Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/60—Salicylic acid; Derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• 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.
• Sclerosis namely the clinical disappearance of a varix
• Sclerosis 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.
• 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.
• the whole histological process of fibro ⁇ clero ⁇ is 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.
• GAGs Glucosaminoglycanes
• 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 tetradecyl ⁇ ulfate 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.
• 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.
• all the sclerosing solutions can determine, in different extent, a series of side effects deriving from the intrinsic chemico-physical properties.
• 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.
• 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.
• 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.
• 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.
• Platinum 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 .
• 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.
• salts of salicylic acid are the salts with sodium, potassium, magnesium, calcium, lysine, proline, ethanloamine , diethanolamine.
• 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".
• 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 corresponds to a concentration of about 0.5 Molar and it has been taken as useful reference for the following disclosure.
• 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
• 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 .
• 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.
• the pharmaceutical compositions can contain ⁇ olubilization 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 .
• 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.
• 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 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:
• 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.
• said value is reached by adjusting pH with the base of the cation of selected salt.
• a sodium hydroxide solution is used.
• the desired pH is stabilized using phosphate or citrate buffer.
• 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.
• 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 .
• 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
• Nitrogen is used to reduce the presence of oxygen dissolved in the solution down to a residue value lower than 0.5 ppm.
• Nitrogen is used to reduce the presence of the oxygen dissolved in the solution down to a residue value lower than 0.5 ppm.
• 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.
• the preparation must be performed in protected environment (or of class 100.000).
• 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.
• lidocaine hydrochloride is added under ⁇ tirring and, after it ⁇ di ⁇ olution, 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
• Oxygen content is determined and, if neces ⁇ ary, 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 ⁇ and 0.22 ⁇ ) 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.
• 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, bacterial 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.
• the filled vials are put in autoclave and ⁇ ubjected 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 mean ⁇ of a suitable automatic machine.
• 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

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• Dermatology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 1997
  • 1997-03-25 IT ITMI970700 patent/IT1290439B1/it active IP Right Grant
• 1998
  • 1998-03-23 EP EP98920482A patent/EP0971697A2/de not_active Withdrawn
  • 1998-03-23 WO PCT/EP1998/001699 patent/WO1998042312A2/en not_active Application Discontinuation

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