MEDICAMENT HAVING SCLEROSING ACTIVITY

Abstract: This invention relates to the use of a solution of a soluble, pharmaceutically acceptable salt of salicylic acid, said solution having a pH between 7.0 (+/-1) and 9.0 (+/-1), as active ingredient for the preparation of a medicament having sclerosing activity useful for the treatment of varixes.

Description: MEDICAMENT HAVING SCLEROSING ACTIVITY The present invention relates to a medicament having sclerosing activity, in particular to a medicament whose active ingredient consists in a water- soluble, pharmaceutically acceptable salicylic acid salt. Background of the invention Sclerosis, namely the clinical disappearance of a varix, can be obtained by injecting in the varix, with appropriate techniques and equipment (needle, syringe), a suitable chemical solution capable of causing an endothelial lesion with reactive formation of an adhering thrombus and its subsequent fibrotic organization, so that the occlusion and disappearance of the varix is finally obtained. Generally, the whole histological process of fibroεcleroεis of a varix subjected to sclerosing therapy lasts about 2-3 months, even if the disappearance of the varix is apparent in shorter times. The endothelial damage of the treated varix takes place substantially through an alteration of the electronegative surface charge established by GAGs (Glucosaminoglycanes) depending on the surfactant action of the sclerosing agent, or by pH or by the osmolarity values of the solution. A great number of studies in international specialistic literature demonstrate that sclerosing substances can be classified in three groups according to their mode of action: 1- Detergent solutions: which act causing an endothelial damage by lowering surface tension of the plasma membrane, thus triggering the fibrosclerotic process. Examples are polydodecanol , sodium tetradecylεulfate or ethanolamine oleate solutions. 2- Osmotic solutions: which have a high osmolarity and act causing a "drying effect" on endothelial cells by damaging and destroying them. Examples are hypertonic sodium chloride or glucose solutions. 3- Chemical solutions: which determine the endothelial damage because of their "irritating" activity, depending on a mechanism of "chemical aggressiveness" of oxidative or caustic type. Examples are polyiodinated solutions or chromic glycerin solutions. According to the French school of Sclerotherapy (R.Tournay), sclerosing solutions are also classified on the basis of their "sclerosing potency" in relation to the size of the varix to be treated: a) - Major Sclerosing Agents: polyiodinated solutions, sodium tedradecylsulfate; b) - Medium- Sclerosing Agents: polydodecane , salicylic acid, sodium orruate; c) - Minor Sclerosing Agents: chromic glycerin, hypertonic solutions. Definition of the technical problem Apart from their correct use and from a correct sclerotherapical technique, all the sclerosing solutions can determine, in different extent, a series of side effects deriving from the intrinsic chemico-physical properties. Thus, for example, according to the sclerosing potency and to the degree of vasal aggres- sivity, painful inflammatory periphlebitis processes can occur, resulting in a generally irreversible pigmentation or, in the case of tissutal extravasation, the formation of necrotic-cicatricial exitus. For some of them (sodium morruate, ethanolamine oleate, sodium tetradecylsulfate ) , particular allergies are observed, sometimes having the character of anaphylactic shock. However, the absolutely more frequent complications occurring during sclerotherapy are: I - Haemosiderinic (ferric) pigmentations . Said complication consists in the appearance, in the treated site, of dark cutaneous pigmentations which are a serious aesthetical damage for the patient, who is inclined to refuse sclerotherapy. Said complication is more frequent for small vessels, such as teleangectasis , known to represent 80% of the sclerotherapical applications. According to some Authors (M.P. Goldman, USA), about 10-30 % of the patients, who have been subjected to sclerosing therapy, suffer from said post- sclerosis hyperpigmentations, independently from the active agent used. II - Teleangectatic matting, namely the appearance of neo-capillaries in the treated site, due to still not completely understood mechanisms, but can be attributed to neoangiogenesis coming out as a reaction to the sclerotherapy. According to Goldman, said secondary microvaricosis affects 10-15% of the patients subjected to sclerotherapy and is a further unwanted "aesthetical danger" of the sclerotherapy, both for the patient and for the physician because of its difficult treatment (Laser, etc.. ) . The prevention of both the above side effects is obtained especially by practising a correct sclerotherapical technique, with the right selection of the type of sclerosing agent and in