ITMI20121205A1 - COMPOSITION WITH ANTI-INFLAMMATORY AND ANALGESIC ACTIVITY TO BE GIVEN FOR EXTERNAL USE BY VAPORIZATION - Google Patents

Description

OBJECT OF THE INVENTION

The present invention relates to a silicone-based pharmaceutical or veterinary composition containing, as an active ingredient, diclofenac or an organic-based pharmaceutical salt thereof with anti-inflammatory and analgesic activity to be administered through a spray system for external use.

BACKGROUND OF THE INVENTION

The topical application of formulations based on diclofenac, or [(2,6-dichlorophenyl) amino] benzeneacetic acid, has been known for a long time. This product, initially developed as a sodium salt for oral or injectable solid pharmaceuticals, has also been formulated for topical applications in the form of cream or patches. The characteristics of poor solubility in water do not give formulation problems for the preparation of powders but, for example for the injectable form, it is necessary to solubilize the sodium diclofenac with a mixture of water and propylene glycol (Voltaren injectable <®>) or, more recently, diclofenac sodium is solubilized by a complex with hydroxypropylcyclodextrin (EP1609481). To develop topical applications with sodium or potassium diclofenac different lipophilic mixtures have been used as described in WO2004030665 and in WO9857624 and in EP0834312, or by resorting to liposomal systems as in US2004121987. Also described have been a gel and a foam containing sodium diclofenac obtainable using the dimethyl sulfoxide WO2008049020 and WO2011112875. Still to convey the diclofenac sodium salt in WO2004017998 an aqueous gel with low dosage is described which, despite the low concentration of active principle, is opaque. In WO2009007764 volatile silicone-based gels are described for the administration of sodium diclofenac. Furthermore in WO2010087947 the acid diclofenac is salified with biologically active basic molecules in order to obtain aqueous solutions.

Basically it is evident that a topical formulation with pharmaceutical characteristics cannot be developed with sodium diclofenac without using mixtures with solvents or lipophilic solubilizing agents. Since, in order to obtain a good permeation, the active principle must have a favorable water / oil partition ratio and that, in said partition ratio, the sodium diclofenac is displaced towards the lipophilic fraction, various alternative salts have been studied in the past. sodium such as potassium, ethylamine, diethylamine. and 1- (2-hydroxyethyl) pyrrolidine, also referred to as 2-pyrrolidinoethanol, hydroxyethylpyrrolidine or with its DCIepolamine. Minghetti et al., Â € œEx vivo study of transdermal permeation of four diclofenac salts from different vehiclesâ €, J. Of Pharm. Sci, 96 n.4 pp. 814-914 (2007) describes the characteristics of solubility in water and other solvents of the various salts of diclofenac and confirms that organic salts are more soluble in water while sodium and potassium are more soluble in lipophilic solvents. In particular, the aforementioned work establishes that the epolamine salt is very soluble in water and much less soluble in organic solvents. This characteristic seems to indicate a better skin permeation of the organic salts of diclofenac. This particular characteristic of high aqueous solubility of the epolamine salt was originally described by Fini et.al â € œDiclofenac / N- (2- hydroxyethyl) pyrrolindine: a new salt for an olddrug.â € DrugsExptl.Clin. Res., 1993, XIX: 81-88., In which the solubility in water is given as much as 40% P / V.

Pharmaceutical formulations containing diclofenac salts with organic bases such as diethylamine or epolamine are described for example in EP2055298, in CN101224186 and in WO2010060798. In all cases, water-based gels or solutions are described. Diclofenac sodium and epolamine salt have been described in the preparation of topical patches. For example WO2011049058 and EP0621263 describe complex systems in which the diclofenac salt is homogenized and fixed in the semi-solid gel of the patch. In the case of the document describing the patch with diclofenac epolamine even pure water is used for the dissolution of diclofenac epolamine.

All the formulations described above, both in gel and in patch, which in solution show different types of application problems. Creams containing sodium or potassium salts allow low skin permeations while if you pass gel systems with dimethyl sulfoxide you have to consider the intrinsic toxicity of the dimethyl sulfoxide itself. Ethylene amino salts appear to have better permeation capacity, but the recent request to reduce the nitrosamine content in ethylene amines discourages their use. Finally, the epolamine salt, which is very soluble in water, is suitable for the preparation of aqueous patches or gels; however, the permeation still remains very low due to the poor release capacity of diclofenac by the semi-solid gel.

