HUT75863A - Matrix system for the transdermal delivery of ibuprofen, and method for preparing same - Google Patents

Description

The present invention relates to a transdermal matrix system for delivery of ibuprofen, comprising a carrier and an acrylate copolymer-based self-adhesive matrix comprising ibuprofen and containing diethyl phthalate to provide stability over time.

The invention further relates to a process for the preparation of the above system.

Ibuprofen, systematically named α-methyl-4- (2-methylpropyl) -benzole acetic acid and having the structure of formula (I), is a non-steroidal compound known to have anti-inflammatory and analgesic properties. This compound in the form of a gel or cream is commonly used for topical treatment, in particular for the treatment of tendinitis, sports-related trauma and certain types of joint diseases. Ibuprofen is usually used in the form of a racemic mixture of two enantiomers, S (+) -? -Methyl-4- (2-methylpropyl) -benzole acetic acid (hereinafter referred to as S (+) - ibuprofen) and R (-) - α-methyl-4- (2-methylpropyl) -benzole acetic acid (hereinafter referred to as R (-) - ibuprofen). However, it is also known to use the S (+) - ibuprofen enantiomer alone as the active ingredient.

However, a self-adhesive matrix system for transdermal administration of ibuprofen has not yet been commercialized despite the benefits that such a system can provide.

Numerous self-adhesive transdermal systems for the delivery of an active ingredient dissolved in an acrylate copolymer-based matrix have been described.

Of these, US-A-4,765,974.

3 discloses an acrylate copolymer based transdermal composition which inhibits the degradation of clonidine or its salts.

Many patents disclose acrylate polymer-based matrix systems for transdermal delivery of non-steroidal anti-inflammatory agents, for example, FR-A-2,493,144 for indomethacin, EP-A-0 319 988 for ketoprofen. See, for example, JA-57 091 913, which relates mainly to an ester of ibuprofen, and EP-A-0 225 005, which relates mainly to an ibuprofen salt.

It is known that heating ibuprofen-based formulations to a temperature above the melting point of ibuprofen [75-77 ° C for racemic mixture and 51 ° C for S (+) - ibuprofen enantiomer] can cause degradation of ibuprofen by oxidation and other with its components. Various solutions have been proposed to overcome this problem, for example, in U.S. Patent Nos. J-A-60,185,712, EP-A-0,279,519 and US-A-5,185,373.

However, none of the above publications refer to the problems associated with the stability of ibuprofen in free form in acrylate copolymer based matrices nor to the present invention.

Finally, although phthalic acid derivatives are commonly used as plasticizers in acrylate copolymers (see, for example, EP-A-0 435 199 and EP-A-0 531 938), no mention is made of their role or ability in stabilizing an active ingredient in acrylic matrices.

4 does not mention the role of the diethyl phthalate stabilizer in the acrylate compositions containing ibuprofen according to the invention.

The large number of publications on the use of non-steroidal anti-inflammatory drugs in the form of transdermal systems is evidence of the need for such devices, for example, for the local treatment of bruises, sprains, tendinitis or various inflammatory pains, such as arthritis. However, the disadvantage of the transdermal systems described in the above patents is that, when they contain ibuprofen as an active ingredient, they do not ensure the stability of the active ingredient over time, particularly during storage.

Transdermal systems, which, like the gels and creams used today, have the advantage of acting only on the part to be treated and avoiding the risk of oral administration of such compounds, do not have the disadvantages of gels and creams. The product does not need to be re-applied several times a day. There is no need to spread the dose to be applied to the area to be treated, thus eliminating the problem of applying creams or gels to the laundry. Generally, the duration of the effect may be several days; moreover, due to their good adhesion, they can be applied even under water and do not lose their activity when the subject is showering or bathing.

Regarding the preparation of such a device, we have attempted to provide a self-adhesive matrix system for transdermal delivery of ibuprofen dissolved in the free acid form in an acrylate copolymer based matrix. We found that

- 5 ibuprofen is unstable and undergoes chemical degradation over time in such matrices.

This is undoubtedly due to the degradation reactions (especially oxidation) of ibuprofen and the reaction with other components present in the matrix (solvents, monomers, short-chain polymers, etc.). However, excessive degradation of the active ingredient over time cannot be accepted in devices, such as transdermal systems, that they wish to place on the market.

