WO2014009793A1

WO2014009793A1 - Diclofenac solution for external use

Info

Publication number: WO2014009793A1
Application number: PCT/IB2013/001500
Authority: WO
Inventors: Giorgio Zoppetti; Pasqua Oreste
Original assignee: Glycores 2000 S.R.L.
Priority date: 2012-07-11
Filing date: 2013-07-10
Publication date: 2014-01-16
Also published as: ITMI20121205A1

Abstract

There is described a pharmaceutical composition with anti-inflammatory and analgesic activity to be delivered by a vaporisation (spray) system for external use comprising, as active ingredient, diclofenac, 2-[(2,6- dichlorophenyl)amino]benzeneacetic acid, preferably as an organic base salt thereof, in particular as a secondary or tertiary amine salt and more particularly as a cyclic, tertiary amine salt. Said active ingredient is dissolved in a volatile silicone in the presence of 2-4C alcohol mixture and is free from water and from non-volatile silicones.

Description

DICLOFENAC SOLUTION FOR EXTERNAL USE

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OBJECT OF THE INVENTION

The present invention relates to a volatile-silicone-based pharmaceutical or veterinary composition containing, as an active ingredient, diclofenac or a diclofenac organic base salt which, when dissolved in said volatile silicone base, exerts its anti-inflammatory and analgesic activity upon a topical application involving a deep penetration of the active ingredient through the skin, down to the sub-derma. The composition is useful for being administered through a spray device for external use in the treatment of musculoskeletal disorders, in particular of musculoskeletal inflammations and of pains associated therewith.

STATE OF THE ART

The use of diclofenac, or [(2,6-dichlorophenyl)amino]benzeneacetic acid in formulations for topical applications is well known. This product, initially developed as sodium salt for solid oral or injectable formulations, has been developed also for topical applications as creams or plasters. Diclofenac sodium can be easily formulated as powder for oral formulations, but due to its low water solubility the formulations in gel or plasters can be problematic. Also, the injectable formulations can be made only if a mixture of water with appropriate solvent is selected as in Voltaren^® in which diclofeanc sodium is solubilized in a mixture of water and propylene glycol, or recently diclofenac sodium has been solubilized through a hydroxypropylcyclodextrin complex (EP 1609481).

To develop topical applications with diclofenac sodium or potassium, several lipophilic mixtures have been used as described in WO2004030665, in W09857624 and in EP0834312, or by using liposomal systems as described in US2004121987. A gel and a foam containing diclofenac sodium, have also been described. These formulations also contain dimethylsulfoxide as reported in WO2008049020 and in WO2011112875.

Further attempts to deliver diclofenac sodium for topical application are described in WO2004017998, in which, in spite of the diclofenac sodium low dosage, a turbid water-based gel was obtained. In WO2009007764, volatile silicone-based gels are described for the administration of diclofenac sodium.

Further, in WO2010087947 diclofenac acid is ion paired with biologically active molecules to obtain a water solution. In summary, it is evident that a topical formulation with diclofenac sodium cannot be developed without the use of solvent mixtures or lipophilic solubilizing agents. It is known that to obtain an efficient skin permeation the active ingredient shall have a favorable water/oil partition ratio, and in that partition ratio diclofenac sodium is oriented toward the lipophilic fraction. In the past, alternative salts to sodium or potassium have been studied like ethylamine, diethylamine, l-(2-hydroxyethyl)pyrrolidine, known also as 2-pirrolidinethanol, 1- (2- hydroxyethyl)pyrrolidine or epolamine. The paper by Minghetti et al., "Ex vivo study of transdermal permeation of four diclofenac salts from different vehicles", J. of Pharm. Sci, 96 n.4 pp. 814-914 (2007) describes the solubility in water and other solvents of the aforementioned diclofenac salts and confirms that the organic salts are more soluble in water while the sodium and potassium salts are more soluble in lipophilic solvents. In particular, the paper states that the epolamine salt is very soluble in water and comparatively less soluble in organic solvents. It is known that this characteristic gives a better skin permeation of organic salts of diclofenac. This high water solubility of diclofenac epolamine has been described by Fini et.al. "Diclofenac/N-(2-hydroxyethyl) pyrrolidine: a new salt for an old drug." Drugs Exptl.Clin. Res., 1993, XIX: 81-88., in which the water solubility of diclofenac epolamine is reported to be 40% w/v.

Pharmaceutical formulations containing diclofenac salts of organic bases like diethylamine or epolamine are described in EP2055298, in CN101224186 and in WO2010060798 in form of gels or water-based solutions. Diclofenac sodium and epolamine salts have been described in the preparation of topical tapes. For instance WO2011049058 and EP0621263 describe complex systems in which the diclofenac is homogenized and fixed in the semisolid gel of the tape. In the case of the patent describing the patch with diclofenac epolamine, pure water is used to make a concentrate solution of diclofenac epolamine.

All the formulations described above in gel, patch or solutions show different application problems. Creams with sodium or potassium salts allow low skin permeations, that is enhanced in gels in presence of dimethylsulfoxide, even if dimethylsulfoxide side effects are to be taken into account. Ethylenamine salts seem to have good permeation properties, but the use of substances producing nitrosamines has been recently discouraged by Authorities. Finally, the epolamine salt is useful for the preparation of water-based patches or gels, however the skin permeation is still low due to the scarce capability of the semisolid gel to release diclofenac.

PRIOR ART

The document CN 1150541 concerns a spray formulation containing diclofenac sodium and various excipients. In details, the document describes two compositions containing 10 g of diclofenac sodium and 231 g of excipients and 20 g of diclofenac sodium and 247 g of excipients respectively, both in 1000 ml of water, thus confirming that, in order to prepare a diclofenac sodium composition for external use, like gel or spray, a water-based composition is required.

