Title of Invention

"PROCESS FOR THE PREPARATION OF AN ANTI-SPASMODIC COMPOSITION TO BE USED AS INJECTION"

Abstract

A process for the preparation of a synergestic anti-spasmodic composition to be used as injection which comprises distilling Benzyl alcohol as pain reducer and dissolving it in a solvent propylene glycol, separately dissolving Diclofenac or its salts, in water, mixing the said pain reducer solution with the Diclofenac or its salts solution to form a dissolved mixture, mixing pitofenone hydrochoride with said dissolved mixture and adding thereto Fenpiverinium bromide to form the desired injectable composition wherein Diclofenac or its salts, pitofenone hydrochloride and Fenpiverinium bromide are present in the following proportions : Diclofenac or its salts .. from 1.0 to 10 % w/v. Pitofenone hydrochloride .. from 0.05 to 2.0 % w/v. Fenpiverinium bromide . . from 0.001 to 0.2 % w/v. Reference has been made to US Patent No. 5202159.

Full Text

The present invention relates to a process for the preparation of a synergestic Anti-spasmodic composition to be used as an injection. More specifically the present invention relates to the preparation of an Anti-spasmodic composition comprising Diclofenac or its salts and two drugs Pitofenone hydrochloride and Fenpiveriniurn bromide in a pharmaceutical1y acceptable combination. The present application has been divided out of patent application No. 792/Del/96 filed on 12th April, 1996. BACKGROUND OF THE INVENTION Amongst the various Non-steroidal anti-inf1ammatory drugs Diclofenac particularly sodium diclofenac is widely used in the treatment of rheumatoid arthiritis, osteoarthirities and ankylosing spondylitis. This has been disclosed in the following references (references from US Patent 5202159). As such, intestinal, ureteric and biliary colic are extremely common clinical conditions requiring prompt medical attention to relieve the symptoms and help the patient get back to his/her vocation to avoid/minimize economic loss and reduce the load on the medical institution. Non-surgical treatment can provide immediate relief to the patient while investigations are being carried out to determine the future course of management. Currently available treatment modalities include anticholinergics like, atropine and its derivatives, ambutonium, glycopyrroniurn, isoperopamide,pripenzolate and the like. Combination therapy with an,algin, pitofenone and fenpive.rinium are also used. In addition, drugs such as meberverine valetliamate bromide, clidiniutn are also used with. All drugs do not provide 'predictably uniform results in all patients. All the drugs used in 'these conditions do carry some side effects. Anticholinergics produce dry mouth, tachycardia in some patients, are contraindicated in glaucoma and prostatic hypertrophy and other antispasmodic agents may cause drowsiness as a side effect. Analgin is implicated in causing bone marrow depression. In the comprehensive review of a pharmacological properties of Diclofenac Sodium (Brogden et al, Drugs 20/24-48 (1980) it has been reported to have anti inflammatory activity, analgesic activity and anti pyretic activity. Conventionally it has been used in clinical condition for rheumatic disorders. Recently it has been reported to be of use in- painful non-rheumatic syndromes for example biliary colic, (Grossi et al. current Therapeutic Research, volumes 40 No 5 (1986)} and acute renal colic {Garcia Alonso F. et al, Evr. J. din Pharmacol 40/543-546 (1991)} However it has been reported .that Diclofenac Sodium intramuscular is more effective than Narcotic analgesic like pethidine intramuscular in the management of acute renal colic and has fewer side effects. Based on the market survey among the various products available as antispasmodic one major product is composed of Analgin with two spasmolytic agents that is pitofenone hydrochloride and fenpiverenium bromide'. No pharmacological compos.it;ion lias been reported in literature as well as no product is available where Diclofenac sodium is employed in combination with Spasmolytic agents. Our findings as disclosed in this patent application indicate that non-steroidal antiinflammatory drugs such as diclofenac sodium when combined with fenpiverenium bromide and pitofenone hydrochloride forms an excellent antispasmodic composition. The composition when given orally and intramuscuiarally is not only clinically effective but is superior to the existing therapeutic agents. It is superior in two ways one it has more effective action and second it has fewer side .effects. Accordingly, it is an object of the present invention to provide a novel anti-spasmodic composition