Technical Field of the Invention;

The present invention relates to a pharmaceutical composition comprising Ubidecarenone (Coenzyme Q10), together with Diosmin; a compound belonging to the class of bioflavonoids and Magnesium sulphate along with pharmaceutically acceptable excipients useful for improving blood circulation, more particularly, for preventing or treating varicose veins and other inflammatory disorders.

Background and Prior Art:

Varicose veins and spider veins are swollen, twisted, and are sometimes painful veins with itching and irritation that have filled with an abnormal collection of blood. Varicose veins generally appear in the veins of the legs due to the pressure of body weight, force of gravity, and task of carrying blood from the bottom of the body up to the heart, although it may occur in other parts of the body. Poor blood circulation which may result into venous insufficiency and weakening of the one-way valves that prevent blood in veins from flowing backwards lead to varicose veins. Although for some people it is a cosmetic problem, varicose veins may lead to further serious complications. There are different methods available for the treatment of varicose veins, both surgical and non-surgical. The surgical procedure is often considered the effective varicose vein treatment; it involves removing the vein while under a general anaesthetic. But the surgical procedure may lead to further complications which include deep vein thrombosis, pulmonary embolism, and wound complications including infection.

The non-surgical types of procedure include either injecting foam into the vein, which is guided by ultrasound, or heating up the vein to seal it from within by passing a probe into the vein. US4707360 discloses a pharmaceutical composition having vasculoprotecting activity, containing as the active ingredients component (a) which is coen2yme Q10 and component (b) which is a member selected from the group consisting of diosmin, delphinidin, asiaticoside, escin, tribenoside and O-(.beta.-hydroxyethylrutoside) in the ratios between 10:1 and 1:4 of said component (a) to component (b). WO2003053336 discloses a composition for peripheral neural and vascular ailments formulated from a therapeutically effective amount of a flavonoid having antioxidant properties and wherein the non-flavonoid antioxidant compound is coenzyme Q10. In view of the above drawbacks of the surgical and non-surgical methods, there remains a need in the art to develop the composition or formulation for treating varicose veins. Hence, the inventors of the present invention have come up with a topical pharmaceutical composition having enhanced absorbability and better therapeutic applicability for improving blood circulation and preventing or treating varicose veins and other inflammatory disorders.

Summary of the Invention:

Accordingly, the present invention provides a topical pharmaceutical composition comprising Ubidecarenone (Coenzyme Q 10), Diosmin, Magnesium sulphate, Methyl salicylate and at least one penetration enhancer along with one or more pharmaceutically acceptable excipients, useful for improving blood circulation and preventing or treating varicose veins and other inflammatory disorders. The present invention also provides a process for preparation of said pharmaceutical composition.

Detailed Description of the Invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. The present invention discloses a topical pharmaceutical composition comprising combination of 0.1 to l%w/w of Ubidecarenone or Coenzyme Q 10; 0.1 to 3% w/w of Diosmin; 2 to 10%w/w of Magnesium Sulphate; 2 to 2.5%w/w of methyl salicylate, and at least one penetration enhancer along with one or more pharmaceutically acceptable excipients, useful for improving blood circulation and preventing or treating varicose veins and other inflammatory disorders. Ubidecarenone is a 2-[(all-E)-3,7,l 1,15,19,23,27,31,3 5,39-Decamethyltetraconta-2,6, 10,14 ,18, 22, 26, 30, 34,38-decaenyl]-5,6-dimethoxy-3-methylbenzene-l,4-dione. It is yellow to orange coloured crystalline powder, insoluble in water. Coenzyme Q10 (CoQ10, Ubidecarenone) is found in the mitochondria of all cells and is involved in energy production. It is found at its highest concentrations in the heart, liver, kidney and pancreas. CoQ10 is a potent antioxidant in human blood where it also acts to preserve vitamin E, another major antioxidant. As a result of CoQ10's antioxidant activity it exerts a protective effect on mitochondrial membranes, insuring the integrity of the membrane-receptor interface.

Diosmin is a (5-Hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one) semisynthetic phlebotropic drug (modified hesperidin), a member of the flavonoid family. It is an oral phlebotropic drug used in the treatment of venous disease, i.e., chronic venous insufficiency (CVI) and hemorrhoidal disease (HD), in acute or chronic hemorrhoids, in place of rubber-band ligation, in combination with fiber supplement, or as an adjuvant therapy to hemorrhoidectomy, in order to reduce secondary bleeding. Diosmin prolongs the vasoconstrictor effect of norepinephrine on the vein wall, increasing venous tone, and therefore reducing venous capacitance, distensibility and stasis. This increases the venous return and reduces venous hyperpressure present in patients suffering from CVI.

Magnesium sulphate (Epsom salts) is an inorganic salt and naturally occuring sources to treat electroyte balance, cadiac arrhythmia etc. Hypomagnesemia (or hypomagnesaemia) is an electrolyte disturbance in which there is an abnormally low level of magnesium in the blood. Normal magnesium levels in humans fall between 1.5 - 2.5 mg/dL. Usually a serum level less than 0.7 mmol/L is used as reference for Hypomagnesemia. Inadequate intake of magnesium leads to weakness, muscle cramps, increased irritability of the nervous system with tremors, athetosis jerking, nystagmus and an extensor plantar reflex. Methyl salicylate is generally used to treat minor aches and pains of the muscles/joints (e.g., arthritis, backache, sprains) in the topical formulations for pain management and is known as counterirritant. Penetration enhancer is a pharmaceutical ingredient added to topical products to increase penetration through the skin. For the purpose of present invention, penetration enhancer is selected from the group of fatty alcohols, fatty acid esters, fatty acids, fatty alcohol esters, ethers, solvents either alone or in combination thereof.

