KR20130103297A - Combination composition, comprising as active ingredients l-carnitine or propionyl l-carnitine, for the prevention or treatment of chronic venous insufficiency - Google Patents

Abstract

Complex compositions useful for the prophylaxis and / or treatment of chronic venous diseases are described, including L-carnitine or propionyl L-carnitine, troxertin, diosmin and hesperidin as active ingredients.

Description

Combination composition, comprising as active ingredients L-carnitine or propionyl L-carnitine, for the prevention or treatment of L-carnitine or propionyl L-carnitine chronic venous insufficiency}

The present invention relates to complex compositions useful for the prevention and / or treatment of chronic venous insufficiency (CVI), comprising L-carnitine or derivatives thereof or salts thereof, troxertin, diosmin and hesperidine as active ingredients.

In humans, arteries bring oxygen-rich blood from the heart to the rest of the body, and veins return oxygen-deficient blood to the heart. Chronic venous insufficiency (CVI) is initiated when the human leg vein is unable to pump enough blood into the heart. CVI is sometimes called chronic venous disease, or CVD.

Humans have three types of veins: the shallow vein lies near the skin, the deep vein lies within the muscle group, and the through vein connects the shallow vein with the deep vein. The deep veins lead to the vena cava, the largest vein in the human body that goes directly to the heart.

When a human is in a straight posture, blood in the leg veins must return to the heart against gravity. To do this, the leg muscles compress the deep veins of the legs and feet to help blood return to the heart. In the vein, a one-way plate called a valve keeps blood flowing in the right direction. When the leg muscles relax, the valve inside the vein closes. This in turn prevents the blood from flowing back under the leg. The whole process of returning blood to the heart is called a venous pump.

When humans walk and leg muscles squeeze, the venous pump works well. However, when the patient is seated or standing, especially for long periods of time, blood in the leg veins may gather to increase venous blood pressure. Deep veins and penetrating veins can usually withstand short-term increased pressure. However, sitting or standing for a long time can elongate the venous wall because it is flexible. Over time, susceptible individuals can weaken the vein wall and damage the venous valves, causing CVI.

During CVI, the ankle may swell and the calf may feel stiff. Your legs may be heavy, tired, uncomfortable, or tingling. The patient may feel pain during walking or immediately after stopping.

CVI may be associated with varicose veins. Varicose veins are swollen veins that can be seen through the skin. Often blue and swells and twists. Giant varicose veins can cause skin changes such as erythema, redness and ulcers.

CVI can also cause problems with leg swelling due to dead blood pressure in the veins. The lymphatic system can also produce a liquid called lymph to compensate for CVI. Human leg tissue may then absorb some of this liquid, which may increase the tendency of the legs to swell. In severe cases, CVI and leg edema can cause ulceration in the bottom of the leg.

Over a long period, blood pressure higher than normal pressure inside the leg veins causes CVI. Other causes of CVI include deep vein thrombosis (DVT) and phlebitis, both of which block the free flow of blood through the vein, causing pressure in the vein.

DVT occurs when blood coagulation (called appropriate thrombus) blocks blood flow from the deep or penetrating veins to the heart. Blood passing through the blocked vein can increase intravenous blood pressure, which in turn overloads the valve. Vein valves that do not work properly are called powerless because they are stretched and no longer operate efficiently, and helpless valves contribute to CVI. Because intravenous blood clots can sometimes break off and travel to the lungs, DVT is a potentially serious condition that causes leg swelling and requires immediate medical attention. This condition is called pulmonary embolism.

Phlebitis occurs when a shallow or deep vein swells, causing inflammation. The inflammation forms blood clots and can also cause DVT.

Factors that may increase the risk for CVI include varicose veins family history, overweight, pregnancy, lack of exercise, smoking and prolonged standing or sitting. CVI can be taken by anyone, but age and gender can also be factors that can increase the tendency of CVI to develop; Women over 50 most often get CVI.

For mild CVI, your doctor may recommend compression stockings. Compression stockings are elastic stockings that compress the veins and stop the return of excess blood. In this way, compression stockings often help to heal skin ulcers and prevent them from recurring. Patients may need to wear compression stockings every day of their lives.