the right doses. However, notwithstanding the above described precautions, also the more expert sclerotherapist experiences said complications. Therefore, the availability of a sclerosing agent capable of removing or reducing to a minimum the occurrence of the above side effects is of the utmost importance for the therapist. Salicylic acid, when dissolved as sodium salt, is known to have a sclerosing action of mean potency and combinations proposed by several Authors (Tournay, Fegan and others) with other substances such as chromic glycerin or sodium tetradecylsulfate, in the attempt to enhance its sclerosing activity by means of a synergism, failed to show some efficacy in clinical practice, having presented effects no better than those of the single compound,- therefore they have been abandoned. Therefore, due to its "mean" activity, salicylic acid is used (since 1923 by Sicard) exclusively in the therapy of small varixes and teleangectasies (red or blue capillaries) in solutions having a concentration between 12 and 30% w/v; said solutions have pH between 6.0 and 6.5. Italian Patent n. 1.257.345 discloses a sclerosing solution consisting of salicylic glycerin, which does not give iatrogenic effects. It is therefore still felt the need of a medicament having sclerosing activity, whose active ingredient consists of only salicylic acid, suitably salified. Said medicament should have enhanced sclerosing activity, but the activity must be highly constant in the different clinical conditions and at the same time the risks of local or regional aesthetical complications are eliminated or minimized. In particular, recent studies (U.Carcassi: Trattato di Reumatologia. Ediz. SEU, Roma; Vol.I 0 pag.673-674, 1993), demonstrated the following properties of sodium εalicylate : antiinflammatory activity is largely independent from the block of prostaglandin cyclooxygenase (sodium salicylate is a weak in-vitro inhibitor of said cyclooxygenase) with no platelet antiaggregating activity; sodium salicylate is a potent PAF inhibitor (Platelet Activator Factor produced by endothelial cells when damaged) which notoriously is one of the more active mediators of phlogosis and is one of the several neoangiogenetic inducers; sodium salicylate inhibits leucocyte migration and activation in the focus acting as scavenger of the free radicals (superoxide anion) produced by the macrophages and by the polymorphonucleate granulocytes . Therefore, a preparation of sodium salicylate with enhanced sclerosing activity with a higher constancy of effects is expected to produce also the disappearance or reduction of the teleangectic matting negative side effect . Summary of the invention It has now surprisingly been found that solutions of a water-soluble, pharmaceutically acceptable salt of salicylic acid having pH comprised between 7.0 (±1) and 9.0 (±1), preferably between 8.2 and 8.4 resolve the above mentioned problems. Therefore it is an object of the present invention the use as active ingredient of a solution of a water- soluble, pharmaceutically acceptable salt of salicylic acid having pH comprised between 7.0 (±1) and 9.0 (±1), preferably between 8.2 and 8.4, for the preparation of a medicament having sclerosing activity useful for the treatment of varixes. This and other objects of the present invention will be described below in detail also by means of examples . Detailed disclosure of the invention The solution according to the present invention, when used in a medicament having sclerosing activity reveals particularly advantageous properties, such as a minor risk of post-sclerosis pigmentations, due to enhanced characteristics of chelating agent of the iron ion by the active ingredient, a higher antiphlogistic, antipyretic and analgesic action. Water-soluble pharmaceutically acceptable salts of salicylic acid are well-known to the expert in this art. and can be easily determined. Examples of salts of salicylic acid according to the present invention are the salts with sodium, potassium, magnesium, calcium, lysine, proline, ethanloamine , diethanolamine. According to a first preferred embodiment of the present invention, sodium, potassium, magnesium and calcium salts of salicylic acid are provided. Sodium and potassium salts are particularly preferred. Water solubility of salicylic acid is very low but strongly increases when it is salified with sodium or potassium ion: this behaviour can be explained by the ionized structure of salicylic acid which is stabilized by its so called "ortho effect". In fact, when the salt is the sodium one, solubility goes from 1 g into 460 ml of water (about 0.02%, equal to 1.57*10 ~2 Moles/1) to the far higher value of 100 g into 90 ml of water. The 8% solution of sodium salt (applicable to normal therapies) corresponds to a concentration of about 0.5 Molar and it has been taken as useful reference for the following