Sustained release medical plaster

Abstract

Dichlofenac-based sustained release medical plasters, in particular medical plasters based on the sodium salt of dichlofenac, whose formulation allows the active ingredient to be released continuously and at a locally therapeutically active concentration over 24 hours, and also polymer adhesive matrices (PSA) for medical plasters based on the sodium salt of dichlofenac are described.

Description

[0001] OBJECT OF THE INVENTION

[0002] The present invention describes a sustained-release medical plaster based on diclofenac, in particular a medical plaster based on the sodium salt of diclofenac, whose formulation allows the active ingredient to be released continuously and at a locally therapeutically active concentration for 24 hours, and also describes a polymer adhesive matrix (PSA) for medical plasters based on the sodium salt of diclofenac.

[0003] The plaster is soft, flexible, adheres perfectly to the skin, does not come off even when applied to the joint area, can be removed without causing pain or irritation. These characteristics, together with the fact that the plaster must be replaced only once every 24 hours, make it particularly satisfactory for the patient. State of the art

[0004] The possibility of administering drugs through the skin has been known for some time and is particularly interesting because it is a non-invasive way of administration, which does not require metabolism by the body and is more comfortable for the patient than other administration routes. The patient in fact can relieve local pain without having to take or inject drugs. Over time, many adhesive release systems have been developed, which, when applied to the skin, release the active ingredient. These systems are usually composed of a polymer adhesive matrix called "pressure-sensitive adhesive" (PSA), which contains the active ingredient of interest in dispersion or solution. The matrix is in turn laid on a support and coated with a protective layer, which is removed before application. The polymer matrix can be of various kinds, but acrylic and methacrylic polymers and their copolymers are usually used.

[0005] Within the general category of adhesive release systems described above, a distinction can be made between transdermal patches and medical plasters, which are defined as different pharmaceutical forms in the International Pharmacopoeia.

[0006] Transdermal patches (Transdermal Patches, European Pharmacopoeia 5.0, 616) are defined as flexible pharmaceutical formulations for topical application, of various shapes and sizes, containing one or more active ingredients, to be applied to healthy skin: the active ingredient is released progressively and, after crossing the skin, it reaches the bloodstream in a therapeutically active amount. Transdermal patches therefore represent an administration route aimed at producing systemic effects and in fact, by way of example, transdermal patches based on nicotine are known in the state of the art for smoking cessation, patches based on sex hormones (usually estrogens) for menopausal syndrome or based on opioid drugs for the treatment of pain in terminal patients.

[0007] As already mentioned, these patches introduce the drug into the bloodstream in a therapeutically active amount, so that it reaches the specific site of action. Their application is in essence a substitute for the more classic systemic administration routes such as oral and injection.

[0008] On the other hand, medical plasters are something else, defined by definition (Medical Plaster, European Pharmacopoeia 5.0, 626) as flexible preparations for topical application, containing one or more active ingredients, to be applied on the skin, formulated so as to maintain the active ingredient in intimate contact with the skin, so that it is released slowly while remaining enriched in the area of application.

[0009] Therefore, in this case, in addition to being in a completely minimal and therapeutically insignificant trace, the active ingredient does not enter the bloodstream and acts only in its area of release. Medical plasters therefore well define a topical administration route with local action and are therefore extremely useful in the treatment of local joint or muscle pain, even chronic pain; they in fact act where they are needed, without entering the bloodstream and avoiding the systemic administration of drugs with moderate toxicity, such as non-steroidal anti-inflammatory drugs (NSAIDs) used selectively for the diseases mentioned above.

[0010] Many medical plasters based on NSAIDs for topical use are described in the prior art, in particular diclofenac, which is known to be an acidic molecule and poorly soluble in water. The formulability of diclofenac is complex when it is administered by application through the skin: it must be ensured that it penetrates through the skin in sufficient quantity for maintaining therapeutic concentration levels on the site of administration.