comprising diclofenac and like non-steroidal antiinflammatory drugs and their salts and pitofenone hydrochloride and fer.piverinium bromide. It is a further objective of the present invention to provide a process for the manufacture of a novel anti-spasmodic composition comprising sodium diclofeneic and pitofenone' hydrochloride and fenpiverinium bromide. It is a further objective of the invention to provide a novel injectable delivery system for the anti-spasmodic, composition. Accordingly the present invention provides a process for the preparation of a synergestic anti-spasmodic composition to be used as injection which comprises distilling Benzyl alcohol as pain reducer and dissolving it in a solvent propylene glycol, separately dissolving Diclofenac or its salts in water, mixing the said pain reducer solution with the Diclofenac or its salts solution to form a dissolved mixture, mixing Pitofenone hydrochloride with said dissolved mixture and adding thereto Fenpiverinium bromide to form the desired injectable composition wherein Diclofenac or its salts, Pitofenone hydrochloride and Fenpiverinium bromide are present in the following proportions : Diclofenac or its salts .. from 1.0 to 10 % w/v. Pitofenone hydrochloride .. from 0.05 to 2.0 % w/v. Fenpiverinium bromide .. from 0.001 to 0.2 % w/v. The said salts of Diclofenac are sodium, ammonium, potassium, or epolamine. Preferably Diclofenac sodium salt is used. Preferably the pH of the injectable composition is adusted between 8.2 to 8.8 by the addition of Hydrochloric acid. EXAMPLE SI.No. Component per ml for 1.0 1ac Ampoules 1. Diclofenac sodium 25.0 mg 7.5 Kg. 2. Pitofenone hydrochloride 2.0 mg 0.6 Kg. 3. Fenpiverinium bromide 0.02 mg 0.006 Kg. 4. Benzyl alcohol 5.12 mg 1.536 Kg. 5. Propylene glycol 0.4 ml 12.0 Ltr. 6. Sodium sulphite 1.0 mg 0.3 Kg. (anhydrous),if required. 7. Hydrochloric acid 0.002 ml 0.6 Ltr. (concent rated)if required. 8. D-Mannitol 5.0 mg 1.5 Kg. 9. Disodium edetate 0.67 mg 0.201 Kg. 10. water for injection qs to 1.0 ml qs to 300 Ltr. N8 1.0 Lac ampules = 300 Ltr. Step 1. Benzyl alcohol (1.8 Kg) is distilled at 204 to 208 degrees C. The first and last portion is rejected and stored under nit rogen. Step 2. Diclofnac sodium (17.5 Kg) is dissolved in water for injection (75.0 ltr) and warmed, if required. Step 3 .nanny 3. Alcohol (1.636 Kg) , j.o - dintiolvad In propylene glycol (120.0/ ltr) . fll-.np 4. Bulk of Rtep 3 is added to birik of step 2 and mixed. Step 5. Pitofenpiie Hcl (0:6 kg) is dissolved, in WFI (3.0 ltr) nnd ndclotl.to bulk of ntop 4 find ,tnixad. Step 6. Fenpiverenium bromide (0.0S Kg) is dissolved in WFI, (1.0 ltr) , and added to the bulk of step 5 and mixed. Step 7. D-Mannitol (1.5 Kg), Sodium sulphite (0.3 Kg) and Disodium Edetate (0.201 Kg) is dissolved' in WFI (10.0 ltr), added to the bulk of step 6 and mixed. : Step 8. The pH of the bulk of step 7 is adjusted to between 8.2 and 8.8 if required by addition of hydrochloric acid. Step 9. The volume' is made to 3C0.0 ltr.by the addition of EFI. Step 10. The bulk is sterilised by filtration using 2 u'prefilter and 0.22 u filter under nitrogen. Step 11. The sterilised liquid is fi'lled in amber coloured ampoules (3.0 ml per ampoule), /flushed with nitrogen and sealed using ampoule filling and sealirg machine., NOTE- Step 10 and 11 is carried out in aseptic area. CLINICAL TRIALS The following patients were included: * Patients in the age group of 16-60 years • * Non-pregnant females were also included * Patients with biliary, intestinal and ureteric colic * Patients with any of the above conditions who could not be administered antispasmodic drugs belonging to the anticholinergic group (patients with glaucomam prostatic hypertrophy ) were also included. The following patients were excluded: * Patients with peptic ulcer disease * Patients requiring immediate surgery for their underlying condition were ,also excluded from the study. SAMPLE SIZE: Fifty patients. STUDY PROCEDURE: The study was open labeled. Patients attending the surgical OPD with complaint of moderate to severe abdominal pain and diagnosed to have one of the conditions listed in the inclusion criteria were enrolled. According to the study protocol, patients could be hospitalized for the acute condition for observation, and parenteral drug to relieve the acute pain was permitted. If on "observation for a few hours, the patient is relieved of the pain' but requires oral medication for continued relief of pain after discharge from the ward, the patient was put on test medication if the patient qualified the inclusion criteria. ADMINISTRATION OF THE TEST DRUG.. The test drug was administered orally, The dose