FIELD OF INVENTION

This invention relates to a synergistic formulation consisting of a muscle relaxant and at least one analgesic in an injectable pharmaceutical dosage form and to a method of making the same.

WHAT THE INVENTION ENVISAGES

This invention envisages a synergistic formulation composition containing muscle relaxant methocarbamol and at least one analgesic selected from a group containing paracetamol and diclofenac sodium.

The fixed dose combination of methocarbamol and the analgesic produces a synergistic response for the effective relief of pain.

In particular this invention envisages an injectable formulation for parenteral administration of methocarbamol with diclofenac sodium and/or paracetamol.

The formulation is meant to be administrating into the human body either by slow intravenous infusion, or by intramuscular route.

Methocarbamol is centrally acting skeletal muscle relaxant useful in painful musculoskeletal conditions associated with spasm.

Paracetamol is one of the most widely used analgesics and is regarded to offer highest degree of safety and tolerability in the recommended dose. Although I ts mode of action is not fully understood, Paracetamol is believed to inhibit cyclo- oxygenase (COX) in the central nervous system, besides exerting action on the peripheral pain chemoreceptors (Bradykinin).

Like Methocarbamol, Paracetamol is immediately acting, thus has a matching

pharmacokinetic and pharmacodinamic profile

Diclofenac is one of the most trusted NS AID, since the drug achieves excellent concentration in the synovial fluids. Thus the addition of Diclofenac Potassium alongwith Methocarbamol and Paracetamol, not only exhibits a matching pharmacokinetic profile/ but more importantly the synergistic effect in alleviating painful conditions of skeletal muscle spasm- The major indications are- Dorstagia and to combat muscle spas with pain in inflammatory iritative conditions like arthritis, bursitis, tendonitis and also in chronic condition of pain.

The aspect of the invention comprises the incorporation of ingredients or excipients for making a stable pH adjusted formulation and preventing occurrence of any precipitation reaction during storage. The formulation mainly comprise of at least one adjuvant co-solvent, optionally one preservative(s), one surfactant, and pH adjusting/ buffering agent and a carrier aqueous base (water for injection)

According to this invention there is provided a stable injectable formulation comprising active ingredients that consist of

(a) 25 to 100 mg of Methocarbamol per ml of the injection

(b) 5 to 25 mg of Diclofenac sodium per ml of the injection and/or

(c) 10 to 75 mg of Paracetamol per ml of the injection

(d) at least one adjuvant glycolic co-solvent 20 % to 65 % of the total volume of the injectable formulation;

(e) pH-adjusting/ buffering agents.

(f) Optionally one antioxidant 0.1 % to 5 wt% with or without a chelating agent of the total volume of the formulation.

(g) Optionally one preservative from 0.01% to 5 wt % of the total volume of the formulation

(h) Optionally one surfactant 1% to 10 % of the total volume of the formulation.

The formulation includes glycolic co-solvents along with the water for injection, which may be one or in combination that is selected from the glycols such as propylene glycol, polyethylene glycols - 300, polyethylene glycols - 400, glycerin, esters of fatty acids, cremophor RS40 and other oil solvents suitable for the parenteral formulation. These co solvents can also prevent the microbial growth and act as a preservative when used in higher concentration.

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 the group consisting of sodium metabisulfide, sodium sulfide, and sodium disulfide.

The formulation contains chelating agent that forms a complex with the oxidizing agent and thus prevent oxidation of the active drug and thus potentiate the stabilizing action of the other antioxidants used thus stabilize 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).

The formulation contains 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 4.5 to 7.5 throughout its shelf life.

The formulation contains preservatives that mainly prevent the deterioration of the formulation from the microbial contamination. The preservative used in the formulation is a pharmaceutically acceptable material and is preferably selected from the group of benzyl alcohol, methyl paraben, propyl paraben and the like. 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 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 of making a stable injectable antispasmodic and analgesic formulation comprising methocarbamol with paracetamol and/or diclofenac sodium which comprises the steps, carried out throughout in an inert atmosphere, of

[a] Dissolving dispensed quantity of methocarbamol in co-solvent and if required heat to 50 °C and stir properly to obtain a clear solution;

[b] Add dispensed quantity of paracetamol and / diclofenac [add one after another when both diclofenac and paracetamol are in the formulation] to the solution of the co-solvent and mix properly to get a clear solution.

[c] stirring the clear solution and the co solvent for about 10 to 30 minutes to obtain a homogenous solution;

[d] mixing together dispensed quantities of an antioxidant and a chelating agent in water for injection to form an antioxidant-chelating agent solution and adding the an antioxidant - chelating agent solution to the homogenous solution and stirring for about 10 to 30 minutes to obtain an active ingredient- antioxidant-chelating agent solution.

[e] Add the preservative to the solution and checking the pH of the non pH adjusted injectable formulation;

[f] adjusting the pH of the non pH adjusted injectable formulation to lie between pH 5.5 to 7.