[0011] The active ingredient must therefore pass through the stratum corneum, which is a hydrophobic barrier, and diffuse in the underlying tissues, characterized by structures and compartments that are both hydrophobic and hydrophilic. The acidic, non-ionized form of diclofenac has a very high partition coefficient: the partition coefficient is the ratio of the concentrations of a compound in a mixture of two immiscible solvents at equilibrium (hydrophobic / hydrophilic). It therefore represents the degree of hydrophobicity of the compound: the higher this coefficient, the higher the hydrophobicity of the compound. This means that, by virtue of its partition coefficient, the acidic form of diclofenac can easily pass through the stratum corneum of the skin, but, highly similar to this, due to its low solubility in water, it does not diffuse so easily in the underlying tissues. On the other hand, when in its salted, less hydrophobic form, it can diffuse in the underlying tissues, however remembering that the degree of hydrophobicity is of course related to the type of salt considered. This explains why products for topical application based on diclofenac are usually formulated with various salted forms of diclofenac, independently of the PSA matrix used. The fact of salification in fact attenuates the hydrophobicity of the molecule, making it have a biphasic feature that mimics the skin as a whole, thus ensuring a facilitated permeation and, above all, allowing a suitable formulability.

[0012] For the purposes of this invention, the following should be kept in mind:

[0013] WO2006097149 describes a transdermal patch whose PSA matrix is ​​based on Eudragit® NE40 (poly(ethyl acrylate, methyl methacrylate) 2:1) which releases various active ingredients into the bloodstream, especially when containing some active ingredients, notably oxybutynin, eliminating the problem of shrinkage of the matrix itself during the preparation stage of the patch;

[0014] WO2016059583 describes a medical plaster, the PSA matrix of which is composed of 387-2516 / 87-2516 (acrylic acid-vinyl acetate copolymer, CAS 326602-88-4) and E100 (poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1) is composed in a specific ratio (50-60%: 6-16%); this mixture has been shown to ensure high adhesion to the plaster, excellent stability, and sufficient release of the active ingredient dispersed therein, particularly diclofenac in the form of its sodium salt, hydroxyethylpyrrolidinoyl salt (also known as epolamine), or diethylammonium salt (DEA). Regardless of the type of salt, the concentration of diclofenac present in the plaster ranges from 8 to 20%, and averages slightly above 15%. However, the matrix thus formulated is strongly hydrophobic, and therefore significantly slows down the complete release of the active ingredient.

[0015] WO2012089256 describes a medical plaster composed of 30-55% of The invention relates to a PSA matrix composed of NE40 (poly(ethyl acrylate, methyl methacrylate) 2:1) and 42-55% of an ester of citric acid as a plasticizer, in which diclofenac diethylammonium salt (DEA) is dispersed, which is released continuously over a period of 24 hours. The choice of diclofenac salt is not accidental, since the inventors themselves have demonstrated that, with the same composition in terms of matrix, active ingredient and excipients, diclofenac DEA salt is released in a constant, continuous, prolonged and therapeutically effective manner over a period of 24 hours; in contrast, diclofenac sodium salt is released in a minimal manner and is absolutely unsuitable for exerting the desired pharmacological effect over a time interval of 24 hours or less. Basically, it follows that diclofenac sodium salt is absolutely unsuitable for inclusion in a formulation based on NE40 is used in medical plasters based on PSA formulated with citrate.

[0016] The object of the present invention is to overcome the previously indicated disadvantages and problems characterizing the prior art.

[0017] The Applicant has in fact surprisingly found that starting from a PSA matrix of ethyl acrylate-methyl methacrylate mixed with suitable excipients, it is possible to prepare a medical plaster which is able to release diclofenac sodium salt in a constant, continuous, prolonged manner, with local therapeutic active doses, for 24 hours. The release of diclofenac sodium salt has a profile similar to that of the market leader products, as will be demonstrated hereinafter.