Heavier CVI can be treated by injection called sclerotherapy or by surgical procedure. Less than 10% of patients with CVI require surgery to fix the problem. Surgical treatments include venous resection, venous stripping, bypass surgery, valve repair, and angioplasty or stent surgery.

Flavonoids, Troxertin, Diosmin and Hesperidin, also called rutin, oxerutin or rutoside, are well known for their antioxidant properties, and they also have other properties that affect the circulatory system, ie blood and microvascular endothelial cells. (GIOT 2009; 35: 23-33).

Several epidemiologic studies suggest that these flavonoids are associated with improved circulation and reduced general risk for cardiovascular diseases. Mechanisms inherent in these protective actions include antithrombotic, antiischemic, antioxidant and vasodilation properties. In particular, these flavonoids act to improve circulation by vasodilation, platelet coagulation and prevention of low density lipoprotein (LDL) oxidation (Journal of Agricultural and Food Chemistry 2008 56 (15), pp 6185-6205).

These flavonoids also exhibit potent anti-inflammatory properties that are believed to be the result of the synthesis of different proinflammatory mediators, primarily arachidonic acid derivatives, prostaglandin E2, F2 and thromboxane A2 and the inhibition of biological activities. These procedures improve venous tension and lymphatic drainage and reduce capillary permeability by protecting microcirculation from inflammatory procedures.

This effect has also been shown in clinical studies. Belcaro et al. (Angiology, 59; 5S) showed that these flavonoids were effective in increasing capillary filtration and controlling and treating edema in venous hypertension and diabetic microangiopathy.

Another study by Belcaro et al. (Angiology, March 1, 2008; 59 (1) suppl. 7S-13S) also revealed the symptoms and symptoms of chronic venous insufficiency (CVI), varicose veins, and deep vein disease and chronic venous disease. The use of these flavonoids in the treatment was observed.

Rev Fr Gynecol Obstet. 1991 Feb 25; 86 (2 Pt 2): 209-12] report that troxeroutin has been useful for the treatment of vaginal insufficiency of the lower extremities and vaginal varices in women (half with premenstrual syndrome and half pregnant).

Br. J. Surg. 2000, 87; 868-872 reported that diosmin has anti-inflammatory effects that participate in vascular protection, contributes to maintaining good blood circulation, and maintains venous tension.

Farmaco, 40 (11); 709-712 have been reported to have hesperidin antioxidant activity and to promote healthy vascular functions in combination with Troxertin and Diosmin.

In US 4255449, L-carnitine is reported to be useful for increasing HDL cholesterol and treating diseases associated with high cholesterol levels.

In WO04091602 9 it is reported that L-carnitine is useful for the treatment of cardiovascular diseases.

In US 5811457 propionyl L-carnitine is reported to be useful for the treatment of chronic obstructive atherosclerosis.

In WO 2007045639 propionyl L-carnitine is reported to be useful for the treatment of left ventricular hypertrophy in dialysis patients.

In US 4343816 propionyl L-carnitine is reported to be useful for the treatment of peripheral vascular diseases.

In addition, while there are other documents in which the compounds of the present invention have been shown to be useful for the treatment of venous diseases, none of them mention or suggest the unexpected synergistic effects exhibited by the compositions of the present invention.

Chronic venous insufficiency (CVI) and chronic venous disease (CVD) in complex compositions comprising L-carnitine or derivatives thereof (e.g. propionyl L-carnitine) or salts thereof, troxerutin, diosmin and hesperidine as active ingredients or It has now been found that a surprising synergistic effect is conferred on the prevention and / or treatment of venous diseases selected from their complications.

Examples of venous complications or diseases (due to CVI or CVD) are reported in the following: swelling and inflammation of rectal, anal and vaginal veins; Venous hypertension; Increase in permeability; edema; Capillary injury; Skin changes; Venous leg ulcers; Ankle swelling; Heavy legs; varicose veins; Swelling of the legs; ulcer; Venous thrombosis; phlebitis; Thrombus-veinitis; Pulmonary embolism; hemorrhoids.

One object of the present invention is therefore a composite composition comprising L-carnitine or a salt thereof, troxertin, diosmin and hesperidin as active ingredients.

Another object of the present invention is a composite composition comprising propionyl L-carnitine or a salt thereof, troxeroutine, diosmin and hesperidin as active ingredients.

