USE OF COUMARIN OR ITS HYDROXY DERIVATIVE FOR THE TREATMENT OF MEDIUM OR SEVERE VASCULAR AND/OR LYMPHATIC EDEMA

Abstract: The invention concerns the use of coumarin or its hydroxy derivative, preferably 7-hydroxycoumarin, for the preparation of a medicament for the treatment of medium and severe lymphatic and/or vascular edema. The amount of coumarin or its hydroxy derivative is between 35 and 55 mg pro drug unit, preferably of 45 mg. The sublingual pharmaceutical form is described for the first time.

Description: SE OF COUMARIN OR ITS HYDROXY DERIVATIVE FOR THE TREATMENT OF MEDIUM OR SEVERE VASCULAR AND/OR LYMPHATIC EDEMA TESTO DELIA DESCRIZIONE The present invention concerns the use of benzo-pyrone derivatives for the treatment of vascular and/or lymphatic edema of middle and high amplitude. Particularly the invention concerns the treatment of vascular and/or lymphatic edema of middle and high amplitude through the use of coumarin (5, 6-benzopyran-2-one) or its hydroxy derivative . The therapy of lymphoedema of middle and high amplitude nowadays makes use of a pharmaceutical therapy based on some diuretic, anticoagulants, flebotonic drugs, antibiotics for the infective complications, but only in order to complete the surgical treatment, elasto- compressive treatment, manipulative treatment and in any case they are non sufficient to eliminate the aetiology of such anatomic, physio-pathological manifestations. As a matter of fact in order to apply an effective therapy it is necessary to use a synergism of more approaches such as pharmaceutical, elasto-co pressive and manual lympho-drainage treatments. It is well known to use a lot of drugs able to be effective at the vein-lymphatic level in order to treat lymphoedema and hyperproteic angioede a of the limbs. Among these drugs attention was paid to benzopyrones derivative, and specifically to coumarin. It is known that coumarin acts with a receptor pharmaco-dynamic mechanism at immuno-competent cell level of white series (monocytes, macrophages, and with a less affect on NK) , enhancing the migration to the interested part of the edema of such cells (interleukin-like effect and the production from the same cells of lytic enzymes, which are able to cleave the proteins which are present in the plasma and are the reason of the high oncotic pressure being responsible of the edema . The use of coumarin at very high doses, which in very critical cases correspond to 400-800 g/day, for the treatment of lymphoedema, is well known. When the amounts of coumarin are so high some cases of even serious hepatic toxicity are described. Some studies pointed out the possible toxicity of the coumarin at the hepatic tissue level after a repeated systemic administration (especially orally) of variable doses. According to such studies it seems that oral doses of coumarin of about 200 mg/day are associated to high concentrations of some cytosolytic hepatocytic enzymes in the plasma, which are biochemical markers of the hepatic damage. Other studies supposed that the possible tissue toxicity after a chronic acute administration of coumarin should be ascribed to idiosyncrasy and hence to genetic and immunologic factors rather than the formation of toxic compounds due to the action of the said enzymes. Regardless of the mechanism causing the tissue toxicity, the toxicity cases made coumarin to be abandoned in the lymphoedema therapy. Subsequently some experts tried a safer use of coumarin starting from melilotus officinalis extracts, corresponding to a 5-25 mg/capsule of coumarin as melilotus officinalis extract. On one hand the clinic titration allowed a use of coumarin to be safer, on the other hand it resulted in being clinically insignificant in the case of vascular and lymphatic edema of middle and high amplitude. The object of the present invention is hence to provide a therapy of treatment of lymphoedema of middle and high amplitude. It is also another object of the present invention to allow the use of coumarin in such conditions which result safer in the toxicological point of view. The above indicated objects are achieved through the use of coumarin or its hydroxy derivative for the preparation of a drug for the treatment of vascular and/or lymphatic edema of middle and high amplitude, wherein the amount of coumarin or its hydroxy derivative is between 35 and 55 mg in the medicament as recited in claim 1. Advantages and characteristics are recited in the dependent claims. In order to treat these kinds of vascular and/or lymphatic edema the coumarin or its hydroxy derivative is use in amount of 35-55 mg. Preferably