In addition, if the drug loss becomes too high, this will result in a decrease in the expected activity of the device as the amount of available ibuprofen decreases.

One object of the present invention was to reduce this phenomenon or to bring it within acceptable limits, i.e. to obtain a product which is stable or substantially stable over an extended period of time.

It is a further object of the present invention to provide a process for the preparation of such a transdermal matrix system.

The above objects have been achieved by a novel technique in which a matrix system comprising acrylate or methacrylate based copolymers and ibuprofen in free form is added to provide a stable formulation. The compound used in the present invention is diethyl phthalate.

Thus, one object of the present invention is to provide a self-adhesive transdermal matrix system for transdermal delivery of ibuprofen as a novel industrial product comprising a matrix system comprising a carrier and an adhesive matrix.

- 6 (a) 55 to 75 parts by weight of an acrylate adhesive copolymer having a glass transition temperature of -70 to -10 ° C,

b) 5 to 15 parts by weight of a cationic acrylate copolymer having a glass transition temperature of 20 to 80 ° C,

(c) 5 to 15 parts by weight of ibuprofen in free acid form and

d) 10 to 25 parts by weight of diethyl phthalate.

Another object of the present invention is a process for the preparation of the above transdermal matrix system comprising the steps of:

a) solubilizing the cationic acrylate copolymer, ibuprofen and diethyl phthalate with a glass transition temperature of 20 to 80 ° C in an organic solvent with stirring and homogenizing the resulting mixture;

β) introducing into said homogeneous mixture a solution of an adhesive acrylate copolymer having a glass transition temperature of -70 ° C to -10 ° C in the form of a solution of an organic solvent or a mixture of organic solvents, then homogenizing and degassing;

γ) applying the resulting homogeneous mixture to a non-adherent, temporary carrier, which is coated with 50 to 300 g / m ² ; δ) evaporating the solvents from the resulting coating by drying and, if desired, curing the adhesive acrylate copolymer by gradually heating to a temperature of 40 to 130 ° C; and

ε) transferring the resulting coating onto a final substrate.

The figures are briefly described below. 1 and 2.

Figure 1b shows ibuprofen present in the transdermal system

- 7 quantities (Q, as a percentage) versus time (t, in months).

In particular, Figure 1 compares curve 1 (product of Example 1) and curve A (product of Example 2 CE) showing the amount of ibuprofen present in the matrix system under study when the transdermal system is 23 °. Maintained at C; and - Figure 2 compares curve 1 (product of example 1), curve A (product of Example 2 CE) and curve B (product of product CE example 5) of the matrix system tested the amount of ibuprofen present in the transdermal system at 40 ° C. Ibuprofen, as used herein, refers only to the a-methyl-4- (2-methylpropyl) -benzole acetic acid of formula (I), wherein the acid group is in free form and is provided by R (-) - ibuprofen and S (+) - ibuprofen. as the racemic mixture of enantiomers or as the S (+) - ibuprofen enantiomer only.

Preferably, the matrix system of the invention comprises a support and a self-adhesive matrix which

(a) 55-75% by weight of an acrylate adhesive copolymer having a glass transition temperature of -70 ° C to -10 ° C,

(b) 15 to 5 parts by weight of a cationic acrylate copolymer having a glass transition temperature of 20 ° C to 80 ° C,

(c) 15 to 5 parts by weight of ibuprofen in free acid form; and

d) 25 to 10 parts by weight of diethyl phthalate per 100 parts by weight of the matrix.

The present invention provides ibuprofen for use in a matrix

- The amount of 8 is 5-15 parts by weight. The amount of ibuprofen used is preferably in the order of 10 parts by weight for a total of 100 parts by weight of the matrix.

Our attempts to form ibuprofen into acrylate copolymer-based matrices have surprisingly found that the addition of diethyl phthalate provides a system with acceptable stability.

The above property essential for the commercialization of the product is achieved by the addition of 10 to 25 parts by weight of diethyl phthalate, preferably 15 to 20 parts by weight per 100 parts by weight of the total matrix. These ratios, which are sufficient to solve the stability problem, are also sufficient to maintain the proper adhesion and cohesion properties of the device.

In addition, due to its plasticizing properties, diethyl phthalate also promotes the release of ibuprofen through its action on the macromolecular matrix network.