disclosure. Another basic characteristic of salicylic acid is to be a mean organic acid, in fact its pK a is 2.97; then it is an acid (of first dissociation) weaker than phosphoric acid (p a = 2.16), than glycine (pK a = 2.35); comparable to monochloroacetic acid ( K a = 2.85), bromobenzoic acid (p a = 2.84) and ortho-phthalic acid (pK a = 2.89). Although the inventors does not wish to be bound to any theory, however the advantageous effects of the present invention can possibly be explained by the following considerations. Assuming that the activity is essentially due to the dissociated form which is present in the solutions of sodium or potassium salicylate, the inventors have found a correlation of the higher sclerosing activity with those pH values which are an indication of the maximum presence of the dissociated form and where the hydrophilic and lipophilic characteristics of the molecule and its chelating activity against the iron ion are exalted. A stoichiometric study was effected to this purpose by applying the simplified relationship for the determination of pH of weak acids: pH = 0.5 * [ pK a - Log C fl ] and the simplified one for the determination of pH related to the hydrolysis of salts: pH = 0.5 A [pK w + pK a + Log C ε ] Taking into account of the known meanings, the following results are obtained: Saturated solution of salicylic acid (about 0.02%) equal to 1.57 * 10 -2 Moles/1 pH = 2.4 Solution of sodium salicylate at the same concentration of 1.57 * 10 ~2 Moles/1 pH = 7.6 8% Solution of sodium salicylate equal to about 0.5 Moles/1 pH = 8.3 These scientific and technical evaluations lead to the consideration that, in order to have the maximum efficacy, the solutions must be kept at pH values not lower than 7.0 (±1), the particularly preferred pH values equal to 8.3 +/- 1. The study has then brought to the preferred formulation of solutions containing a water-soluble, pharmaceutically acceptable salt of salicylic acid, in particular sodium or potassium salt, at a pH 8.2 - 8.4, in concentrations that can range from few percent units up to high values (60% w/v). The solutions according to the present invention can be used at different concentrations, up to a maximum of 60%. Among these, the concentrations of 8%, 15% and 30% w/v are preferred. If desired, the solution according to the present invention can be used in the medicament also in combination with other active principles, in particular local anaesthetics, preferably lidocaine hydrochloride . In its another aspect, the present invention relates to a pharmaceutical composition containing a solution of a water-soluble, pharmaceutically acceptable salt of salicylic acid, preferably selected from sodium salicylate and potassium salicylate, having pH ranging between 7.0 (±1) and 9.0 (±1), preferably between 8.2 and 8.4 as active ingredient. In a further preferred aspect, the pharmaceutical compositions can contain εolubilization adjuvants, preferably polyvinylpyrrolidone (PVP or povidone). The medicament according to the present invention and the related compositions are characterized by physico-chemical parameters which give a higher sclerosing activity with respect to the sclerosing substances of mean entity today used and, at the same time, advantageously annul or anyway enormously minimize some of the negative side effects which are very often, if not always, present in the sclerosing therapy of the varixes . As a further advantage, the components of the compositions of the present invention are very stable for long periods of time thus avoiding the addition of suitable stabilizing agents or preservatives, which, as well-known, are poorly tolerated or can cause allergies. In a preferred embodiment of the present invention, the solution is further added with lidocaine hydrochloride, for example 0.25% w/v, which gives the known anaesthetic effect. The present invention also comprises a process for the preparation of the compositions above described. The procesε shall be described referred to the preferred embodiment of sodium salt, but the skilled person will be able to carry out the whole invention by simply recurring to the common technical knowledge. Conventionally, the solution is prepared in sterile nitrogen atmosphere, since the complete removal of oxygen allows to safeguard the stability of the salicylic acid in non-oxidative environment (oxygen concentration shall be lower than 0.5 p. p.m., determined by means of specific Oxidigit system). Vial filling takes place in vials, preferably of actinic yellow glass, to annul the sensitivity of the preparations against the effects of light. The solutions further present physico-chemical characteristics which make them compatible with those of blood; as an example the following values are given: Elood: pH = 7.27 - 7.43 specific weight = 1.050 - 1.060 osmolarity = 275 - 295 Milliosmoles Solutions : cone. = 8% cone. =15% cone.