Document WO 2009/047785 describes a composition in a non- water-based solution for topical use comprising an effective amount of a pharmaceutical acceptable diclofenac salt, in particular the sodium salt or diethylamine salt, from 10 to 39% v/v of a short-chain alcohol as solubilizer and skin permeation enhancer, a solvent consisting of propylene glycol, glycofurol or of a mixture thereof and optionally by a humectant or antioxidant agent and by another agent favoring the permeation, and in which the short-chain alcohol is C₂-C_5; in particular ethanol in quantity of about 10- 20% v/v are used. The solvents described in this document, glycofurol and propylene glycol, are high boiling point solvents.

Document US2006/0147383. discloses a sprayable composition comprising (a) a pharmaceutical active agent, (b) at least one volatile silicone, and (c) a non-volatile oily phase formulated into a physiologically acceptable medium, said medium consisting of a series of active agent-solubilizing excipients including water. As pharmaceutical active agents, this document mentions various categories of drugs and specific drugs including diclofenac and salts and derivatives thereof, but US2006/0147383 does not specifically disclose any composition comprising diclofenac and salts and derivatives thereof. The disclosed composition is particularly suitable for the treatment of dermatological conditions and afflictions and may be used for the treatment of a series of diseases according to the pharmacological action of the used drugs but no mention is made of the treatment of inflammation and pains of the musculoskeletal apparatus. According to US2006/0147383, the composition is prepared by mixing the various components until a homogeneous and clear solution is obtained, but no specific disclosure of any formulation of a composition comprising diclofenac and salts and derivatives thereof is made in this document.

The literature does not report any information on the solubility of diclofenac and salts thereof in a volatile silicone.

SUMMARY OF THE INVENTION

It has now been found that diclofenac in acidic form is very slightly soluble in a volatile silicone having a viscosity of less than 1 cSt, that diclofenac as an organic base, in particular secondary or tertiary amine, salt thereof, is slightly soluble in said volatile silicone having a viscosity of less than 1 cSt and that a little amount of an ethanol/isopropanol mixture (10-15% v/v), added to a volume of said volatile silicone, easily solubilizes diclofenac in acidic form or as an organic base salt thereof.

It has also been found that a solution of diclofenac in acidic form or as an organic base salt thereof in at least one volatile silicone in the presence of a little volume of an alcoholic co-solvent consisting of a mixture of (C₂-C₄)alkanols and, optionally, of a skin permeation enhancer, can be used as spray for the transcutaneous treatment of musculoskeletal inflammations and pains in a mammal, more particularly for the treatment of bone, articulation, muscle, joints and tendon inflammations or injuries and of the pains associated therewith, said treatment involving a skin permeation and, as a consequence, an improved therapeutic and functional effect. This effect is much higher than that obtainable with water-based compositions with diclofenac sodium or with diclofenac diethylamine salt in compositions comprising non alcoholic, high boiling point solvents.

In particular, it has been found that diclofenac acid and its cyclic organic base salts of the followin formula I:

in which X is a direct bond or a methylene group, is at least partially soluble in a volatile silicone with a dynamic viscosity lower than 5 cSt.

It has further been found that the addition of a mixture of aliphatic alcohols containing from 2 to 4 carbon atoms, herein below also referred to as (C₂- C₄)alkanols, in a percent in volume of 10-15%, up to 30%, favors both the solubilization of the active ingredient together with a possible refreshing agents, such as for example menthol or camphor, and the spraying of the solution, thus allowing the use of said solution in a spray device.

The optional addition of a skin permeation enhancer allows, after each spray delivery, an absorption of the active ingredient which is much higher than that obtainable with water-based spray solutions with diclofenac sodium or with non- aqueous-based diclofenac organic base salt solutions in high-boiling solvents.

The solution thus obtained maintains diclofenac or its organic base salts very stable for a long time and can be delivered as spray in topical applications for the relief muscular or arthrose/arthritis-caused pains.

Furthermore, it has been found that, in the above described mixture, diclofenac acid and its organic base salts, in particular its tertiary organic bases and preferentially the salts with 2-pyrrolidinethanol (hydroxyethylpyrrolidine) and with 2- piperidinilethanol (hydroxyethylpiperidine), permeate through the skin in high quantities, much higher than those obtainable after treatment with water-based spray or gel containing diclofenac sodium or with non-aqueous lotions or gels containing a diclofenac salt without volatile silicones.

Diclofenac acid and its salts with hydroxyethylpyrrolidine (Formula I, X=direct bond) and with hydroxyethylpiperidine (Formula I, X= methylene) are hereafter called DIA, DIEP and DIEPP, respectively.

The expression "volatile silicone", as used hereafter, defines a fully methylated polysiloxane having from 2 to 6 silicon atoms and a dynamic viscosity lower than 5 cSt.

The expression "skin permeation enhancer", as used hereafter, and also simply indicated as "enhancer", defines one of the well-known products capable to enhance the permeation of the active product. If a permeation enhancer is present in the composition, it will preferably be a non-volatile compound having a dynamic viscosity lower than 5 cSt.