the amount the coumarin or its hydroxy derivative is of 45 mg pro-unit. In the attempt of making minimal the risk of hepatotoxicity a micronized perioral pharmaceutical form was also envisaged, using as administration route the sublingual capillary network which, not only guarantees a extremely rapid systemic absorption, being the sublingual mucosa extremely vascularized, but also allows to bypass the portal circulation avoiding a spread hepatic passage. Therefore the invention concerns also the use of coumarin or its hydroxy derivative as micronized form administrable as sublingual pharmaceutical form according to claim 6. Particularly coumarin or its hydroxy derivative is subjected to a process of icronization in order to reach a granule size of 2 μm diameter or less. In spite of the fact that sublingual embodiment resulted preferable according to the present invention same other pharmaceutical forms are also possible. Among them capsules, tablets, transdermal, intramuscular or intravenous systems are cited provided that the amount of the coumarin or its hydroxy derivative pro-unit be comprised between 35 and 55 mg. Among these pharmaceutical forms, capsules resulted more preferable. As hydroxy derivative of coumarin 7-hydroxy derivative or umbelliferone is described, which represents the metabolic intermediate of coumarin and is the most important in vivo in the human species. Such 7-hydroxy derivative was resulted from some studies absolutely not involved in the generation of the above described idiosyncratic hepatopathy which is generated by the formation in vivo of epoxydate derivatives in position 3 and 4 of alfa-pyronic ring. As a matter of fact the in vivo coumarin metabolization which provides for the formation of 7- hydroxy derivative or umbelliferone, facilitates the formation of 7-glycuronides, which are easily eliminable by the renal emunctory action. Therefore the present invention relates to the use of umbelliferone as recited in claim 2. Coumarin or its 7-hydroxy derivative in suitable amounts can then be added with suitable excipients, which are well known to the man skilled in the art of the preparation of drug administration pharmaceutical forms. Suitable excipients for the sublingual preparation are e.g. microcristalline cellulose, corn starch, magnesium stearate, sodium metabisolphite, silica gel; for the transdermal administration hydroxyethylcellulose, carboxyethylcellulose, PEG, alone or with other balsamic agents or local anaesthetic agents such as menthol, benzocaine, procaine, lidocaine, tetracaine and the like. Preferable solvents for dissolution of coumarin are ethanol or other lyposoluble organic solvent as chloroform, ethyl ether, toluene, oils and other alkalis such as alkaline hydrates. Preferable solvents for the solution of umbelliferone are ethanol, dichloromethane, chloroform and any other lyposoluble aliphatic or aromatic solvents. When coumarin or umbelliferone are in solution a local anaesthetic agent or balsamic agent can be added (e.g. benzocaine and menthol) in order to avoid the possible local irritation. In the case of sublingual tablet preparations the amount of excipients will not be above the range of 65-85 mg, being coumarin or its 7-hydroxy derivative amount comprised between 35 and 55 mg pro drug unit. More preferably the amount of excipients will not be above 75 mg pro unit, the coumarin amount being 45 mg pro unit. In the preferred subligual embodiment the tablets will have preferably sizes of about 8 mm diameter and of 2- 3 mm thickness so as to assure the easiest administration and hence patient compliance, contemporaneously satisfying an effective sublingual absorption. Preferably the treatment protocol comprises the administration of the claimed coumarin or its hydroxy derivative amount once a day, preferably during the daytime hours in order to avoid the excessive night diuresis associated to coumarin compounds. Some illustrative embodiments of the medicament as sublingual tablet and capsule according to the invention follow by way of example. A series of clinical use tests of different coumarin capsules, containing 45 and 50 mg of coumarin respectively in the treatment of patients affected by lymphoedema of limbs, follow. Such tests show the advantages achieved by the present invention. Preparation of a sublingual tablet containing coumarin 450 g of coumarin as polymorphous crystals were subjected to a process of making a powder through a steel ball mill, obtaining a powder consisting of particles of size of about 2 μm. The sieving and size checking steps of the obtained particles were carried