Title of Invention	"A NOVEL ANTISPASMODIC COMPOSITION"
Abstract	An injectable anti-spasmodic composition comprising: Diclofenac or its salts or its chirally pure forms - From 1.0 to 10 % w/w Pitofenone hydrochloride - From 0.05 to 2.0 % w/w Fenpiverinium bromide - From 0.001 to 0.2 % w/w alongwith a vehicle and optionally one or more agents selected from pain reducers, antioxidant, pH adjuster, stabilizer, chelating agent and other conventional ingredients.

Full Text

TECHNICAL FIELD The present invention describes a novel composition comprising a non-steroidal anti-inflammatory drug and their salts and their chirally pure forms and two drugs pitofenone hydrochloride and fenpiverinium bromide in a pharmaceutically acceptable combination. BACKGROUND OF THE INVENTION Amongst the various non-steroidal anti-inflammatory drugs diclofenac particularly sodium diclofenac is widely used in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. This has been disclosed in the following references (references from US Pat. No. 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, glycopyrronium, isoperopamide, pripenzolate, etc. Combination therapy with analgin, pitofenone and fenpiverinium are also used. In addition, drugs such as mebeverine valethamate bromide, clidinium 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, is 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 (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, volume 40, No. 5, (1986)} and acute renal colic {Garcia Alonso F. et al, Eur. J. Clin 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 fenpiverinium bromide. No pharmacological composition has 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 anti-inflammatory drugs such as diclofenac sodium when combined with fenpiverinium bromide and pitofenone hydrochloride forms an excellent antispasmodic composition. The composition when given orally and intramuscularly 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 anti-inflammatory drugs and their salts and pitofenone hydrochloride and fenpiverinium bromide. It is a further objective of the present invention to provide a process for the manufacture of a novel anti-spasmodic composition comprising diclofenac, 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. It is a further objective of the invention to provide an anti-spasmodic composition, which can be taken orally by way of a Pediatric suspension, capsule/tablet. SUMMARY OF THE INVENTION An anti-spasmodic composition comprising a non-steroidal anti-inflammatory drug or their salts or their chirally pure forms and two drugs pitofenone hydrochloride and fenpiverinium bromide. The composition is capable of being used in an oral and parenteral dosage form. DETAILED DESCRIPTION OF THE INVENTION The various non-steroidal anti-inflammatory drugs that can be used alongwith Pitofenone hydrochloride and Fenpiverinium bromide are selected from Aspirin, Diclofenac, Diflunisal, Etodolac, Flurbiprofen Flurbiprofen sodium, Ibuprofen, Indomethacin/ Indomethacin sodium, Ketoprofen, Mefenamic acid, Naproxen/Naproxen Sodium, Paracetamol, Phenylbutazone, Piroxicam, Sulindac, Ketorolac, Nimesulide and the like. Several formulations can be made in the form of tablets or injections comprising the three ingredients Diclofenac and like non-steroidal anti-inflammatory drugs or their salts, pitofenone hydrochloride and fenpiverinium bromide. Besides the ingredients disclosed above the composition also comprises the usual excipients like starch, microcrystalline cellulose, DCP, purified talc, magnesium stearate etc. described in the standard text. Tablets may be film coated, sugar coated or specially coated as described in the existing art. (Pharmaceutical Dosage forms : Tablets, vol 1-3, Eds., H.A. Lieberman and L. Lachman Dekker New York.) Such composition can be administered orally or by intramuscular route they can also be administered in form of modified release, sustained release, controlled release, timed release formulations. They can also be administered by ocular, intranasal, buccal, sublingual, transdermal, rectal, vaginal and others related administration routes. In the tablet form the concentration of the three ingredients are: Non-steroidal anti-inflammatory drug or its salts or its chirally pure forms - From 6.188 to 61.88 % w/w Pitofenone hydrochloride - From 0.39 to 12.38 w/w Fenpiverinium bromide - From 0.006 to 1.24 % w/w The tablets may contain specialized ingredients to modify, sustain or control release on one or more ingredients resulting in modified, sustained or controlled release products. (Controlled Drug Delivery Fundamentals and Applications, second edition eds., J.R. Robinson and V.H. Lee, Marcel Dekker, New York.) In the injection form the concentration of the ingredients are