CLIAMS:We claim,
1. A pharmaceutical formulation for treatment of muscle cramp comprising of,
dextrose, vitamin E, vitamin B5, magnesium, vitamin B6, calcium ascorbate, methylcobalamin, levocarnitine, taurine, zinc and pharmaceutically acceptable excipients and carriers.
2. The pharmaceutical formulation as claimed in claim 1, wherein formulation comprises 0.5-2.0% w/w of dextrose, 1.0 - 3.0% w/w of vitamin E, 0.1 - 0.5% w/w of vitamin B5, 5 - 25% w/w of magnesium, 0.1 – 0.4% w/w of vitamin B6, 30 - 45% w/w of calcium ascorbate, 0.00001 – 0.00003% w/w of methylcobalamin, 15 - 35% w/w of levocarnitine, 10 - 30% w/w of taurine, 0.5 – 1% w/w of zinc.
3. The pharmaceutical formulation as claimed in claim 2, wherein formulation preferably comprises 1.0 - 1.5% w/w of dextrose, 1.5 - 2.0% w/w of vitamin E, 0.2 - 0.4% w/w of vitamin B5, 10 - 20% w/w of magnesium, 0.1 – 0.2% w/w of vitamin B6, 35 - 40% w/w of calcium ascorbate, 0.00001 – 0.00002% w/w of methylcobalamin, 20 - 30 % w/w of levocarnitine, 15 - 20% w/w of taurine, 0.7 – 0.8 % w/w of zinc.
4. The pharmaceutical formulation as claimed in any claim 1-3, wherein source of magnesium is selected from magnesium citrate, magnesium sulphate or magnesium orotate.
5. The pharmaceutical formulation as claimed in any claim 1-3, wherein source of zinc is selected from zinc citrate, zinc gluconate, zinc ascorbate and zinc sulphate.
6. The pharmaceutical formulation as claimed in any claim 1-3, wherein the fix dose formulation is introduced through oral, parentral, topical, insufation as per the ultimate requirement of relief.

Dated this: 27th day of June, 2015

,TagSPECI:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION:
A PHARMACEUTICAL FORMULATION FOR TREATMENT OF MUSCULAR CRAMP

2. APPLICANT:
(a) NAME : NV Lifecare Pvt. Ltd.
(b) NATIONALITY : Indian
(c) ADDRESS : 407, Mangalmurti Complex,
Opp. City Gold Multiplex,
Ashram Road, Ahmedabad-380009
Gujarat, India
3. PREMABLE TO THE DESCRIPTION
PROVISIONAL

The following specification describes the invention. ? COMPLETE

The following specification particularly describes the invention and the manner in which it is to be performed.

Field of Invention
The present invention describes the pharmaceutical formulation for treatment of muscular cramp more particularly relates to pharmaceutically acceptable composition containing dextrose, vitamin E, vitamin B5, magnesium, vitamin B6, calcium ascorbate, methylcobalamin, levocarnitine, taurine and zinc.