Finally, the phthalic acid derivative also enables problems associated with skin irritation or pain to be minimized by removing the transdermal system containing adhesives such as acrylate copolymers. This is a significant advantage for treatment where several devices have to be placed one after the other in the already sore area.

Apart from its primary role in the production of a stable device containing ibuprofen, the use of diethyl phthalate allows the preparation of a final product that is more tolerable by the patient.

By glass transition temperature (Tg) between -70 ° C and -10 ° C, the term "sticky acrylate copolymers" refers to a synthetic acrylate resin which may be self-curing or non-curing.

These resins, which are well known in the art, are copolymers of at least two monomers selected from the group consisting of:

la) hydroxyalkyl esters of acrylic acid or methacrylic acid wherein the alkyl group contains from 2 to 4 carbon atoms, such as (2-hydroxyethyl) acrylate, (2-hydroxyethyl) methacrylate, (2-hydroxypropyl) acrylate and (2-hydroxypropyl) methacrylate;

2a) alkyl esters of acrylic acid or methacrylic acid in which the esterifying alkyl group contains from 4 to 18 carbon atoms, such as (n-butyl) acrylate or methacrylate, isopropyl acrylate or methacrylate, (n-hexyl) methacrylate and (2) ethyl hexyl) acrylate;

3a) α, β-unsaturated monocarboxylic or dicarboxylic acids, their anhydrides and alkyl or alkenyl esters wherein the alkyl group contains from 1 to 3 carbon atoms and the alkenyl group contains from 2 to 5 carbon atoms, such as acrylic acid, itaconic acid, maleic acid, maleic anhydride, alkyl methacrylate and diethyl ester of fumaric acid or maleic acid;

4a) vinyl monomers, in particular vinyl acetate, acrylonitrile, vinyl propionate, vinyl pyrrolidone and styrene;

5a) alkylaminoalkyl and aminoalkyl derivatives of functional groups selected from amido, amino and epoxy functional groups such as acrylamide, N-butylacrylamide, acrylic acid or methacrylic acid, such as (aminoethyl) acrylate, (aminoethyl) methacrylate and [2- (dimethylamino) ethyl] methacrylate, glycidyl methacrylate and glycidyl acrylate;

- 6a) alkoxyalkyl esters of acrylic acid or methacrylic acid, such as methoxyethyl acrylates or methacrylates, butoxyethyl acrylates or methacrylates, methoxy polypropylene glycol acrylates or methacrylates; and

7a) hexamethylene glycol dimethacrylate.

Preferred are:

- (2-hydroxyethyl) acrylate from group la), - (n-butyl) acrylate and / or (2-ethylhexyl) acrylate in group 2a), - acrylic acid and / or allyl methacrylate, - vinyl acetate and / or N-vinyl 2-pyrrolidone from group 4a, - acrylamide, [2- (dimethylethylamino) ethyl] methacrylate from group 5a) and / or glycidyl methacrylate, and - (2-methoxyethyl) acrylate from group 6a).

The appropriate ratio or percentage of the various monomers described above is adjusted to give the desired copolymer having a glass transition temperature of from -70 ° C to -10 ° C.

Since these copolymers are self-crosslinking, they may contain cross-linking agents commonly used in the art, such as organic peroxides, polyisocyanates, metal chelates such as titanium or aluminum chelates, or metal acetylacetonates, especially zinc, magnesium, aluminum acetone.

These adhesive acrylate copolymers generally form a solution with a solvent system (consisting of a single organic solvent, or preferably a mixture of several organic solvents), containing from 25 to 55% by weight of a copolymer such as National Starch, Avery Dennison, UCB SA, and a Sekisui • ·

- Products sold by 11 Chemical Co. under the brand names DUROTAK®, POLITEX®, SOLUCRYL® and TSR®.

Non-self-curing adhesive copolymers include the following acrylate copolymer solutions: SOLUCRYL® 110, SOLUCRYL® SB 1147, POLITEX® 200, TSR® and DUROTAK® 280-2287.

Among the self-curing adhesive copolymers are the following acrylate copolymer solutions: SOLUCRYL® LRA 1144, DUROTAK® 280-2516, DUROTAK® 380-2819 and DUROTAK® 380-2954.

