SLOW-RELEASE MEDICAL PLASTER

Abstract

The invention relates to a slow-release medical plaster based on diclofenac, in particular a medical plaster based on diclofenac sodium salt, the formulation of which allows the release of the active ingredient continuously and at locally therapeutically active concentrations for 24 hours, as well as an adhesive polymeric matrix (PSA) for use in a medical plaster based on diclofenac sodium salt.

Description

Title of the invention: SLOW-RELEASE MEDICAL PLASTER Technical field

[0001] The present invention describes a slow-release medical plaster based on diclofenac, in particular a medical plaster based on diclofenac sodium salt, the formulation of which allows the release of the active ingredient continuously and at locally therapeutically active concentrations for 24 hours, as well as an adhesive polymer matrix (PSA) for use in a medical plaster based on diclofenac sodium salt.

[0002] The plaster is soft, flexible, adheres perfectly to the skin, does not come off even when applied to a joint area, it can be removed without causing pain or irritation. These characteristics, as well as the fact that the plaster only needs to be replaced once every 24 hours, make it particularly pleasant for the patient. PREVIOUS ART

[0003] The possibility of administering drugs through the skin has been known for a long time and is particularly interesting because it is a non-invasive means of administration, metabolically undemanding for the body and more pleasant for the patient than other routes of administration. Patients can indeed find relief from localized pain without necessarily taking medication orally or by injection. Over time, many adhesive delivery systems have been developed which, when applied to the skin, release the active ingredient. These systems generally consist of an adhesive polymer matrix, called "Pressure Sensitive Adhesive" (PSA), which contains, in dispersion or solution, the active ingredient of interest. The matrix is ​​in turn spread on a support and covered with a protective layer, to be removed before application.The polymer matrix can be of different types, but generally acrylic and methacrylic polymers and their copolymers are used.

[0004] Within the generic category of adhesive delivery systems described above, transdermal patches and medical plasters can be distinguished, defined in international pharmacopoeias as distinct pharmaceutical forms.

[0005] Transdermal patches (Transdermal Patches, European Pharmacopoeia 5.0, 616) are defined as flexible pharmaceutical preparations for topical application, having various shapes and sizes, containing one or more active ingredients, to be applied to healthy skin: the active ingredient is released gradually and, after passing through the skin, it reaches the bloodstream in a therapeutically active quantity. Transdermal patches therefore represent a route of administration intended to give a systemic effect and, in fact, by way of example, the prior art knows nicotine-based transdermal patches for smoking cessation, sex hormone-based patches, generally estrogens, for menopausal syndrome or opiate-based drugs for the treatment of pain in terminally ill patients.

[0006] As already mentioned, these are patches that introduce the drug into the bloodstream in a therapeutically active amount, so that it reaches the specific site of action. Their use is essentially an alternative to more conventional systemic routes of administration, such as oral and injection.

[0007] Medical plasters, on the other hand, are another thing which, according to the definition (Medical Plasters, European Pharmacopoeia 5.0, 626), are flexible preparations for topical application, containing one or more active ingredients, to be applied to the skin, formulated in such a way as to keep the active ingredient in close contact with the skin, so that it is released slowly while remaining concentrated in the area of ​​application.

[0008] In this case, the active ingredient does not enter the bloodstream, except in very minimal and non-therapeutically significant traces, and acts exclusively in the area in which it has been released. Medical plasters therefore clearly define a topical administration route with local action and are therefore extremely useful in the treatment, even chronic, of localized joint or muscle pain; they act where necessary, without passing into the bloodstream, and avoid the systemic administration of drugs with a moderate degree of toxicity, such as non-steroidal anti-inflammatory drugs (NSAIDs), used electively in the aforementioned diseases.

[0009] Many medical plasters for topical use based on NSAIDs are described in the prior art, in particular diclofenac which, as is known, is an acidic molecule and poorly soluble in water. The formulability of diclofenac, when it is to be administered by cutaneous application, is complex: it must be ensured that it penetrates through the skin in sufficient quantity to maintain therapeutic concentration levels at the administration site.