Herein below, the term "diclofenac", when used alone, designates the active ingredient endowed with anti-inflammatory and analgesic activity or, globally, any diclofenac active ingredient of known pharmaceutical compositions; "diclofenac acid (DIA)" designates the diclofenac chemical compound or active ingredient in acidic form; the term "diclofenac salt(s)" genetically designates the diclofenac chemical compound or active ingredient in form of salt(s) thereof; specific diclofenac salts are designated with the term "diclofenac" followed by the name of the salifying amine or with a corresponding acronym as defined above.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the diclofenac sodium equivalent cumulative concentration of the composition of Example 1 and of a commercial gel containing 1,3% DIEP, measured in the receiving compartment of a Franz cell system, as described in Example 10. Figure 2, in combination with the data of Figure 1 , shows the amount of diclofenac sodium equivalent of the sample of the composition of Example 1 and of the sample of the commercial gel containing 1,3% DIEP, measured in 24 hours in the tissue of the same Franz cell system.

Figure 3 shows the UV profiles of the composition of Example 1 and of a composition prepared by reproducing Example 6 of US 2006/0147383, using diclofenac acid as active ingredient, the latter being characterized by an evident shoulder indicating the unclearness of the composition.

DETAILED DESCRIPTION

Thus, the present invention provides a composition comprising:

(a) diclofenac as free acid or as a pharmaceutically acceptable organic base salt thereof;

(b) a solvent constituted by at least a volatile silicone having a dynamic viscosity lower than 5 cSt; and

(c) a co-solvent constituted by a mixture of saturated aliphatic alcohols containing from 2 to 4 carbon;

provided that said composition is free from water and from any non- volatile silicone. The composition of the invention is a clear solution and constitutes a pharmaceutical composition for external use in the transcutaneous treatment of musculoskeletal inflammations and pains in human and animal, in particular for the treatment of bone, articulation, muscle, joint and tendon inflammations or injuries and of the pains associated therewith, for example in the treatment of muscular or arthritis pains.

The solution of the present invention may be straightforwardly used for filling a suitable spray nebulizer and may be nebulized onto the skin of a human or an animal in order to make the active substance to penetrate through the skin up to the sub- derma, thus allowing a rapid anti-inflammatory action due to a reception by the derma of an amount of active ingredient, measured as diclofenac, which is far higher than that obtained with the commonly used diclofenac gels or lotions. In particular, it has been observed that, after a single skin treatment with this solution, the amount of diclofenac which reaches the sub-derma of horse skin within 24 hours may be greater than 30 times the amount obtained with the use of a single treatment with common diclofenac gels or lotions.

Clear solutions can be prepared with a content of the Component (a), diclofenac acid or organic base salt, preferentially a secondary or tertiary amine, more preferentially with an organic base of formula I described above, at concentrations from 0.1% to 6.5 % w/w with respect to the total weight of the composition, preferably from 0.1% to 6.47 % w/w, in a mixture wherein the Component (b), the volatile silicone, is present at concentrations from 45% to 90% v/v with respect to the total volume of the composition, preferentially from 50% to 87 %, the Component (c), the alcohol mixture, is present at a concentration of from 10% to 30% v/v with respect to the total volume of the composition, preferably from 10% to 15% v/v.

The active ingredient Component (a) of the composition is diclofenac, as free acid or as a pharmaceutically acceptable organic base salt thereof, advantageously a secondary, more advantageously tertiary, preferentially cyclic, amine salt such as for example the diclofenac methylamine, diethylamine, triethylamine, pyrrolidine, piperidine, morpholine, 1-ethylpiperidine, 2-aminoethanol, dimethylaminoethanol, diethylaminoethanol (described in US 3558690) salt or, preferentially, the diclofenac salt of one of the aforementioned amines of Formula I, i.e. the diclofenac pyrrolidinethanol (epolamine) and diclofenac piperidinethanol salts, obtainable as described by Ziggiotti et al. in EP 0271709 A, which are the diclofenac preferred salts.

The composition is prepared by mixing a volume of from 40% to 80 %, up to 90%, preferentially from 50% to 80%, up to 87%, of the targeted total volume, of the volatile silicone, under mild stirring at 15-25°C, with a mixture of saturated aliphatic alcohols containing from 2 to 4 carbon atoms like ethanol, w-propanol, isopropanol or «-butanol, in particular with a mixture ethanol/isopropanol in a ratio of from 1/0.3 to 0.3/1, in an amount in volume of from 10% to 40%, preferentially from 10% to 30% of the final targeted volume, and this solution is added with the active ingredient from 0.1% to 11 % w/w, preferentially from 0.1% to 6.5% to give a stable solution.

The Component (b), the volatile silicone which, as principal volatile solvent, constitutes the basis of the present invention, may be a methylpolysiloxane with from 2 to 6 silicon atoms, in which the silicon atoms are all methylated, for example hexamethyldisiloxane (for example "Dow Corning^® Q7-9180 Silicone Fluid 0.65"), with a dynamic viscosity of 0.59-0.71 cSt, octamethyltrisiloxane (for example "Dow Coming^® Q7-9180 Silicone Fluid") with a dynamic viscosity of from 0.9 to 1.1 cSt or decamethylcyclopentasiloxane (for example "Dow Corning^® ST-Cyclomethicone 5 - NF") with a dynamic viscosity of from 3.8 to 4 cSt, as commercially available under the brand Dow Corning^®, distributed also by other companies, such volatile silicone having a dynamic viscosity lower than 5 cSt, preferentially from 0.06 to 4 cSt. The Component (b), the volatile silicone which, as principal volatile solvent, constitutes the basis of the present invention, may be a methylpolysiloxane with from 2 to 6 silicon atoms, in which the silicon atoms are all methylated, for example hexamethyldisiloxane (for example "Dow Corning^® Q7-9180 Silicone Fluid 0.65"), with a dynamic viscosity of 0.59-0.71 cSt, octamethyltrisiloxane (for example "Dow Corning^® Q7-9180 Silicone Fluid") with a dynamic viscosity of from 0.9 to 1.1 cSt or decamethylcyclopentasiloxane (for example "Dow Corning^® ST-Cyclomethicone 5 - NF") with a dynamic viscosity of from 3.8 to 4 cSt, as commercially available under the brand Dow Corning^®, distributed also by other companies, such volatile silicone having a dynamic viscosity lower than 5 cSt, preferentially from 0.06 to 4 cSt.

