirring for 30 minutes. The pH value of solution was checked and found to be between 5.36. Add 20 % of ammonium acetate solution under continuous stirring to adjust the pH Value of injection solution between 5.4 and 7.5. Sufficient fresh water for injection was added to make up the final volume of the batch to 100.0 lits and Mixed by stirring for 30 minutes. Actual pH recorded was 6.21. Filtration:
The Injection solution was filtered through sterile membrane filter assembly (0.22 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent). Filling of Ampoules The hopper of the fiiling machine was loaded with sterile ampoules.
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I Claim:
[1] A stable injectable antispasmodic and analgesic formulation comprising
[a] 10 to 30 mg of camylofin dihydrochloride per ml of the injection;
[b] 15 to 30 mg of Diclofenac sodium per ml of the injection;
[c] at least one adjuvant glycolic co-solvent from 20 % to 65 % of the total volume of the injectable formulation;
[d] at least one pH-adjusting/buffering agent for maintaining the pH of the formulation between 5.4 to 7.5 throughout its shelf life;
[e] at least one antioxidant from 0.1 wt% to 5 wt% of the total volume of the formulation;
[f] at least one surfactant from 1% to 10 % of the total volume of the formulation; and
[g] optionally, at least one preservative from 0.01% to 5 wt % of the total volume of the formulation.
[2] A stable injectable antispasmodic and analgesic formulation, as claimed in claim 1, in which the adjuvant glycolic co-solvent which is at least one solvent selected from a group of solvents consisting of propylene glycol, polyethylene glycols - 300, polyethylene glycols - 400 and glycerin.
[3] A stable injectable antispasmodic and analgesic formulation as claimed in claim 1, in which the anti-oxidant is selected from a group consisting of sodium metabisulfide, sodium sulfide, and sodium disulfide.
[4] A stable injectable antispasmodic and analgesic formulation as claimed in claim 1, in which chelating agent preferably sodium salt of EDTA (ethylene diamino tetra acetic acid) is optionally included.
[5] A stable injectable antispasmodic and analgesic formulation as claimed in claim 1, in which the surfactant is selected from the group of polysorbates.
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[6] A stable injectable antispasmodic and analgesic formulation as claimed in claim 5, in which the surfactant is polysorbate 80.
[7] A stable injectable antispasmodic and analgesic formulation as claimed in claim 1, in which the pH-adjusting agent in its dilute solution is an agent selected from a group consisting of sodium hydroxide, hydrochloric acid, citric acid, ammonium acetate, glacial acetic acid, ammonium acetate, sodium acetate and sodium phosphates.
[8] A stable injectable antispasmodic and analgesic formulation as claimed in claim 1, in which the preservative used in the formulation is a pharmaceutically acceptable material selected from the group consisting of benzyl alcohol, methyl paraben, propyl paraben or glycols such as propylene glycol, polyethylene glycols - 300, polyethylene glycols - 400.
[9] A process for making a stable injectable antispasmodic and analgesic formulation as claimed in claims 1 to 8, comprising the steps throughout in an inert atmosphere of:
[a] dissolving dispensed quantity of camylofin dihydrochloride in fresh water for injection to obtain a clear solution;
[b] transferring the clear solution to a stainless steel reaction vessel containing a dispensed quantity of an adjuvant co solvent;
[c] stirring the clear solution and co solvent for 10 to 30 minutes to obtain a homogenous solution;

[d] mixing together dispensed quantities of an antioxidant and a chelating agent in fresh water for injection to form an antioxidant-chelating agent solution and adding the antioxidant -chelating agent solution to the homogenous solution of step ( c) and stirring for 10 to 30 minutes to obtain an active ingredient- antioxidant-chelating agent solution;
[e] adding an alkaline pH adjusting agent to the active ingredient-antioxidant-chelating agent solution to raise the pH of the said solution up to 4.0;
12

[f] adding diclofenac sodium to co-solvent and slowly adding fresh water for injection with stirring to get a clear diclofenac sodium solution;
[g] slowly adding the diclofenac sodium solution to the pH adjusted active ingredient- antioxidant-chelating agent solution of camylofin dihydrochloride to form a solution of active agents;
[h] adding dispensed quantity of a surfactant dissolved in fresh water
for injection to the solution of active ingredients;
[i] optionally adding a preservative to the solution of active agents;
[j] checking the pH of the solution of active agents;
[k] adjusting the pH of the solution of the active agents to provide a pH
adjusted stable injectable formulation having pH adjusted to lie
between pH 5.4 to 7; and
[I] filtering the injectable formulation through a sterile membrane filter
assembly using nitrogen pressure and collecting the filtered injectable
solution to form the stable injectable antispasmodic and analgesic
formuation for filing in sterile nitrogen flushed ampules.
Dated this 4th day of March 2005
Marian Dewan
»f R K Dewan & Co
Applicant's Patent Attorney
13

Documents:

209-mum-2004-abstract(complete)-(4-3-2005).pdf

209-mum-2004-cancelled pages(11-9-2006).pdf

209-mum-2004-claims(complete)-(4-3-2005).pdf

209-mum-2004-claims(granted)-(11-9-2006).doc

209-mum-2004-claims(granted)-(11-9-2006).pdf

209-mum-2004-claims(granted)-(17-10-2007).pdf

209-mum-2004-correspondence(11-9-2006).pdf

209-mum-2004-correspondence(ipo)-(19-12-2007).pdf

209-mum-2004-correspondence(ipo)-(4-8-2006).pdf

209-mum-2004-description(complete)-(4-3-2005).pdf

209-mum-2004-description(granted)-(17-10-2007).pdf

209-mum-2004-description(provisional)-(23-2-2004).pdf

209-mum-2004-form 1(23-2-2004).pdf

209-mum-2004-form 18(2-6-2005).pdf

209-mum-2004-form 2(complete)-(4-3-2005).pdf

209-mum-2004-form 2(granted)-(11-9-2006).doc

209-mum-2004-form 2(granted)-(11-9-2006).pdf

209-mum-2004-form 2(granted)-(17-10-2007).pdf

209-mum-2004-form 2(provisional)-(23-2-2004).pdf

209-mum-2004-form 2(title page)-(complete)-(4-3-2005).pdf

209-mum-2004-form 2(title page)-(granted)-(17-10-2007).pdf

209-mum-2004-form 2(title page)-(provisional)-(23-2-2004).pdf

209-mum-2004-form 3(23-2-2004).pdf

209-mum-2004-form 4(30-12-2004).pdf

209-mum-2004-form 5(4-3-2005).pdf

209-mum-2004-form 9(16-3-2005).pdf

209-mum-2004-power of attorney(23-2-2004).pdf

209-mum-2004-specification(amended)-(1-9-2006).pdf


Patent Number 211089
Indian Patent Application Number 209/MUM/2004
PG Journal Number 45/2007
Publication Date 09-Nov-2007
Grant Date 17-Oct-2007
Date of Filing 23-Feb-2004
Name of Patentee SANJEEV KHANDELWAL
Applicant Address PREM NIVAS, 13, ALTAMOUNT ROAD, MUMBAI,
Inventors:
# Inventor's Name Inventor's Address
1 SANJEEV KHANDELWAL PREM NIVAS, 13, ALTAMOUNT ROAD, MUMBAI 400 026,
PCT International Classification Number A61K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA