Title of Invention

A NOVEL METHOD OF PREPARATION OF DICLOFENAC INJECTION

Abstract

The water soluble salt of Diclofenac e.g. Sodium Diclofenac is used as an Anti- inflammatory agent in injection form. In this invention, Diclofenac injectable preparation is made by using Diclofenac salt, water for injection,. Benzyl Alcohol, buffer/alkalis, antioxidants and stabilizers without using propylene glycol. In this invention Nitrogen gassing is used to impart stability. Diclofenac is susceptible to oxidation, and Nitrogen prevents its oxidation. The present injection is given intramuscularly in case of inflammation. This injection is less viscous and less painful to the patient as compared to present available preparations of Diclofenac injection. 19

Full Text

FORM-2 THE PATENTS ACT, 1970 COMPLETE SPECIFICATION [Section 10] 1. A NOVEL METHOD OF PREPARATION OF DICLOFENAC INJECTION 2. (a) KETAN RAJNIBHAI PATEL (b) 12, Nandihill, Opp. ISRO Station, Satellite Road, Ahmedabad-380 015. Gujarat, India. (c) Nationality Indian. (a) MILAN RAJNIBHAI PATEL (b) 12, Nandihill, Opp. ISRO Station, Satellite Road, Ahmedabad-380 015. Gujarat, Ind'ia. (c) Nationality Indian. The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed. This invention relates to A NOVEL METHOD OF PREPARATION OF DICLOFENAC INJECTION. Diclofenac is mainly used as the Sodium salt for the relief of pain and inflammation in various conditions; musculoskeletal and joint disorders such as rheumatoid arthritis, osteoarthrities and ankylosing spondylitis; peri-articular disorders such as renal colic, acute gout, dysmenorrhoea and following surgical procedures. It has also been used in some countries for the management of fever. U.S. Patent 3,558,690 describes, for parenteral administration, fluid unit dosage forms can be prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium. 2 One of the formulations mentioned under the said patent is described as under: "Ampoules for parenteral, particularly intramuscular, administration, preferably contain a water soluble salt, e.g. The sodium salt, of a substituted phenyl acetic acid falling under Formula 1, in a concentration of, preferably 0.5 to 5% in aqueous solution, optionally together with suitable stabilizing agents and buffer substances". State of art is, water soluble salt of Diclofenac is dissolved in propylene glycol and water, together with benzyl alcohol, buffer substances and stabilizing agents. The invention is described with respect to the accompanying figures of chromatograms of Diclofenac Injection. Fig 1 represents Chromatogram of Diclofenac injection of brand 1. 3 Fig 2 represents Chromatogram of Diclofenac injection of brand 2. Fig 3 represents Chromatogram of Diclofenac injection of brand 3. Fig 4 represents Chromatogram of Diclofenac injection of brand 4. Fig 5 represents Chromatogram of Diclofenac injection made in accordance with the present invention. Chromatograms of four leading brands of Diclofenac injections being manufactured and marketed at present, confirming presence of propylene glycol (20%-50%) as solvent are shown at Fig. 1, Fig. 2, Fig. 3 and Fig. 4. We have also analyzed several other brands of Diclofenac injections on the market and confirmed the presence of propylene glycol as solvent in all of them. 4 The above chromatograms establish the fact that Diclofenac injections are being manufactured by a process which involves solubilizing water soluble salt of Diclofenac in aqueous solution system comprising propylene glycol and water for injection. Therefore the general formula for Diclofenac injection products available in the market can be stated under: Each ml contains: Diclofenac 0.5% Propylene Glycol 20% to 50% Benzyl Alcohol 4% (as preservative) Suitable Antioxidant and Stabilizers Quantity sufficient Water for Injection Quantity sufficient The present invention describes process to manufacture Diclofenac injections without using 5 propylene glycol. Water for injection is the safest & ideal solvent for parenteral preparations. Hence parenteral preparation having water for injection predominantly as solvent would certainly be preferable over those having solvent like propylene glycol. In this process, water soluble salt of Diclofenac (e.g. Diclofenac Sodium) is dissolved in water for injection. The general formula of the present invention is as under: Water soluble salt of Diclofenac 0.5 to 3.5% Benzyl Alcohol 4% Water for injection Quantity Sufficient Buffers/alkalis, antioxidants and stabilizers Quantity Sufficient The chromatogram confirming the absence of propylene glycol in Diclofenac injections made in accordance with the present invention is shown at Fig. 5. 6 The present invention is an analgesic anti-inflammatory injection particularly administered intramuscularly. In the present invention water for injectibn used, is water (H2O) free from bacteria and pyrogens. In this process Nitrogen gassing is done while making slurry of Diclofenac salt and Benzyl Alcohol, cooling, stirring, and filling of ampoules for injection. Nitrogen gassing is used to impart stability. Diclofenac is susceptible to oxidation, and Nitrogen prevents its oxidation. pH of the injection is maintained or adjusted between 8.1 to 9.0 with the help of suitable buffer or alkali. In the present invention Diclofenac injection is manufactured by a process which involves solubilising water soluble salt of Diclofenac in water for injection. 7 Therefore, Diclofenac injections manufactured by this new process have two advantages - a) the solution is free from propylene glycol. Propylene glycol is an irritant and causes pain and irritation at site of subcutaneous or intramuscular injection (Martindale, The Extra pharmacopoeia 28th Edition; Hand-Book of excepients). Further, it has also been reported that aqueous solution of 2% propylene glycol iso-osmotic with serum caused 100% haemolysis of erythrocytes in 45 minutes (Martindale, The Extrapharmacopoeia, 28th Edition) b) being free from propylene glycol, the injection solution is less viscous as compared to 8 Diclofenac injections manufactured by a process which uses propylene glycol as a solvent. The viscosity of present injection was measured on 'U1 Tube Viscometer type BS/U, catalogue No. 16395 (of Durga Scientific Pvt. Ltd). Measurement of viscosity was done as per formula given hereunder, on the U tube 'viscometer at 20°c, using the value of viscosity of glycerol 50% v/v given in the Merck Index (6.05 cps at 20°c) as the reference substance. V = kdt V is viscosity k is the constant d is the density t is the time Viscosity of the solution of the present invention was found to be 1.10 cps at 20° C. The viscosity of the 9 solution of the present invention was marginally higher than water for injection. We also tested viscosity of Diclofenac injections of other brands from the market and we found viscosity ranging from 2.06 cps to 5.42 cps. The results of the other brands are as under: This lower viscosity of the present invention helps in faster diffusion of the drug from the site of the 10 injection and also contributes to ease of administration resulting in lesser pain at site of injection. The maximum total dose of Diclofenac by parenteral route is 75 mg 1 to 2 times daily in adults. In children of 1 to 2 years of age, it is 1 to 3 mg/kg body weight in divided doses. The range of concentration of water soluble salt of Diclofenac is 0.5% to 3.5%. The chemical structure of water soluble salt of Diclofenac is : Molecular Formula : C14H10Cl2NRO2 Wherein R is Na+ or K+ Molecular Weight : 318.13 11 For the preparation of the present invention water for injection is heated to boil in a pressure vessel and cooled to 50° C temperature under constant nitrogen gassing. Requisite quantity of buffers/alkalis, antioxidants and stabilizers are added to water for injection under nitrogen gassing. In this prepared solution, slurry of Diclofenac salt made in benzyl alcohol under nitrogen gassing is dissolved with stirring under nitrogen gassing. The pH is maintained between 8.1 to 9.0 with suitable buffers/alkalis. Alternatively, a second method, soluble salt of diclofenac can be dissolved in water for injection at 50 C under nitrogen gassing, followed by addition of benzyl alcohol, antioxidants, buffers/alkalis, stabilizers. Therefore suitable ampoules/vials are filled under ;nitrogen gassing. Nitrogen gassing is used to impart stability. Diclofenac is susceptible to oxidation, and 12 Nitrogen prevents its-oxidation. The sequence of addition of all the ingredients in the preparation of the present invention does not affect the final product. A third method of preparing the solution of the present invention is to dissolve the buffers/alkalis, antioxidants, stabilizers in boiling water for injection cooled to 50° C under Nitrogen gassing followed by the addition of benzyl alcohol and soluble salt of Diclofenac. Thus changing the sequence of addition of all the ingredients does not affect the final product. 13 We claim, 1. The method of preparation of Diclofenac injection comprises use of Water for injection as solvent alongwith Benzyl Alcohol, stabilizers, antioxidants and buffers/alkalis. 2. The method of preparation of Diclofenac injection as claimed in claim 1 wherein water soluble salt of Diclofenac is mixed with Benzyl Alcohol to make slurry. 3. The method of preparation of Diclofenac injection as claimed in claim 1 and 2 wherein slurry of Diclofenac salt in Benzyl Alcohol made under nitrogen gassing is dissolved in water for injection which is free from bacteria and pyrogens. 4. The method of preparation of Diclofenac injection as claimed in claim 1, 2 and 3 wherein 14 stabilizers, antioxidants and buffer/alkalis are added into the mixture of Diclofenac salt, Benzyl Alcohol and water for injection under nitrogen gassing. 5.- The method of preparation of Diclofenac injection as claimed in claim 1 wherein Diclofenac salt is dissolved into water for injection at 50°C. 6. The method of preparation of Diclofenac injection as claimed in claim 1 and 5 wherein Benzyl Alcohol is added into solution of 'Diclofenac salt into water for injection under nitrogen gassing. 7. The method of preparation of Diclofenac injection as claimed in claim 1,5 and 6 wherein stabilizers, antioxidants and buffers/alkalis are 15 7. added into mixture of Diclofenac salt, water for injection and Benzyl Alcohol. 8. The method of preparation of Diclofenac injection as claimed in claim 1 wherein stabilizers, antioxidants and buffers/alkalis are mixed with water for injection. 9. The method of preparation of Diclofenac injection as claimed in claim 1 and 8 wherein Benzyl Alcohol is added into the mixture of stabilizers, antioxidants, buffers/alkalis and water for injection under nitrogen gassing. 10. The method of preparation of Diclofenac injection as claimed in claim 1, 8 and 9 wherein Diclofenc salt is added into the mixture of stabilizers, antioxidants, buffers/alkalis, water for injection and- Benzyl Alcohol under nitrogen 16 gassing. 11. The method of preparation of Diclofenac injection as claimed in claim 1 wherein pH is maintained or adjusted in the range of 8.1 to 9 by adding buffer or suitable alkalis in the mixture of Diclofenac salt, Benzyl Alcohol, water for injection, stabilizers and antioxidants. 12. The method of preparation of Diclofenac injection as claimed in claim 1 wherein amount of water soluble salt of Diclofenac is 0.5% to 3.5%. 13. The method of preparation of Diclofenac injection as claimed in claim 1 wherein amount of Benzyl Alcohol is 4%. 14. The method of preparation of Diclofenac injection as claimed in claim 1 wherein Diclofenac salt, Benzyl Alcohol, water for 17 injection, stabilizers, antioxidants and buffers/alkalis are mixed in any sequence. Dated this on 19th of January, 2002. Dr. Rajeshkumar H. Acharya. Advocate & Patent agent for and on behalf of the applicants