=30% pH = 8.3 8.2 8.2 sp. weight = 1.032 1.057 1.071 osmolarity = 1010 1725 3512 For the preparation of the solutions according to the present invention, starting material suitable for pharmaceutical purpose shall be used, for example sodium or potassium salicylate or any other salt suitable to the purpose of the present invention complying with the requirements of the European Pharmacopoeia. The pH of the preparation is set to the desired value, for example, preferably 8.3 (+/-1) which corresponds to the presence of the maximum concentration of the undissociated form. During the preparation and whenever necessary, said value is reached by adjusting pH with the base of the cation of selected salt. In the particular preferred embodiment of sodium εalicylate, a sodium hydroxide solution is used. In alternative, the desired pH is stabilized using phosphate or citrate buffer. If desired, lidocaine hydrochloride F.U. is added at 0.25% concentration, in order to achieve the well- known anaesthetic power. Sterile and apyrogen, freshly distilled water for injectable preparations is used, oxygen having been previously eliminated by means of extrapure nitrogen bubbling, which was filtered on a suitable membrane (0.22 micron), till a residue value of oxygen lower than 0.5 p. .m. is reached. During the preparation phases of the solution and at the end, before the sterilizing filtration, the residue value of oxygen is checked and registered in order to verify that it remains below the set limit, optionally taking it again to the set limit by means of subsequent nitrogen bubbling. The so prepared solution, filtered to sterility on a 0.22 micron filter (and 0.45 micron prefilter), is used for filling 2.0 ml class I actinic glass vials, working in a dedicated sterile area, complying with International Good Manufacturing Practice for the preparation of autoclave-sterilized, injectable solutions . In alternative, filling can be done in dedicated sterile area complying with the conditions provided for the preparation of injectable solutions which can be sterilely filtered but can not be subjected to final sterilization (autoclaving) , so called "Production in Asepsis Conditions". The above described conditions allow to produce stable preparations, which maintain their efficacy for long periods (up to three years), without the addition of further stabilizing substances. Therefore the advantages and improvements which characterize the preparations according to the present invention are the following: 1 - higher rapidity in the fibrosclerotic process with disappearance of the treated vessels in shorter times, thus reducing the number of necessary sclerotherapy operations, with consequent reductions of costs for the patient. Said enhancement of the activity is fundamentally due to the formulation of the present invention and to its pH which intensifies the presence of the ionized form of the chemical species; 2 - higher constancy of the sclerosing activity in the different clinical conditions; 3 - the higher efficacy of the composition is also due to the physico-chemical parameters: density: the values analogues to the plasma value enhance the diffusion in the part of the varix to be subjected to therapy; osmolarity: the experimental values give the composition an activity comparable to hypertonic co poεitionε; 4 - optimal tolerability with absence of allergic phenomena because the formulation is devoid of preservatives (the only risk is that of patients allergic to salicylic acid and its derivatives); 5 - reduction of phlogosis phenomena with absence of periphlebitic reactions due to the improved antiinflammatory activity with respect to similar preparations; 6 - reduction of the Teleangectasic Matting due to the activity inhibiting its neoangiogenesis; 7 - reduction, in many cases till disappearance, of the haemosiderinic pigmentation due to the chelating activity of iron and subsequent inhibition of the formation of tissutal hae osiderin; The following examples further illustrate the invention. Example 1 Formulations for the preparation of the solutions at various concentrations. Formulation for the preparation of 100 litres of solution of salicylic acid, sodium salt, respectively at 8%, 15% and 30% w/v, without buffer system: Starting material Sodium Salicylate Lidocaine ( E . Ph. ) Hydrochloride Amount in grams to obtain: 8% Solution 8000 250 15% Solution 15000 250 30% Solution 30000 250 Distilled water for injectable preparations (Eu.Ph.) q.