[0010] The active ingredient must therefore cross the stratum corneum, which is a hydrophobic barrier, and be diffused into the underlying tissue, characterized by structures and compartments of both a hydrophobic and hydrophilic nature. Diclofenac in its acidic, undissociated form has an extremely high partition coefficient: the partition coefficient is the ratio of the concentrations of a compound in a mixture of two immiscible solvents (hydrophobic / hydrophilic) at equilibrium. It therefore expresses the degree of hydrophobicity of a compound: the higher this coefficient, the more hydrophobic the compound. This means that diclofenac in acid form, by virtue of its partition coefficient, is able to easily cross the stratum corneum of the skin, being very similar to it, but, due to its low solubility in water, it does not diffuse with the same ease into the underlying tissues. It is, however, able to diffuse into the underlying tissue when it is in its salinized form, which is less hydrophobic, knowing however that the degree of hydrophobicity is naturally linked to the type of salt considered. This explains why, in general, products for topical application based on diclofenac are formulated with diclofenac in various salinized forms, independently of the PSA matrix used.Salinization in fact attenuates the hydrophobic nature of the molecule, giving it a biphasic character which reproduces the biphasic nature of the skin as a whole, thus ensuring appropriate penetration and above all allowing adequate formability.

[0011] In the context of the present invention, the following should be recalled:

[0012] WO2006097149 which describes a transdermal patch whose PSA matrix based Eudragit® NE40 (poly(ethyl-acrylate, methyl-methacrylate) 2:1) releases various active ingredients into the bloodstream and, especially when it contains certain active ingredients, including oxybutynin, eliminates the problem of shrinkage of the matrix itself during the patch preparation phases;

[0013] WO2016059583 which describes a medical plaster whose PSA matrix is ​​composed of DuroTak® 387-2516 / 87-2516 (acrylic-vinyl acetate copolymer, CAS 326602-88-4) and Eudragit® E100 (poly(butyl-methacrylate, (2-dimethylaminoethyl)methacrylate, methyl-methacrylate) 1:2:1), in specific proportions (50-60% : 6-16%); this mixture has proven to ensure strong adhesion to the plaster, excellent stability and adequate release of the active ingredient dispersed in it, in particular diclofenac, in the form of sodium salt, hydroxyethylpyrrolidine salt (also called epolamine) or diethylammonium salt (DEA). The concentration of diclofenac present in the plaster, regardless of the type of salinization, varies from 8 to 20% and is on average slightly above 15%. The matrix thus formulated is however highly hydrophobic and therefore significantly slows down the complete release of the active ingredient;

[0014] WO2012089256 which describes a medical plaster made of a PSA matrix of Eudragit® NE40 (poly(ethyl-acrylate, methyl-methacrylate) 2:1) at 30-55% and a citric acid ester at 42-55% as plasticizer, in which the diethylammonium salt of diclofenac (DEA) is dispersed, which is released continuously over a period of 24 hours. The choice of the diclofenac salt is not accidental because it has been demonstrated by the inventors themselves that, with the same composition in terms of matrix, active ingredient and excipients, the DEA salt of diclofenac is released constantly, continuous, prolonged and therapeutically effective for 24 hours; diclofenac sodium salt, on the contrary, is released minimally, absolutely unsuitable for exerting the desired pharmacological effect, either for 24 hours or for shorter time intervals. Basically, it follows that diclofenac sodium salt is absolutely unsuitable for inclusion in a medical plaster whose PSA matrix is ​​based on Eudragit® NE40 in formulation with a citric acid ester.

[0015] The objective of the present invention is to overcome the previously indicated drawbacks and problems which characterize the prior art.

[0016] The applicant has indeed surprisingly discovered that, from a PSA matrix of ethylacrylate-methyl methacrylate mixed with suitable excipients, it is possible to prepare a medical plaster capable of releasing the diclofenac sodium salt in a constant, continuous and prolonged manner, at locally therapeutically active doses for 24 hours. The release of the diclofenac sodium salt has a profile similar to that of a market-leading product, as will be demonstrated below.

[0017] This result, which is obtained by adding to the matrix a component normally used as an antioxidant but never used for the purposes described here, represents a clear improvement over the prior art: a long-lasting, easy-to-formulate medical plaster is in fact made available, practically free of toxicity and side effects and pleasant for the patient, who may replace it only once in 24 hours. Summary of the invention

[0018] The present invention relates to a medical plaster comprising

[0019] • a base layer (support),

[0020] • a “Pressure Sensitive Adhesive” (PSA) matrix,

[0021] • a protective coating layer (coating),

[0022] wherein the PSA matrix comprises

[0023] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio, at a concentration of between 40 and 49% by dry weight relative to the dry weight of the matrix;

[0024] • a plasticizing agent chosen from citric acid esters, at a concentration between 40 and 49% by weight relative to the dry weight of the matrix;

[0025] • butylhydroxyanisole (BHA) at a concentration of between 0.10 and 0.20% by weight relative to the dry weight of the matrix;

[0026] being dispersed in said PSA matrix

[0027] • an active ingredient, which is diclofenac sodium, at a concentration of between 1 and 20% by weight relative to the dry weight of the matrix.