The above-mentioned compositions may further comprise other active ingredients useful for the treatment of venous diseases.

Another object of the invention is a composition comprising:

(a) Dose 10-3000 mg, preferred dose 50 mg-400 mg, most preferred dose 136 mg L-carnitine or propionyl L-carnitine.

(b) a dose of 900 mg to 50 mg, a preferred dose of 400 mg to 200 mg, the most preferred dose of 300 mg of troxeroutine;

(c) doses of 900 mg to 50 mg, preferred dose 400 mg to 200 mg, most preferred dose 300 mg of diosmin; And

(d) doses of 10 mg to 500 mg, preferred dose 50 mg to 200 mg, most preferred dose 100 mg of hesperidin.

Another object of the present invention is the above-described composition for use in anti-chronic venous insufficiency and complications thereof.

Another object of the present invention is the aforementioned composition for use in anti-chronic venous disease and complications thereof.

Another object of the present invention is the use of the aforementioned composition for the preparation of a medicament for the prevention or treatment of chronic venous insufficiency, chronic venous disease and complications thereof, wherein the complications include swelling and inflammation of rectal, anal and vaginal veins; Venous hypertension; Increase in permeability; edema; Capillary injury; Skin changes; Venous leg ulcers; Ankle swelling; Heavy legs; varicose veins; Swelling of the legs; ulcer; Venous thrombosis; phlebitis; Thrombus-veinitis; Pulmonary embolism; Selected from the group comprising hemorrhoids.

Another object of the present invention is the use of the above-described composition for the preparation of a dietary supplement for the prevention or treatment of chronic venous insufficiency, chronic venous disease and complications thereof.

The compositions of the present invention may further comprise agents useful for the treatment of coenzymes, mineral substances, antioxidants, vitamins, anticoagulants and venous diseases.

By salts of L-carnitine is meant any salt of L-carnitine with acid that does not cause toxicity or side effects.

Non-limiting examples of such salts are: chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lac Tate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, acid sulphate, glucose phosphate, tartrate and acid tartrate, glycerophosphate, catenate, magnesium tartrate, 2 -Amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate, and trifluoroacetate.

A list of FDA-approved pharmaceutically acceptable salts is described in Int. J. of Pharm. 33 (1986), 201-217.

L-Carnitine, Propionyl L-Carnitine, Troxertin, Diosmin and Hesperidin according to the present invention may be administered in a "harmonized manner." "In a harmonized manner" of said compounds is a co-administration, ie a substantially simultaneous or sequential supplementation of L-carnitine or propionyl L-carnitine and one or more troxerutine, diosmin, hesperidin or pharmaceutically acceptable It is synonymous with administration of a composition comprising said active ingredients in a complex and mixture, optionally further comprising one or more excipients or diluents as possible.

The compositions of the present invention may be administered orally, parenterally, intravenously, topically and / or transdermally in any suitable form. Oral administration is preferred.

Examples of dosage forms include sachets, pills, vials, ointments, gels or liposomes in liquid, semi-liquid or solid form.

L-carnitine and propionyl L-carnitine are known compounds and methods for their preparation are described in US 4,254,053.

Troxerutin, diosmin and hesperidin are widely commercially available, and their CAS-Nos are 7085-55-4; 520-27-4 and 520-26-3.

The pharmaceutical composition according to the invention consists of the active ingredients which are familiar to the worker in the medical field and are already in use.

Thus, as long as they are currently on the market for a long time and are graded products suitable for human administration, their procurement is very easy.

A therapeutically effective dose for any compound can be initially predicted in cell culture assays or animal models, typically mice or rats.

Animal models can also be used to determine appropriate concentration ranges and routes of administration. The information can then be used to determine useful doses and routes of administration in humans.

The exact effective dose for a human subject depends on the severity of the disease state, the subject's general health, the subject's age, weight and sex, diet, time and frequency of administration, drug combination (s), response sensitivity, and resistance / response to treatment. Will depend. The amount can be determined by routine experimentation and is within the judgment of the physician.

The following non-limiting examples further illustrate the invention.