[0018] The results achieved by adding to the matrix a component normally used as an antioxidant but never for the purposes described herein, show a clear overcoming of the prior art: a long-acting medical plaster which is easy to formulate, which is virtually free of toxicity and side effects, and which is satisfactory for the patient who can change it only once in 24 hours, is in fact available.

[0019] DETAILED DESCRIPTION

[0020] The present application relates to a medical plaster comprising

[0021] • a base layer (backing),

[0022] • a "pressure sensitive adhesive" (PSA) matrix,

[0023] • a protective coating layer (lining),

[0024] wherein said PSA matrix comprises

[0025] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio, in a concentration ranging from 40 to 49% by weight with respect to the dry weight of the matrix;

[0026] • a plasticizer selected from esters of citric acid, in a concentration ranging from 40 to 49% by weight with respect to the dry weight of the matrix;

[0027] • butylated hydroxyanisole (BHA), in a concentration ranging from 0.10 to 0.20% by weight with respect to the dry weight of the matrix;

[0028] dispersed in said PSA matrix

[0029] • an active ingredient which is sodium diclofenac, in a concentration ranging from 1 to 20% by weight with respect to the dry weight of the matrix.

[0030] It is specified that neutral copolymers based on ethyl acrylate and methyl methacrylate in a 2:1 ratio are available on the market in aqueous dispersion at 30% or 40% by weight of dry product (respectively NE30D and NE40D, Evonik Industries AG technical information).

[0031] According to the present invention, the applicant claims a medical plaster comprising a PSA matrix and the PSA matrix itself, said PSA matrix comprising

[0032] Based on a neutral copolymer of ethyl acrylate and methyl methacrylate in a 2:1 ratio, with a concentration ranging from 40 to 49% dry weight relative to the dry weight of the matrix

[0033] The range of 40 to 49% dry weight of the copolymer thus refers to the weight of the dry product contained in the aqueous dispersion as disclosed above. Preferably, the neutral copolymer of ethyl acrylate and methyl methacrylate in a ratio of 2:1 is present in an aqueous dispersion at 40% by weight ( NE40D).

[0034] In the medical plaster according to the invention, a "pressure-sensitive adhesive" (PSA) matrix is ​​applied by laying on a base layer (backing), said matrix being then coated with a protective coating layer (liner) which is removed before application.

[0035] The main advantage of the medical plaster containing diclofenac sodium salt according to the present invention lies in the fact that, after topical application, it releases the active ingredient at a therapeutically active concentration at the site of application for the next 24 hours. The plaster is soft, flexible, adheres perfectly to the skin, does not cause pain or irritation when removed, maintains the stability of the active ingredient over time, and ensures its pharmacological effect for 24 hours, significantly improving patient compliance, as the patient will need to replace the plaster only once a day, rather than twice or more.

[0036] The invention also relates to said medical plaster for the once-a-day treatment of painful and inflammatory conditions affecting the musculoskeletal system, such as, for example, osteoarthritis, and also wounds, such as sprains, muscle tears, abrasions with intact skin, more particularly when a local effect is desired and it is preferred or necessary to avoid the administration of analgesics / anti-inflammatory drugs orally or by injection.

[0037] The present invention also relates to a polymeric adhesive matrix (PSA) comprising or consisting of:

[0038] Based on a neutral copolymer of ethyl acrylate and methyl methacrylate in a 2:1 ratio, with a concentration ranging from 40 to 49% dry weight relative to the dry weight of the matrix;

[0039] a plasticizer chosen from esters of citric acid, in a concentration ranging from 40 to 49% by weight relative to the dry weight of the matrix, as defined above;

[0040] Butylated hydroxyanisole (BHA) in a concentration range of 0.10 to 0.20% by weight relative to the dry weight of the matrix;

[0041] in which are dispersed

[0042] • an active ingredient which is diclofenac sodium, in a concentration ranging from 1 to 20% by weight with respect to the dry weight of the matrix.