For example, a solution containing 40% by weight of (2-ethylhexyl) acrylate / vinyl acetate / acrylic acid copolymer and titanium chelate ester in a mixture of ethyl acetate / ethanol / heptane / methanol which is DUROTAK® 280-2516 is preferred. (glass transition temperature about -47 ° C) and DUROTAK® 380-2819 (glass transition temperature -53 ° C). More preferably, a solution of about 47.7% w / w (2-ethylhexyl) acrylate / vinyl acetate / butyl acrylate / acrylic acid copolymer and aluminum acetyl acetate (as a crosslinking agent) is used in the present invention. acetate / heptane / isopropanol / toluene / acetylacetone having a glass transition temperature of -60 ° C and sold under the trade name DUROTAK® 380-1054.

a cationic acrylate copolymer having a glass transition temperature (Tg) of from 80 to 80 ° C is understood to mean an acrylate or methacrylate copolymer having cationic functional groups which enable one or more of the above-mentioned self-curing or non-curing adhesive acrylate copolymers to form a homogeneous mixture.

- 12 Cationic copolymers well known in the art are obtained from a mixture of monomers selected from the group consisting of:

1b) alkyl esters of acrylic acid or methacrylic acid wherein the alkyl group contains from 1 to 4 carbon atoms, and

2b) acrylate or methacrylate, wherein the cationic group is a dialkylaminoalkyl or trialkylammoniumalkyl group in which the alkyl group contains from 1 to 4 carbon atoms. In practice, the cationic copolymer having a glass transition temperature of 20 to 80 ° C is always prepared using at least one monomer of Group 1b) and at least one monomer of Group 2b).

Preferably, the following are used:

- butyl, ethyl and / or methyl methacrylate from group 1b) and [2- (dimethylamino) ethyl] methacrylate and / or [2- (trimethylammonium) - from group 2b), ethyl] methacrylate chloride.

The percentage and ratio of the various monomers are selected to give the desired polymer with a glass transition temperature of 20 to 80 ° C.

The cationic acrylate copolymers marketed by Rohm Pharma under the trade name EUDRAGIT® are preferred, and methyl methacrylate / ethyl acrylate / [2- (trimethylammonium)] marketed under the trade names EUDRAGIT® RL100 and EUDRAGIT® RS100. chloride methacrylate copolymers, and particularly preferred is the butyl methacrylate / [2-diethylamino) ethyl] methacrylate / methyl methacrylate copolymer (EUDRAGIT® El00) having a glass transition temperature of 50 ° C.

The combination of the two acrylate copolymers (a) and (b) with different Tg values provides or contributes to the cohesion of the adhesive-based matrix device. If necessary, the cohesion of the matrix can be further improved by introducing a woven or nonwoven layer into the mass of the matrix. Such an applied layer is generally not required for the present invention.

Despite the addition of a compound with known plasticizing properties, more particularly a phthalic acid ester, namely diethyl phthalate, which is essential for the formation of a stable product, the mechanical properties are retained, allowing the above advantages over creams and gels to be maintained.

The matrix according to the invention necessarily contains only the four compounds a), b), c) and d) above, including the crosslinking agent which is incorporated into or admixed with the adhesive copolymer a) if the copolymer is self-curing.

The carrier to which the matrix is applied may be a carrier used in transdermal systems, is of variable thickness, and is not permeable to the components of the matrix. Preferably, the support may be in the form of a film made of, for example, polyethylene, polyester or ethylene / vinyl acetate copolymer, or in the form of a cellular film, for example a foam sheet.

In practical terms, the matrix may be coated with a protective layer which may be peeled off prior to application of the device, and the device itself may be packaged in a leakproof protective layer such as a polyethylene / aluminum composition.

The transdermal system of the present invention is commonly used in the art for solvent-phase coating.

- We can produce it in 14 ways.

Large-scale industrial production involves coating large areas and cutting them to provide devices whose surface and shape is adapted to the area to be treated, depending on the amount of ibuprofen present per unit surface area at a selected dose of active ingredient over a period of time.