ε. to 100.0 litres - Hydrochloric Acid and/or Sodium Hydroxide 1 N (when necessary): to obtain pH = 8.3 Manufacturin g adjuvant: Ultrapure Nitrogen filtered to sterility. Nitrogen is used to reduce the presence of oxygen dissolved in the solution down to a residue value lower than 0.5 ppm. Example 2 Formula for the preparation of 100 litres of 8% solution of salicylic acid, sodium salt in the presence of sodium phosphate buffer system: Starting materials Amounts in grams for 8% Solution Sodium Salicylate (Eu.Ph.) 8000 Lidocaine Hydrochloride 250 - Sodium Phosphate, bibasic (Na 2 HP0 4 * 7H 2 0 - Eu.Ph) 6702.0 Sodium Phoεphate monobasic (Na 2 HP0 4 * K 2 0 - Eu.Ph) 690.0 Distilled water for injectable preparations (Eu.Ph.) q.s. to 100.0 litres Hydrochloric Acid and/or Sodium Hydroxide 1 N (when necessary) to obtain pH = 8.3 Manufacturing adjuvant: Ultrapure Nitrogen filtered to sterility. Nitrogen is used to reduce the presence of the oxygen dissolved in the solution down to a residue value lower than 0.5 ppm. Example 3 Industrial production process. 3.1- Preparation of the vials. Both closed tip vials and open tip vials can be used, for which it is necessary to use a filling equipment of the "compact" type, fitted with waεhing- sterilization-depyrogenization modules connected in line with the vial filling module. As example of production process, the operations referred to this last case are reported. The empty vials, having open tip, are washed with depurated, sterile, filtered water according to the program of the vial washing module. Sterilization and depyrogenation of the washed vials takes place at about 280 °C and for the duration of about 1 hour. The operation conditions are continuously registered and documented by the system. 3.2- Preparation of the solution and filling of the vials. The preparation must be performed in protected environment (or of class 100.000). About 80-90 litres of distilled water for injectable preparations are introduced in a 150 liter stainless steel mixer-dissolver , fitted with an electromagnetic stirrer (water must be prepared immediately before use or sampled from a suitable recycle plant capable of guarantee the compliance with the specifications of European Pharmacopoeia). Water temperature is set to 25°C (+/- 2°C). Sterile filtered nitrogen is bubbled, under stirring, till an oxygen level lower than 0.5 mg/1 is obtained. Subsequently, lidocaine hydrochloride is added under εtirring and, after itε diεεolution, the amount of sodium salicylate Eu.Ph. according to the formulation is added, always keeping the liquid under nitrogen flux; pH is measured and, if necessary, adjusted to pH 8.3 (limits 8.2-8.4) with hydrochloric acid and/or sodium hydroxide 1 N solution . The solution is brought to a volume of 100 1 with distilled water kept under nitrogen flux. Stirring is continued for at least 10 minutes. Oxygen content is determined and, if necesεary, corrected to the value lower than 0.5 mg/1 by means of sterile filtered nitrogen bubbling. The solution is then filtered, forcing it by means of sterile nitrogen pressure through sterilizing filters set in series (0.45 μ and 0.22 μ) in a closed system, which was previously sterilized with flowing steam, and the solution is then collected in stainless steel sterile storage tank, previously kept under flux of sterile filtered nitrogen. At the end of the collection, and for the whole period necessary to complete the filling of the vials, the solution is kept in the storage tank under low pressure flux of sterile filtered nitrogen. The nitrogen bubbling in the solution makes it to be transferred to the feeding lung placed on the vial filling module. The filter-storage tank-vial filling apparatus system is normally placed in a sterile area; the vial filling apparatus is further placed under laminar flux hood: all the environment complies with the hygienical, icrobial and particle contamination conditions according to the Good Manufacturing Practice for the preparation of sterile injectable solutions. The sterile empty vials, coming from the sterilization tunnel are distributed in sterile area on the filling machine which blows them with sterile filtered nitrogen and fills them with 2.0 ml of solution. The remaining empty part is further blown with sterile filtered nitrogen and closed with flame. 3.3- Final sterilization and controls according to Pharmacopoeia . The filled vials are put in autoclave and εubjected to high vacuum for the control of microfractures or other damages, if any, then sterilization is carried out according to a determined program at 121°C for 30 min, and subsequently cooled and washed. The dried vials are tested to control the absence of particles or other suspended materials in the solution by meanε of a suitable automatic machine. The εubsequent phases of packaging and final distribution are performed. Sterility tests, according to European Pharmacopoeia, are carried out on a suitable statistical sampling, representative of the lot size, are carried out and all the other tests of physico-chemical character suitable to guarantee the compliance of the lot quality to specific requirements are also performed. The packages of the finished vials are stored in a suitable storehouse until the clearance by Quality Control .