[0043] The medical plaster according to the present application comprises or consists entirely of:

[0044] • a layer which acts as a base (backing) which is uniformly spread over the base (backing)

[0045] • a "pressure-sensitive adhesive" matrix dispersed therein,

[0046] • an active ingredient which coats the matrix

[0047] • a protective layer which acts as a lining, which is removed before application.

[0048] The backing is made of a soft and flexible material, which can be shaped in any form and size: generally a polymeric base is used, in particular a polyester. In the plaster described herein, the backing is a non-porous 100% polyester non-woven fabric, which increases the adhesion to the skin and prevents the adhesive matrix and the drug dispersed therewith from leaking out.

[0049] The lining is a protective sheet of single-silicone paper, which can be easily removed.

[0050] The active ingredient used in the medical plaster according to the present application is the diclofenac sodium salt (DicloNa); as already mentioned, the choice of the salified diclofenac is necessary in view of the chemical-physical properties of this active ingredient. With regard to the choice of the salt, it is known in the prior art that the properties of the counterion with which the diclofenac is salified are extremely important: in particular, it is necessary for the salt to maintain a sufficient hydrophobicity, in order to be able to cross the stratum corneum of the skin, but also a sufficient hydrophilicity, in order to be able to diffuse in the underlying layers, reaching the local therapeutic active concentration, as required by the medical plaster. The diclofenac salt which has shown the best performance in this sense is the organic salt with a fatty amine (linear and cyclic). Conversely, the diclofenac salts with inorganic bases, in particular with potassium or sodium, are not suitable for this type of application, since they have a very low partition coefficient, which is up to 3000 times lower than that of the acid diclofenac; their very high hydrophilicity thus strongly limits their passage through the stratum corneum of the skin (Fini et al., 2012, Pharmaceutics, 4, 413-429).

[0051] To confirm this, on the market there are products for topical application in the form of emulsions based on diclofenac, in which the active ingredient is salified with diethylamine, which is a linear amine (for example, Voltaren Emulgel®). The use of a linear amine as counterion is not suitable for the purposes of the present application, since it does not allow the active ingredient to be sufficiently hydrophobic to cross the stratum corneum of the skin, but also sufficiently hydrophilic to diffuse in the underlying layers, reaching the local therapeutic active concentration, as required by the medical plaster. ), or more interestingly for the purposes of the present invention in the form of a medical plaster in which a salt is formed with a hydroxyethylpyrrolidine which is a cyclic amine (e.g. a medical plaster ).

[0052] The possibility of using diclofenac sodium salt represents a significant improvement over the prior art with regard to industrial processing and potential side effects of the end product. With regard to industrial aspects, the synthesis of the sodium salt is very simple and economical to carry out, without the use of toxic reagents and without the need for controlled disposal of process waste. With regard to potential side effects of the end product, it is known that aliphatic amines, especially cyclic amines, can be toxic or at least very frequently cause irritation, either due to the release of the amine itself or of its metabolites (Myers et al., 1997, J Tox Subst Mech, 16, 2; Greim et al., 1998, Chemosphere, 36, 271-295).

[0053] The use of diclofenac sodium salt thus eliminates these problems and makes the subject plasters of the invention also suitable for sensitive and allergy-prone skin, such as, for example, the skin of elderly patients or potentially allergic or atopic subjects.

[0054] The PSA matrix consists of an aqueous dispersion of a copolymer derived from esters of acrylic acid and methacrylic acid, preferably consisting of NE40D (Evonik Industries), consisting of a 40% by weight poly(ethyl acrylate, methyl methacrylate) copolymer in a 2:1 ratio in aqueous dispersion. A plasticizer selected from esters of citric acid, preferably tributyl citrate, is added to this copolymer; this results in a matrix similar to that described, for example, in WO2012089256. The release of diclofenac in the form of its sodium salt has been tested without success.

[0055] However, the applicants have surprisingly discovered that the addition of minimal amounts of butylated hydroxyanisole (BHA) to the matrix described above significantly improves its properties, allowing the DicloNa dispersed therein to be released in a constant, continuous, extended manner in a locally therapeutically active dose for a duration of up to 24 hours.