The self-adhesive matrix system of the present invention may be prepared by a process comprising the following steps:

1 °), at room temperature, a cationic acrylate copolymer having a glass transition temperature of 20 to 80 ° C and a solvent for this copolymer, in particular acetone, ibuprofen and diethyl phthalate, are added and the mixture is stirred until the cationic copolymer is completely solubilized and the resulting mixture becomes homogeneous;

2) pouring the resulting homogeneous mixture under stirring into a self-curing adherent acrylate copolymer having a glass transition temperature of -70 ° C to -10 ° C and mixing until a homogeneous mixture is obtained;

3) stirring was stopped and the resulting mixture was allowed to degass until the bubbles had completely disappeared;

4) coating the mixture obtained in step 3) at room temperature with a non-adhesive temporary carrier, in particular a siliconized polyester film, on which a layer of 50-300 g / m ² is formed;

5) gradually increasing the temperature to 40 to 130 ° C, preferably 40 to 80 ° C, depending on the boiling point of the solvent or solvents present and evaporating, and optionally crosslinking the adhesive acrylate copolymer; and

- 15 ° -) the resulting dry matrix is transferred to the final substrate of choice.

The transdermal systems of the present invention are particularly suitable for the treatment of tendinitis, sports-related traumatology (sprains, bruises, etc.), certain types of diseases such as small joint joints, back pain, or any other transdermal anti-inflammatory treatment that requires the use of ibuprofen.

In a most preferred embodiment of the invention, a transdermal matrix system is used in which the matrix comprises a total of 100 parts by weight.

(a) 60 parts by weight of a solution of a self-curing adhesive acrylate copolymer in the form of a solution containing about 47.7% by weight of (2-ethylhexyl) acrylate / vinyl acetate / butyl acrylate / acrylic acid and aluminum acetylacetonate as the crosslinking agent. the glass transition temperature of the adhesive copolymer is -60 ° C,

(b) 10 parts by weight of a cationic acrylate copolymer of butyl methacrylate / [2- (dimethylamino) ethyl] methacrylate / methyl methacrylate having a glass transition temperature of + 50 ° C,

(c) 10 parts by weight of ibuprofen in the form of the free acid as a racemic mixture; and

d) 20 parts by weight of diethyl phthalate.

Further advantages and features of the invention will be illustrated by the following examples and comparative examples, which are, of course, not intended to be limiting.

Example 1

1761 g of acetone and 300 g of EUDRAGIT® 100 (a cationic copolymer consisting of (dimethylaminoethyl) methacrylate and neutral methacrylic acid ester, manufactured by Rohm Pharma and having a glass transition temperature of 50 ° C), and stirring at room temperature for at least 40 minutes. 300 g of ibuprofen and 600 g of diethyl phthalate are then added and stirring is continued until a homogeneous mixture is obtained.

At a lower rate of stirring, 3773.6 g of DUROTAK® 380-1054 (ethyl acetate / heptane / isopropanol / toluene / pentanedione) and 47.7% w / w of a self-crosslinking acrylate copolymer which is 2-ethylhexyl acrylate / vinyl acetate / butyl acrylate / acrylic acid and a solution of aluminum acetylacetonate as a crosslinking agent, glass transition temperature -60 ° C, manufactured by National Starch Chemical BV). Stirring is continued until a homogeneous mixture is obtained. The mixture is then degassed for about 30 minutes.

The resulting mixture is applied to a siliconized polyester support at 100 ± 10 g / m ² . The whole is dried from 40 ° C to 80 ° C at gradually increased temperatures to remove solvents and thereby allow the acrylic adhesive to cure. The resulting matrix is then transferred to a polyethylene / ethylene / vinyl acetate support. The product is cut to the desired size and packed in heat-sealed bags.

Example 2

The procedure described in Example 1 was followed using the following starting materials:

1761 g of acetone,

330 g EUDRAGIT® 100,

300 g of ibuprofen,

- 17 540 g of diethyl phthalate and

- 3836.5 g DUROTAK® 380-1054.

The coating is prepared using 100 ± 10 g / m ² and the resulting matrix is applied to a polyethylene support.

Example 3

Following the procedure of Example 1, the resulting matrix is transferred to a polyethylene support.

CE Comparative Example 1

2389.9 g of the solution containing 47.7% w / v DUROTAK® 380-1054 acrylic adhesive are placed in a 60 g ibuprofen mixer. The mixture is stirred at room temperature until the active ingredient is completely dissolved. Stirring was then stopped and the mixture was allowed to degass for about 30 minutes. The mixture is applied to a silicone polyester support in an amount of 100 g ± 10 g / m ² . The whole was dried at 40 ° C to 80 ° C to evaporate the solvents and allow the acrylic adhesive to cure.

The resulting matrix is transferred to a polyethylene support. The product is cut into the desired shape and packed in heat-sealed bags.