The Component (c), i.e. the co-solvent used to facilitate the nebulization of the solution and to easily dissolve the active ingredient, consists of a mixture aliphatic alcohols containing from 2 to 4 carbon atoms, preferentially of a mixture of ethanol and a 3-4 carbon atom chain alcohol, more preferentially of a mixture of ethanol/isopropanol in a ratio from 1/0.4 to 1/2.3.

Thus, according to an advantageous embodiment, the invention provides a pharmaceutical composition consisting of a clear solution comprising

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

(b) a volatile silicone, in an amount from 45% to 90%, preferentially from 50% to

87% of the volume of the solution; and

(c) a saturated aliphatic alcohol mixture having from 2 to 4 carbon atoms, in an amount of from 10% to 40%, preferably from 10% to 15% of the volume of the solution.

In order to enhance the penetration of the active ingredient through the skin, the solution consisting of diclofenac or of a diclofenac organic base salt in the mixture of volatile silicone and the alcoholic mixture, obtained as above, may be added with a penetration enhancer. The optional penetration enhancer, which will preferably have a dynamic viscosity lower than 5 cSt, when added to the diclofenac/silicone/alkanols-mixture, allows an even higher penetration through the skin into the sub-derma. It has been observed that that, after a single skin treatment with a diclofenac/silicone/alkanols-mixture solution also containing a penetration enhancer, the amount of diclofenac which reaches the sub-derma of horse skin within 24 hours may even reach 50-70 times the amount obtained with the use of a single treatment with common diclofenac gels or lotions.

In order to have a better patient compliance in the transcutaneous treatment of musculoskeletal inflammations and pains according to the present invention, refreshing substances like menthol, camphor or a mixture thereof may also be added, in the presence or in the absence of an enhancer, in an amount by weight of from 0.1% to 3% w/w, without influencing the clearness of the solution.

If a permeation enhancer is present, it will be in an amount of from 2% to 15% v/v. Accordingly, the volatile silicone, in an amount of from 40% to 80 % in volume, preferentially from 50% to 80%, of the total targeted volume, is mixed under mild stirring with a mixture of saturated aliphatic alcohols containing from 2 to 4 carbon atoms like ethanol, propanol, isopropanol or butanol, in particular ethanol/isopropanol in the 1/0.3-0.3/1 ratio, in an amount from 10% to 40% by volume, preferentially from 10% to 30% by volume; then the enhancer is added in an amount of from 2% to 15% by volume, preferentially from 6% to 15% by volume at a temperature from 15 to 25 °C, and this solution is added with the active ingredient in an amount of from 0.1% to 11 % w/w, preferentially from 0.1% to 6.5% w/w, to give a stable solution.

The skin permeation enhancer, can be any one substance, well-known from the literature as skin permeation enhancers (see for example the review in Pharmaceutical Technology, November 1997, pages.58-66), which allow the improved permeation of drugs through the skin. Such substances, which preferably have a viscosity lower than 5 cSt, may be fatty alcohols such as lauryl alcohol (dodecanol); fatty acids such as linolenic acid or oleic acid; fatty acid esters such as isopropyl palmitate, stearate, linoleate, oleate or myristate, glycerol or sucrose monostearate, monolinoleate or monooleate; or fatty alcohol ethers having from 10 to 20 carbon atoms.

Very performing, clear solutions containing a permeation enhancer can be prepared with a content of the Component (a), diclofenac acid or organic base salt, preferentially a secondary or tertiary amine, more preferentially with an organic base of formula I described above, at concentrations from 0.1% to 6.5 % w/w, preferably from 0.1% to 6.47%, in a mixture wherein the Component (b), the volatile silicone, is present at concentrations from 45% to 80% v/v, preferentially from 50% to 80 %, the Component (c), the alcohol mixture, is present at a concentration from 12% to 40% v/v, preferably from 12% to 15%, and the concentration of the Component (d), the enhancer, is from 6% to 15%, generally v/v.

Thus, as an embodiment, the present invention provides a pharmaceutical composition consisting of a clear solution comprising

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

(b) a volatile silicone, in an amount from 45% to 80%» v/v, preferentially from 50% to 80 % of the volume of the solution; and

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

(d) a skin permeation enhancer having a viscosity lower that 5 cSt, in an amount of from 2% to 15%, preferentially from 6% to 15% of the volume of the solution. Preferably, the saturated alcohol mixture is an ethanol/isopropanol mixture in a ratio range of from 1/0.3 to 0.3/1 v/v.

A particularly preferred enhancer is isopropyl myristate.

According to this particular embodiment of the present invention, a calculated volume of the volatile silicone and, optionally, a calculated volume of the enhancer are added, in any order, to a mixture of ethanol and another saturated aliphatic alcohol with 3-4 carbon atom chain, preferentially to a mixture ethanol/isopropanol in the aforementioned ratio range, under stirring at a temperature from 15 to 25 °C and then a calculated amount by weight of active ingredient is added to the obtained solution.