[0056] The release profile is fully comparable to the commercial product widely used as a once-daily plaster The release profile of the commercial product contains diclofenac salt of hydroxyethylpyrrolidine, thus with salts of cyclic amines and a completely different PSA matrix (based on gelatin, polyvinylpyrrolidone, carboxymethylcellulose and other polymers).

[0057] BHA is an antioxidant and antiseptic ingredient widely used in the food, cosmetic and animal feed industry, to avoid the rancidity of the fats contained therein. It is also used in pharmaceuticals, as an excipient in solid formulations of active ingredients of lipid nature, particularly to avoid oxidation and, therefore, the loss or at least reduction of pharmacological activity: they are formulated with BHA, for example, isotretinoin, some statins and ketoconazole (Braz J Pharm Sci, 2012, 48, 405-4015). BHA is also used in liquid pharmaceutical formulations, such as injections, when there are unstable active ingredients present.

[0058] Within the scope of the present application, BHA is used for the first time in a solid composition free of lipid components, for topical use, and it therefore does not require antioxidants, as will be demonstrated below, thus ensuring the release of diclofenac sodium dispersed in the PSA matrix of the medical plaster of the object of the present application in a constant and continuous manner over 24 hours, possibly reaching the circulating flow only in trace amounts, thus respecting the definition of medical plaster.

[0059] This result is completely opposite and unexpected with respect to the teachings of the prior art.

[0060] The release evaluation of diclofenac is carried out by means of the dissolution test described in the official pharmacopoeias, more specifically in the present application by means of the dissolution test described in the European Pharmacopoeia (Ph. Eur. 5.0, 2.9.4). The equipment used to carry out the dissolution test differs from each other in the type of support in which the material to be analyzed is placed, with respect to the different pharmaceutical forms to be tested. The general method for carrying out the test is the same: briefly, the sample to be analyzed is placed in a suitable support, which is in turn inserted into a larger container in which a medium (dissolution medium) heated to a specific temperature is placed, which comes into contact with the sample. The drug is gradually transferred from the sample to the dissolution medium; portions of the dissolution medium are periodically collected and analyzed in order to calculate the amount of drug present therein. The analysis is usually carried out with a spectroscope or with high-performance liquid chromatography (HPLC), more frequently with HPLC. In the dissolution test, it is necessary to operate under sink conditions, i.e. with a large volume of dissolution medium: in fact, only in this way it is possible to avoid that the degree of dissolution of the active ingredient is lower than the actual one, since the concentration in the receiving medium increases gradually, if it is a small volume of receiving medium, it quickly approaches saturation.

[0061] [2] The PSA matrix of the medical plaster according to the present application comprises or consists of:

[0062] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio, in a concentration ranging from 40 to 49% by dry weight with respect to the dry weight of the matrix, as defined above;

[0063] • a plasticizer selected from esters of citric acid, in a concentration ranging from 40 to 49% by weight with respect to the dry weight of the matrix;

[0064] • butylhydroxyanisole (BHA) in a concentration ranging from 0.10 to 0.20% by weight with respect to the dry weight of the matrix;

[0065] dispersed in said PSA matrix is

[0066] • an active ingredient which is diclofenac sodium in a concentration ranging from 1 to 20% by weight with respect to the dry weight of the matrix.

[0067] Preferably the ester of citric acid is selected from triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, more preferably said ester is tributyl citrate.

[0068] The composition of the PSA matrix of the medical plaster according to the present application preferably comprises or consists of:

[0069] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio in a 40% by weight aqueous dispersion, in a concentration ranging from 45 to 48% by weight with respect to the dry weight of the matrix, as defined above;

[0070] • the plasticizer is tributyl citrate in a concentration ranging from 45 to 48% by weight with respect to the dry weight of the matrix;

[0071] • BHA in a concentration ranging from 0.13 to 0.18% by weight with respect to the dry weight of the matrix;

[0072] Diclofenac sodium is dispersed in said PSA matrix in a concentration ranging from 5 to 10% by weight with respect to the dry weight of the matrix.