ANTERIOR ART

Document CN 1150541 concerns a spray containing sodium diclofenac and various excipients. In particular, said document describes two compositions containing 10 g of diclofenac sodium with 231 g of excipients and, respectively, 20 g of diclofenac sodium and 247 g of excipients, both in water at a volume of 1,000 ml. This document therefore confirms the foregoing, namely that to prepare a composition for external use, for example a gel or a spray, based on diclofenac sodium, it is necessary that said composition be on a water basis.

WO 2009/047785 discloses a composition of a non-aqueous topical solution comprising an effective amount of a pharmaceutically acceptable diclofenac salt, e.g. sodium or diethylamine salt, 10% to 30% v / v of a lower favoring alcohol. penetration and solubilizer, a solvent consisting of propylene glycol, glycofurol or their mixtures and optionally a wetting or antioxidant agent and another penetrating agent, and in which said lower alcohol is C2-C5, in particular ethanol in a quantity of about 10-20% v / v. The solvents mentioned in this document, glycofurol and propylene glycol, are at a high boiling point.

SUMMARY OF THE INVENTION

It has now been found that diclofenac, in acid form or in the form of its organic base salt, in particular with a tertiary amine, dissolved in at least one volatile silicone in the presence of an alcoholic cosolvent and a skin permeation adjuvant, can be used as a spray for the transcutaneous treatment of inflammatory forms, with a transcutaneous permeation effect, and consequently a better functional and therapeutic effect, much higher than that obtainable with aqueous-based compositions of sodium diclofenac or with non-aqueous compositions but in solvents having a high boiling point.

In particular, it has been found that diclofenac and its cyclic organic base salts having formula I

X N-CH2-CH2OH <(I)>

where X is a direct bond or a methylene group, it is partially dissolved in a volatile silicone having a viscosity not exceeding 4 cSt.

It has also been found that the addition of a mixture of saturated aliphatic alcohols containing from 2 to 4 carbon atoms favors both the solubilization of the active principle and any refreshing agents, such as menthol or camphor, and the vaporization of the solution. thus allowing the use of said composition in the form of a spray.

Furthermore, the addition of a skin permeation adjuvant agent allows for the absorption, after each spray, of a much higher quantity of active ingredient than that obtained with a spray of sodium diclofenac on aqueous basis or of non-aqueous solutions containing organic bases of diclofenac.

The solution thus obtained keeps diclofenac or its salt stable for a long time and can be used as a spray in topical applications against muscular and arthritic pains.

It was finally found that, in the above mixture, diclofenac and its salts with organic bases, in particular with tertiary organic bases and preferably with 2-pyrrolidinoethanol (â € œhydroxyethylpyrrolidineâ €) and 2-piperidinoethanol (â € œhydroxyethylpiperidineâ €), they penetrate through the skin in very high quantities, much higher than those obtained after treatment with a spray or gel containing sodium diclofenac in an aqueous environment or even with non-aqueous lotions or gels that do not contain volatile silicones.

Diclofenac in acid form and its salts with hydroxyethylpyrrolidine (Formula I, X = direct bond), and with hydroxyethylpiperidine (Formula I, X = methylene) are hereinafter referred to as DIA, DIEP and DIEPP respectively.

The expression â € œvolatile siliconeâ €, as used below, designates a completely methylated polysiloxane having from 2 to 6 silicon atoms and a dynamic viscosity of less than 5 cSt.

The expression `` adjuvant skin permeation '' (in English: cutaneouspenetrationenhancer), as used and illustrated below, and also indicated with the sole term `` adjuvant '', designates one of the well-known products capable of increasing skin permeation of the active ingredient.

DETAILED DESCRIPTION

Thus, the present invention provides a solution comprising (a) diclofenac in the form of a free acid or a salt thereof with a pharmaceutically acceptable organic base;

(b) a solvent consisting of at least one volatile silicone having a dynamic viscosity lower than 5 cSt;

(c) a cosolvent consisting of a mixture of saturated aliphatic alcohols containing from 2 to 4 carbon atoms; And

(d) at least one skin permeation promoting agent.

Said solution can be easily vaporized and therefore suitable as a pharmaceutical composition for external use, for example in the treatment of inflammation and muscle pain or due to arthrosis.