Back-ground of Invention:
A cramp is a sudden, severe, and involuntary muscle contraction or over-shortening which can cause mild-to-excruciating pain and a paralysis-like immobility of the affected muscles. The onset of cramp is usually sudden, and it resolves on its own over a period of several seconds, minutes, or hours. When any person utilizes the muscles that can be controlled voluntarily, such as those of his arms and legs, they alternately contract and relax as he moves limbs. A muscle or a few fibers of a muscle that involuntarily contracts is called a spasm. If the spasm is forceful and sustained, it becomes a cramp. Muscle cramps often cause a visible or palpable hardening of the involved muscle. It is not uncommon for a cramp to recur multiple times until it finally resolves. The cramp may involve a part of a muscle, the entire muscle, or several muscles that usually act together, such as flex adjacent fingers. In certain circumstances cramps involve the simultaneous contraction of muscles that ordinarily move body parts in opposite directions.
The physiology of cramping include hyperflexion, hypoxia, exposure to large changes in temperature, dehydration, or low blood salt, complication of pregnancy, kidney disease, thyroid disease, hypokalemia, restless-leg syndrome syndrome, varicose veins, and multiple sclerosis. Electrolyte disturbance may cause cramping and muscle tetany, particularly hypokalaemia and hypocalcaemia. This disturbance arises as the body loses large amounts of interstitial fluid, during exercise or intense physical work-out, through sweat.
Preventative measures for treatment of muscle cramps have been suggested, including stretching devices (US 6,966,883 and 6,027,434) and an electrical stimulation device (US 5,759,198) by use of a heating pad on the legs before bed, dietary changes and exercise is also known in state of the art.
Quinine is effective in treatment of muscle cramp, however, due to side effects its use should only be considered if other treatments have failed. Quinine acts by decreasing the excitability of the muscles however, quinine is known for its plenty of side effects like birth defects, hypersensitivity reactions, a deficien cy of platelets (thrombocytopenia), cinchonism (nausea, vomiting, headaches, and deafness), vision and heart irregularities which are considered to be fatal.
Vitamin B complex, naftidrofuryl, lidocaine, nortriptyline, diltiazem, orphenadrine, cyclobenzaprine and verapamil shows effective for muscle cramps, although data suggests that effectiveness decreases when this substances are taken for more than several weeks.
In a concluding remark, all of these proposed remedies have been found to be less than optimal. None of the above remedies is designed to ameliorate an acute muscle spasm once it has begun.

Summary of the Invention:
The present invention describes a pharmaceutical formulation for treatment of muscular cramp; the formulation made-up by combination of dextrose, vitamin E, vitamin B5, magnesium, vitamin B6, calcium ascorbate, methylcobalamin, levocarnitine, taurine and zinc. Optimized dose of the present invention provides instant relief from the muscle cramps, stiffness, pain and spasms. The composition comprises the ingredients such as vitamins, essential minerals which gives relief to exercised induced muscle cramps and nocturnal cramps in elderly people. The present invention facilitates the formulation which can be administered in body through various dosage forms as per its ultimate requirement of relief different conditions like in elderly and young individuals.

Object of this invention
The important object of the present invention is to provide pharmaceutical composition made-up of dextrose, vitamin E, vitamin B5, magnesium, vitamin B6, calcium ascorbate, methylcobalamin, levocarnitine, taurine and zinc, for the treatment of muscle cramp effectively which gives good results in short time
The other object of the present invention is to provide optimized ratio of the pharmaceutical acceptable ingredients for fast relief from muscle cramp.
Another object of the present invention is to provide formulation which gives instant relief from exercised induced muscle cramps and nocturnal cramps with greater relief in comparing with the conventional composition.