The pharmaceutical^ acceptable excipients are selected from one or more lipids such as cetostearyl alcohol, glyceryl monostearate and stearic acid; an emulsifier or a surfactant such as Cetomacrogol 1000; a gelling agent selected from xanthan gum, methyl cellulose, hydroxy propyl methyl cellulose; a solubilizer/cosolvent, such as propylene glycol, glycerin, cremophor RH 40; an emollient like isopropyl myristate; preservative such as methyl paraben, propyl paraben and topical bases such as Liquid paraffin, white soft paraffin, lanolin and such like. In another embodiment, the topical pharmaceutical composition of the present invention is in the form of ointment, cream, lotion and gels, liniments and the like. In another embodiment, the present invention provides a process for preparation of topical cream comprises the following steps;

1. Heating a mix of lipids, solubilizers, emulsifying agents along with penetration enhancer and active ingredient Ubidecarenone;

2. heating a mix of glycerin, preservatives and purified water;

3. mixing the contents of step 1 with step 2 to obtain a homogeneous cream;

4. dissolving magnesium sulphate in purified water and mix into step 3 under constant stirring; and

5. dispersing Diosmin in propylene glycol and homogenizing with step 4 to obtain the desired product.

In another embodiment, the present invention provides a process for preparation of topical lotion comprises the following steps;

1. Melting Ubidecarenohe and lipids;

2. heating mix of glycerin, preservatives and purified water;

3. mixing step 2 to step 1 in planetary mixer with continued stirring;

4. dissolving magnesium sulphate in purified water and adding to step 3 under constant stirring; and

5. dispersing Diosmin in penetration enhancer and adding to step 4 to obtain the lotion. In another embodiment, the present invention provides a process for preparation of topical ointment comprises the following steps;

1. Melting and mixing oil base excipients along with active ingredients Ubidecarenone and Methyl salicylate;

2. Passing Magnesium sulphate and Diosmin through 200#mesh; and

3. mixing the contents of step 1 with step 2 to obtain the ointment. In another embodiment, the present invention provides a process for preparation of topical gel comprises the following steps;

1. Dissolving Magnesium sulphate and preservatives in purified water followed by dissolving or dispersing thickening agent or gelling agent to the above solution under constant stirring to obtain uniform gel;

2. adding Diosmin to step 1 by sprinkling method under constant stirring;

3. dissolving Ubidecarenone in Cremophor RH 40, and adding to step 1 under constant stirring and adjusting the pH to 4.5 - 5.

In another embodiment, the present invention advantageously provides a novel and effective pharmaceutical combination of Ubidecarenone, magnesium sulphate and Diosmin along with other inactive ingredients and pharmaceutically acceptable excipients for improving blood circulation in various disease conditions such as chronic venous insufficiency (CVI), hemorrhoidal disease (HD) and other inflammatory disorders.

The present invention can be summarized as follows,

■ The present invention provides new combination comprising Ubidecarenone, Magnesium sulphate and Diosmin and other inactive ingredients for improving blood circulation in various disease conditions such as vein chronic venous insufficiency (CVI) and hemorrhoidal disease (HD).

■ Addition of inorganic salt such as Magnesium sulphate to emulsified system generally results in emulsion separation. However, the present invention successfully provides stable emulsion of above said ingredients even in presence of magnesium sulphate.

■ Cream with methyl salicylate has tendency of denature the emulsion. However, the present topical formulation containing methyl salicylate is formulated with suitable emulsifiers to provide stable emulsion.

■ Ubidecarenone is added either oil phase or after emulsification.

■ The poor consistency of gel formation due to addition of magnesium sulphate is averted using colloidal swelling agents such as xanthan gum.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:
We Claim,

1. A topical pharmaceutical composition comprising;
a) 0.1 to l%w/w of Ubidecarenone or Coenzyme Q10;
b) 0.1 to 3% w/w of Diosmin;
c) 2 to 10%w/w of Magnesium sulphate and
d) 2 to 2.5%w/w of Methyl salicylate, along with at least one penetration enhancer together with one or more pharmaceutically acceptable excipients; useful for improving blood circulation, preventing or treating varicose veins, chronic venous insufficiency (CVI), hemorrhoidal disease (HD), and other inflammatory disorders.

2. The topical pharmaceutical composition according to claim 1; wherein said penetration enhancer selected from the group of fatty alcohols, fatty acid esters, fatty acids, fatty alcohol esters, ethers, solvents either alone or in combination thereof.

3. The topical pharmaceutical composition according to claim 1; wherein said pharmaceutically acceptable excipients are selected from one or more lipids such as cetostearyl alcohol, glyceryl monostearate and stearic acid; an emulsifier or a surfactant such as Cetomacrogol 1000; a gelling agent selected from xanthan gum, methyl cellulose, hydroxy propyl methyl cellulose; a solubilizer/cosolvent, such as propylene glycol, glycerin, cremophor RH 40; an emollient like isopropyl myristate; preservative such as methyl paraben, propyl paraben and topical bases such as Liquid paraffin, white soft paraffin, lanolin and such like.

4. The topical pharmaceutical composition according to claim 1; wherein said composition is in the form of ointment, cream, lotion and gels, liniments and the like.