The active principle of the pharmaceutical composition of the present invention is diclofenac, as such (free acid) or in the form of salt of a pharmaceutically acceptable organic base, preferably of a tertiary amine, such as for example the salts of methylamine, triethylamine, pyrrolidine , piperidine, morpholine, 1-ethylpiperidine, 2-aminoethanol. dimethylaminoethanol, diethylaminoethanol (described in US 3558690) or, preferably, of the aforementioned amines of formula I pyrrolidinoethanol (epolamine) and piperidinoethanol, obtainable as described by Ziggiotti et al. in EP-0271709A, which constitute the preferential salts.

The composition is prepared by mixing the volatile silicone under stirring, in an amount by volume from 40% to 80%, preferably from 50% to 80%, the mixture of saturated aliphatic alcohols from 2 to 4 carbon atoms such as ethanol, propanol, isopropanol or a butanol, in particular ethanol / isopropanol in the ratio 1 / 0.3-0.3 / 1, in an amount by volume from 10% to 40%, preferably from 12 to 40%; the adjuvant in an amount by volume from 2% to 15%, preferably from 6% to 15% under stirring and at a temperature from 15 ° C to 25 ° C, and to the solution thus obtained is added, always under stirring, a quantity by weight from 0.1% to 11%, preferably from 0.1% to 6.5% of active principle, preferably to give a stable solution.

Clear solutions can be produced with a component (a) content, i.e. diclofenac acid or salified with an organic base, advantageously tertiary, preferably with an organic base of formula I above, at concentrations from 0.1% to 6.5%, preferably from 0.1% to 6.47%, in a mixture in which Component (b), that is the volatile silicone, is present at a concentration from 45% to 80%, preferably from 50% to 80% , Component (c), i.e. the mixture of alcohols, is present at a concentration from 12% to 40%, and the concentration of Component (d), i.e. the adjuvant, is from 6% to 15%.

Finally, to make the pain-relieving and anti-inflammatory treatment more pleasant, the present invention also provides for the possible addition to the mixture of refreshing agents such as menthol and camphor or their mixtures in a quantity by weight from 0.1% to 3% without affecting the clarity of the solution.

According to this particular aspect of the present invention, a calculated volume of the volatile silicone and a calculated volume of the skin permeation aid are added, in any order, to a mixture of ethanol with another 3-4 carbon saturated aliphatic alcohol, preferably to an ethanol / isopropanol mixture in the above mentioned ratios, under stirring and at a temperature from 15 ° C to 25 ° C and, subsequently, a calculated quantity of active principle is added to the solution thus obtained.

Component (b), i.e. the volatile silicone which, as the main volatile solvent, forms the basis of the composition of the present invention, can be a methylpolysiloxane containing from 2 to 6 silicon atoms, in which the silicon atoms are all methylated, for example hexamethyldisiloxane, as such (for example â € œDow Corning <®> Q7-9180 Silicone Fluid 0,65â €), with a dynamic viscosity of 0.59-0.71 cSt, or possibly containing 1% silicone rubber ( in English â € œsilicone gumâ €) (for example the â € œDow Corning <®> Silmogencarrierâ €) with a dynamic viscosity from 1.5 to 4 cSt, octamethyltrisiloxane (for example the â € œDow Corning <®> Q7-9180 Silicone Fluidâ €) with a dynamic viscosity from 0.9 to 1.1 cSt or decamethylcyclopentasiloxane (for example â € œDow Corning <®> ST-Cyclomethicone 5 â € “NFâ €) with a dynamic viscosity from 3.8 to 4 cSt , as well as commercially available under the Dow Corning <®> trademarks, also distributed by other companies, de volatile silicone having a dynamic viscosity lower than 5 cSt, preferably from 0.6 cSt to 4 cSt.

Component (c), i.e. the cosolvent used to facilitate the vaporization of the solution, consists of a mixture of saturated aliphatic alcohols having from 2 to 4 carbon atoms, advantageously in a mixture of ethanol and an alcohol with 3-4 atoms of carbon, preferably in an ethanol / isopropanol mixture in a ratio of 1 / 0.4 to 1 / 2.3

Component (d), i.e. the skin permeation adjuvant, can be any of the substances, well known in the literature (see for example the review on Pharmaceutical Technology, November 1997, pp. 58-66) as favoring skin permeation, which allow better absorption of drugs through the skin. These substances can be fatty alcohols, such as lauryl alcohol, fatty acids such as linolenic or oleic; fatty acid esters such as palmitate, stearate, linoleate, oleate or isopropyl myristate, monostearate, monolinoleate or monooleate of glycerin or sucrose; or fatty alcohol ethers having 10 to 20 carbon atoms.