out through microscope. The so obtained powder was mixed with 12 g of micronized talc, 60 g of microcrystalline cellulose powder, obtained mixture was subjected to a wet fluid bed granulation process by using the minumum amount of sucrose solution, and the obtained granulate was then kneaded, sieved and dried. The size check of the granules was then carried out. Granules were then pressed and tablets of 8 mm diameter and weight of 120 mg were obtained. They were subjected to technological and biopharmaceutical examination as from official Pharmacopoeia. The composition of each tablet was as follows: Coumarin: 37,5% Microcrystalline cellulose: 6,6% by weight corn starch: 25% by weight Magnesium stearate: 8,3% by weight Sodium metabisolphite : 0,3% by weight Silica gel: 4,2% by weight Saturated sucrose solution (for coating): q.s. to 100% Preparation of a sublingual tablet containing 7- hydroxycoumarin 450 g of 7-hydroxycoumarin as polymorphous crystals were subjected to a process of making a powder through a steel ball mill, obtaining a powder composed of particles of size of about 2 μm. The sieving and size checking steps of the obtained particles were carried out through microscope. The so obtained powder was mixed with 12 g of micronized talc, 60g of microcrystalline cellulose powder, 350g of lactose powder through a screw mixer. The so obtained mixture was subjected to a granulation wet fluid bed process by using the minimum amount of sucrose solution, and the obtained granulate was then kneaded, sieved and dried. The size check of the granules was then carried out. Granules were then pressed and tablets of 8 mm diameter and weight of 120 mg were obtained. They are subjected to technological and biopharmaceutical examination as from official Pharmacopoeia. The composition of each tablet was as follows: 7-hydroxycoumarin: 37,5% Microcrystalline cellulose: 6,6% by weight corn starch: 25% by weight Magnesium stearate: 8,3% by weight Sodium metabisolphite: 0,3% by weight Silica gel: 4,2% by weight Saturated sucrose solution (for coating): q.s. to 100% Preparation of capsules containing 45 mg of coumarin 45 g of coumarin powder (particle size of about 2 μm) were mixed in a screw mixer with 10 g of micronized talc, 10 g of microcrystalline cellulose powder and pregelatinized starch in order to reach the weight of 130g. The so obtained mixture of such powders was delivered to a plate of an automatic encapsulating machine and uniformly spread on the capsular bodies which were previously separated from caps. (1000 size 2 CUCKI SNAP capsules were prepared) . Once the capsules were closed and sealed they were subjected to uniformity tests of weight and of contents as established for the "pharmaceutical forms in single unit" by the official Pharmacopoeia. Preparation of capsules containing 45 mg of 7- hydroxycoumarin 45 g of 7-hydroxycoumarin powder (particle size of about 2 μm) were mixed in a screw mixer with 10 g of micronized talc, 10 g of microcrystalline cellulose powder and pregelatinized starch in order to reach the weight of 130g. The so obtained mixture of such powders was delivered to the plate of an automatic encapsulating machine and uniformly spread on the capsular bodies which were previously separated from the caps. (1000 size 2 CUCKI SNAP capsules were prepared) . Once the capsules were closed and sealed, they were subjected to uniformity tests of weight and of contents as established for the "pharmaceutical forms in single unit" by the official Pharmacopoeia. Study about the clinical use of capsules containing 45 mg of coumarin Patients e methods 7 patients affected by primitive lymphoedema of the lower limbs, one of which with flebolymphostatic ulcer and another one with dermalymphoangioadhenite, 2 patients affected by secondary lymphoedema of the lower limb, 1 patient affected by secondary lymphoedema post-mastectomy of the upper limb were subjected to the following protocol of the drug administration: one capsule containing 45 mg of micronized coumarin was taken by each patient at 4 p.m. every day for a period of about one month in a continuos way. All patients were subjected to routine bioumural tests, comprising hepatic functionality indixes, before starting the treatments and 2-10 days after treatment interruption. All the patients were furthermore subjected to eco-color-doppler and vascular tests with centimetre measurements of the circumference of limb on admission and discharge. During the intensive treatment in hospitalized regimen, the patients were subjected to manual lymphatic drainage, elastocompression and complementary