Detailed description of invention
Before explaining the present invention in detail, it is to be understood that the invention is not limited to the details of the ingredients and its proportions used in formulation. The invention is capable of other combination, as depicted in different modes as described herewith and of being practiced or carried out in a variety of ways. It is to be understood that the phraseology and terminology employed herein is for the purpose of description and not of limitation.
The present invention discloses formulation for treatment of muscle cramps comprises dextrose, vitamin E, vitamin B5, magnesium, vitamin B6, calcium ascorbate, methylcobalamin, levocarnitine, taurine, zinc and pharmaceutically acceptable excipients and carriers.
Dextrose, a carbohydrate, is used for aid in minimizing liver glycogen depletion and exerts a protein-sparing action. Water is added to glucose during synthesis of dextrose from starch. Dextrose is known for an energy source in most organisms, from bacteria to humans. Dextrose mainly used as added sweeteners, analyst in laboratory and indicated in the treatment of insulin hypoglycemia to restore blood glucose levels. For the preparation of this fix dose composition 0.5-2.0% w/w of dextrose is used.
Vitamin-E refers to a group of compounds that include both tocopherols and tocotrienols. a-tocopherol, the most biologically active form of vitamin E, is the second-most common form of vitamin E in the diet. Vitamin E is known for its antioxidant, enzymatic activities and gene expression. The most important function of vitamin E has been suggested to be in cell signaling and neurological function. The basic nature of water insolubility in preparation of present invention is overcome by using 50 % water soluble vitamin E substituent. For the preparation of this fix dose composition 1-3% w/w of vitamin-E is used.
Vitamin B5, also known as Pantothenic acid, is the amide between pantoic acid and ß-alanine. Vitamin B5 plays important roll in reducing stress, toxicity and producing hormones and red blood cells. It’s mainly crucial in body for its requirement in conversion of fat and carbohydrates into the energy. Small quantities of vitamin B5 are found in nearly every food, with high amounts in avocado, wholegrain cereals, legumes, eggs, meat, royal jelly, and yogurt. For the preparation of this fix dose composition 0.1-0.5% w/w of vitamin B5 is used.
Magnesium is an essential element in both plant and animal life. Magnesium is essential element for the proper function of nerves, muscles, and many other parts of the body. Chlorophyll, crucial component in photo-synthesis, is a magnesium-centred porphyrin complex. Magnesium has widely recommended compound in medical science also used for treating attention deficit-hyperactivity disorder (ADHD), anxiety, chronic fatigue syndrome (CFS), Lyme disease, fibromyalgia, diabetes, kidney stones, migraine headaches, weak bones (osteoporosis), premenstrual syndrome (PMS), altitude sickness, urinary incontinence, restless leg syndrome, asthma, hayfever, multiple sclerosis, and for preventing hearing loss. Magnesium salts are frequently included in various foods, fertilizers, and culture media. Magnesium citrate, magnesium sulphate or magnesium orotate can be used as salts in the present Fixed Dose Composition as per the requirement of formulation development in the range of 5-25 %w/w is used in this formulation.
Vitamin B6, also known as pyridoxine, serves as a cofactor in many enzyme reactions in amino acid, glucose, and lipid metabolism. It’s a key factor in protein and glucose metabolism, as well as in the formation of hemoglobin. Vitamin B6 is also involved in keeping the lymph nodes, thymus and spleen healthy. Vitamin B6 has been used to treat Parkinson’s disease, depression, motion sickness and the metabolically active form of vitamin B6, is involved in many aspects of macronutrient, metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function, and gene expression. The Vitamin B6 is used in the range between 0.1-0.4% w/w in this formulation.
Calcium ascorbate is a natural form of vitamin C, which is readily absorbed in the blood stream. It is known for an immune, antioxidant and anti-bacterial property. It is a strong antioxidant destroying free radicals in the body therefore used as anti-carcinogenic, antitumorigenic and promoting bone and tooth formation. It may aid in lowering blood cholesterol level and slows the aging process. It’s recommended in nausea and diarrhea where absorption from gut wall is highly compromised. For the preparation of this fix dose composition 30-45% w/w of calcium ascorbate is used.
Methylcobalamin, a form of vitamin B12, differs from cyanocobalamin in that the cyanide is replaced by methyl group. Eggs, dairy products, fish and meat, especially organ meat like liver, are good sources of Vitamin B-12. Methylcobalamin is also used in the treatment of peripheral neuropathy, diabetic neuropathy, and as a preliminary treatment for amyotrophic lateral sclerosis. The Methylcobalamin is used in the range between 0.00001-0.00003% w/w in this fix dose composition.
Levocarnitine, one form of carnitine, is an amino acid derivative and biosynthesized from the amino acids lysine and methionine. Carnitine is a substance made in the body from meat and dairy products. Carnitine is found at significantly lower levels in many other foods including nuts and seeds (e.g. pumpkin, sunflower, sesame), legumes or pulses. Low blood levels of carnitine may occur in people whose bodies cannot properly use carnitine from their diets, people on dialysis due to serious kidney disease, and people being treated with certain drugs (e.g., valproic acid, zidovudine). The levocarnitine is used in the range between 15-35% w/w in this fix dose composition.
Taurine, 2-aminoethanesulfonic acid, is an organic acid widely distributed in animal tissues. Physiologically taurine has many fundamental biological roles, such as conjugation of bile acids, antioxidation, osmoregulation, membrane stabilization, and modulation of calcium signaling. Taurine is a major constituent of bile and can be found in the large intestine. Taurine occurs naturally in fish and meat. It’s known for antihypertensive property and decreasing blood pressure in individual. The taurine is used in the range between 10-30% w/w in this fix dose composition.