In view of the improvement of the compliance during its vaporization, the solution of the present invention can include a Component (e), that is a cooling agent such as camphor or menthol, more easily soluble in the alcoholic mixture than in the volatile silicone. This refreshing agent is preferably added before the addition of the active ingredient, in an amount such as to provide a weight ratio of the active ingredient / refreshing agent from 1 / 0.3 to 1 / 0.9.

According to a preferential procedure, a volume of ethanol / isopropanol mixture in a ratio of 1 / 0.4 to 1 / 2.3 (alcoholic mixture) is prepared under gentle stirring and the mixture thus obtained is added, in any order, the volatile silicone in a volume from 1.2 times to 4.5 times that of the alcoholic mixture and isopropyl myristate in a volume from 0.15 times to 0.6 times that of the alcoholic mixture, maintaining the mild agitation and the temperature of 15-25 ° C. Under the same conditions of stirring and temperature, to the limpid solution thus obtained menthol, camphor, or a mixture thereof, is added in an amount of 0.5-3% by weight with respect to the total weight of said solution and finally diclofenacsal of epolamine or diclofenac salt of piperidinoethanol in an amount by weight from 0.1% to 11%, preferably from 0.1% to 6.5% of the total weight of the solution.

The solution thus obtained has a density (w / v) from 0.6 to 1.0 g / mL, advantageously from 0.7 to 0.9 g / mL, preferably from 0.75 to 0.85 g / mL

Thus, according to a particular aspect, the present invention provides a pharmaceutical composition consisting of a solution comprising

(a) diclofenac or a pharmaceutically acceptable salt thereof of an organic base, in an amount by weight (w / w) equivalent to 0.1% -11%, preferably 0.1% -6.5% sodium diclofenac of weight of the solution;

(b) a volatile silicone in an amount of 45% to 80%, preferably 50% to 80% of the volume of the solution,

(c) a mixture of saturated aliphatic alcohols having from 2 to 4 carbon atoms in an amount from 10% to 40%, preferably from 12% to 40% of the volume of the solution;

(d) a skin permeation adjuvant in an amount from 2% to 15%, preferably from 6% to 15% of the volume of the solution; And

(e) a cooling agent in an amount of 0.1% to 3 by weight of the solution.

According to a preferential aspect, Component (a) is the diclofenac salt with a tertiary organic base, preferably the salt of epolamine or 1- (2-hydroxyethyl) piperidine.

According to a second preferential aspect, Component (b) of the solution is a volatile silicone selected from the group consisting of hexamethyldisiloxane, octamethyltrisiloxane and decamethylcyclopentasiloxane, having a dynamic viscosity lower than 5, preferably from 0.6 to 4 CSt.

According to a third preferential aspect, Component (c) is an ethanol / isopropanol mixture from 1 / 0.4 to 1 / 2.3 v / v.

According to a fourth preferential aspect, Component (d) is isopropyl myristate.

According to a fifth preferential aspect, the Component (s) is menthol, camphor or a mixture thereof.

The products obtainable according to the present invention show improved skin permeation properties demonstrable with known analytical methods such as the system described by Shah V.P. et al inâ € œEvaluation of test systemused for in vitro release of drugs for topicaldermatologicaldrugproducts. Pharm.Dev. and Technol. 4 (3), 377-385 (1999) â € in which an animal membrane is used, deprived of skin hair, and mounted between two compartments in a double compartment cell (Franz cell) in which the receiving compartment consists of a buffered aqueous solution and represents the blood flow below the skin tissue and the donor compartment represents the area outside the body in contact with the skin. Once the sample to be analyzed has been deposited, the active ingredient released by the pharmaceutical product passes through the various layers of the skin used, and is then released into the receiving compartment. At predefined times, and usually within 24 hours, aliquots of buffer are withdrawn from the receiving compartment and the content of active principle measured. A curve is constructed with the points obtained and the efficiency of the formulation is calculated as the quantity of active ingredient per area used (normally 1 cm <2>) per observation time (normally 24 hours) and expressed as µg / cm <2> . At the end of the experimentation, the skin used is ground and the active extracted according to validated methods. The value obtained from the ground skin represents the amount of active released by the pharmaceutical product but which has not transferred into the receiving compartment. The two values correspond to the total released in 24 hours.