CE Comparative Example 2

The procedure of Example 1 CE was followed using 120 g of ibuprofen and 2264.1 g of solution containing 47.7% w / v DUROTAK® 380-1054.

CE Comparative Example 3

704.4 g of acetone and 132 g of EUDRAGIT® 100 were placed in a mixer and stirred for at least 40 minutes. 120 g of ibuprofen and 216 g of MOD® (2-octyldodecyl myristate,

- 18 (GATTEFOSSE) and stirring is continued until a homogeneous mixture is obtained. A solution of 1534.6 g containing 47.7% w / v DUROTAK® 380-1054 acrylic adhesive is then added while stirring at low speed and stirring is continued until homogeneous. The mixture was allowed to degass for about 30 minutes without stirring. The resulting mixture is applied to a siliconized polyester support at 100 ± 10 g / m. The whole was dried at 40 ° C to 80 ° C with gradually rising temperatures to evaporate the solvents and allow the acrylic adhesive to cure. The resulting matrix is transferred to a polyethylene support. The product is cut to the desired size and packed in heat-sealed bags.

CE Comparative Example 4

The procedure of Example 3 CE is followed except that LAUROGLYCOL® (monoester and diester of propylene glycol and lauric acid, commercially available from GATTEFOSSE) is used in place of MODE®.

CE Comparative Example 5

The procedure of Example 3 CE was followed except that 50% by weight of LAUROGLYCOL® / lauryl alcohol, i.e. 108g of LAUROGLYCOL® and 108g of lauryl alcohol, were used in place of MODE®.

CE Comparative Example 6

The procedure described in Example 3 CE, except that the following starting materials are used:

704.4 g of acetone,

132 g EUDRAGIT® 100,

- 19,120 g of ibuprofen, g of LAUROGLYCOL®, g of lauryl alcohol and

- 1735.8 g DUROTAK® 380-1054.

Stability studies

To evaluate the stability of ibuprofen in the transdermal systems of the present invention, the matrix system behavior at 23 ° C and 40 ° C was investigated. For this purpose, the amount of ibuprofen in the device was determined after manufacture and at 1, 2, 3, 4, 6 and 9 months, respectively.

After extraction with acetylacetone, the amount of recovered ibuprofen was determined by high performance liquid chromatography (HPLC). determined

(i) the percentage of ibuprofen found, and (ii) the percentage loss relative to the initial amount of ibuprofen produced after manufacture.

Table 1 shows the results at 23 ° C and Table 2 shows the results at 40 ° C.

Examination of the data in Table 2 shows that in all formulations that do not contain diethyl phthalate, the amount of ibuprofen is reduced by about 5% after the first month. This phenomenon continues or accelerates over time, and after 9 months the loss reaches 13-28%.

This is particularly important in formulations containing ibuprofen acrylate copolymers (see CE Comparison Examples 1 and CE 2) containing 5-10% ibuprofen. The loss in this case is more than 1/4 of the initial amount of ibuprofen. These results indicate that ibuprofen is not stable in the acrylic systems in question.

In addition, at 40 ° C, formulations according to Comparative Examples CE 3 to CE 6 containing 2-octyldodecyl myristate, LAUROGLYCOL® or a mixture of 18% LAUROGLYCOL® and 10% lauryl alcohol together with a mixture of two acrylate copolymers, having different glass transition temperatures, each formulation has a loss of ibuprofen of greater than 8% after 6 months and a loss of about 13% (13.5% in CE example 3) and 28% (22.5% in CE example 5) ) after 9 months.

Surprisingly, only formulations containing diethyl phthalate formed a stable or acceptable system. Thus, at 40 ° C a

The system of Example 2 containing 18% diethyl phthalate has an acceptable loss after 6 and 9 months. After 9 months, 9.21% of ibuprofen is still present compared to the initial 9.79% of ibuprofen, a loss of only 5.9%.

At 0 ° C in the formulations of Examples 1 and 3 containing 20% diethyl phthalate, the corresponding losses were 0.41% and 2.45% ibuprofen after 6 months.

Although the fatty character of the products of Examples CE-3 to CE 6 is similar in properties to those of the diethyl phthalate-containing product, in particular, they do not provide an acceptable system of stability.

Table 1 compares the results obtained when the systems were kept at 23 ° C so that the loss in Example 2 CE after 6 months is already 10%,

In all formulations according to the Comparative Examples except 21 and CE 5, the loss after 9 months is greater than 5%.