In order to optimize the patient compliance upon the spraying, the solution of the present invention may include a Component (e), i.e. a refreshing agent such as camphor or menthol, better soluble in the alcohol mixture than in the volatile silicone. Such a refreshing agent is preferentially added before the active ingredient, in an amount to give an active ingredient/refreshing agent ratio of from 1/0.3 to 1/0.9 w/w.

According to an advantageous embodiment, a volume of the ethanol/isopropanol mixture in a ratio of from 1/0.4 to 1/2.3 (alcoholic mixture) is prepared under mild stirring and this volume of mixture is added with from 1.3 to 5.1 volumes of the volatile silicone. Under gentle stirring and at a temperature of from 15 to 25 °C, menthol, camphor or a mixture thereof is added in an amount of from 0.5% to 3 % by weight with respect to the total weight of the solution and, finally, the diclofenac epolamine or piperidinoethanol salt is added in an amount of from 0.1 to 11 % by weight, preferentially from 0.1 to 6.5 % by weight with respect to the total weight of the solution. The obtained solution has a density of 0.74 and a diclofenac sodium equivalent assay of 1.01 % measured by quantitative HPLC analysis.

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

(b) a volatile silicone, in an amount from 45% to 80% v/v, preferentially from 50% to 80 % of the volume of the solution;

(c) a mixture of saturated aliphatic alcohol having from 2 to 4 carbon atoms, in an amount of from 10% to 40%, preferably from 10% to 15% or from 10% to 30%, of the volume of the solution; and

(d) a refreshing agent in an amount from 0.1% to 3% by weight of the total weight of the solution.

According to a preferred embodiment, a volume of the ethanol/isopropanol mixture in a ratio of from 1/0.4 to 1/2.3 (alcoholic mixture) is prepared under mild stirring and this volume of mixture is added with from 1.2 to 4.5 volumes of the volatile silicone, from 0.15 to 0.6 volumes of isopropyl myristate, in any order, by keeping the mild stirring and a temperature range of from 15 to 25 °C. Under the same conditions of stirring and temperature, menthol, camphor or a mixture thereof is added in a quantity from 0,5 to 3 % by weight with respect to the total weight of the solution and, finally, the diclofenac epolamine or piperidinoethanol salt is added in an amount of from 0.1 to 11 % by weight, preferentially from 0.1 to 6.5 % by weight with respect to the total weight of the solution.

The solution obtained has a density (w/v) of from 0.6 to 1.0 g mL, preferentially from 0.7 to 0.9 g mL, more preferentially from 0.75 to 0.85 g/mL.

Therefore, according to a particular embodiment, the present invention provides a pharmaceutical composition consisting of a solution comprising:

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

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

(d) a skin permeation enhancer in an amount of from 2% to 15%, preferentially from 6% to 15% of the volume of the solution; and

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

According to a preferential embodiment, the Component (a) is a diclofenac salt of a secondary or tertiary organic base, preferentially the epolamine or l-(2- hydroxyethyl)piperidine, salt.

According to a second preferential aspect of the present invention, the 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, preferentially from 0.6 to 4, cSt.

According to a third preferential embodiment, the Component (c) is an ethanol/isopropanol mixture in a ratio of from 1/0.4 to 1/2.3 v/v.

According to a fourth preferential aspect, the component (d) is isopropyl myristate. According to a fifth preferential embodiment, the Component (e) is menthol, camphor or a mixture thereof.

The products obtainable according to the present invention show improved skin permeation properties measurable with known analytical methods such as for example the system described by Shah V.P. et al in "Evaluation of test system used for in vitro release of drugs for topical dermatological drug products. Pharm. Dev. and Technol. 4(3), 377-385 (1999)" in which a shaved biological membrane is used mounted between two chambers in a two chamber cell (Franz cell), in which the receiving compartment is an aqueous buffer solution and represents the under skin blood stream, and the donor compartment represents the external skin area. Once the sample has been deposited in the donor compartment, the active ingredient released by the pharmaceutical compound is diffused through the different skin layers and then is released in the receiving compartment. At specific timeframe, usually within 24 hours measured buffer samples are withdrawn from the receiving compartment and the active content is assayed. With the data obtained a kinetic curve is constructed and the diffusion efficiency is calculated as the amount of active ingredient/used area (usually 1 cm )/observation time (usually 24 hours) and expressed as μg/cm².

At the end of the experiment the tissue used is minced in small pieces and the active extracted according to validated methodologies. The value obtained from the minced tissue represents the active released from the pharmaceutical preparation fraction not diffused in the receiving compartment. The two values correspond to the total active released within the observation time frame (24 h).

The preferential aspect of the present invention gives a new product, in which DIA, or DIEP or DIEPP is dissolved in a solvent mixture in the absence water, which is particularly advantageous for the administration method and for the skin permeation. Similarly, the absence of any non-volatile silicone allows both a better dissolution of DIA, DIEP or DIEPP in the volatile silicone and a better penetration of the active ingredient of the invention through the skin down to the sub-derma.

The spray device can be for example the Bag-On- Valve system (Type BOV-1 series NKLCU or type 20BOV series 20KNLC from Coster Group-Italy), constituted by a valve welded to a bag and inserted in an aluminum container. The chamber pressurization is made with an inert gas (usually nitrogen) in the same time of the valve crimping to the aluminum container. Then the bag is filled through the valve with the solutions obtainable as described in the examples in the desired quantity. Finally the spray device is completed with an actuator and caps (type V05.701 or type V05.1801 Coster group - Italy). As alternative to the BOV device, to deliver a fixed volume (normally 1-2 ml equivalent to 8 or 16 mg of diclofenac sodium equivalent with the product of example 1), a mechanical high dosage Spray Pump LCP series (fixed delivery of 1 or 2 ml) from Coster-Italy can be used.