[0073] The concentrations are always expressed by weight with respect to the dry weight of the matrix; since the pharmacological action is exerted by the single diclofenac sodium dispersed in the PSA matrix, as the concentration of the PSA matrix varies with respect to the amount of active ingredient inserted into the plaster, the amounts of copolymer and plasticizer will also vary, up to the full 100% of the final composition. The composition of the PSA matrix of the medical plaster according to the present application even more preferably comprises or consists of:

[0074] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio in a 40% by weight aqueous dispersion, in a concentration equal to 46.3% by weight with respect to the dry weight of the matrix, as defined above;

[0075] • tributyl citrate in a concentration equal to 46.3% by weight with respect to the dry weight of the matrix;

[0076] • BHA at a concentration equal to 0.15% by weight with respect to the dry weight of the matrix;

[0077] Diclofenac sodium is dispersed in the PSA matrix described above at a concentration equal to 7.25% by weight with respect to the dry weight of the matrix.

[0078] The method for preparing the medical plaster of the object of the present application containing Diclofenac sodium (DicloNa) dispersed in the PSA matrix described above, consists of various phases, which can be summarized as follows:

[0079] • mixing the selected plasticizer and BHA until dissolution;

[0080] • adding DicloNa and mixing until dissolution;

[0081] • adding the selected neutral copolymer in aqueous dispersion, based on ethyl acrylate and methyl methacrylate in a 2: 1 ratio, and mixing until complete dispersion;

[0082] • pouring the PSA / DicloNa matrix mass on a temporary liner;

[0083] • drying the mass and coupling it with the backing;

[0084] • replacing the temporary liner with the final liner;

[0085] • cutting the plaster to the desired size;

[0086] • inserting each plaster in its primary packaging.

[0087] Some examples are provided for a better illustration of the purposes and advantages of the present application, which in no way limit the scope of the claims.

[0088] Example 1

[0089] Preparation of a medical plaster containing DicloNa 140 mg

[0090] The ingredients for preparing a medical plaster having a size of 140 x 100 mm, containing 140 mg of Diclofenac sodium, are:

[0091]

[0092] Method

[0093] TBC and BHA are mixed under stirring and under vacuum for about 15 minutes until they are completely dissolved. Then Diclofenac sodium is added to the mixture, under stirring and under vacuum at a temperature not exceeding 25°C until complete dissolution. Then NE 40D, at a temperature not higher than 25°C, continue the operation under vacuum, with fast stirring for about 1 minute, then with moderate stirring for 10 minutes, and finally reduce the stirring speed to the minimum and maintain for 2 hours.

[0094] The substance is finally left to rest under vacuum for 8 hours in succession.

[0095] The substance thus obtained is spread on a temporary backing made of siliconized polyester and is placed in a forced-air drying machine at a temperature gradient ranging from 65 to 115°C for 5 minutes to dry. The product thus obtained is then coupled with a 100% non-woven polyester backing by pressing, and subsequently the temporary backing is replaced with a final backing consisting of a monosiloxane paper, then the plaster is cut to the desired size (140 x 100 mm), thus obtaining the plaster with the final primary packaging.

[0096] Example 2

[0097] Diflunisal release (dissolution test)

[0098] The release of diclofenac from the medical plaster of the present application was evaluated with a dissolution test, using a commercial product that releases the active ingredient in 24 hours as a comparison. The reference product is (Batch 1506031), containing 180 mg of diclofenac hydroxyethylpyrrolidine salt, corresponding to 140 mg of sodium diclofenac.

[0099] The active ingredient that exerts the pharmacological activity and whose release needs to be evaluated is diclofenac, and not its salt, whatever it can be.