In contrast, in the systems of the invention containing diethyl phthalate, the losses are always less than 3% after 6 and 9 months. No loss of iduprofen was found after 9 months of storage for the formulations of Examples 1 or 3.

A product in which the loss of ibuprofen is less than 5% when stored at 23 ° C and less than 10% when stored at 40 ° C is considered acceptable for stability. It was found that only the systems according to the invention containing diethyl phthalate could achieve the desired stability.

The above is clearly illustrated in Figure 1, which shows the change in ibuprofen concentration over time at 23 ° C for Example 1 and Comparative Example 2 CE (without diethyl phthalate), and Figure 2, shows this change over time at 40 ° C for Example 1 and Comparative Examples CE 2 and CE 5 (based on a mixture of LAUROGLYCOL® / lauryl alcohol). It will be appreciated that the devices of the present invention used for the preparation of a transdermal adhesive matrix system for transdermal delivery of ibuprofen are particularly preferred.

The permeation kinetics of the stable devices of the present invention were studied ex vivo on the abdominal skin of male nude mice by the following method: measurements were made with a 2.54 cm transdermal device in a static glass chamber using a static glass chamber. ·· ·

- placed on discs of the skin of 22 bare mice with a surface area of 3.14 cm ² . The chamber is kept at 37 ° C and has a 31 ml receptor tank containing phosphate buffer (pH 7.4) as the receptor phase.

At the end of the kinetic assay, the total amount of ibuprofen released is divided by the surface of the device and the diffusion time, giving the mean flux of the drug, expressed as pg / cm / hr.

The following results were obtained:

Example 1 device: Mean fux = 10.0 ± 1.1 pg / cm ² / h

Example 2 Device: Mean Fux - 9.7 ± 1.2 pg / cm / hr

Example 3 Device: Mean fux = 13.3 ± 2.5 pg / cm ² / h.

- 23 Table 1

Changes in the stability of Ibuprofen over time at 23 ° C

Comment:

T _n measurement after n months

Row is the ibuprofen content of the matrix (% by weight)

Row B ibuprofen loss (% w / w) relative to baseline.

Example T ^M 0 Τχ τ ₂ T ₃ T ₄ T ₆ T ₉ First THE 9.69 9.69 - 9.69 - 9.69 9.69 B 0 0 - 0 - 0 0 Second THE 9.79 9.79 - 9.65 - 9.5 9.5 B 0 0 - 1.43 - 2.96 2.96 Third THE 9.79 9.79 - 9.73 - 9.74 9.8 B 0 0 - 0.61 - 0.51 0 CE 1. THE 4.64 4.64 - - 4.44 4.34 4.27 B 0 0 - - 4.31 6.47 7.97 CE 2. THE 9.64 9.49 8.93 8.96 8.76 8.59 8.47 B 0 1.56 7.37 7.05 9.13 10.9 12.14 CE 3. THE 9.53 9.53 9.65 9.49 9.53 9.45 8.95 B 0 0 0 0.42 0 0.84 6.09 CE 4. THE 9.76 9.62 9.74 9.68 9.71 9.68 9.23 B 0 1.43 0.2 0.82 0.51 0.82 5.43 CE 5. THE 9.73 9.73 9.73 9.70 9.72 9.73 9.4 B 0 0 0 0.31 0.1 0 3.4 CE 6. THE 9.88 9.75 9.74 9.73 9.73 9.72 9.38 B 0 1.31 1.41 1.51 1.51 1.61 5.06

- 24 Table 2

Changes in the stability of Ibuprofen over time at 40 ° C

Comment:

T _n measurement after n months

Row is the ibuprofen content of the matrix (% by weight)

Row B ibuprofen loss (% w / w) relative to baseline.