According to another of its aspects, the present invention provides the herein above illustrated, sprayable composition for use in the treatment of a human patient or of a medium/big size animal suffering from musculoskeletal disorders and from pains associated to said disorders. This use is by nebulization applied onto any external human and medium-big size mammal body area by a spray device, for the transcutaneous treatment of musculoskeletal inflammations, and of pains associated therewith, in said human or mammal.

According to a further aspect, the invention provides a method for the treatment of musculoskeletal disorders, in particular inflammations such as arthritic inflammations, muscle contractures or tendinitis in a mammal, in particular to humans or medium-big size other mammals in need of such a treatment, as well as the pains associated with said disorders, which comprises the spray administration of a composition as described above.

The use of the composition as a spray by specific delivery systems allows an efficient application onto all the external parts of the human body, including parts which are difficult to treat with tapes or plasters as, for example, in the case of foot and hand fingers and folder parts of the body like axilla or groin. Such body parts can be treated with a gel formulation by a spreading action which is normally performed by hands or fingers of the patient in case of auto medication, or with the help of a third party in patients in need of assistance.

In particular, the aforementioned composition can be sprayed onto the human skin without needing additional operations for the spreading of the product onto the surface area, for the transcutaneous treatment of musculoskeletal disorders and pains, in particular for the treatment of bone, articulation, muscle, joints and tendon inflammations or injuries and of the pains associated therewith, such as arthritic pain, muscle contracture or tendon injuries. As second advantage over the commercial topical diclofenac-based preparations, the composition of the present invention used as spray, can be easily applied as auto medication in most of the cases and also, in those cases in which the help of third party is required, the procedure can be performed without the subsequent spreading action. After the application, the delivered solution quickly dry without the formation of the drops that normally appear when the spray is performed with water-based lotions or with aforementioned, known compositions comprising highly boiling solvents.

The use of the composition as a spray by specific delivery systems also allows its use in the veterinary medicine by applications to medium-big size animal-mammals, in particular on any race of dogs or horses suffering from musculoskeletal disorders, by transcutaneous treatment of musculoskeletal disorders and pains, in particular for the treatment of bone, articulation, muscle, joints and tendon inflammations or injuries and of the pains associated therewith, especially to treat inflammations caused by muscle contracture or tendon injuries.

For example it is possible a topical treatment of the superficial or deep digital flexor tendinitis in horses with an administration of 1-2 ml (8-16 mg of diclofenac sodium equivalent) twice a day for 10 days with a reduction of lameless and no systemic absorption measurable by the diclofenac plasma level with HPLC method described hereafter in Example 10.

The following examples illustrate the invention. Example 1-9 and 11-14 are referred to the formulations of the present invention while example 10 is related to the in vitro comparison of the product obtained according to example 1 and a commercial cream containing the same active ingredient at the same concentration. The Comparative Example reproduces a disclosure of the prior art. The assay of diclofenac is expressed as diclofenac sodium equivalent, taking in account that 1 gram equivalent of diclofenac sodium corresponds to 0.93 grams of diclofenac acid (DIA), to 1.3 grams of diclofenac hydroxyethylpyrrolidine (DIEP) and to 1.34 grams of diclofenac hydroxyethylpiperidine (DIEPP)

EXAMPLE 1

In a 30-liter container 5.5 liters of absolute ethanol (Fluka-CH) are mixed with 2.4 liters of isopropanol (Fluka-CH) mixed under mild stirring. To this mixture, 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 under mild stirring. To this solution 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 216.18 g of DIEP, obtained as described by Ziggiotti et al (EP-0271709), are added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.81 g/mL and a diclofenac sodium equivalent assay of 1.05% measured by quantitative HPLC analysis as described hereafter. The assay is performed by a HPLC instrument with auto-injector, pump and UV detector, with a RP-18 column and as a isocratic mobile phase a 0.05 M phosphate buffer pH 7/ acetonitrile/methanol 58/21/21 with a flux of 1,5 ml/min. To obtain a calibration curve which must have a regression coefficient higher than 0.99 to be used as quantitative reference curve DIEP internal standard at known concentration is dissolved with the mobile phase and different volumes of the solution are injected. The resulting area of the diclofenac signal measured at 205 nm are used to set-up the standard curve. The solution obtained in the present example is diluted 200 times and 75 μΐ are analyzed as described. The resulting area at 205 nm is compared with the calibration curve and the DIEP content is calculated considering the dilution factor. EXAMPLE 2

In a 30 liters container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 liters of isopropanol (Fluka-CH) are mixed under mild stirring. To this mixture 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 under mild stirring. To this solution 100 g of camphor (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 156 g of DIA is added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.81 g/mL and a diclofenac sodium equivalent content of 0.99%, measured by quantitative HPLC analysis as described herein above.

EXAMPLE 3 In a 30 liters container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 liters of isopropanol (Fluka-CH) are mixed under mild stirring. To this mixture, 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 under mild stirring. To this solution 100 g of camphor (Fluka-CH) and 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 224 g of DIEPP is added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.82 g/mL and a diclofenac sodium equivalent content of 1.03%, measured by quantitative HPLC analysis as described herein above.

EXAMPLE 4

In a 30 liters container, 2.4 liters of absolute ethanol (Fluka-CH) and 5.5 liters of isopropanol (Fluka-CH) are mixed under mild stirring. To this mixture 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 under mild stirring. To this solution 150 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. 216.68 g of DIEP are added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.78 g/mL and a diclofenac sodium equivalent content of 1.05%, measured by quantitative HPLC analysis as described herein above.