The preferential aspect of the present invention provides a new product in which the DIA or DIEP or DIEPP are solubilized in a mixture of waterless solvents, which is particularly advantageous from the point of view of the method of administration and skin permeation. . The use of the spray composition through special dispensing systems allows a capillary application of the composition itself on all parts of the body, including those difficult to treat with plasters such as the fingers or toes and the external parts of the body folded up like armpits or groin. These parts can be treated with gels or creams, however, passing through a coating that normally takes place through the patient's own hands or fingers in case of self-medication or by third parties if the patient is not self-sufficient.

As a second advantage, the composition of the present invention, used in spray according to the present invention, has the possibility of being easily applied in self-medication in most cases and even in the case of applications by third parties the procedure can be performed without a subsequent coating. . Furthermore, the dispensed solution dries quickly without the formation of drops that normally form from lotions or sprays containing water or solvents having a high boiling point previously described or used.

The spray dispensing system can be any system known in the art, for example the bag-on-valve system (BOV-1 series NKLCU or 20BOV series 20KNLCCostergroupItalia), consisting of a valve welded to a bag and inserted in an aluminum container . Proceed with the pressurization of the chamber external to the bag by means of a gaseous fluid (normally nitrogen) and the simultaneous crimping of the valve to the aluminum container. The bag is then filled through the valve stem with the solutions obtainable as described in the following examples in the desired quantity. The device is then completed with the dispenser and the protective cap (V05.701 or V05.1801 Costergroup - Italy). A further advantage of using the solution according to the present invention as a spray is the treatment of pets or wild animals that may need anti-inflammatory treatment. For example, the treatment with the spray instead of a gel or a cream appears to be better administered by veterinarians on race horses that suffer from contracture in the legs or on dogs that often have arthritis in the hips and more generally any animal that needs to be treated. with anti-inflammatories and which commonly also reacts violently to any attempt at treatment.

According to another aspect, the invention thus provides a method for the treatment of inflammation due to osteoarthritis, muscle contractures or tendinitis in a human being or in an animal of medium-large size that requires such treatment, which includes the administration by vaporization of a composition as described above.

In particular, the above composition can be applied to any external part of the human body, through a spray device, without the need for further operations of distributing the product on the surface, to treat arthritic pain, muscle contractures or tendon injuries.

Furthermore, the aforesaid composition can be used in the veterinary field by means of applications on medium-large sized animals, in particular on dogs or horses of all breeds and sizes to treat inflammation due to muscle contractures or tendon injuries. For example, it is possible to treat superficial or deep tendinitis of the digital flexor of the horse with administrations of 1-2 ml twice a day for 10 days, obtaining evident relief by the horse and without detectable systemic absorption through the plasma measurement of diclofenac with HPLC method performed as described in example 10 below.

The following examples illustrate the present invention.

Examples 1-9 refer to the formulations object of the present invention while example 10 relates to the comparison of the product obtained in example 1 and compared in vitro with a commercial cream containing the same active principle at the same concentration. The measured diclofenac content is expressed as diclofenac sodium equivalent taking into account that 1 gram equivalent of diclofenac sodium corresponds to 0.93 grams of diclofenac acid (DIA), 1.3 grams of diclofenac hydroxyethylpyrrolidine (DIEP) and 1.34 grams of diclofenac hydroxyethylpiperidine (DIEP).