[0028] It is specified that the neutral copolymer based on ethyl acrylate and methyl methacrylate in a ratio of 2:1 is available on the market in aqueous dispersion at 30% or 40% by weight of dry product (respectively Eudragit® NE30D and Eudragit® NE40D, Evonik Industries AG Technical Information).

[0029] According to the present invention, the applicant claims a medical plaster comprising a PSA matrix, and the PSA matrix itself, comprising

[0030] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio, at a concentration of between 40 and 49% by dry weight relative to the dry weight of the matrix

[0031] the range of 40 to 49% by dry weight of said copolymer thus referring to the weight of the dry product contained in the aqueous dispersion as described above. The neutral copolymer based on ethyl acrylate and methyl methacrylate in a ratio of 2:1, in aqueous dispersion at 40% by weight (Eudragit® NE40D) is preferred.

[0032] In the medical plaster according to the present invention, the "Pressure Sensitive Adhesive" (PSA) matrix is ​​applied by spreading on the base layer (support), said matrix then being covered by the protective coating layer (covering), to be removed before application.

[0033] The main advantage of the medical plaster containing diclofenac sodium salt according to the present invention is that, after local application, it releases the active ingredient during the following 24 hours at therapeutically active concentrations at the site of application. The plaster is soft, flexible, adheres perfectly to the skin, can be removed without causing pain or irritation, maintains the stability of the active ingredient over time and, by ensuring its pharmacological effect for 24 hours, significantly improves the compliance of the patient, who will have to replace the plaster only once a day, and not twice or more.

[0034] The present invention also relates to said medical plaster intended for use in the once-daily treatment of painful and inflammatory conditions affecting the musculoskeletal system, such as for example osteoarthritis, and also traumas such as sprains, muscle tears, bruises with intact skin, more specifically when a localized effect is desired and it is preferable or necessary to avoid the administration of analgesic / anti-inflammatory drugs orally or by injection.

[0035] The present invention also relates to an adhesive polymeric matrix (PSA) comprising or consisting of:

[0036] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio, at a concentration of between 40 and 49% by dry weight relative to the dry weight of the matrix;

[0037] • a plasticizing agent chosen from citric acid esters, at a concentration between 40 and 49% by weight relative to the dry weight of the matrix, as defined above;

[0038] • butylhydroxyanisole (BHA) at a concentration of between 0.10 and 0.20% by weight relative to the dry weight of the matrix;

[0039] said PSA matrix in which is dispersed

[0040] • an active ingredient, which is diclofenac sodium, at a concentration of between 1 and 20% by weight relative to the dry weight of the matrix.

[0041] The medical plaster according to the present invention comprises or consists in its entirety of:

[0042] • a layer acting as a base (support), on which is uniformly spread out

[0043] • a "Pressure Sensitive Adhesive" matrix on which is dispersed

[0044] • the active ingredient, this matrix being covered by

[0045] • a protective layer which acts as a coating, to be removed before application.

[0046] The support is made of a soft and flexible material, which can be shaped into any What shape and size: a polymer base is generally used, especially polyester. In the plaster described here, the backing is a 100% polyester non-perforated non-woven fabric, which improves adhesion to the skin and prevents the adhesive matrix, and with it the dispersed drug, from escaping.

[0047] The coating is a protective sheet of monosilicone paper, which can be easily removed.

[0048] The active ingredient used in the medical plaster according to the present invention is diclofenac sodium salt (DicloNa); as already mentioned, the choice of salinizing diclofenac is necessary, given the chemical-physical properties of this active ingredient. As regards the choice of salt, it is known in the prior art that the nature of the counterion with which diclofenac is salinized is extremely important: in particular, it is essential that the salt maintains sufficient hydrophobicity to be able to pass through the stratum corneum of the skin, but that it is sufficiently hydrophilic to be able to be diffused into the underlying layers, locally reaching therapeutically active concentrations, as required for a medical plaster. The diclofenac salts that have shown the best performance in this sense are organic salts with aliphatic amines, both linear and cyclic.Diclofenac salts with inorganic bases, particularly with potassium or sodium, are on the contrary less suitable for this type of application because they have very low partition coefficients, up to 3,000 times lower than those of diclofenac acid; their very high hydrophilicity therefore strongly limits their passage through the stratum corneum of the skin (Fini et al., 2012, Pharmaceutics, 4, 413-429).