EXAMPLE 5

In a 30 liters container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 liters of isopropanol (Fluka-CH) are mixed under mild stirring. To this mixture 2 liters of isopropyl myristate (Fluka-CH) and 10 liters of Dow Corning® ST-Cyclometicone Fluid 5 - NF (from Dow Corning USA) are added under mild stirring. To this solution 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. 216.68 gr. of DIEP are added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.87 g/mL and a diclofenac sodium equivalent content of 1.00%., measured by quantitative HPLC analysis as described herein above.

EXAMPLE 6

In a 30 liters container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 liters of isopropanol (Fluka-CH) are mixed under mild stirring. To this mixture, 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 under mild stirring. To this solution 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. 21.67 g of DIEP are added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.79 g/mL and a diclofenac sodium equivalent content of 0.10%, measured by quantitative HPLC analysis as described herein above.

EXAMPLE 7

In a 30 liters container, 5.5 liters of absolute ethanol (Fluka-CH) and 2.4 liters of isopropanol (Fluka-CH) are mixed under mild stirring. To this mixture, 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 under stirring. To this solution 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. 1085.00 g of DIEP are added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.81 g/mL and a diclofenac sodium equivalent content of 4.98 %, measured by quantitative HPLC analysis as described herein above.

EXAMPLE 8

A volume of 4.4 liters of absolute ethanol (Fluka-CH) and 2.2 liters of isopropanol (Fluka-CH) is mixed in a 30 liter container under mild stirring. To this mixture, 1.1 liters of isopropyl myristate (Fluka-CH) and 11 liters of Dow Corning^® Silicone Fluid Q7-9180 0.65 cSt (from Dow Corning USA) are added under mild stirring. To this solution, 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 895.00 g of DIEP is added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.89 g/mL and a diclofenac sodium equivalent content of 4.71 %, measured by quantitative HPLC analysis as described herein above.

EXAMPLE 9

A volume of 3.75 liters of absolute ethanol (Fluka-CH) and 1.85 liters of isopropanol (Fluka-CH) is mixed in a 30 liters container under mild stirring. To this mixture, 1.25 liters of isopropyl myristate (Fluka-CH) and 12.45 liters of Dow Corning^® Silmogen carrier (from Dow Corning USA) are added under mild stirring. To this solution, 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 895.00 g of DIEP is added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution thus obtained has a density of 0.78 g/mL and a diclofenac sodium equivalent content of 2.46 %, .measured by quantitative HPLC analysis as described herein above.

EXAMPLE 10

To test the diclofenac delivery and skin permeation capability the product obtained as described in Example 1 has been compared in a Franz cell system described above with a commercial product Flector^® EP Gel (gel containing 1.3 % of DIEP). The membrane used in the experiment was obtained from pig ear after removal of external hairs by the Air Dermatome (Zimmer; Munsingen, Switzerland). From the treated skin, 2 cm discs have been obtained to efficaciously cover the operative area of the Franz cell (1 cm²). The experiment was performed with a conventional Franz cell in which the donor compartment was filled with 25 μΐ/cm² of the product obtained as described in example 1 or with 20 mg/ cm2 of Flector^® EP gel (under shelf life obtained from a local Pharmacy), both corresponding to 200 ng of diclofenac sodium equivalent. The receiving compartment was filled with phosphate buffer pH 7.4. During the experiment 1 ml samples were withdrawn 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 washing the skin surface twice with phosphate buffer and passing a cotton tip twice to eliminate any superficial residue. The skin samples were minced in small pieces and extracted with phosphate buffer for 4 hours, then sonicated for 15 minutes to extract all the active ingredient from the tissue. The extraction solution was filtrated and analyzed by the HPLC/UV method already described in Example 1, together with the samples obtained during the experiment. Each experiment was repeated 6 times.

In Figure 1 the diclofenac sodium equivalent cumulative concentration of the two products measured in the receiving compartment is reported.

In Figure 2 together with the data of Figure 1 , the amount of diclofenac sodium equivalent of the two samples measured at 24 hours in the tissue is reported.

The obtained data show that the product of Example 1 has a permeation capacity after 24 hours of 15 μg/cm² while Flector^® EP Gel shows a permeation of 0.3 μg/cm . The absolute amount of the permeated compound of Example 1 is 3 times higher than the amount of the permeated commercial product.

EXAMPLE 11

A volume of 1.53 liters of absolute ethanol (Fluka-CH) and 0.765 liters of isopropanol (Fluka-CH) is mixed in a 30 liters container under mild stirring. To this mixture, 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 under mild stirring. To this solution, 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 46.00 g of DIEP is added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution thus obtained has a density of 0.92 g/mL and a diclofenac sodium equivalent content of 0.20 %, .measured by quantitative HPLC analysis as described herein above.

EXAMPLE 12

A volume of 1.017 liters of absolute ethanol (Fluka-CH) and 0.44 liters of isopropanol (Fluka-CH) for a total percentage of 11% w/w are mixed in a 20-liter container under mild stirring. To this mixture, 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 under mild stirring. To this solution, 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 99 g of DIA is added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution thus obtained has a density of 0.78 and a diclofenac sodium equivalent assay of 1.02% measured by quantitative HPLC analysis as described in Example 1.