[0100] The dissolution test was performed according to that described in the European Pharmacopoeia (Ph. Eur. 5.0, 2.9.4), with the rotating cylinder method, using as dissolution medium a phosphate buffer in a physiological saline solution, with pH = 7.4 (PBS - Ph. Eur. 4.1.3), under the following operating conditions:

[0101]

[0102] The analysis of the sampling medium was performed with an HPLC apparatus (Agilent 1100), according to what is known by the person skilled in the art.

[0103] Sample A is a plaster prepared according to Example 1, while sample B is

[0104] From each sample, 20 cm 2(2 x 10 cm) and applied to the outer surface of the cylinder with double-sided adhesive tape, so as to expose to the dissolution medium a surface containing the PSA matrix and having dispersed therein diclofenac, and in such a way that the larger axis of the plaster portion corresponds perfectly to the circumference of the cylinder. When the temperature of the dissolution medium reaches the expected value, the protective liner is removed, the sample is coated with a Cuprophan membrane, which exceeds the sample size by at least 1 cm, and is fixed with adhesive tape; finally the cylinder is immersed in the medium and immediately the rotation is started at the prescribed speed. At the established time intervals, 2 ml samples are taken from the intermediate region between the surface of the dissolution medium and the upper edge of the cylinder. The volume removed is immediately replaced with an equal volume of fresh dissolution medium.

[0105] The dissolution values and the relative curves are shown in Table 1 below and in the graphs shown in Figure 1 Table 1.

[0106] Table 1

[0107]

[0108] It is evident that the diclofenac present in sample A has an absolutely comparable release profile to the diclofenac contained in the product (sample B), which is the reference product in long-acting medical plasters. Therefore, sample A, in particular the medical plaster object of the present application, releases diclofenac from its sodium salt in a constant, continuous and progressive manner over 24 hours, which can effectively exert its pharmacological effect.

[0109] These data are extremely surprising, since they show that

[0110] • starting from a PSA matrix known to release diclofenac diethylamine salt, but not diclofenac sodium salt, in a sufficient manner, and

[0111] • using diclofenac sodium salt known not to be suitable for use in medical plasters

[0112] • by adding BHA to the PSA matrix formulation, i.e. a substance known for its antioxidant properties, not essential in this context,

[0113] obtained a medical plaster which

[0114] • releases the active ingredient in a constant, continuous, prolonged manner, at a locally therapeutically active dose, for a duration of 24 hours, and therefore can be replaced only once a day by the person using it;

[0115] • does not contain linear aliphatic amines or cyclic amines, and therefore does not pose the risk of exposure to toxic or irritating phenomena, and therefore can also be applied on sensitive or easily allergic skin;

[0116] • is industrially convenient, since the process for the preparation of the sodium salt is fast, economical and does not include the controlled disposal of operating waste.

Claims

1. A medical plaster comprising • Grassroots, • "pressure sensitive adhesive" matrix, • Protective coating, Wherein the "pressure-sensitive adhesive" matrix comprises or consists of: • Based on a neutral copolymer of ethyl acrylate and methyl methacrylate in a 2:1 ratio, with concentrations ranging from 40 to 49% dry weight relative to the dry weight of the matrix; • a plasticizer chosen from esters of citric acid, in a concentration ranging from 40 to 49% by weight relative to the dry weight of the matrix; • Butylated hydroxyanisole in a concentration range of 0.10 to 0.20% by weight relative to the dry weight of the matrix; Dispersed in the "pressure sensitive adhesive" matrix are • The active ingredient, which is diclofenac sodium, is present in a concentration ranging from 1 to 20% by weight relative to the dry weight of the matrix.

2. The medical plaster according to claim 1, wherein the ester of citric acid is selected from the group consisting of triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, and tributyl citrate.