Example  One

In rats Croton  Reduced Swelling of the Rectal-anal in an Oil-induced Hemorrhoid Model

Male SD rats (6 weeks old, approximately 140 g) were purchased from Harlan Sprague Dawley and acclimated for 1 week. Rats were maintained in sterile facilities according to the National Laboratory Council Laboratory Animal Care and Use Guidelines. Each experiment was performed with age-matched 7-8 week old rats. Croton oil derived hemorrhoid models in rats were performed according to methods published in Nishiki (Nishiki et al. (1988) Folia Pharmacology Japan 92: 215-225; Nishiki et al. (1988) Folia Pharmacol. Japan 92: 227-240). Briefly, a 4 mm diameter swab moistened with 0.16 mL of inducer (distilled water: pyridine: ethyl ether: 6% croton oil / ethyl ether (1: 4: 5: 10)) was applied to the rat's anus for 12 seconds. The final concentration of croton oil was 3%. Edema occurred proportionally to 7-8 hours after application, and the severity of edema was maintained for more than 24 hours. After 24 hours, rats were euthanized and rectal-anal tissue (approximately 10 mm long) was isolated. Rat weight and rectal-anal weight were measured. Rectal-Anal Coefficient (RAC) was calculated using the formula: Rectal-Anal Weight (mg) / Weight (g).

Compounds of the present invention suspended in saline (1 mL) once daily for 5 days were administered orally. Final treatment with the compounds of the present invention was performed on the day of induction of edema with croton oil.

Compounds of the invention were administered alone or in combination in the following doses: 20 mg / kg propionyl L-carnitine or L-carnitine; 30 mg / kg Troxerutin, Diosmin or Hesperidin.

After 24 hours of hemorrhoid induction into croton oil, RAC of rats was determined.

The results are reported in Table 1 below.

The results reported in Table 1 indicate that the use of the compositions of the present invention resulted in statistically significantly higher activity (relative to the use of a single component).

In fact, the results reported in Table 1 indicate that the compositions of the present invention completely inhibited the swelling of the rectal-anality induced by croton oil.

Example  2

Relaxant Effect of Test Compounds on the Annular Aorta

The purpose of this study was to investigate the vasorelaxant effect of the compositions of the present invention using the aorta isolated from naturally occurring hypertensive rats.

Materials and methods

Test compounds were used at the concentrations indicated in the final concentrations in the tissue chamber.

Animals

Male spontaneously hypertensive rats (SHR) of 10-12 weeks of age and 250-300 g body weight were housed at 24 W 2 ° C. and 60 W 20% relative humidity in a 12 hour contrast cycle. Rats were given free intake of standard and water diets. All experiments were performed in accordance with the guidelines for ethical treatment of animals in the European Union. Rats were killed by cervical dislocation and the aorta quickly detached.

Annular aortic preparation

The descending thoracic aorta was placed in modified Krebs-Henseleit solution (PSS) containing NaCl 118, KCl 4.75, NaHCO ₃ 25, MgSO ₄ 1.2, CaCl ₂ 1.8, KH ₂ PO ₄ 1.2 and glucose 11 in mM units.

After removal of excess fat and connective tissue, the aorta was cut into 2-3 mm rings. The annular aorta was mounted under a base tension of 2 g in a 20 mL tissue containing PSS and attached to an isometric transducer (Harvard UF-1); Signals were recorded with a Powerlab data acquisition system (AD-Instruments). The tissue bath was maintained at 37 ° C. with a bubble of 95% O ₂ and 5% CO ₂ gas mixture.

Relaxant effect of test compounds.

Compounds were added to the annular aorta preshrunk with phenylephrine (1 μM) to assess the relaxant effect of the test compounds.

After the aorta was contracted with phenylephrine and the contraction reaction was reached, test compounds were added to the bath. All results are expressed as a percentage of the maximum shrinkage of phenylephrine-induced reactions.

Statistical analysis

Results are expressed as a percentage of the initial preshrinkage level.

Significance was calculated as the mean contraction value actual mean SE (n = 8 aortic preparations per group). Eight preparations from one aorta were studied. Student t-test was used as a comparative test for statistical analysis.

p <0.05 values were considered to represent significant differences.

The results are reported in Table 2 below.

The results reported in Table 2 indicate that the addition of the compositions of the present invention to the annular aorta preshrunk with phenylephrine caused endothelial dependent relaxation that was statistically significantly more active than the single components.