EXAMPLE 13

A volume of 0.832 liters of absolute ethanol (Fluka-CH) and 0.36 liters of isopropanol (Fluka-CH) for a total percentage of 11% w/w is mixed in a 20-liter container under mild stirring. To this mixture, 10 liters of Dow Corning^® Silicone Fluid Q7-9180 0.65 cSt (from Dow Corning USA) are added under mild stirring. To this solution, 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 81 g of DIA is added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution thus obtained has a density of 0.74 and a diclofenac sodium equivalent assay of 1.01% measured by quantitative HPLC analysis as described in Example 1.

EXAMPLE 14

A volume of 0.832 liters of absolute ethanol (Fluka-CH) and 0.36 liters of isopropanol (Fluka-CH) for a total percentage of 11% w/w is mixed in a 20-liter container under mild stirring. To this mixture, 10 liters of Dow Corning^® Silicone Fluid Q7-9180 0.65 cSt (from Dow Corning USA) are added under mild stirring. To this solution, 100 g of menthol (Fluka-CH) are added and the stirring proceeds until complete dissolution. An amount of 114 g of DIEP is added to the solution and the stirring is maintained until complete dissolution. All the operations are performed at 15-25 °C. The solution obtained has a density of 0.73 and a diclofenac sodium equivalent assay of 1.03% measured by quantitative HPLC analysis as described in example 1.

COMPARATIVE EXAMPLE

The preparation described in Example 6 of US 2006/0147383 was reproduced by substituting diclofenac acid (DIA) for the active ingredient described therein, clindamycin.

A volume of 6.0 liters of absolute ethanol (Fluka-CH), for a total percentage of 34% w/w over the final total volume, was poured into a 20-liter container under mild stirring, then 0.8 liters of isopropyl myristate (Fluka-CH) and 11 liters of Dow Corning^® Silmogen carrier (mixture of 99 % of Dow Corning^® Silicone Fluid Q7- 9180 0.65 cSt and 1 % of silicone gum from Dow Corning USA) were added thereinto under mild stirring. To this solution 130 g of DIA were added and the stirring was maintained until apparent dissolution. All the operations were performed at 15-25 °C. The solution obtained showed a density of 0.78 and a diclofenac sodium equivalent assay of 1.02% measured by quantitative HPLC analysis as described in Example 1.

The sample thus obtained was analyzed for its UV profile from 600 to 300 nm without dilution and said UV profile was obtained by the V550 UV spectrometer (Jasco-J) with quartz coupled 1 ml cuvettes. The UV profile reported in Fig. 3 below presents an increased absorbance in the 359-400 nm showing that the solution obtained under the conditions of US 2006/0147383 is not clear.

Claims

1. A composition consisting of a solution comprising:

(a) 2-[(2,6-dichlorofenil)amino]benzenacetic acid or a pharmaceutically acceptable organic base salt thereof;

(c) a co-solvent constituted by a mixture of saturated aliphatic alcohols containing from 2 to 4 carbon,

provided that said composition is free from water and from any non-volatile silicone.

2. The composition of claim 1, wherein the Component (a) is a member selected from the group consisting of 2-[(2,6-dichlorofenil)amino]benzenacetic acid and its pharmaceutically acceptable secondary or tertiary organic base salts.

3. The composition of claim 2, wherein the organic tertiary base has the formula I

wherein X is a direct bond or a methylene group.

4. The composition of claim 3, wherein said organic base is l-(2- hydroxyethyl)pyrrolidine.

5. The composition of claim 1, wherein the volatile silicone Component (b) is a methylpolysiloxane having a dynamic viscosity lower than 5 cSt.

6. The composition of claim 5, wherein said methylpolysiloxane is selected from the group consisting of hexamethyldisiloxane, octamethyldisiloxane and decamethylcyclopentasiloxane.

7. The composition according to any one of claims 1 to 6, wherein the alcohol mixture is a ethanol/isopropanol mixture in a ratio of from 1/0.4 to 1/2.3 v/v.

8. The composition according to any one of claims 1 to 7, also comprising a skin permeation enhancer having a dynamic viscosity lower than 5 cSt.

9. The composition of claim 8, wherein said skin permeation enhancer is isopropyl myristate.

10. The composition according to any one of claims 1 to 8 also comprising a refreshing agent.

11. The composition according to any one of claims 1 to 10, having a density (w/v) from 0.6 to 1.0 g/mL.

12. The composition according to any one of claims 1 to 11, characterized in that it is a liquid, sprayable composition.

13. The composition according to any one of claims 1 to 12 consisting of a solution comprising

(b) a volatile silicone, in an amount from 45% to 90%, preferentially from 50% to 87% of the volume of the solution; and

14. The composition according to any one of claims 1 to 13, for use in the transcutaneous treatment of musculoskeletal disorders and pains in a mammal,

15. The composition of claim 13, wherein said mammal is a human patient or a medium/big size animal-mammal.

16. The composition according to any one of claims 14 and 15, wherein said musculoskeletal disorder is selected from the group consisting of bone, articulation, muscle, joint, tendon inflammations and injuries and pains associated therewith.,

17. The composition according to any one of claims 14 and 15, wherein said mammal is a human patient suffering from a musculoskeletal disorder selected from the group consisting of arthritic pain, muscle contracture and tendon injuries.

18. The composition according to any one of claims 14 and 15, wherein said mammal is a dog or a horse suffering from a musculoskeletal disorder selected from the group consisting of muscle contractures and tendon injuries.

19. A method for the transcutaneous treatment of musculoskeletal inflammations, and of pains associated therewith, in a mammal in need of such a treatment, which comprises the spray administration of the composition according to anyone of claims 1 to 12 onto any external body area of said mammal.

20. The method of claim 19, wherein said mammal is a human being, or a medium/big size animal-mammal.

21. The method of claim 20 wherein said animal -mammal is a horse or a dog.