was one tablet three times daily for a maximum period of five days. Patients administered the test drug were kept in the emergency ward for observation till such time the patient was relieved of' the symptoms. The protocol permitted patients to receive parenteral antispasmodic in cases of severe and disabling colic. Such patients were discharged on the oral test drug given in the dose of one tablet threice daily for a maximum period' of.five days. CONCOMITANT MEDICATION AND DIETARY ADVICE: Concomitant medication such as antifaiotiqa., urinary anti septias, medical therapy for gall stonns, etc were continued during the protocol therapy. Similarly, any _specif ic dietary restrictions/ advice were also continued. Patients were not permitted any concomitant antispasmodic therapy during the trial. ESCAPE MEDICATION AND TERMINATION OF PROTOCOL THERAPY: Patients not responding to the test medication within a period.of two (2) hours were administered parenteral analgesic. Such patients were deemed treated and not replaced by fresh patients. All patients on enrollment were subjected to history, clinical examination and history of past drug therapy which included: 1. Duration of illness 2. Severity of pain 3. Frequency of antispasmodic drug intake 4. Duration of antispasmodic drug use 5. Relief with existing therapy;' excellent, good, fair poor 6. Need to take parenteral antispasmodic while on existing oral therapy 7. Side effects with current therapy EVALUATION PARAMETERS: The following parameters were used to determine the efficacy and safety of the test medication. 1. Did the patient receive parenteral antispasmodic prior to oral therapy with the test drug. 2. Severity of pain after the first dose 3. Speed of relief 4. Did the patient need parenteral drug for .pain relief after administration of the first dose of the' test drug. 5. Severity of pain at home 'after subsequent doses 6. Duration of intake of test drug , 7. Patient's evaluation of the test drug 8. Investigator's'evaluation of the'test drug FINAL EVALUATION: EXCELLENT: Acute pain, relieved in less 'than half an hour. Parental drug for pain relief not needed. Drug well tolerated with out any side effects GOOD :Acute pain relieved in one to two hours without any need for parenteral drug'for pain relief. Drug well tolerated without . any side effects. POOR : Drug not effective in relieving pain. Parental drug required to control symptoms. RESULTS Total number of patients enrolled : 50 Number of patients completing the study : 50 DIAGNOSTIC BREAKUP OF PATIENTS ENROLLED DIAGNOSIS NUMBER MALE FEMALE Intestinal colic 23 11 12 Ureteric colic 19 12 7 Biliary colic 8 0 8 Total • 50 23 27 MEAN AGE OF PATIENTs- YEARS Males 33.5 Females 40.6 DURATION OF ILLNESS- years DIAGNOSIS MALES FEMALES Intestinal colic (n=23) 5.8 (11) 6.9 (12) Ureteric colic ' (n=19) 6.8 (12) 7.2 (7) Biliary colic (n=8) , (0) 7.3 (8) DURATION OF ANTISPASMODIC DRUG USE-Years DIAGNOSIS ' MALES, FEMALES Intestinal colic 5.1 6.4 Ureteric colic 5.0 , 7.0 Biliary colic 6.8 FREQUENCY OF ANTISPASMODIC DRUG INTAKE Tablets/week DIAGNOSIS , MALES FEMALES Intestinal colic 6 10 Ureteric colic 7 12* Biliary colic 15 *p From the above tables of demographic details, there is no statistically significant difference between the two sexes with relation to age, diagnosis ant| duration of: illness. However, there is a statistically significant dirrerence in the mean number of tablets per week consumed for' the relief of ureteric colic for female patients in comparison to males (p,0.05). Since there wera no mala pat fan to with biliary eolie, it is not possible to determine the difference between the two sexes. Past history of parenteral antispasmodic drug intake ' Almost all patients needed parenteral antispasmodic drugs for symptomatic relief while on oral 'antispasmodic drugs. Although all patients were not able to exactly remember, the frequency of - parenteral antispasmodic drug therapy varied from once every one month to two to four times every month. Most of the patients of both sexes reported uniformly good response with existing antispasmodic drug therapy. Five patients of intestinal colic, three of ureterip colic and two of biliary colic reported uncomfortable side effects such as, dry mouth and pa;petitions with anticholinergic drugs. Need for additional parenteral antispasmodic drug in the present s tudy: No patient required parenteral antispasmodic in the present study. INTENSITY OF PAIN AFTER THE FIRST DOSE As measured on visual analogue scale 0-100 mm) DIAGNOSIS INTENSITY OF PAIN 3 0 minutes' 1 hour 2 hours Intestinal colic 55 23* 12* Ureteric colic 64 22* 13* Biliary colic 70 25* 17* *P There was a