[0049] In confirmation of this, there are diclofenac-based products on the market for topical application in the form of an emulgel, in which the active ingredient is salinized with diethylamine, which is a linear amine (for example Voltaren Emulgel®), or in the form of a medical plaster, more interesting for the objects of the present invention, in which the salification takes place with hydroxyethylpyrrolidine, which is a cyclic amine (for example Flector® medical plaster).

[0050] The possibility of using the sodium salt of diclofenac represents a clear improvement over the prior art in terms of industrial processing and potential side effects of the final product. As far as the industrial aspect is concerned, the synthesis of the sodium salt is carried out very simply and economically, without the use of toxic reagents, without the need for controlled disposal of processing waste. As far as the potential side effects of the final product are concerned, it is known that aliphatic amines, especially cyclic amines, can be toxic or at least very frequently give rise to irritation phenomena, due to the release of the amine as such or its metabolites (Myers et al, 1997, J Tox Subst Mech, 16, 2; Greim et al, 1998, Chemosphere, 36, 271-295).

[0051] The use of diclofenac sodium salt therefore eliminates these problems and makes the plaster which is the subject of the invention also applicable to sensitive and easily irritable skin, such as that, for example, of an elderly patient or of potentially allergic or atopic subjects.

[0052] The PSA matrix is ​​composed of an aqueous dispersion of copolymers derived from acrylic and methacrylic acid esters, preferably it is composed of Eudragit® NE40D (Evonik Industries), i.e. a copolymer of poly(ethyl-acrylate, methyl-methacrylate) in a ratio of 2:1 in aqueous dispersion at 40% by weight. A plasticizing agent chosen from citric acid esters is added to this copolymer, preferably a plasticizing agent which is tributyl citrate; thus a matrix similar to that described for example in WO2012089256, already tested, without success, for the release of diclofenac in the form of sodium salt, is obtained.

[0053] The applicant has however surprisingly discovered that the addition to the matrix described above of minimal quantities of butylhydroxyanisole (BHA) significantly modifies its properties, allowing the constant, continuous and prolonged release of the DicloNa dispersed therein, at doses which are locally therapeutically active, for a period of 24 hours.

[0054] The release profile is quite comparable to that of a commercial product widely used as a once-daily plaster (Flector®), containing diclofenac salt of hydroxyethylpyrrolidine, i.e. a salt with a cyclic amine, and a completely different PSA matrix (based on gelatin, polyvinylpyrrolidone, of carboxymethylcellulose and other polymers).

[0055] BHA is an ingredient with antioxidant and preservative action, widely used in the food, cosmetic and animal feed industries to prevent rancidity of the fats it contains. It is also used in pharmacy, as an excipient in solid formulations of lipid-based active ingredients, specifically to prevent oxidation and therefore the loss, or at least the 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, for example injections, in the presence of unstable active ingredients.

[0056] In the context of the present invention, BHA is used for the first time in a solid composition for topical use devoid of lipid components and which therefore does not require an antioxidant, thus ensuring that, as will be demonstrated below, the sodium diclofenac dispersed in the PSA matrix of the medical plaster which is the subject of the invention is released constantly and continuously for 24 hours, possibly only reaching the circulatory flow in trace amounts, thus respecting the definition of medical plaster.

[0057] This result is totally unexpected and contrary to the teachings of the prior art.

[0058] The evaluation of the release of diclofenac is carried out by the Dissolution Test described in the Official Pharmacopoeias, more specifically in the present application by the Dissolution Test described in the European Pharmacopoeia (Ph. Eur. 5.0, 2.9.4). Depending on the different pharmaceutical forms to be tested, the devices for carrying out the Dissolution Test are distinguished from each other by the type of support in which the material to be analyzed is placed. The general methods for carrying out the test are the same: briefly, the sample to be analyzed is placed in a suitable support, itself 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; at regular intervals, fractions of the dissolution medium are collected and analyzed in order to calculate the amount of drug present in it. The analysis is usually carried out using a spectroscope or high-pressure liquid chromatography (HPLC), most commonly by HPLC. In the Dissolution Test, it is essential to operate in sink conditions, i.e. with large volumes of dissolution medium: only in this way is it possible, in fact, to avoid the degree of dissolution of the active ingredient being lower than the actual dissolution, due to the progressive increase in the concentration in the receiving medium which, if in small volumes, quickly approaches saturation.