therapy when necessary. At home the patients continued to take the drug, associating occasionally manual lymphatic drainage sittings and elasto-compression with stockings or armlets suitable for daytime hours. Results All treated patients showed a significative improvement of lymphoedema resulting in a reduction of edema consistency and entity. The limb circumferences, being measured in some predetermined points, was diminished after the first seven days of combined intensive treatment of 0, 8-8 cm, according the various patients and zones as indicated in the following table. Group 1: n. 3 patients affected by lymphoedema of middle amplitude Group 2: n. 4 patients affected by lymphoedema of middle-high amplitude The ecographic measurements of the fibrous and edematous tissue thickness showed significative reductions in all patients, particularly in those with edematous tissue with scarce fibrosis as indicate in the following table; furthermore a good resolution of the flebolymphostatic ulcer was noted. Group 1: n. 3 patients affected by lymphoedema of middle amplitude Group 2: n. 4 patients affected by lymphoedema of middle-high amplitude The obtained results concerning symptoms were good, all the patients underlined an improvement in the weight feeling and paresthesia of the limbs affected by limphoedema. From the patient's point of view the drug resulted well tolerated, generating no unpleasant secondary effects or compliance problems. Study about the clinical use of capsules containing 50 mg of coumarin Patients e methods 12 patients affected by primitive lymphoedema of the lower limbs, three of which with flebolymphostatic ulcer and five ones with dermatolimphoangioadhenite, 2 patients affected by secondary lymphoedema of the lower limb, 4 patients affected by secondary lymphoedema post-mastectomy of the upper limb were subjected to the following protocol of drug administration: one capsule containing 50 mg of micronized coumarin and excipients pro capsule was taken by each patient at 4 p.m. every day for a period of about 45 days in a continuos way. All patients were subjected to routine bioumural tests, comprising hepatic functionality indexes (ALT, AST, LH, etc) and protein dosage, said proteins being present in the interstitial liquid the day before of the treatment start and 2-10 days after the treatment interruption. All the patients were furthermore subjected to eco-color-doppler and vascular tests with centimetre measurements of the circumference of limb on admission and discharge. During the intensive treatment in hospitalized regimen, the patients were subjected to manual limphatic drainage, elastocompression and complementary therapy when necessary. At home the patients continued to take the drug, associating occasionally manual limphatic drainage sittings and elasto-co pression with stockings or armlets suitable for daytime hours. Results All the treated patients showed a significative improvement of lymphoedema resulting in a reduction of edema consistency and entity. The limb circumference, being measured in some predetermined points, was diminished after the first seven days of combined intensive treatment of 1.5-10 cm, according the various patients and zones as indicated in the following table. Group 1: n. 7 patients affected by lymphoedema of middle amplitude Group 2: n. 5 patients affected by lymphoedema of middle-high amplitude The ecographic measurements of the fibrous and edematous tissue thickness showed significative reductions in all patients, particularly in those with edematous tissue with scarce fibrosis as indicated in the following table Group 1: n. 3 patients affected by lymphoedema of middle amplitude Group 2: n. 4 patients affected by lymphoedema of middle-high amplitude The obtained results concerning symptoms were good, all the patients underlined an improvement in the weight feeling and paresthesia of the limbs affected by lymphoedema. From the patient's point of view the drug resulted well tolerated, generating no unpleasant secondary effects or compliance problems. Study about the clinical use of the treatment with capsules of coumarin (45 mg) in daily dual administration. Patients e methods 6 patients affected by primitive lymphoedema of the lower limbs, three of which with secondary lymphoedema of the lower limb and five ones affected by secondary lymphoedema post-mastectomy of the upper limb were subjected to the following protocol of the drug administration: one capsule containing 45 mg of micronized coumarin and excipients pro capsule up to 130 mg was taken by each patient at 8 a.m. and 4 p.m. every day for