Zinc is an important trace mineral that people need to stay healthy which is found in cells throughout the body. It plays a role in cell division, cell growth, blood clotting, thyroid function, wound healing, and the breakdown of carbohydrates. Meats, seafood, dairy products, nuts, legumes, and whole grains offer relatively high levels of zinc. Zinc is effective in rhinovirus (common cold) and also known for antiviral activity against the herpes virus. The zinc is used in the range between 0.5-1.0% w/w in this fix dose composition.
The pharmaceutical formulation for treatment of muscle cramp comprises 0.5-2.0% w/w of dextrose, 1.0 - 3.0% w/w of vitamin E, 0.1 - 0.5% w/w of vitamin B5, 5 - 25% w/w of magnesium, 0.1 – 0.4% w/w of vitamin B6, 30-45% w/w of calcium ascorbate, 0.00001–0.00003% w/w of methylcobalamin, 15 - 35% w/w of levocarnitine, 10 - 30% w/w of taurine and 0.5 – 1% w/w of zinc.
In another embodiment, the pharmaceutical formulation for treatment of muscle cramp formulation preferably comprises 1.0 - 1.5% w/w of dextrose, 1.5 - 2.0% w/w of vitamin E, 0.2 - 0.4% w/w of vitamin B5, 10 - 20% w/w of magnesium, 0.1 – 0.2% w/w of vitamin B6, 35 - 40% w/w of calcium ascorbate, 0.00001 – 0.00002% w/w of methylcobalamin, 20 - 30 % w/w of levocarnitine, 15 - 20% w/w of taurine and 0.7 – 0.8 % w/w of zinc.
The fix dose composition provided by this invention is administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the composition is administered as a rectal suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. Furthermore, the composition is administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch mediated drug delivery or in nanoparticles.
The composition is administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical composition formed by the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions etc. This pharmaceutical composition contains additional ingredients such as flavorings, binders, excipients etc. The carrier is having one or more suitable excipients for the formulation of tablets. Examples of suitable excipients include, but are not limited to, fillers, binders, disintegrants, lubricants, glidants, release-modifying excipients, super disintegrants, antioxidants, and mixtures thereof.
Suitable fillers include, but not limited to dibasic calcium phosphate, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate and mixtures thereof.
Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pus stulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof.
Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked poly-vinylpyrrolidone, cross-linked carboxy methylcellulose, starches, microcrystalline cellulose, and mixtures thereof.
Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.
Suitable glidants include, but are not limited to, colloidal silicon dioxide.
Suitable release-modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof.
Suitable effervescent tablet is prepared by solid acid and solid basic material which react to produce CO2 when dissolved in water, causing the effervescence. The acid is an organic such as fumaric, citric, tar taric, etc., or a corresponding anhydride or an inorganic, such as sulfamic or phosphonic acid derivative. The basic materials are the metal salts such as alkali or alkaline earth carbonates and bicarbonates. The acid is an organic such as fumaric, citric, tar taric, etc., or a corresponding anhydride or an inorganic, such as sulfamic or phosphonic acid derivative. The basic material is metal salts such as alkali or alkaline earth carbonates and bicarbonates.
Suitable liquid preparations is prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propy1-p-hydroben zoates or sorbic acid). The preparation is also contain one or more buffer salts, flavoring, coloring and sweetening agents as appropriate.
The composition is formulated for parenteral administration by injection, e.g. by bolus injection or continuous infusion. Formulations for injection is presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. The composition is taken in such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient is in powder form for constitution with a suitable vehicle, e. g., sterile pyrogen free water, before use.
Generally, a composition as described herein is administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration is indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a muscle as determined by the attending physician. Localized administration is indicated, for example, when a high dose is desired at the target muscle. For buccal administration the active composition is taken in the form of tablets or lozenges formulated in a conventional manner.
Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. A subject composition is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants are required. For transdermal administration, the complexes are including lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.
The ointments, pastes, creams and gels are contain, in addition to subject composition, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays are contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of such substances. A spray is additionally contains customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
The compound is formulated in rectal composition such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter, other glycerides or carbowaxes. The preparations can also take the form of powdered preparations or nutritional formulas.
The invention is illustrated more in details in the following example. The example describes and demonstrates embodiments within the scope of the present invention. This example is given solely for the purpose of illustration and is not to be construed as limitations of the present invention, as many variations thereof are possible without departing from spirit and scope. Effervescent formulation of the present formulation is prepared by following example.