[0059] The PSA matrix of the medical plaster according to the present invention comprises or is consisting of:

[0060] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio, at a concentration of between 40 and 49% by dry weight relative to the dry weight of the matrix, as defined above;

[0061] • a plasticizing agent chosen from citric acid esters, at a concentration between 40 and 49% by weight relative to the dry weight of the matrix;

[0062] • butylhydroxyanisole (BHA) at a concentration of between 0.10 and 0.20% by weight relative to the dry weight of the matrix;

[0063] said PSA matrix in which is dispersed

[0064] • an active ingredient, which is diclofenac sodium, at a concentration of between 1 and 20% by weight relative to the dry weight of the matrix.

[0065] Preferably, the citric acid esters are chosen from triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, more preferably the ester is tributyl citrate.

[0066] Preferably, the composition of the PSA matrix of the medical plaster according to the present invention comprises or consists of:

[0067] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio in aqueous dispersion at 40% by weight, at a concentration of between 45 and 48% by dry weight relative to the dry weight of the matrix, as defined above;

[0068] • the plasticizing agent is tributyl citrate, at a concentration of between 45 and 48% by weight relative to the dry weight of the matrix;

[0069] • BHA at a concentration of between 0.13 and 0.18% by weight relative to the dry weight of the matrix;

[0070] diclofenac sodium being dispersed in said PSA matrix at a concentration of between 5 and 10% by weight relative to the dry weight of the matrix.

[0071] The concentrations are always expressed by weight relative to the dry weight of the matrix; as the pharmacological effect is exerted by sodium diclofenac alone dispersed in the PSA matrix, as the concentration of the latter varies according to the quantity of active ingredient to be inserted into the plaster, the quantities of copolymer and plasticizer will consequently also vary, to complete 100% of the final composition.

[0072] Even more preferably, the composition of the PSA matrix of the medical plaster according to the present invention comprises or consists of:

[0073] • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio in aqueous dispersion at 40% by weight, at a concentration equal to 46.3% by dry weight relative to the dry weight of the matrix, as defined above;

[0074] • tributyl citrate, at a concentration equal to 46.3% by weight relative to the dry weight of the matrix;

[0075] • BHA, at a concentration equal to 0.15% by weight relative to the dry weight of the matrix;

[0076] diclofenac sodium being dispersed in said PSA matrix at a concentration equal to 7.25% by weight relative to the dry weight of the matrix.

[0077] The process for preparing the medical plaster which is the subject of the invention, containing sodium diclofenac (DicloNa) dispersed in the PSA matrix described above, comprises different phases which can be summarized as follows:

[0078] • mixing the chosen plasticizing agent and the BHA until dissolved;

[0079] • addition of DicloNa and mixing until dissolved;

[0080] • addition of the chosen neutral copolymer based on ethyl acrylate and methacrylate methyl in a 2:1 ratio in aqueous dispersion and mixed until completely dispersed;

[0081] • pouring the mass of the PSA / DicloNa matrix onto a temporary coating;

[0082] • drying of the mass and its coupling with the support;

[0083] • replacement of the temporary coating with the definitive coating;

[0084] • cutting the plasters to the desired size;

[0085] • insertion of each plaster into its primary packaging.

[0086] Some examples are provided to better illustrate the aims and advantages of the present invention, which however do not limit in any way the scope of the claims. Example 1

[0087] Preparation of a medical plaster containing 140 mg of DicloNa

[0088] The ingredients for the preparation of each medical plaster having dimensions of 140x100mm containing 140 mg of diclofenac sodium are: Ingredients mg / patch % Diclofenac sodium 140 7.25 Eudragit® NE40D 894.5 46.3 (dry weight corresponding to 2236.38 mg wet weight) Tributyl citrate (TBC) 894.5 46.3 (Proviplast 2604 - Proviron) Butylated hydroxyanisole (BHA) 2.9 0.15

[0089] Method

[0090] The TBC and BHA were mixed under stirring and vacuum for approximately 15 minutes, until completely dissolved. Diclofenac sodium was then added to the mixture, stirring under vacuum until completely dissolved, at a temperature not exceeding 25°C. Eudragit® NE40D was then added, stirring rapidly for about 1 minute, then switching to medium stirring for 10 minutes and finally reducing the stirring speed to minimum and maintaining it for 2 hours, at a temperature not exceeding 25°C, continuing to operate under vacuum.

