ITMI970700A1 - DRESSING WITH SCLEROSANT ACTIVITY - Google Patents

Description

The present invention relates to a medicament with sclerosing activity, in particular a medicament whose active principle consists of a salicylic acid salt selected from the sodium salt and the potassium salt.

Background of the invention

Sclerosis, i.e. the clinical disappearance of a varice, can be obtained by injecting it into it, with suitable techniques and equipment (needle, syringe), of an appropriate chemical solution capable of causing an endothelial lesion with reactive formation of an adherent thrombus and its subsequent fibrotic organization with the final result of the occlusion and disappearance of the varice.

On average, the entire histological process of fibrosclerosis of one

varice undergoing sclerosing therapy is about 2-3 months though

visually the disappearance of the varice occurs in a shorter time.

The endothelial damage of the treated varice occurs substantially through an alteration of the surface electronegative charge

determined by action-dependent GAGs (Glucosaminoglycans)

surfactant of the sclerosing agent, yet from the pH or osmolarity values of the solution.

The numerous studies reported by the specialized international literature show that sclerosing substances can be classified, based on their type of action, in three groups:

1- Detergent solutions: which act by causing endothelial damage with triggering of the fibrosclerotic process by lowering the surface tension of the plasma membranes (for example solutions of polidodecanol, sodium tetradecyl sulfate or ethanolamine oleate).

2- Osmotic solutions: which act by causing a "drying effect" on endothelial cells with their damage and destruction thanks to their high osmolarity (for example hypertonic solutions of sodium chloride or glucose).

3- Chemical solutions: which cause endothelial damage thanks to their "irritating" activity, dependent on an oxidative or caustic "chemical aggression" mechanism (for example polyiodate solutions or chromated glycerin solutions).

According to the French school of Sclerotherapy (R.Toumay), sclerosing solutions are also classified, on the basis of their "sclerosing power" in relation to the size of the varicosities to be treated, in:

a) - Major sclerosing agents: polyiodate solutions, sodium tedradecyl sulfate;

b) - Medium sclerosing agents: polydodecane, salicylic acid, sodium morruate;

c) - Minor sclerosing agents: chromic glycerin, hypertonic solutions. Definition of the technical problem

Regardless of their correct use and therefore of a correct sclerotherapy technique, all sclerosing solutions with varying incidence can cause a series of side effects linked to the intrinsic physicochemical properties. Thus, for example, in relation to the sclerosing power and therefore to the degree of potter aggression, inflammatory processes of painful peri-lebitis can occur with generally irreversible pigmentations or, in the case of tissue extravasation, the formation of necrotic-cicatricial results.

For some of them (sodium morruate, ethanolamine oleate, sodium tetradecyl sulfate), particular allergies are observed, sometimes with the character of anaphylactic shock.

However, by far, the most frequent complications during sclerotherapy are represented by 2 occurrences:

I - The hemosiderinic (ferric) pigmentations - This complication is constituted by the appearance, in the treated site, of dark skin pigmentations which represent a serious aesthetic damage for the patient for which some of them have reasons for refusal towards sclerotherapy. This complication is more frequent for small vessels such as telangiectasias which are known to represent 80% of sclerotherapy applications. According to some authors (M.P. Goldman, USA), the incidence of such post-sclerosis hyperpigmentation is estimated at around 10-30% of patients undergoing sclerosing therapy regardless of the type of preparation used.

II - Teleangectatic matting, ie the appearance, in the treated site, of neo-capillaries due to mechanisms that are still partly obscure but attributable to a reactive neoangiogenesis to sclerotherapy. This secondary microvaricosis, which according to Goldman affects 10-15% of patients undergoing sclerotherapy, represents an additional "aesthetic danger" of unwanted sclerotherapy for both the patient and the doctor due to its difficult treatment (Laser, etc.) .

The prevention of both side effects mentioned is obtained above all with the implementation of a correct sclerotherapy technique, with the right choice of the type of sclerosant and in the right doses. However, despite the measures described, these complications are possible even in the hands of the most experienced sclerotherapist.

It is therefore extremely important for the therapist to have a preparation that has the ability to eliminate or minimize the incidence of these side effects.