Example
Effervescent Tablet
Ingredients Amount
Dextrose 16 mg
Vitamin E 22.5 IU
Vitamin B5 5 mg
Magnesium 200 mg
Vitamin B6 2.0 mg
Calcium ascorbate 500 mg
Methylcobalamin 1.0 mcg
Levocarnitine 330 mg
Taurine 250 mg
Zinc 10 mg
Effervescent Mixture q.s.

The present invention was prepared using effervescent mixture made up of citric acid, tartaric acid and sodium bicarbonate.
First of all the humidification of the effervescent mixture and the present formulation was done by means of a quantity of water less than 1% by weight with respect to the alkaline bicarbonate; the pro-drying of the humidified effervescent mixture in a fluidized bed, by hot air, the moisture content was controlled at temperature of 60° C, this operation was done by a sequence of short drying operations so as to stop the chemical reaction; and in final step the content was passed through mesh for preparation of granules and the resulting granules is compressed into tablets of desired shape, thickness, and hardness.
One or two tablet was dissolved in 300 ml of water before use.

Clinical studies and results:
Efficacy/synergistic data – The safety of this formulation has been demonstrated in -vivo in animal models using oral administration along with food.
In a rat ischemic hind limb model, using nonradioactive colored microspheres and by determining the femoral arteriovenous oxygen difference post-ligation, the severity of the ischemic cramp was demonstrated. To assess angiogenesis and increased blood flow, histologic evaluation and angiography were done. It was concluded this formulation demonstrate improved deteriorated exercise capacity in the animal. Also, the anti diabetic effect was examined in the ischemic hind limb in a diabetic rat model, wherein diabetes mellitus was induced by streptozotocin. This study demonstrates that oral administration of present formulation promoted better glucose control and promoted collateral vessel formation.
Preclinical safety studies were conducted using this formulation, which include following:
• Acute toxicity studies (14 day single dose and repeat dose) by oral administration of this formulation.
• Subchronic toxicity studies (90 days single dose) in two animal species (rats and rabbits) by oral administration and conducted using human equivalent doses in respective animals.
This formulation was orally administered to 24 post menopausal women and men with leg cramps. This was compared with 12 controls with age and sex matched to the study group.
The group treated with present formulation observed significant improvement in the arterial blood flow, increased O2 consumption and increase in painless walking time, increase in the flow with laser Doppler. Administration of this formulation results in improved rest pain, demonstrating the efficiency of this invention.
The safety and efficacy of this formulation were conducted in 28 patients with leg cramps. This study reiterated the fact that formulation was effective in improving the rest pain, peak walking time and quality of life. Total pain relief was seen in 83%. The above mentioned Fix Dose Composition (FDC) has an excellent result as compared to conventional formulation, patients got relieved in 30 min. as compared to 90 min. as compared to earlier one.
Although the preferred embodiment as well as the preparation and use have been specifically described, it should be understood that variations in the preferred embodiment could be achieved by a person skilled in the art without departing from the spirit of the invention. The invention has been described with reference to specific embodiments which are merely illustrative and not intended to limit the scope of the invention as defined in the claims.
The present formulation is a research based (Fix Dose Composition) FDC designed on the basis of scientific knowledge and clinical experience along with evidence based medicine, to ameliorate the current available treatment options for leg cramps in non-pregnant women and men. The current formulation is aimed at curbing all possible causes of leg cramps in above mentioned populations, making it a multifaceted formulations with minimum possible side effects of over dosage.