[0091] The mass was finally left to rest for 8 hours, continuing to operate under vacuum.

[0092] The mass thus obtained was spread on a temporary coating of silicone polyester, and placed in a forced ventilation dryer for 5 minutes to dry, in a temperature gradient ranging from 65 to 115°C. The product thus obtained was then coupled by compression with the 100% non-woven polyester support and the temporary coating was then replaced by the definitive coating, made of monosilicone paper, the plasters were then cut to the desired format (140x100mm) with the final primary packaging of the plasters thus obtained. Example 2 Diclofenac release (dissolution test)

[0093] The release of diclofenac from the medical plasters of the present invention was evaluated with the Dissolution Test, using as a comparison a commercial product that releases the active ingredient within 24 hours. The reference product is Flector® (lot 1506031), which contains 180 mg of diclofenac hydroxyethylpyrrolidine salt corresponding to 140 mg of diclofenac sodium.

[0094] The active ingredient which exerts the pharmacological activity and whose release must be evaluated is diclofenac and not its salt, whatever it may be.

[0095] The Dissolution Test is carried out as 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 saline solution with a pH = 7.4 (PBS - Ph. Eur. 4.1.3), under the following operating conditions: Volume of Dissolving Medium 900 ml Temperature 32°C ± 0.5°C Rotation speed 100 rpm (revolutions / minute) Sampling time 1, 3, 6, 24 hours Quantity sampled 2 ml

[0096] The analysis of the sampled medium was carried out with HPLC equipment (Agilent 1100), according to what is known to persons skilled in the field.

[0097] Sample A is the plaster prepared according to Example 1, while Sample B is Flector®.

[0098] A portion of 20 cm2 (2x10 cm) was cut from each sample and, without remove the protective coating, was applied to the outer surface of the cylinder with double-sided adhesive tape, so as to expose the surface containing the PSA matrix and the diclofenac dispersed therein to the Dissolving Medium, and so that the long axis of the plaster portion perfectly corresponded to the circumference of the cylinder. When the temperature of the Dissolving Medium reached the expected value, the protective coating was removed, the sample was covered with a Cuprophan membrane, exceeding the sample size by at least 1 cm, and fixed with adhesive tape; the cylinder was finally immersed in the medium and immediately rotated at the prescribed speed. At the established intervals, a 2 ml sample was taken from an intermediate area between the surface of the Dissolving Medium and the upper edge of the cylinder. The withdrawn volume was immediately replaced with an equal volume of fresh Dissolving Medium.

[0099] The dissolution values ​​and the relative profile are presented respectively in the following Table 1 and in the graph of [Fig. 1].

[0100] [Tableauxl] Time (hours) Sample A Sample B % Diclofenac Released % Diclofenac Released 1 29.66 27.35 3 57.38 57.34 6 78.67 80.75 24 100.24 104.66

[0101] It is evident that the diclofenac present in sample A has a release profile absolutely comparable to the diclofenac contained in the Flector® product (sample B), a reference product among long-lasting medical plasters.

[0102] Sample A, in particular the medical plaster which is the subject of the invention, therefore releases diclofenac from its sodium salt in a constant, continuous and progressive manner over 24 hours, which makes it possible to effectively exert its pharmacological effect.

[0103] These data are quite surprising because they show that

[0104] • starting from a PSA matrix which is known to adequately release the diethylamine salt of diclofenac, but not the sodium salt of diclofenac and

[0105] • using diclofenac sodium salt, which is known to be unsuitable for use in medical plasters

[0106] by adding BHA to the formulation of the PSA matrix, i.e. a substance known for its antioxidant properties not required here, a medical plaster is obtained which

[0107] • releases the active ingredient in a constant, continuous, prolonged manner, at low doses therapeutically active for a period of 24 hours, and can therefore only be replaced once a day by the person using it;

[0108] • does not contain linear aliphatic amines or cyclic amines, and does not therefore does not cause exposure to the risk of toxic or irritating phenomena, and can therefore also be applied to sensitive or easily irritated skin;

[0109] • is industrially practical, because the process for preparing the sodium salt is fast, economical and does not involve controlled disposal of treatment waste.