3. The medical plaster according to claim 1 or 2, wherein the "pressure-sensitive adhesive" matrix comprises or consists of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a ratio of 2:1 at 40% by weight in aqueous dispersion at a concentration ranging from 45 to 48% by dry weight relative to the dry weight of the matrix; • a plasticizer which is tributyl citrate in a concentration range of 45 to 48% by weight relative to the dry weight of the matrix; • Butylated hydroxyanisole, in a concentration range of 0.13 to 0.18% by weight relative to the dry weight of the matrix; Diclofenac sodium is dispersed in the "pressure-sensitive adhesive" matrix at a concentration ranging from 5 to 10% by weight relative to the dry weight of the matrix.

4. The medical plaster according to claim 1 or 2, wherein the "pressure-sensitive adhesive" matrix comprises or consists of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a ratio of 2:1, in an aqueous dispersion at 40% by weight, relative to the dry weight of the matrix, for a concentration equal to 46.3% by dry weight; • tributyl citrate, at a concentration equal to 46.3% by weight relative to the dry weight of the matrix; • Butylated hydroxyanisole, at a concentration equal to 0.15% by weight relative to the dry weight of the matrix; Diclofenac sodium is dispersed in the "pressure-sensitive adhesive" matrix at a concentration equal to 7.25% by weight relative to the dry weight of the matrix.

5. The medical plaster according to claim 1 or 2, wherein the base layer is composed of a non-porous 100% polyester non-woven fabric.

6. The medical plaster according to claim 1 or 2, wherein the protective coating layer is a protective sheet of a single silicone paper.

7. The medical plaster according to claim 1, wherein the ester is tributyl citrate.

8. Use of a medical plaster according to claim 1 or 2 for the preparation of a medicament for the once-a-day treatment of painful and inflammatory conditions affecting the musculoskeletal system and also wounds.

9. Use according to claim 8, wherein the pain and inflammatory disorder affecting the musculoskeletal system is osteoarthritis, and wherein the wound is a sprain, a muscle tear, an abrasion with intact skin.

10. A "pressure-sensitive adhesive" matrix comprising or consisting of: • Based on a neutral copolymer of ethyl acrylate and methyl methacrylate in a 2:1 ratio, with concentrations ranging from 40 to 49% dry weight relative to the dry weight of the matrix; • a plasticizer chosen from esters of citric acid, in a concentration ranging from 40 to 49% by weight relative to the dry weight of the matrix; • Butylated hydroxyanisole in a concentration range of 0.10 to 0.20% by weight relative to the dry weight of the matrix; Dispersed in the "pressure sensitive adhesive" matrix are • The active ingredient, which is diclofenac sodium, is present in a concentration ranging from 1 to 20% by weight relative to the dry weight of the matrix.

11. "Pressure sensitive adhesive" matrix according to claim 10, wherein the ester is selected from triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate.

12. A "pressure sensitive adhesive" matrix according to claim 10, wherein the ester is tributyl citrate.

13. A "pressure-sensitive adhesive" matrix according to claim 10, comprising or consisting of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a ratio of 2:1 at 40% by weight in aqueous dispersion at a concentration ranging from 45 to 48% by dry weight relative to the dry weight of the matrix; • a plasticizer which is tributyl citrate in a concentration range of 45 to 48% by weight relative to the dry weight of the matrix; • Butylated hydroxyanisole, in a concentration range of 0.13 to 0.18% by weight relative to the dry weight of the matrix; The concentration of diclofenac sodium dispersed in the "pressure-sensitive adhesive" matrix is ​​in the range of 5 to 10% by weight relative to the dry weight of the matrix.

14. A "pressure-sensitive adhesive" matrix according to claim 10, comprising or consisting of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a ratio of 2:1, in an aqueous dispersion at 40% by weight, relative to the dry weight of the matrix, for a concentration equal to 46.3% by dry weight; • tributyl citrate, at a concentration equal to 46.3% by weight relative to the dry weight of the matrix; • Butylated hydroxyanisole, at a concentration equal to 0.15% by weight relative to the dry weight of the matrix; Diclofenac sodium is dispersed in the said "pressure-sensitive adhesive" matrix at a concentration equal to 7.25% by weight relative to the dry weight of the matrix.

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