Example 1

In a 30-liter container, 5.5 liters of absolute ethanol (Fluka-CH) and 5.5 liters of isopropanol (Fluka-CH) are mixed while maintaining gentle agitation. Then 2 liters of isopropyl myristate (Fluka-CH) and 10 liters of Dow Corning <®> Silicone Fluid Q7-9180 0.65 cSt (from Dow Corning USA) are added, always maintaining gentle agitation. To this solution 100 g are added. of menthol (Fluka-CH) and stirring is continued until complete dissolution. 216.68 g are then added. of DIEP produced according to Ziggiotti et al (EP-0271709) and stirred until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The solution obtained has a density of 0.81 g / ml and a w / w content of diclofenac sodium equivalent measured by quantitative HPLC analysis as described below equal to 1.05%: the analysis is carried out with an HPLC instrument equipped with auto-injector, pump and UV detector with RP-18 column and an isocratic mobile phase composed of phosphate buffer 0.05 MpH 7 / acetonitrile / methanol 58/21/21 with flow of 1.5 ml / min. With the internal standard DIEP, a solution of known concentration is prepared and various volumes are injected to obtain a calibration curve which must have a regression coefficient of at least 0.99 in order to be used for quantitative analysis. The diclofenac signal areas measured at 205 nm are used to construct the calibration curve. The solution obtained in the present example is diluted 200 times and 75 µl are analyzed as described. The resulting area at 205 nm is compared with the calibration curve and the DIEP content is calculated taking into account the dilution made.

Example 2

In a 30-liter container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 liters of isopropanol (Fluka-CH) are mixed while maintaining gentle agitation. Then 2 liters of isopropyl myristate (Fluka-CH) and 10 liters of Dow Corning <®> Silicone Fluid Q7-9180 0.65 cSt are added, always maintaining gentle agitation. 100 g of camphor are added to this solution and stirring is continued until complete dissolution. 156 g of free acid diclofenac are then added and stirred until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.81 g / mL and a content of diclofenac sodium equivalent of 0.99%.

Example 3

In a 30-liter container, 5.5 liters of absolute ethanol (Fluka) and 2.4 liters of isopropanol (Fluka) are mixed with gentle agitation. Then 2 liters of isopropyl myristate (Fluka) and 10 liters of Dow Corning <®> Silicone Fluid Q7-91800.65 cSt (from Dow Corning USA) are added, always maintaining gentle agitation. 100 g of camphor and 100 g of menthol are added to this solution and stirring is continued until complete dissolution. 224 g of DIEPP are then added and the mixture is stirred until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.82 g / mL and a content of diclofenac sodium equivalent of 1.03%.

Example 4

In a 30 liter container, 2.4 liters of absolute ethanol (Fluka) and 5.5 liters of isopropanol (Fluka) are mixed, maintaining a gentle stirring. Then 2 liters of isopropyl myristate (Fluka) and 10 liters of Dow Corning <®> Silicone Fluid Q7-91800.65 cSt (Dow Corning USA) are added, always maintaining gentle agitation. 150 g of menthol (Fluka) are added to this solution and stirring is continued until complete dissolution. 216.68 g are then added. of DIEP and stir until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.780 g / mL and a content of diclofenac sodium equivalent of 1.05%.

Example 5

In a 30 liter container, 2.4 liters of absolute ethanol (Fluka) and 5.5 liters of isopropanol (Fluka) are mixed, maintaining a gentle stirring. Then 2 liters of isopropyl myristate (Fluka) and 10 liters of Dow Corning <®> Silmogencarrier (from Dow Corning USA) are added, always maintaining gentle agitation. 150 g of menthol (Fluka) are added to this solution and stirring is continued until complete dissolution. 216.68 g are then added. of DIEP and stir until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.79 g / ml and a content of diclofenac sodium equivalent of 1.03%.

Example 6

In a 30 liter container, 2.4 liters of absolute ethanol (Fluka) and 5.5 liters of isopropanol (Fluka) are mixed, maintaining a gentle stirring. Then 2 liters of isopropyl myristate (Fluka) and 10 liters of Dow Corning <®> Silmogencarrier (from Dow Corning USA) are added, always maintaining gentle agitation. 150 g of camphor are added to this solution and stirring is continued until complete dissolution. 216.68 g are then added. of DIEP and stir until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.78 g / mL and a content of diclofenac sodium equivalent of 1.01%.

Example 7

In a 30-liter container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 liters of isopropanol (Fluka-CH) are mixed while maintaining gentle agitation. Then 2 liters of isopropyl myristate (Fluka-CH) and 10 liters of Dow Corning <®> ST-CyclomethiconeFluid 5 - NF (from Dow Corning USA) are added, always maintaining gentle agitation. To this solution 100 g are added. of menthol (Fluka-CH) and stirring is continued until complete dissolution. 216.68 g are then added. of DIEP and stir until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.87 g / mL and a content of diclofenac sodium equivalent of 1.00%.