Claims

Claims

1. Medical plaster comprising: • a base layer (backing), • a "Pressure Sensitive Adhesive" (PSA) matrix, • a protective coating layer (covering), wherein the PSA matrix comprises or consists of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a ratio of 2:1, at a concentration of between 40 and 49% by dry weight relative to the dry weight of the matrix; • a plasticizing agent chosen from citric acid esters, at a concentration of between 40 and 49% by weight relative to the dry weight of the matrix; • butylhydroxyanisole (BHA) at a concentration of between 0.10 and 0.20% by weight relative to the dry weight of the matrix; said PSA matrix in which is dispersed • an active ingredient, which is sodium diclofenac, at a concentration of between 1 and 20% by weight relative to the dry weight of the matrix.

2. A medical plaster according to claim 1, wherein the citric acid esters are selected from triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, preferably the ester is tributyl citrate.

3. Medical plaster according to one or more of the preceding claims, wherein the PSA matrix comprises or consists of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio in aqueous dispersion at 40% by weight, at a concentration of between 45 and 48% by dry weight relative to the dry weight of the matrix; • a plasticizing agent which is tributyl citrate, at a concentration of between 45 and 48% by weight relative to the dry weight of the matrix; • BHA in a concentration of between 0.13 and 0.18% by weight relative to the dry weight of the matrix; sodium diclofenac being dispersed in said PSA matrix, at a concentration of between 5 and 10% by weight relative to the dry weight of the matrix.

4. A medical plaster according to one or more of the preceding claims, wherein the PSA matrix comprises or consists of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio in aqueous dispersion at 40% by weight, at a concentration equal to 46.3% by dry weight relative to the dry weight of the matrix; • tributyl citrate, at a concentration equal to 46.3% by weight relative to the dry weight of the matrix; • BHA at a concentration equal to 0.15% by weight relative to the dry weight of the matrix; sodium diclofenac being dispersed in said PSA matrix, at a concentration equal to 7.25% by weight relative to the dry weight of the matrix.

5. Medical plaster according to one or more of the preceding claims, wherein the base layer (backing) consists of a 100% polyester non-perforated non-woven fabric.

6. A medical plaster according to one or more of the preceding claims, wherein the protective coating layer (coating) is a monosilicone paper protective sheet.

7. Adhesive polymer matrix (PSA) comprising or consisting of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio, at a concentration of between 40 and 49% by dry weight relative to the dry weight of the matrix; • a plasticizing agent chosen from citric acid esters, at a concentration of between 40 and 49% by weight relative to the dry weight of the matrix; • butylhydroxyanisole (BHA) at a concentration of between 0.10 and 0.20% by weight relative to the dry weight of the matrix; said PSA matrix in which is dispersed • an active ingredient, which is sodium diclofenac, at a concentration of between 1 and 20% by weight relative to the dry weight of the matrix.

8. Adhesive polymer matrix (PSA) according to claim 7, wherein the esters are selected from triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, preferably the ester is tributyl citrate.

9. Adhesive polymer matrix (PSA) according to claim 7, comprising or consisting of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio in aqueous dispersion at 40% by weight, a concentration of between 45 and 48% by dry weight relative to the dry weight of the matrix; • a plasticizing agent which is tributyl citrate, at a concentration of between 45 and 48% by weight relative to the dry weight of the matrix; • BHA at a concentration between 0.13 and 0.18% by weight relative to the dry weight of the matrix; diclofenac sodium being dispersed in said PSA matrix, at a concentration of between 5 and 10% by weight relative to the dry weight of the matrix.

10. Adhesive polymeric matrix (PSA) according to claim 7, comprising or consisting of: • a neutral copolymer based on ethyl acrylate and methyl methacrylate in a 2:1 ratio in aqueous dispersion at 40% by weight, at a concentration equal to 46.3% by dry weight relative to the dry weight of the matrix; • tributyl citrate, at a concentration equal to 46.3% by weight relative to the dry weight of the matrix; • BHA at a concentration equal to 0.15% by weight relative to the dry weight of the matrix; diclofenac sodium being dispersed in said PSA matrix, at a concentration equal to 7.25% by weight relative to the dry weight of the matrix.

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