Salicylic acid, in solution as sodium salt, is known to have a sclerosing action of medium power and the associations proposed by various authors (Toumay, Fegan and others) with other substances such as chromated glycerin or sodium tetradecyl sulfate, in an attempt to enhancing its sclerosing activity through a synergism, have proved fallacious in clinical practice as they have not shown better effects than those of the single compounds and therefore have fallen into disuse.

Therefore, due to its "average" activity, it is used (since 1923 with Sicard) exclusively in the therapy of small varicosities and telangiectasias (red or blue capillaries) in solutions having a concentration between 12 - 30%: such solutions have pH between 6.0 and 6.5.

The Italian patent n. 1,257,345 describes a salicylic glycerin-based sclerosing solution which does not give iatrogenic effects.

The need is therefore still felt. have a medicament with sclerosing activity whose active principle consists solely of salicylic acid, suitably salified, in which its sclerosing activity is enhanced with a greater constancy of effects in the various clinical conditions and while the risks of locoregional complications are canceled or minimized of the aesthetic type described above.

In particular, recent studies (U.Carcassi: Treatise on Rheumatology. Ediz. SEU, Rome; Vol. I <e> pag.673-674, 1993), have documented the following properties for sodium salicylate:

the anti-inflammatory activity is largely independent of the prostaglandin cyclooxygenase block (sodium salicylate is a weak in vitro inhibitor of this cyclooxygenase) with the absence of antiplatelet activity;

sodium salicylate is a powerful inhibitor of PAF (Platelet Activator Factor produced by endothelial cells when injured) which is notoriously one of the most active mediators of inflammation and is one of the various neoangiogenic inducers;

- sodium salicylate inhibits migration and 1 <1> leukocyte activation in the focus by acting as a "Scavenger" for free radicals (superoxide anion) produced by macrophages and polymorphonuclear granulocytes.

Therefore, its preparation in which the sclerosing activity was enhanced with a greater constancy of effects would also produce a disappearance or reduction of the negative side effect of telangiectic matting.

Summary of the invention

It has now been surprisingly found that solutions of a salicylic acid salt selected from sodium salicylate and potassium salicylate having a pH between 7.0 (+1) and 9.0 (± 1), preferably between 8.2 and 8.4 solve the above problems.

Therefore an object of the present invention is the use as active principle of a solution of a salicylic acid salt selected from sodium salicylate and potassium salicylate having a pH between 7.0 (± 1) and 9.0 (+1), preferably between 8.2 and 8.4 for the preparation of a medicament with sclerosing activity useful for the treatment of varicose veins.

This and other objects of the present invention will be described below in detail also by means of examples.

Detailed description of the invention

The solution according to the present invention, when used in a medicament with sclerosing activity, has revealed particularly advantageous properties, such as a lower risk of post-sclerosis pigmentations, due to the enhanced characteristics of the chelating agent of the iron ion by the active ingredient, a greater action anti-inflammatory, antipyretic and analgesic.

The solubility of salicylic acid in water is very low but increases considerably when it is salified with the sodium or potassium ion: this behavior finds its justification in the ionized structure of salicylic acid which is stabilized for its so-called "ortho effect".

The solubility, when in the form of sodium salt, in fact passes from the value of 1 g in 460 ml of water (about 0.02%, equal to 1.57 * 10 <-2> Moli / l) to a much higher value of 100 g in 90 ml of water. The 8% sodium salt solution (applicable to normal therapies) corresponds to a concentration of approximately 0.5 Molar and has been taken as a useful reference for the following treatment.

Another fundamental characteristic of salicylic acid is that of being an organic acid of medium strength in fact it has a value of pKa = 2.97; it is therefore an acid (of first dissociation) weaker than phosphoric acid (pKa = 2.16), than glyein (pKa = 2.35); comparable to monochloroacetic acid (pKa = 2.85), bromobenzoic acid (pKa = 2.84) and o-phthalic acid (pKa = 2.89).

On the basis of these considerations and assuming that the activity is essentially due to the dissociated form that is present in the sodium or potassium salicylate solutions, we wanted to correlate its greater sclerosing activity to those pH values that are indicative of the maximum presence of the form dissociated and to which the hydro- and lipoaffin characteristics of the molecule and its chelating activity towards the iron ion are also enhanced.