Some non-limiting examples of the compositions of the present invention are reported below.

Composition 1

L-carnitine tartrate 200 mg

L-carnitine equivalent 136 mg

-Troxerucine NEC ㄾ 700 mg

300 mg with Troxerutina

-Diosmin 300 mg

Hesperidin 98% 100 mg

Hesperidin Equivalent 98 mg

Composition 2

Propionyl L-Carnitine Tartrate 250 mg

Propionyl L-Carnitine Equivalent 136 mg

-Troxerucine NEC ㄾ 700 mg

300 mg with Troxerutina

-Diosmin 300 mg

Hesperidin 98% 100 mg

Hesperidin Equivalent 98 mg

Composition 3

L-carnitine fumarate 200 mg

L-carnitine equivalent 136 mg

-Troxerucine NEC ㄾ 700 mg

300 mg with Troxerutina

-Diosmin 300 mg

Hesperidin 98% 100 mg

Hesperidin Equivalent 98 mg

Composition 4

Propionyl L-Carnitine Fumarate 250 mg

Propionyl L-Carnitine Equivalent 136 mg

-Troxerucine NEC ㄾ 700 mg

300 mg with Troxerutina

-Diosmin 300 mg

Hesperidin 98% 100 mg

Hesperidin Equivalent 98 mg

Claims (14)

A composite composition comprising L-carnitine or a derivative or salt thereof as the active ingredient, troxeroutine, diosmin, hesperidin and optionally one or more pharmaceutically acceptable excipients. The composite composition of claim 1, wherein the derivative of L-carnitine is propionyl L-carnitine. The composite composition of claim 1 or 2 comprising:
(a) doses 10 to 3000 mg, preferred dose 50 mg to 400 mg, most preferred dose 136 mg of L-carnitine or propionyl L-carnitine;
(b) a dose of 900 mg to 50 mg, a preferred dose of 400 mg to 200 mg, the most preferred dose of 300 mg of troxeroutine;
(c) doses of 900 mg to 50 mg, preferred dose 400 mg to 200 mg, most preferred dose 300 mg of diosmin; And
(d) doses of 10 mg to 500 mg, preferred dose 50 mg to 200 mg, most preferred dose 100 mg of hesperidin. The composite composition of claim 1, which is a dietary supplement. The composite composition of claim 1, which is a medicament. The composite composition of claim 1, further comprising agents useful for the treatment of coenzymes, mineral substances, antioxidants, vitamins, anticoagulants, and venous diseases. The complex composition of claim 1 or 2 for use in the prevention or treatment of venous diseases. Use of a composite composition for the manufacture of a medicament for the prevention or treatment of venous diseases, comprising L-carnitine or a derivative or salt thereof, troxertin, diosmin, and hesperidin as an active ingredient. 9. Use according to claim 8, wherein the derivative of L-carnitine is propionyl L-carnitine. Use according to claim 8 or 9, wherein said venous diseases are selected from the group consisting of chronic venous insufficiency, chronic venous disease and complications thereof. The method of claim 10, wherein the complication is swelling and inflammation of rectal, anal and vaginal veins; Venous hypertension; Increase in permeability; edema; Capillary injury; Skin changes; Venous leg ulcers; Ankle swelling; Heavy legs; varicose veins; Swelling of the legs; ulcer; Venous thrombosis; phlebitis; Thrombus-veinitis; Use selected from the group consisting of pulmonary embolism or hemorrhoids. The salt of claim 8 or 9, wherein the salt of L-carnitine or propionyl L-carnitine is selected from chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, magnesium citrate, phosphate, acid phosphate, Fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, oxalate, acid oxalate, pamoate, acid pamoate, sulfate, acid sulfate, glucose phosphate, tartrate and acid tartrate, glycerol Selected from the group consisting of lophosphate, mate free, magnesium tartrate, 2-amino-ethanesulfonate, magnesium 2-amino-ethanesulfonate, methanesulfonate, choline tartrate, trichloroacetate, and trifluoroacetate Usage. Use according to claim 8 or 9 for oral, parenteral, intravenous, topical and / or transdermal administration. Use according to claim 8 or 9 for oral administration.