Documents:

57-mum-2002-abstract(22-1-2002).doc

57-mum-2002-abstract(complete)-(22-1-2002).pdf

57-mum-2002-abstract(granted)-(20-9-2005).pdf

57-mum-2002-cancelled pages(23-7-2003).pdf

57-mum-2002-claims(22-1-2002).doc

57-mum-2002-claims(amended)-(17-4-2003).pdf

57-mum-2002-claims(amended)-(23-7-2003).pdf

57-mum-2002-claims(complete)-(22-1-2002).pdf

57-mum-2002-claims(granted)-(20-9-2005).doc

57-mum-2002-claims(granted)-(20-9-2005).pdf

57-mum-2002-correspondence(23-7-2003).pdf

57-mum-2002-correspondence(ipo)-(20-9-2005).pdf

57-mum-2002-description(complete)-(22-1-2002).pdf

57-mum-2002-description(granted)-(20-9-2005).pdf

57-mum-2002-drawing(25-7-2002).pdf

57-mum-2002-drawing(complete)-(22-1-2002).pdf

57-mum-2002-drawing(granted)-(20-9-2005).pdf

57-mum-2002-form 1(22-1-2002).pdf

57-mum-2002-form 2(22-1-2002).doc

57-mum-2002-form 2(complete)-(22-1-2002).pdf

57-mum-2002-form 2(granted)-(20-9-2005).doc

57-mum-2002-form 2(granted)-(20-9-2005).pdf

57-mum-2002-form 2(title page)-(complete)-(22-1-2002).pdf

57-mum-2002-form 2(title page)-(granted)-(20-9-2005).pdf

57-mum-2002-form 26(22-1-2002).pdf

57-mum-2002-form 3(17-4-2003).pdf

57-mum-2002-form 3(22-1-2002).pdf

57-mum-2002-form 5(22-1-2002).pdf

57-mum-2002-specification(amended)-(25-7-2002).pdf