The stoichiometric study was conducted for this purpose by applying the simplified relationship for the determination of the pH of weak acids:

and the simplified one for the determination of the pH relative to the hydrolysis of salts:

Therefore, taking into account the known meanings, the following results are obtained:

Saturated solution of salicylic acid (about 0.02%)

equal to 1.57 * IO <-2> Moli / l pH = 2.4 Sodium salicylate solution at the same concentration of 1.57 * IO "<2> Moli / l pH = 7.6 8% solution of sodium salicylate equal to approximately

0,5 Moli / l pH = 8,3 These technical-scientific evaluations have led to the consideration that in order to have maximum efficacy the solutions must be kept at pH values not lower than 7.0 (± 1), with particular preference for pH values equal to 8.3 / - 1.

The study therefore led to the formulation of solutions containing salicylic acid salified as sodium or potassium salt at pH 8.2 - 8.4, in concentrations that can vary from a few percentage units up to high values (60% w / v).

Solutions according to the present invention can be used at different concentrations, up to a maximum of 60%. Among these, the concentrations 8%, 15% and 30% w / v are preferred.

If desired, the solution according to the present invention can also be used in the medicament in association with other active ingredients, in particular local anesthetics, preferably lidocaine hydrochloride.

In another aspect, the present invention relates to a pharmaceutical composition containing a solution of a salicylic acid salt selected from sodium salicylate and potassium salicylate having a pH between 7.0 (± 1) and 9.0 (± 1) , preferably between 8.2 and 8.4 as the active principle.

The medicament according to the present invention and the relative compositions are characterized by chemical-physical parameters capable of conferring a greater sclerosing activity than the medium-sized sclerosing substances in use today and at the same time having the advantage of canceling or in any case greatly minimizing some of the negative side effects that are present absolutely and more frequently in the sclerosing therapy of varicose veins.

Advantageously, the compositions of the present invention entail the stability of the components for long periods of time without the necessary addition of suitable stabilizers or preservatives which are known to cause intolerances or allergies.

In a preferred embodiment of the present invention, the solution is further added with lidocaine hydrochloride, for example at 0.25%, which has the known anesthetic effect.

The present invention also comprises a process for the preparation of the compositions described above.

Conventionally, the solution is prepared in a sterile filtered nitrogen atmosphere to obtain the complete removal of oxygen to ensure the stability of the salicylic acid in a non-oxidative environment (oxygen below the value of 0.5 p.p.m., determined by a specific Oxidigit system).

The filling also takes place in vials, preferably of yellow anactinic glass, to cancel the sensitivity of the preparation to the effects of light.

The solutions also have chemical-physical characteristics that make them compatible with those of blood;

by way of example, the following values are given:

the

For the preparation of the solutions according to the present invention, starting material suitable for pharmaceutical use is used, for example sodium or potassium salicylate conforming to the requirements of the European Pharmacopoeia.

The pH of the preparation is fixed at the established value, as a preferred example is 8.3 (+/- 1) which corresponds to the presence of the maximum concentration of the dissociated form.

This value is reached by correcting, during preparation and if necessary, with sodium hydroxide solution.

Alternatively, the indicated pH is stabilized using

phosphate or citrate buffer.

If desired, lidocaine chlorhydrate F.U. is added. at the

concentration of 0.25% for its well-known anesthetic power.

For the preparation, water for preparations is used

recently distilled injectable, sterile and non-pyrogenic, which comes

previously deprived of the presence of oxygen by means of a. bubbling of extra-pure quality nitrogen in turn filtered on

suitable membrane (0.22 micron) up to a residual oxygen value

less than 0.5 p.p.m ..

During the steps of preparation of the solution and at the end, before

of the sterilizing filtration, it is verified and recorded that the

residual oxygen value has remained below the indicated limit,

eventually returning it to it by subsequent bubbling of

nitrogen.

The solution thus prepared, sterile filtered on a 0.22 filter

micron (and 0.45 micron prefilter), is used for filling in

Class I Anactinic glass vials, 2.0 ml by operating in a special

sterile area in compliance with Good Manufacturing Practices

International for the Preparation of Injectable Solutions

Sterilizable for Autoclaving.

Alternatively, the filling can take place in a specific area

sterile that complies with the conditions required for the preparation of

injectable solutions that can be sterile filtered but cannot be subjected to

final sterilization (autoclaving), otherwise called "Production in Aseptic Conditions".

The aforementioned conditions allow to produce a stable preparation which maintains its effectiveness for long periods (up to three years), without the addition of further stabilizing substances.