Claims: CLAIMS 1. Use of a solution of a water-soluble, pharmaceutically acceptable salt of salicylic acid having pH ranging between 7.0 (+/-1) and 9.0 (+/-1) as active ingredient for the preparation of a medicament having sclerosing activity useful for the treatment of varixes. 2. Use according to claim 1, wherein the pH of said solution is comprised between 8.2 and 8.4. 3. Use according to claim 1 or 2 , wherein said salt is selected from the group consisting of sodium, potassium, magnesium, calcium, lysine, proline, ethanolamine and diethanolamine salicylate. 4. Use according to claim 3, wherein said salt is selected from the group consisting of sodium and potassium salt. 5. Pharmaceutical composition containing a solution of a water-soluble, pharmaceutically acceptable salt of salicylic acid having pH ranging between 7.0 (+/-1) and 9.0 (+/-1) as active ingredient. 6. Composition- according to claim 5, wherein the pH is comprised between 8.2 and 8.4. 7. Composition according to claim 5 or 6, wherein said salt is selected from the group consisting of sodium, potassium, magnesium, calcium, lysine, proline, ethanolamine and diethanolamine salicylate. 8. Composition according to anyone of claims 5-7, wherein the concentration of sodium salicylate is up to 60% w/v. 9. Composition according to claim 8, wherein the concentration of sodium salicylate is up to 30% w/v. 10. Composition according to claim 9, wherein the concentration of sodium salicylate is up to 15% w/v. 11. Composition according to claim 10, wherein the concentration of sodium salicylate is up to 8% w/v. 12. Composition according to anyone of claims 5-11, further containing lidocaine hydrochloride. 13. Composition according to claim 12, containing 0.25% w/v lidocaine hydrochloride. 14. Composition according to anyone of claimε 5-13, which is contained in actinic glass vials. 15. Process for the preparation of a composition of claims 5-14, comprising the preparation of a solution of a water-soluble, pharmaceutically acceptable salt of salicylic acid having pH ranging between 7.0 (+/-1) and 9.0 ( +/-1), characterized in that pH is adjusted with the base of the cation of said salt. 16. Process according to claim 15, wherein pH is adjusted with sodium or potassium hydroxide. 17. Process for the preparation of a composition of claims 5-14, comprising the preparation of a solution of a salt of salicylic acid selected from sodium salicylate and potassium salicylate having pH ranging between 7.0 (+/-1) and 9.0 (+/-1), characterized in that pH is adjusted with phosphate or citrate buffer.

Inventors: IZZO MARCELLO, VERZELLA GIANFRANCO, IZZO, MARCELLO, VERZELLA, GIANFRANCO
Applicants: I V PHARMA S A S, IZZO MARCELLO, VERZELLA GIANFRANCO, I.V. PHARMA S.A.S., IZZO, MARCELLO, VERZELLA, GIANFRANCO
Application year: 1998
Main classification: A61K9
IPC codes: A61K9, A61K31, A61K47