a period of 45 days in a continuos way. All patients were subjected to routine bioumural tests, comprising hepatic functionality indixes (ALT, AST, LH, etc) and protein dosage, said proteins being present in the interstitial liquid, the day before the treatment start and 2-10 days after the treatment interruption. All the patients were furthermore subjected to eco-color-doppler and vascular tests with centimetre measurements of the circumference of limb on admission and discharge. During the intensive treatment in hospitalized regimen, the patients were subjected to manual lymphatic drainage, elastocompression and complementary therapy when necessary. At home the patients continued to take the drug, associating occasionally manual limphatic drainage sittings and elasto-compression with stocking or armlets suitable for daytime hours. Results All the treated patients showed a significative improvement of lymphoedema resulting in a reduction of edema consistency and entity. The limb circumference, being measured in some predetermined points, was diminished after the first seven days of combined intensive treatment of 2-9 cm, according the various patients and zones as indicated in the following table. Group 1: n. 3 patients affected by lymphoedema of middle amplitude Group 2: n. 3 patients affected by lymphoedema of middle-high amplitude The ecographic measurements of the fibrous and edematous tissue thickness showed significative reductions in all patients, particularly in those one with edematous tissue with scarce fibrosis. The obtained results concerning symptoms were good, all the patients underlined an improvement in the weight feeling and paresthesia of the limbs affected by lymphoedema. From the patient's point of view the drug resulted well tolerated, generating no unpleasant secondary effects or compliance problems. Study of the clinical use of treatment with coumarin capsules (50 mg) in daily dual administration Patients e methods 6 patients affected by primitive lymphoedema of the lower limbs, three of which affected by secondary lymphoedema of the lower limb and three ones affected by secondary lymphoedema post-mastectomy of the upper limb were subjected to the following protocol of the drug administration: one capsule containing 50 mg of micronized coumarin and excipients pro capsule up to 130 mg was taken by each patient at 8 a.m. and 4 p.m. every day for a period of 45 days in a continuos way. All patients were subjected to routine bioumural tests, comprising hepatic functionality indexes (ALT, AST, LH, etc) and protein dosage, said proteins being present in the interstitial liquid, the day before the treatment start and 2-10 days after the treatment interruption. All the patients were furthermore subjected to eco-color-doppler and vascular tests with centimetre measurements of the circumference of limb at the moment of the recovery and after on admission and discharge. During the intensive treatment in hpospitalized regimen, the patients were subjected to manual lymphatic drainage, elastocompression and complementary therapy when necessary. At home the patients continued to take the drug, associating occasionally to manual lymphatic drainage sittings and elasto-compression with stockings or armlets suitable for daytime hours. Results All the treated patients showed a significative improvement of lymphoedema resulting in a reduction of edema consistency and entity. The limb circumference, being measured in some predetermined points, was diminished after the first seven days of combined intensive treatment of 3- 10 cm, according the various patients and zones as indicated in the following table. Group 1: n. 3 patients affected by lymphoedema of middle-high amplitude Group 2: n. 3 patients affected by lymphoedema of high amplitude The ecographic measurements of the fibrous and edematous tissue thickness showed significative reductions in all patients, particularly in those with edematous tissue with scarce fibrosis. Study of the clinical use of capsules containing 45 mg of 7-hydroxycoumarin (UMBELLIFERONE) Patients and methods 10 patients affected by primitive lymphoedema of the lower limbs, three of which affected by flebolymphostatic ulcer, three patients affected by secondary lymphoedema of the lower limb, four ones affected by secondary lymphoedema post-mastectomy of the upper limb were subjected to the following protocol of the drug administration: one capsule containing 45 mg of micronized coumarin and excipients pro capsule up to 130 mg was taken by each patient at 4 p.m. every day for a period of about one month in a continuos way. All