The advantages and improvements that distinguish these preparations are therefore:

1 - greater speed in the fibrosclerotic process with disappearance of the treated vessels in a shorter time and therefore the need for a smaller number of sclerotherapy sessions with consequent cost reductions for the patient. This magnification of activity is fundamentally attributable to the formulation of the preparation and its pH which enhances the presence of the ionized form of the chemical species;

2 - greater constancy in sclerosing activity in different conditions.

clinics;

3 - the greater effectiveness of the preparation is also due to the chemical-physical parameters of:

density: the values analogous to the piasmatic value enhance its diffusion in the varices tract to be subjected to therapy; osmolarity: the experimentally determined values give the preparation an activity comparable to hypertonic preparations.

4 - excellent tolerability with absence of allergic manifestations since the formulation is free of preservatives (the only risk is that of patients allergic to salicylic acid and its derivatives -Aspirin); 5 - reduction of phlogosis phenomena with the absence of peripheral reactions due to the improved anti-inflammatory activity compared to similar preparations;

6 - reduction of Telangiectatic Matting due to the inhibiting activity of its neangiogenesis;

7 - reduction, up to the disappearance in many cases, of the hemosiderin pigmentation due to the chelating activity of iron and therefore inhibiting the formation of tissue hemosiderin;

The following examples further illustrate the invention.

Example 1

Formulas for the preparation of Solutions at various concentrations.

Formula for the preparation of 100 liters of salicylic acid solution, sodium salt at 8%, 15% and 30% respectively, in the absence of a buffer system:

Raw materials Rhodium Salicylate (Eu.Ph.) Lidocaine Hydrochloride Quantity in grams

to obtain:

8% solution 8000 250 15% solution 15000 250 30% solution 30000 250 Distilled water for injections (Eu.Ph.) q.s. to 100.0 liters

Hydrochloric Acid and / or Sodium Hydroxide 1 N (when necessary): to obtain pH = 8.3

Manufacturing aid: Sterile filtered ultrapure nitrogen.

Nitrogen is used to reduce the presence of dissolved oxygen in the solution down to a residual value of less than 0.5 ppm.

Example_2

Formula for the preparation of 100 liters of Solution, of Salicylic Acid, Sodium salt at 8% in the presence of Sodium Phosphate Buffer System;

Raw material

Amount in grams per 8% solution

Sodium Salicylate (Eu.Ph.) 8000

Lidocaine Hydrochloride 250

Dibasic Sodium Phosphate

(Na2HP04 * 7H29 - Eu.Ph) 6702.0

Monobasic Sodium Phosphate

(Ka ^ P04 * H2O - Eu.Ph) 690.0

Distilled water for preparations

injectable (Eu.Ph.) q.s. to 100.0 liters Hydrochloric Acid and / or Sodium Hydroxide 1 N (when necessary): 'to obtain pH = 8.3

Manufacturing aid

Sterile filtered ultrapure nitrogen.

Nitrogen is used to reduce the presence of dissolved oxygen in the solution until an s value of 0.5 ppm is obtained.

Example 3

Industrial Production Process.

3.1- Preparation of the vials.

Alternatively, both closed-tip and open-tip vials can be used, for which it is necessary to use a "coopact" type filling system, equipped with washing-sterilization-depyrogenization modules connected in line with the filling module.

The operations referring to the latter case are reported as an example of a production procedure.

The empty, open-tip vials are washed with purified water and sterile filtered according to the wash module program.

The sterilization and depyrogenization of the washed vials takes place at about 280 ° C and for a duration of about an hour. The operating conditions are continuously recorded and documented by the system.

3.2- Preparation of the solution and filling of the vials.

The preparation must be carried out in a protected environment (or class 100,000).

In a 150 liter stainless steel mixer-dissolver equipped with an electromagnetic stirrer, about 80-90 liters of distilled water for injections are introduced (the water must be prepared immediately before use or sampled from a suitable recycling plant and able to guarantee compliance with the European Pharmacopoeia specifications).

It is checked that the water temperature is at 25 * C. (+/- 2'C.).

The sterile filtered nitrogen is then bubbled, under stirring, until an oxygen content <0.5 mg / 1 is obtained.