Non-steroidal anti-inflammatory drug or its salts or its chirally pure forms Pitofenone hydrochloride Fenpiverinium bromide From 1.0 to 10%w/v From 0.05 to 2.0 % w/v From 0.001 to 0.2% w/v The vehicle of the injectable preparation may consists of aqueous, non aqueous or specially formulated amphiphilic base containing suitable stabilizers, antioxidants buffers and other additives. The drug(s) may be dissolved or suspended. The invention will now be described with reference to the foregoing examples : Example 1 Preparation of Antispasmodic tablets S.No. Component 1. Diclofenac sodium 2. Pitofenone hydrochloride 3. Fenpiverinium bromide 4. Microcrystalline cellulose 5. *Starch 7. Purified talc 7. Magnesium stearate 8. Sodium starch glycollate 9. Sodium lauryl sulphate 10. Povidone 11. Isopropyl alcohol Quantity Per tablet 50.0 mg 5.0mg 0.1 mg 23.9 mg 66.0 mg 2.5 mg 2.5 mg 1.5 mg 1.5mg 3.0 mg ** Quantity for 1.0 Lac tablet 5.0 Kg 0.5 Kg 0.01 Kg 2.39 Kg 6.6 Kg 0.25 Kg 0.15 Kg 0.15 Kg 0.15 Kg 0.3 Kg 5.0 Itr. * Taken 10% extra to compensate for loss on drying. FILM COATING FORMULA Hydroxypropylmethyl cellulose 8.0 mg 0.800 Kg PEG 400 0.8 mg 0.08 Kg Isopropyl alcohol ** 7.5 Itr. Methylene chloride ** 15.0 Itr. Purified talc 1.4 mg 0.14 Kg Titanium dioxide 1.4 mg 0.14 Kg Step 1. All the ingredients were weighed and sieved through a sieve of mesh size 60 (linear inch). Step 2. Diclofenac sodium (5.0 Kg was mixed with Microcrystalline cellulose (2.39) and starch (6.6Kg) Step 3. Pitofenone hydrochloride (0.5 Kg) and Fenpiverinium bromide (0.01 Kg) are geometrically mixed and then added to the bulk of step2. Step 4. A solution of polyvinyl pyrrolidone (0.3Kg) in Isopropyl alcohol (5.01tr) was prepared. Step 5. Granulated the bulk of step 3 with the binder solution (bulk of step 4) Step 6. The wet mass was passed through sieve no 18 to obtain granules, which were dried at a temperature of 45-50°C, and dry sieved through sieve no 18. Step 7. Magnesium stearate (0.25 Kg), purified talc (0.25 Kg) Sodium lauryl sulphate (0.15 Kg) and Sodium starch glycolate (0.15 Kg) was passed through sieve of mesh size 60. Step 8. Mixed the bulk of step 7 with that of step 6. Step 9. The bulk of step 8 is compressed into tablets in a tablet compression machine at on average weight of 150.0 mg. Step 10. A film coating solution is passed through colloid mill and the core tablet is coated with it. Example 2 Preparation of anti-spasmodic injection S.No. Component Per ml for 1.0 lac Ampoules 1. Diclofenac Sodium 25.0mg 7.5 Kg 2. Pitofenone Hydrochloride 2.0 mg 0.6 Kg 3. Fenpiverinium bromide 0.02 mg 0.006 Kg 4. Benzyl Alcohol 5.12mg 1.536 Kg 5. Propylene glycol 0.4ml 12.0 Itr 6. Sodium sulphite (anhydrous) 1.0 mg 0.3 Kg 7. "Hydrochloric acid 0.002 ml 0.6 Itr (concentrated) 8. D-Mannitol 5.0 mg 1.5 Kg 9. Disodium Edetate 0.67 mg 0.201 Kg 10. Water for Inejction qs to 1.0 ml qs to 300 Itr. * if required NB 1.0 lac Ampoules = 300 Itr. Stepl. Benzyl alcohol (1.8 Kg) is distilled at 204 to 208° C. The first and last portion is rejected and stored under nitrogen. Step 2. Diclofenac sodium (7.5 Kg) is dissolved in water for injection (75.0 Itr) and warmed, if required. Step 3. Benzyl Alcohol (1.536 Kg), is dissolved in propylene glycol (120.0 Itr.) Step 4. Bulk of step 3 is added to bulk of step 2 and mixed. Step 5. Pitofenone Hcl (0.6 Kg) is dissolved in WFI (3.0 Itr) and added to bulk of step 4 and mixed. Step 6. Fenpiverinium bromide (0.06 Kg) is dissolved in WFI, (1.0 Itr), 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 Itr), 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 300.0 Itr. by the addition of WFI. Step 10. The bulk is sterilized by filtration using 2 u, prefilter and 0.22 \i filter under nitrogen. Step 11. The sterilized liquid is filled in amber coloured ampoules (3.0 ml per ampoule), flushed with nitrogen and sealed using ampoule filling and sealing 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 glaucoma 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 thrice daily for a maximum period of five days. CONCOMITANT MEDICATION AND DIETARY ADVICE: Concomitant medication such as antibiotics, urinary antiseptics, medical therapy for gall stones, etc were continued during the protocol therapy. Similarly, any specific 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. Parenteral drug for pain relief not needed. Drug well tolerated without 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 Intestinal colic Ureteric colic Biliary colic Total NUMBER 23 19 8 50 MALE 11 12 0 23 FEMALE 12 7 8 27 MEAN AGE OF PATIENTS - YEARS Males 33.5 Females 40.6 DURATION OF ILLNESS - Years DIAGNOSIS MALES Intestinal colic (n=23) 5.8(11) Ureteric colic (n=19) 6.8 (12) Biliary colic (n=8) (0) FEMALES 6.9(12) 7.2 (7) 7.3 (8) DURATION OF