statistically significant redaction in the intensity of pain in all groups of patients at the end of one hour of the first dose. This indicates that the onset of action of diclofenac + pitafenone and fenpiverinium starts within this time period. DURATION OF HOSPITALIZATION-HOURS DIAGNOSIS DURATION' Intestinal colic 2:8 Jreteric colic 3.9 Biliary colic 4.3 INTENSITY OF PAIN AT THE TIME OF DISCHARGE DIAGNOSIS INTENSITY OF PAIN Intestinal colic 7.75** Ureteric colic 8.25** Biliary colic 9.12** **p "here was statistically highly significant reduction of pain at the time of discharge as measured by the visual analogue scale. INTENSITY OF PAIN DAY'2-5 (As measured by visual analogue scale 0-100 mm) ' ' INTENSITY OF PAIN. DAY 2-5 DIAGNOSIS DAY 2 D.\Y G DAY 4 DAY 5 Intestinal colic 1.2** 0 0 0 Ureteric colic 2.. 1** '0 0 0 Biliary colic 3.2** 1.3 0 0 **P All patients had paractically no pain from day 2 onwards as nteatfured by the vioual analogue; scale. -All patients had the iast dose of the test drug at approximately 8 p.m on day 1. This indicates that the duration of action of the test antispasmodic is more than 8 hours. INTAKE OF TEST ANTISPASMODIC- DAY 1 TO'DAY 5 NUMBER OF TABLETS PER DAY ' , DIAGNOSIS DAY1 DAY 2 DAY 3 DAY 4 DAY 5 Intestinal colic 3 2:1 0 O Ureteric colic 3 2 1 0 0 Biliary colic 3 2 2 1 0 All the patients irrespective of diagnosis took three tablets on day 1 and 2 tablets on day 2 . However, on day 3 patients of intestinal and ureteric colic took 1 tablet and did not take any tablets on days 4 and 5 while patients of biliary colic continued to take 2 tablets on days 2 and 3 and one tablet on day 4. on day 5 patients of biliary colic did 'not need any medication. Patients were instructed to bring the container along with the unconsumed tablets- to the clinic: on, day 5 to determine the number of tablets the patients actually 'consumed after discharge /£"rom the hospital. EVALUATION OF THE TEST DRUG BY THE PATIENT Worse than previous therapy NIL Same as previous therapy ' 2 4 Better than previous therapy 22 Markedly better than previous therapy 4 EVALUATION OF THE TEST DRUG BYi THE INVESTIGATOR JSXC15LLENT (Relief of pain GOOD (Relief of pain in l-:2 hours 47 Side effects: No side effects observed in any patient. OBSERVATIONS AND COMMENTS: The combination of disclofenac + . pitafenone and fenpiverinium produced good results in patients of intestinal, ureteric and biliary colic in both sexes in the present open labeled study without any side effects, Larger double-blind comparative studies'are needed to further document the efficacy and safety of this combination. We claim : 1. A process for the preparation of a synergestic anti-spasmodic composition to be used as injection which comprises distilling Benzyl alcohol as pain reducer and dissolving it in a solvent Propylene glycol, separately dissolving Diclofenac or its salts, in water, mixing the said pain reducer solution with the Diclofenac or its salts solution to form a dissolved mixture, mixing Pitofenone hydrochloride with said dissolved mixture and adding thereto Fenpiverinium bromide to form the desired injectable composition wherein Diclofenac or its salts, Pitofenone hydrochloride and Fenpiveriniurn bromide are present in the following proportions : Diclofenac or its salts .. from 1.0 to 10 % w/v. Pitofenone hydrochloride .. from 0.05 to 2.0 % w/v. Fenpiverinium bromide . . from 0.001 to 0.2 % w/v. 2. The process as claimed in claim 1 wherein the said salts of Diclofenac are sodium, ammonium, potassium or epolamine. 3. The process as claimed in claims 1 and 2 wherein Diclofenac sodium salt is used. 4. The process as claimed in claims 1 to 3 wherein the pH of the injectable composition is adjusted between 8.2 to 8.8 by the addition of Hydrochloric Acid. The process as claimed in claims 1 to 4 wherein conventional stabilizers, anti-oxidants and chelating agents are added to the injectable composition. The process as claimed in claim 5 wherein D-Mannitol is added as a stabilizer. The process as claimed in claim 5 wherein sodium sulphite is added as an anti-oxidant. The process as claimed in claim 5 wherein disodium edetate is added as a chelating agent. The process for the preparation of a synergestic antispasmodic composition to be used as injection substantially as herein described with reference to the Example herein.

Documents:

289-del-2000-abstract.pdf

289-del-2000-claims.pdf

289-DEL-2000-Correspondence-Others.pdf

289-DEL-2000-Correspondence-PO.pdf

289-del-2000-description (complete).pdf

289-del-2000-form-1.pdf

289-del-2000-form-2.pdf

289-del-2000-form-3.pdf

289-del-2000-gpa.pdf

289-del-2000-pa.pdf

289-del-2000-petition-others.pdf