patients were subjected to routine bioumural tests, comprising hepatic functionality indexes (ALT, AST, LH, isocitric dehydrogenase, γ-GPT ) before the treatment start and 2-10 days after the treatment interruption. All the patients were furthermore subjected to eco-color- doppler and vascular tests with centimetre measurements of the circumference of limb on admission and discharge. During the intensive treatment in hospitalized regimen, the patients were subjected to manual lymphatic drainage, elastocompression and complementary therapy when necessary. At home the patients continued to take the drug, associating occasionally to manual lymphatic drainage sittings and elasto-compression with stockings or armlets suitable for daytime hours. Results All the treated patients showed a significative improvement of limphoedema resulting in a reduction of edema consistency and entity. The limb circumference, being measured in some predetermined points, was diminished after the first seven days of combined intensive treatment of 1.0-9 cm, according the various patients and zones as indicated in the following table. Group 1: n. 3 patients affected by lymphoedema of middle amplitude Group 2: n.3 patients affected by lymphoedema of middle-high amplitude Group 3: n. 4 patients affected by lymphoedema of high amplitude The ecographic measurements of the fibrous and edematous tissue thickness showed significative reductions in all patients, particularly in those with edematous tissue with scarce fibrosis as indicate in the following table . Group 1: n. 3 patients affected by lymphoedema of middle amplitude Group 2: n. 3 patients affected by lymphoedema of middle-high amplitude Group 3: n. 4 patients affected by lymphoedema of high amplitude The obtained results concerning symptoms were good, all the patients underlined an improvement in the weight feeling and paresthesia of the limbs affected by limphoedema. From the patient's point of view the drug resulted well tolerated, generating no unpleasant secondary effects or compliance problems. The difference concerning the clinical improvement of the patients treated with a dosage of two capsules/day containing coumarin or its 7-hydroxyderivative rather than the a dosage correspondent to one sole capsuless/day only has to be taken into consideration: It is evident the greater efficacy of the treatment in dual administration with respect the single administration; the use of one or the other dosage schedule is strictly linked to the valuation of the doctor in charge. Therefore it can be argued that the efficacy of the drug in the treatment of lymphoedema has been shown by providing also a pharmaceutical form with high adsorption and at the same time overcoming the hepatoxicity problem even if of idiosyncratic nature being associated to Coumarin derivatives. The present invention has been described with reference to some exemplificative embodiments, but some other variations concerning either the used excipients or the dosage can be carried out without departing from the scope of the present invention as indicated in the appended claims .

Claims: CLAIMS 1. Use of coumarin or its hydroxy derivative for the preparation of a medicament for the treatment of lymphatic and/or vascular edema of middle and high amplitude, wherein the amount of coumarin or its hydroxy derivative is between 35 and 55 mg pro drug unit. 2. Use according to claim 1 wherein the hydroxy derivative is 7-hydroxycoumarin or umbelliferone. 3. Use according to claim 1 or 2 wherein the amount of coumarin or its hydroxy derivative in the medicament is 45 mg. 4. Use according to any one of the preceding claims wherein coumarin or its hydroxy derivative is in micronized form. 5. Use according to any one of the preceding claims wherein the particles of coumarin or its micronized hydroxy derivative have a size of about 2 μm of diameter. 6. Use according to any one of the preceding claims wherein the medicament is a sublingual tablet. 7. Use according to any one of the preceding claims wherein the medicament is a capsule. 8. Use according to claim 6 or 7 wherein the excipients are between 65 e 85 mg pro drug unit. 9. Use according to any one of the preceding claim wherein the vascular and/or lymphatic edema is associated to flebolymphostatic ulcer and/or dermatolymphangioadhenite .

Inventors: CHIMENTI MASSIMO, FRATTER ANDREA, CHIMENTI, MASSIMO, FRATTER, ANDREA
Applicants: CHIMENTI MASSIMO, FRATTER ANDREA, MAC PHARMA S A S, CHIMENTI, MASSIMO, FRATTER, ANDREA, MAC PHARMA S.A.S.
Application year: 2001
Main classification: A61K31
IPC codes: A61K9, A61K31, A61P7