ANTISPASMODIC DRUG USE - Years DIAGNOSIS MALES Intestinal colic 5.1 Ureteric colic 6.0 Biliary colic FEMALES 6.4 7.0 6.8 FREQUENCY OF ANTISPASMODIC DRUG INTAKE Tablets/week DIAGNOSIS MALES Intestinal colic 6 FEMALES 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 and duration of illness. However, there is a satistically significant difference 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 were no male patients with biliary colic, it is not possible to determine the difference between the two sexes. Past history of patenteral 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 ureteric colic and two of biliary colic reported uncomfortable side effect such as, dry mouth and pa;petitions with anticholinergic drugs. Need for additional parenteral antispasmodic drug in the present study: No patient required parenteral antispasmodic drug in the present study. INTENSITY OF PAIN AFTER THE FIRST DOSE (As measured on visual analogue scale 0-100 mm) DIAGNOSIS INTENSITY OF PAIN(Table Removed)There was a statistically significant reduction 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 -pitofenone and fenpiverinium starts within this time period. DRUG OF HOSPITALIZATION-HOURS DIAGNOSIS DURATION Intestinal colic 2.8 Ureteric 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 There 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 DAYS DAY 4 DAYS 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 practically no pain from day 2 onwards as measured by the visual analogue scale. All patients had the last 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 DAY 1 DAY 2 DAY 3 DAY 4 DAY 5 Intestinal colic 321 00 Ureteric colic 321 00 Biliary colic 322 10 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 aid 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 from the hospital. EVALUATION OF THE TEST DRUG BY THE PATIENT Worse than previous therapy NIL Same as previous therapy 24 Better than previous therapy 22 Markedly better than previous therapy 4 EVALUATION OF THE TEST DRUG BY THE INVESTIGATOR EXCELLENT (Relief of pain GOOD (Relief on pain in 1 -2 hours 47 Side effects: No side effects observed in any patient. OBSERVATIONS AND COMMENTS: The combination of diclofenac + pitofenone 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. Annexure-1 Typographical corrections Table Removed) We Claim: 1. An injectable anti-spasmodic composition comprising: Non-steroidal anti-inflammatory drug or - From 1.0 to 10 % w/w its salts or its chirally pure forms Pitofenone hydrochloride - From 0.05 to 2.0 % w/w Fenpiverinium bromide - From 0.001 to 0.2 % w/w alongwith a vehicle. 2. A composition as claimed in claim 1, wherein the said non-steroidal anti- inflammatory drug is selected from the group comprising Aspirin, Diclofenac, Diflunisal, Etodolac, Flurbiprofen/Flurbiprofen sodium, Ibuprofen, Indomethacin/lndomethacin Sodium, Ketoprofen, Mefenamic acid, Naproxen/Naproxen Sodium, Paracetamol, Phenylbutazone, Piroxicam, Sulindac, Ketorolac and Nimesulide. 3. A composition as claimed in claim 1 or 2, wherein said non-steroidal anti- inflammatory drug is diclofenac or its salts. 4. A composition as claimed in claim 3, wherein the said salt of diclofenac is sodium, ammonium, potassium or epolamine. 5. A composition as claimed in claim 4, wherein the non-steroidal anti-inflammatory drug employed in the composition is diclofenac sodium. 6. A composition as claimed in claim 1, wherein the vehicle for the said composition consists of aqueous, non-aqueous or specially formulated amphiphilic base containing suitable stabilizers, antioxidants, buffers and other additives. 7. A composition as claimed in claim 6, which further comprises pain reducers, antioxidant, pH adjuster, stabilizer, chelating agent and other conventional ingredients. 8. A composition as claimed in claim 7, wherein the said pain reducer is benzyl alcohol. 9. A composition as claimed in claim 7, wherein the said antioxidant is sodium sulphite. 10. A composition as claimed in claim 7, wherein the said pH adjuster is hydrochloric acid. 11. A composition as claimed in claim 7, wherein the said stabilizer is D-mannitol. 12. A composition as claimed in claim 7, wherein the said chelating agent is disodium edetate. 13. An injectable anti-spasmodic composition substantially as herein described with reference to the foregoing description and the accompanying Examples.

Documents:

288-del-2000-abstract.pdf

288-del-2000-claims.pdf

288-del-2000-correspondence-others.pdf

288-del-2000-correspondence-po.pdf

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

288-del-2000-form-1.pdf

288-del-2000-form-13.pdf

288-del-2000-form-19.pdf

288-del-2000-form-2.pdf

288-del-2000-form-26.pdf

288-del-2000-form-3.pdf

288-del-2000-form-4.pdf

288-del-2000-petition-137.pdf