[h] adding water for injection to the pH adjusted injectable formulation to make up volume to obtain unfiltered injectable formulation;

[i] filtering the unfiltered injectable formulation through a sterile membrane filter assembly using nitrogen pressure and collecting the filtered injectable solution being the stable injectable skeletal muscle relaxant and analgesic formuation for filing in sterile nitrogen flushed ampoules..

The invention will now be described with reference to the accompanying examples, which are by no means limiting

EXAMPLES:

Example -1

Fill - 5 ml ampoule/vial

Each ml of the formulation contain

Methocarbamol 100 mg

Diclofenac Sodium 15 mg

Manufacturing process: (Batch Size: 100 liters)

1. Washing and sterilization:

After completion of the process of washing and sterilization of ampoules/vial, 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. 5 liters of Propylene Glycol were transferred to a 100 lits capacity s.s. Vessel (nol) and Add 1.5 kg of diclofenac sodium 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, 10.0 kgs of methocarbamol was dissolved in 50.00 lits of polyethylene glycol 300 in another s.s vessel (no 2). and stirred for 10 minutes. This solution is then transfer slowly with stirring to the diclofenac sodium solution. 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 5.2. 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 6.4.

Filtration:

The Injection solution was filtered through sterile membrane filter assembly (0.45 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 filling machine was loaded with sterile ampoules. Example - 2

Fill -10 ml ampoule/vial

Each ml of the formulation contain

Methocarbamol 75 mg

Paracetamol 30 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/ampoule, 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. 10 liters of Propylene Glycol were transferred to a 100 lits capacity s.s. Vessel (nol) and Add 3.0 Kg of paracetamol to this and mixed with medium speed to obtain a clear solution. Meanwhile, 7.5 kgs of methocarbamol was dissolved in 45 lits of polyethylene glycol 300 in another s.s vessel (no 2). 0.025 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. After the addition was completed the resultant solution was stirred for 10 minutes. This solution is then transfer slowly with stirring to the paracetamol solution. 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 5.4. 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 6.01.

Filtration:

The Injection solution was filtered through sterile membrane filter assembly (0.45 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent).

Filling of vial/ ampoule

The hopper of the filling machine was loaded with sterile vial/ampoule and filled aseptically with nitrogen gas.

Example - 3

Fill - 10 ml ampoule/vial Each ml of the formulation contain

Methocarbamol 75 mg

Diclofenac Sodium ...7.5 mg

Manufacturing process: (Batch Size: 100 liters)

5. Washing and sterilization:

After completion of the process of washing and sterilization of ampoules/vial, these were transferred to a filling area though a double door chamber.

6. Preparation of the solution;

The mixing of injection solution under nitrogen was carried out throughout the manufacturing operation. 10 liters of Propylene Glycol were transferred to a 100 lits capacity s.s. Vessel (nol) and Add 0.75 kg of diclofenac sodium 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, 7.500 kgs of methocarbamol was dissolved in 35 lits of polyethylene glycol in another s.s vessel (no 2) and the solution was added to the s.s Vessel ( no 2). and stirred for 10 minutes. This solution is then transfer slowly with stirring to the diclofenac sodium solution. 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 5.68. 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 6.2.

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 Ampoules/vials

The hopper of the filling machine was loaded with sterile vial/ampoule and filled aseptically with nitrogen gas.

Example - 4

Fill -10 ml ampoules/vial Each ml of the formulation contain

Methocarbamol 75 mg

Diclofenac Sodium 7.5 mg

Paracetamol 30.0 mg Manufacturing process: (Batch Size: 100 liters)

1. Washing and sterilization:

After completion of the process of washing and sterilization of ampoules/vial, 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. 20 liters of Propylene Glycxjl were transferred to a 100 lits capacity s.s. Vessel (nol) and Add 0.75 kg of diclofenac sodium 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. Add, 3.0 kgs of Paracetamol to the above solution and dissolved it properly. After the addition was completed the resultant solution was stirred for 10 minutes. Add 30 liters of propylene glycol 300 to this solution and stir for 10 minutes. Then add methocarbamol 7.5 kg to this solution is then transfer slowly with stirring to the diclofenac sodium solution. 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 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 6.21.

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 filling machine was loaded with sterile ampoules.

Example - 5

Each ml of the formulation contain [Fill - 5 ml ampoules/vtal]

Methocarbamol 100 mg

Diclofenac Sodium 10 mg

Paracetamol 60.0 mg

Manufacturing process: (Batch Size: 100 liters)

3. Washing and sterilization: After completion of the process of washing and sterilization of ampoules/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. 10 liters of Propylene Glycol were transferred to a 100 lits capacity s.s. Vessel (nol) and Add 1.0 kg of diclofenac sodium 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. Add, 6.0 kgs of Paracetamol to the above solution and dissolved it properly. After the addition was completed the resultant solution was stirred for 10 minutes. Add 45 liters of propylene glycol 300 to this solution and stir for 10 minutes.

Then add methocarbamol 10.0 kg to this solution is then transfer slowly with stirring to the diclofenac sodium injection. 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 5.48. Add 5 % of sodium 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 6.25.

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 filling machine was loaded with sterile ampoules.