Then add Lidocaine Hydrochloride to the tank while stirring and, after its dissolution, the quantity of Sodium Salicylate Eu.Ph. provided by the formula, always keeping the liquid under nitrogen flow; measure the pH and, if necessary, correct with 1 N Hydrochloric Acid and / or Sodium Hydroxide solution up to pH 8.3 (pH limits: 8.2-8.4).

Bring the solution to the volume of 100 1 with distilled water

kept under nitrogen flow.

Keep stirring for at least 10 minutes. Measure the oxygen content and, if necessary, bring it back to ≤ 0.5 mg / 1 using

sterile filtered nitrogen bubbling.

The solution is then filtered by sending it by pressing

sterile nitrogen through sterilizing filters placed in series {0.45 μ e

0.22 μ) in a closed system, which had previously been sterilized

with flowing steam, and is collected in the sterile storage tank of

stainless steel, previously kept under filtered nitrogen flow

sterile.

At the end of the collection and for the entire period necessary a

complete the filling of the vials it is kept in the tank

storage under low pressure flow of filtered nitrogen

sterile.

The transfer of the solution to the feeding lung placed

on the filling module of the filling machine takes place for

hydrostatic thrust of the same nitrogen that bubbles in it.

The filter-storage tank-filling device system is

usually housed in a sterile area; the filling machine is

also placed under a laminar flow hood: the whole environmental system

respects the conditions of hygiene and microbiological contamination e

corpuscular in compliance with the provisions contained in the regulations

Good Manufacturing Internationals for the preparation of solutions

sterile injectables.

The sterile empty vials, coming from the sterilization tunnel, are dispensed in a sterile area on the filling machine which insufflates them with sterile filtered nitrogen and fills them with 2.0 ml of solution. They are then further insufflate, for the remaining free part, with sterile filtered nitrogen and closed to the flame.

3.3- Final sterilization and Pharmacopoeia controls.

The vials produced, placed in an autoclave, are subjected to high vacuum to check for any micro-cracks or other damage, are sterilized according to a precise program at 121 ° C for 30 min., And subsequently cooled and washed.

The dry vials are subjected to tests for the control of the absence of corpuscles or other suspended materials in the solution by means of a special automatic machine.

We move on to the next stage of packaging for their final distribution.

Sterility tests according to the European Pharmacopoeia and all the other chemical-physical tests aimed at guaranteeing the correspondence of the quality of the lot to the specific requests are carried out on a suitable statistical sampling that is significant of the size of the lot.

The packs of vials produced are kept in a special room -, warehouse until the release approval of the Quality Control. _

Claims (13)

CLAIMS 1. Use of a solution of a salicylic acid salt selected from sodium salicylate and potassium salicylate with pH between 7.0 (+/- 1) and 9.0 (+/- 1) as an active ingredient for the preparation of a medicament with sclerosing activity useful for the treatment of varicose veins. 2. Use according to claim 1, in which the pH of said solution is comprised between 8.2 and 8.4. 3. Pharmaceutical composition containing a solution of a salicylic acid salt selected from sodium salicylate and potassium salicylate having a pH between 7.0 (+/- 1) and 9.0 (+/- 1) as active ingredient. 4. A composition according to claim 3, wherein the pH is comprised between 8.2 and 8.4. 5. Composition according to claim 3, in which the sodium salicylate concentration is up to 60% 6. Composition according to claim 3, in which the sodium salicylate concentration is up to 30%. 7. Composition according to claim 3, wherein the sodium salicylate concentration is up to 15%. 8. Composition according to claim 3, in which the sodium salicylate concentration is up to 8%. 9. Composition according to any one of claims 3-7, further containing lidocaine hydrochloride. 10. Composition according to claim 8, containing 0.25% w / v lidocaine hydrochloride. 11. Composition according to any one of claims 3-9, contained in anactinic glass vial. 12. Process for the preparation of a composition of claims 3-11, comprising the preparation of a solution of a salicylic acid salt selected from sodium salicylate and potassium salicylate having a pH between 7.0 (+/- 1) and 9, 0 (+/- 1), characterized in that the pH adjustment is done with sodium or potassium hydroxide. 13. Process for the preparation of a composition of claims 3-11, comprising the preparation of a solution of a salicylic acid salt selected from sodium salicylate and potassium salicylate having a pH between 7.0 (+/- 1) and 9, 0 (+/- 1), characterized in that the pH adjustment is done with a phosphate or citrate buffer.