Example 8

In a 30-liter container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 liters of isopropanol (Fluka-CH) are mixed while maintaining gentle agitation. Then 2 liters of isopropyl myristate (Fluka-CH) and 10 liters of Dow Corning <®> Silicone Fluid Q7-9180 0,65 cSt (from Dow Corning USA) are added, always maintaining gentle agitation. 100 g of menthol (Fluka-CH) are added to this solution and stirring is continued until complete dissolution. 21.67 g of DIEP are then added and the mixture is stirred until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.79 g / mL and a content of diclofenac sodium equivalent of 0.10%.

Example 9

In a 30-liter container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 of isopropanol (Fluka-CH) are mixed while maintaining gentle agitation. Then 2 liters of isopropyl myristate (Fluka-CH) and 10 liters of Dow Corning <®> Silicone Fluid Q7-9180 0.65 cSt (from Dow Corning USA) are added, always maintaining gentle agitation. 100 g of menthol (Fluka-CH) are added to this solution and stirring is continued until complete dissolution. 1085 g of DIEP are then added and the mixture is stirred until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.81 g / mL and a content of diclofenac sodium equivalent of 4.98%.

Example 10

The release and permeation capacity of diclofenac through the skin of the product obtained as described in example 1 was compared with that of the commercial product Flector <®> EP Gel (gel containing 1.3% diclofenac epolamine ). The membrane used was obtained from a pig's ear which had external hair removed using the Air Dermatome instrument (Zimmer; MÃ1⁄4nsingen, Switzerland). Discs of 2 cm <2> were obtained from the treated skin to effectively cover the operating area of the Franz cell of 1 cm <2>.

The experiment was performed with a conventional Franz cell in which the donor compartment was filled with 25 µl / cm <2> of the product obtained as described in example 1 or with 20 mg / cm <2> of Flector <®> EP Gel (validity period) purchased at a local pharmacy, both corresponding to 200 ng of diclofenac sodium equivalent. The receiving compartment was filled with phosphate buffer at pH 7.4. During the experiment, aliquots of 1 ml were taken at 20, 40, 60 minutes and 2, 3, 4, 5, 6, 7, 8, 12 and 24 hours from the deposition of the sample. At the end of the experiment, the formulation was removed from the donor compartment by washing the surface of the skin and rapidly passing with cotton twice to eliminate any surface residue. The skin samples were then cut into small pieces and extracted with phosphate buffer for 4 hours followed by 15 minutes of sonication to extract the residual active retained by the tissue. The extraction solution was then filtered and analyzed with the HPLC / UV method together with the samples obtained at various times from the receiving compartment under the operating conditions described in Example 1. Each experiment was repeated six times.

Figure 1 shows the cumulative concentration of diclofenac sodium equivalent present in the receiving compartment for the two products.

In Figure 2, together with the data already present in Figure 1, the quantity of sodium diclofenac equivalent found in the tissue after 24 hours for the two components is also reported.

From the data it is clear that the product obtained according to the present patent as reported in Example 1 shows a permeation capacity after 24 hours of 15 µg / cm <2> against a permeation of 0.3 µg / cm <2 > of the reference gel and an absolute quantity released approximately 3 times higher than the reference gel.

Example 11

4.4 liters of absolute ethanol (Fluka-CH) and 2.2 liters of isopropanol (Fluka-CH) are mixed in a 30-liter container, maintaining gentle agitation. 1.1 liters of isopropyl myristate (Fluka-CH) and 11 liters of Dow Corning <®> Silicone Fluid Q7-91800.65 cSt (from Dow Corning USA) are then added, always maintaining gentle agitation. 100 g of menthol (Fluka-CH) are added to this solution and stirring is continued until complete dissolution. 895 g of DIEP are then added and the mixture is stirred until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.89 g / mL and a content of diclofenac sodium equivalent of 4.71%.

Example 12

3.75 liters of absolute ethanol (Fluka-CH) and 1.85 liters of isopropanol (Fluka-CH) are mixed in a 30-liter container, maintaining gentle agitation. Then 1.25 liters of isopropyl myristate (Fluka-CH) and 12.45 liters of Dow Corning <®> Silmogencarrier (from Dow Corning USA) are added, always maintaining gentle agitation. To this solution 100 g of menthol (Fluka-CH) are added and stirring is continued until complete dissolution. 497 g of DIEP are then added and the mixture is stirred until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.78 g / mL and a content of diclofenac sodium equivalent of 2.46%.

