FORM 2
PATENT ACT 1970
(39 OF 1970)
&
PATENT RULE 2003
(See Section 10 & Rule 13)
(COMPLETE SPECIFICATION)
TITLE- A novel combined pharmaceutical composition containing three active ingredient and methods of making and using the same.
NAME OF APPLICANT- Zota Health Care Limited
ADDRESS OF APPLICANT- Zota Health Care Limited
Zota House,
2/896, Hira Modi Street, Sagrampura, Surat 395002 (Gujarat), India.
PREAMBLE OF INVENTION- This invention in particular describes the nature of the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION-
The present combined pharmaceutical composition relates to the synergistic pharmaceutical composition more preferably an oral and injectable administration of optimized, high bioavailability formulation of the active ingredient which typically is diclofenac, glycofurol and Drotaverine with the pharmaceutically accepted excipients.
BACKGROUND AND PRIOR ART-
Drotaverine (INN, also known as drotaverin) is an antispasmodic drug, structurally related to papaverine. Drotaverine is a selective inhibitor of phosphodiesterase 4, and has no anticholinergic effects. Drotaverine has been shown to possess dose-dependant analgesic effects in animal models.
Drotaverine has been shown to be effective in paracervical block in managing pain during hysteroscopy and endometrial biopsy when administered together with mefenamic acid. Drotaverin has also been tested in combination with rimantadine for antiviral activity against A and B type influenza.
Drotaverine is sold under brand name No-Spa (Chinoin Pharmaceutical and Chemical Works, Hungary, a member of the Sanofi-Aventis.
Diclofenac (marketed under many brand names, see below: Trade names) is a non-steroidal antiinflammatory drug (NSAID) taken to reduce inflammation and as an analgesic reducing pain in certain conditions. The name is derived from its chemical name: 2-(2,6-dichIoranilino) phenylacetic acid.
In the United Kingdom, India, Brazil and the United States, it may be supplied as either the sodium or potassium salt, in China most often as the sodium salt, while in some other countries only as the potassium salt. Diclofenac is available as a generic drug in a number of formulations. Over the counter (OTC) use is approved in some countries for minor aches and pains and fever associated with common infections.

According to United States Patent Application 20070093462 /WO 2007/044693 A 2 wherein Disclosed are ionic liquids and methods of preparing ionic liquid compositions of active pharmaceutical, biological, nutritional, and energetic ingredients.
Also disclosed are methods of using the compositions described herein to overcome polymorphism, overcome solubility and delivery problems, to control release rates, add functionality, enhance efficacy (synergy), and improve ease of use and manufacture.
According to WO/2006/079099/AU 2006/206166 A 1 wherein The present invention relates to a novel chemical process that provides novel vehicle derivatives that are exceptional 1,2- or 1,3-aminothiol specific reagents for conjugation to unprotected targeted compounds (e.g., polypeptides, peptides, or organic compounds) having or modified to have a 1,2- or 1,3 aminothiol group. The invention further relates to the methods of using novel water-soluble polymer derivatives and conjugates thereof.
However there is no formulation or composition of diclofenac, glycofurol and Drotaverine as a synergistic composition with optimized stability and less reconstitution time.
According to a Chinese patent CA Patent 1183454, An injectable formulation containing a soluble salt of clavulanic acid and a soluble salt of an .alpha.-aminopemcillin or cephalosporin has its stability on reconstitution improved by the incorporation therein of glycofurol.
SUMMARY OF THE INVENTION
An object of the present invention is to solve the problem of dry mouth with difficulty in swallowing and thirst, dilatation of pupils with loss of accommodation and sensitivity to light, increased intra-ocular pressure, flushing, dry skin, bradycardia followed by tachycardia, palpitation and arrhythmia, difficulty with micturition; rarely fever, confusional states and rashes, Contraindicated in closed angle glaucoma
An object of the present combined pharmaceutical composition is to provide caution free treatment for patients who suffered from tachycardia, cardiac insufficiency ,urinary retention , prostatic hypertrophy,