Example 13

1.53 liters of absolute ethanol (Fluka-CH) and 0.765 liters of isopropanol (Fluka-CH) are mixed in a 30-liter container, maintaining gentle agitation. Then 1.53 liters of isopropyl myristate (Fluka-CH) and 15.3 liters of Dow Corning <®> ST-Cyclomethicone 5 - NF (from Dow Corning USA) are added, always maintaining gentle agitation. To this solution 100 g of menthol (Fluka-CH) are added and stirring is continued until complete dissolution. 46 g of DIEP are then added and the mixture is stirred until a clear solution is obtained. The whole operation is carried out keeping the temperature between 15 and 25 ° C. The clear solution thus obtained has a density of 0.92 g / mL and a content of diclofenac sodium equivalent of 0.20%.

Claims (15)

CLAIMS 1. Vaporizable pharmaceutical or veterinary composition, consisting of a solution comprising (a) 2 - [(2,6-dichlorophenyl) amino] benzeneacetic acid or a salt thereof with a pharmaceutically acceptable organic base; (b) a volatile silicone; (c) a mixture of saturated aliphatic alcohols having 2 to 4 carbon atoms; (d) a skin permeation adjuvant; and optionally (e) a cooling agent. 2. Composition of claim 1, wherein Component (a) is a member selected from the group consisting of 2 - [(2,6-dichlorophenyl) amino] benzeneacetic acid and its salts with pharmaceutically acceptable organic tertiary bases. 3. Composition of claim 2, wherein said tertiary organic base has the formula I X N-CH2-CH2OH <(I)> where X is direct bond or a methylene group. 4. Composition of claim 3, wherein said organic base is 1- (2-hydroxyethyl) pyrrolidine. The composition of claim 1, wherein the volatile silicone Component (b) is a methylpolysiloxane having a dynamic viscosity of less than 5 cSt and selected from the group consisting of hexamethyldisiloxane, hexamethyldisiloxane containing 1% silicone rubber, octamethyltrisiloxane and decamethylcyclopentasiloxane. The composition of claim 1, wherein the volatile silicone Component (b) is a methylpolysiloxane selected from the group consisting of hexamethyldisiloxane having a dynamic viscosity of 0.59 to 0.71 cSt; hexamethyldisiloxane containing 1% silicone rubber having a dynamic viscosity from 1.5 cSt to 4 cSt; octamethyltrisiloxane having a dynamic viscosity from 0.9 cSt to 1.1cSt; and decamethylcyclopentasiloxane having a dynamic viscosity of 3.8 to 4 cSt. 7. The composition of claim 1, wherein said alcohol mixture is an ethanol / isopropanol mixture in a ratio of 1 / 0.4 to 1 / 2.3 v / v. 8. Composition of claim 1, wherein said skin permeation adjuvant is isopropyl myristate. 9. The composition of claim 1, wherein said optional freshener is selected from the group consisting of menthol, camphor and mixtures thereof. 10. Composition according to any one of claims 1 to 9, wherein the amount of diclofenac sodium equivalent of Component (a) is from 0.1% to 5% w / w. 11. Composition according to any one of claims 1 to 9, wherein the quantity of the volatile silicone Component (b) is from 45% to 88% v / v, that of the alcoholic mixture Component (c) is from 10% to 40 % v / v, that of the adjuvant Component (d) is from 2% and 15% v / v. and that of the cooling agent Optional component (s) is from 0.1% a Composition according to any one of claims 1 to 11, wherein the volatile silicone Component (b) is a member selected from the group consisting of Dow Corning Q7-9180 silicon fluid 0.65 CST, Dow Corning silicon oilSilmogencarrier and Dow Corning ST cyclomethicone 5 NF (Dow Corning USA). 13. Composition according to any one of claims 1 to 12, having a density (w / v) from 0.6 to 1.0 g / mL, advantageously from 0.7 to 0.9 g / mL, preferably from 0.75 at 0.85 g / mL. Composition according to any one of claims 1 to 13 for its use by means of vaporization applied to any external part of the human body or of medium-large sized animals through in the treatment of inflammation due to arthrosis, muscle contractures or tendon injuries. 15. Composition of claim 14 wherein said medium to large sized animals are horses or dogs of any breed and size.