paralytic ileus, ulcerative colitis, pyloric stenosis; may aggravate gastroesophageal reflex ,during pregnancy , blurring of vision, vomiting, palpitation, nervousness, giddiness, blurred vision ,drug-rash, urinary retention, palpitation and fetal tachycardia thereof.
An object of the present invention is to prevent from Anticholinergic side effects. IV administration may lead to increased pulse rate, vision disturbances, Prostate hypertrophy with urinary retention, megacolon, Gl mechanical stenosis and tachycardia thereof.
An object of the present invention is to providing sufficient dosage.
A further object of the present invention is to demonstrate improved stability, solubility characteristics and enhanced appearance compared with currently available compositions.
An additional object of the present invention is to decrease the reconstitution time.
An object of the present invention is to provide the formulation which gives an established, reliable, and accepted and comparatively smooth yet Speedy Recovery,
An object of the present invention is to provide the composition with the Drotaverine and Diclofenac which are well tolerated. Skin rashes, diarrhea, dyspepsia have been reported with Diclofenac in few patients when it is used alone.
An object of the present invention is to provide the formulation which is free from anti cholinergic side effects like blurring of vision and dryness of mouth. Hence, it can be administered to patients with glaucoma or benign prostatic hyperplasia where antispasmodics are contraindicated.

DETAILED DESCRIPTION OF THE INVENTION
The present invention refers to combined pharmaceutical composition comprises diclofenac, drotaverine and glycofurol with the pharmaceutically accepted excipients.
According to a particularly preferred embodiment of the present pharmaceutical composition comprising Drotaverine which is a musculotropic drug acting directly on smooth muscle cells. Drotaverine has a dual mechanism of action. Drotaverine inhibits the enzyme phosphodiesterase IV (PDEIV).
This cause an increase in cyclic adenosine monophosphate level (cAMP), which results in decrease in concentration of free calcium ions (Ca2+). This process inhibits myosin light chain kinase (MLCK) leading to the dephosphorylation of actomyosin phosphate complex thus causing relaxation of smooth muscles.
Simultaneously Drotaverine inhibits calmodulin (CM). The decrease in Ca2+ ions along with the inhibition of CM leads to the inhibition of "Calmodulin-Calcium Complex" (CM-Ca2+) formation. Drotaverine is well and quickly absorbed from jejunum and ileum. The peak plasma concentration reaches between 45-60 minutes. Half-life of absorption of Drotaverine is 12 minutes. The onset of action of Drotaverine on oral administration is about 12 minutes and injectable form is very quick and it's safe in all kind of administration.
Drotaverine rapidly penetrates into the organs after oral administration. The peak concentration of the drug in lungs, kidney etc, appears in half a minute and after the injection proving very rapid distribution of the drug.
The main advantage of this combination is that, the route of administration of Drotaverine does not influence its metabolism. The metabolite of Drotaverine is 4'-desethyl-drotaveraldine. The metabolites are inactive and the spasmolytic effect is exerted by the unchanged drug in the body.
It shows enhanced efficacy for the treatment of some diseases which are Gastrointestinal colic, Biliary colic, Renal colic. Dysmenorrhea, Abdominal pain associated with irritable bowel syndrome, Pre and

Post lithotripsy, Post surgical smooth muscle spasm, Post-MTP (Medical termination of pregnancy) and D&C (Dilatation and curettage)
The Colic is the term that refers to the pain produced by obstruction or spasm of hollow abdominal organs such as:-
Galf Bladder and Bile Ducts - Biliary Colic
Ureter - Ureteric Colic
Stomach / small / large intestine - GI Colic thereof
Its useful for the treatment of dysmenorrhea , which is one of the most common gynecological disease. It is classified as primary and secondary dysmenorrhea.
Another active ingredient is Glycofurol which is used as solvent to dissolve water-insoluble compounds. It is stable but combustible and incompatible with strong oxidizing agents. The main unique feature of this ingredient is less painful, water soluble, less irritant, better bio availability, high effectiveness and ready to use. It has been reported to be non-toxic and non-irritating when diluted in water.
Glycofurol, also called tetrahydrofurane js a substance available on the market with the empiric formula (C2H40) XC4H802, in which X is about 2. This substance is well mixable with water and soluble in ether, ethanol, propanol and glycerol and has a low toxicity.
According to a particularly preferred embodiment of the present pharmaceutical composition comprising diclofenac i.e. 2-[(2,6-dichlorophenyl)amino]benzene acetic acid monosodium salt, has a recognised anti-inflammatory activity and for this reason has long been used as the active principle in various types of pharmaceutical formulations used in treating painful conditions, including post-traumatic and postoperative, and in all rheumatic diseases.
Diclofenac acts by inhibiting the synthesis of prostaglandins, the principal cause of inflammation and pain. To achieve the maximum effectiveness in pain relief the active principle must reach the systemic circulation as soon as possible after administration, so consequently the injectable form has always been favoured particularly for the treatment of acute inflammations of the musculo-skeletal system.

Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea. Inflammatory disorder may include musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, TMJ, spondylarthritis, ankylosing spondylitis, gout attacks, and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines. Diclofenac is used commonly to treat mild to moderate post-operative or post-traumatic pain, particularly when inflammation is also present, and is effective against menstrual pain and endometriosis.
As long-term use of diclofenac and similar NSAIDs predisposes for peptic ulcer, many patients at risk for this complication are prescribed a combination (Arthrotec) of diclofenac and misoprostol, a synthetic prostaglandin analogue, to protect the gastric mucosa.
Mechanism of diclofenac is a unique member of the NSAIDs. There is some evidence that diclofenac inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). There is also speculation that diclofenac may inhibit phospholipase A2 as part of its mechanism of action. These additional actions may explain the high potency of diclofenac - it is the most potent NSAID on a broad basis.

CLAIMS We claim,
1. A novel combined pharmaceutical composition comprises diclofenac, glycofurol and Drotaverine with pharmaceutically accepted excipients.
2. A novel combined pharmaceutical composition as recited in Claim 1 wherein said it's stable and effective combined composition shows enhanced efficacy and synergistic effect to provide protection from Dysmenorrhea, Gastrointestinal colic, Biliary colic, Renal colic. Dysmenorrhea! and Abdominal pain associated with irritable bowel syndrome, Pre and Post lithotripsy, Post surgical smooth muscle spasm, Post-MTP (Medical termination of pregnancy) and D&C Dilatation and curettage thereof
3. A novel combined pharmaceutical composition as recited in Claim 1 wherein said Diclofenac acts by inhibiting the synthesis of prostaglandins, the principal cause of inflammation and pain. To achieve the maximum effectiveness in pain relief the active principle must reach the systemic circulation as soon as possible after administration, so consequently the injectable form has always been favoured particularly for the treatment of acute inflammations of the musculoskeletal system.
4. A novel combined pharmaceutical composition as recited in Claim 3 wherein said Diclofenac is used to treat pain, inflammatory disorders, and dysmenorrhea. Inflammatory disorders may include musculoskeletal complaints, especially arthritis, rheumatoid arthritis, polymyositis, dermatomyositis, osteoarthritis, dental pain, TMJ, spondylarthritis, ankylosing spondylitis, gout attacks, and pain management in cases of kidney stones and gallstones. An additional indication is the treatment of acute migraines. Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain, particularly when inflammation is also present, and is effective against menstrual pain and endometriosis.

5. A novel combined pharmaceutical composition as recited in Claim 1 wherein said another active ingredient is Glycofurol which is used as solvent to dissolve water-insoluble compounds. It is stable but combustible and incompatible with strong oxidizing agents. It is less painful, water soluble, less irritant, better bio availability, high effectiveness and ready to use. It has been reported to be non-toxic and non-irritating when diluted in water.
6. A novel combined pharmaceutical composition as recited in Claim 1 wherein said Drotaverine inhibits calmodulin (CM). The decrease in Ca2+ ions along with the inhibition of CM leads to the inhibition of "Calmodulin-Calcium Complex" (CM-Ca2+) formation. Drotaverine is well and quickly absorbed from jejunum and ileum. The peak plasma concentration reaches between 45-60 minutes. Half-life of absorption of Drotaverine is 12 minutes.
7. A .novel combined pharmaceutical composition as recited in Claim 6 wherein said The onset of action of Drotaverine on oral administration is about 12 minutes and injectable form is very quick and it's safe in all kind of administration.