Example T * 0 You T ₂ T ₃ T ₄ T ₆ T ₉ First THE 9.69 9.69 - 9.68 - 9.65 9.58 B 0 0 - 0.1 - 0.41 1.13 Second THE 9.79 9.76 - 9.72 - 9.34 9.21 B 0 0.31 - 0.72 - 4.6 5.92 Third THE 9.79 9.79 - 9.55 - 9.55 9.48 B 0 0 - 2.45 - 2.45 3.17 CE 1. THE 4.64 4.33 - - 4.03 3.66 3.4 B 0 6.68 - - 13.14 21.12 26.72 CE 2. THE 9.64 8.76 8.23 8.22 - 7.53 6.95 B 0 9.13 14.63 14,73 - 21.9 27.9 CE 3. THE 9.53 9.29 9.26 9.03 8.9 8.75 8.24 B 0 2.52 2.83 5.25 6.61 8.18 13.5 CE 4. THE 9.76 9.29 9.41 9.3 9.17 8.92 8.34 B 0 4.81 3.59 4.71 6.05 8.6 14.55 CE 5. THE 9.73 9.2 9.3 9.04 8.88 8.33 7.54 B 0 5.45 4.42 7.09 8.74 14.39 22.5 CE 6. THE 9.88 9.3 9.44 9.08 9 8.68 8.03 B 0 5.87 4.45 8.1 8.91 12.14 18.72

Claims (11)

1. A self-adhesive transdermal matrix system for transdermal delivery of ibuprofen comprising a matrix system comprising a carrier and an adhesive matrix (a) 55 to 75 parts by weight of an adhesive acrylate copolymer having a glass transition temperature of -70 to -10 ° C, b) 5 to 15 parts by weight of a cationic acrylate copolymer having a glass transition temperature of 20 to 80 ° C, (c) 5 to 15 parts by weight of ibuprofen in free acid form and d) 10 to 25 parts by weight of diethyl phthalate. The matrix system of claim 1, wherein (a) 55-75% by weight of an acrylate adhesive copolymer having a glass transition temperature of -70 ° C to -10 ° C, (b) 15 to 5 parts by weight of a cationic acrylate copolymer having a glass transition temperature of 20 ° C to 80 ° C, (c) 15 to 5 parts by weight of ibuprofen in free acid form and d) 25 to 10 parts by weight of diethyl phthalate per 100 parts by weight of the matrix. The matrix system of claim 1 or 2, wherein the adhesive acrylate copolymer (a) is formed from at least two monomers selected from the group consisting of: la) hydroxyalkyl esters of acrylic acid or methacrylic acid wherein the alkyl group contains from 2 to 4 carbon atoms; 2a) alkyl esters of acrylic acid or methacrylic acid wherein the alkylating ester group contains from 4 to 18 carbon atoms; - 3a) α, β-unsaturated monocarboxylic or dicarboxylic acids, their anhydrides and alkyl or alkenyl esters wherein the alkyl group contains 1 to 3 carbon atoms and the alkenyl group contains 2 to 5 carbon atoms; 4a) vinyl monomers; 5a) monomers containing functional groups selected from amido, amino and epoxy groups; 6a) alkoxyalkyl esters of acrylic acid or methacrylic acid; and 7a) hexamethylene glycol dimethacrylate. 4. A matrix system according to any one of claims 1 to 4, wherein the adhesive acrylate copolymer (a) is self-crosslinking and comprises a crosslinking agent selected from metal chelates, metal acetylacetonates, organic peroxides and polyisocyanates. The matrix system of claim 4, wherein the self-curing adhesive copolymer of (a) is a (2-ethylhexyl) acrylate / vinyl acetate / butyl acrylate / acrylic acid copolymer, wherein the crosslinking agent is aluminum acetylacetonate. and has a glass transition temperature of -60 ° C. The matrix system of claim 1 or 2, wherein the cationic acrylate copolymer (b) is obtained from a mixture of the following monomers: 1b) alkyl esters of acrylic acid or methacrylic acid wherein the alkyl group contains from 1 to 4 carbon atoms, and 2b) acrylate or methacrylate, wherein the cationic group is a dialkylaminoalkyl or trialkylammonioalkyl group, wherein the alkyl groups contain from 1 to 4 carbon atoms. The matrix system of claim 6, wherein the cationic acrylate copolymer is a butyl methacrylate / [2- (dimethylamino) -27-ethyl] methacrylate / methyl methacrylate copolymer having a glass transition temperature of 50 ° C. 8. A matrix system according to any one of claims 1 to 5, wherein the free acid ibuprofen in the matrix is a racemic mixture of S (+) - ibuprofen and R (-) - ibuprofen enantiomers. 9. A matrix system according to any one of claims 1 to 4, wherein the ibuprofen present in the free acid form in the matrix is the S (+) - ibuprofen enantiomer. The matrix system of claim 1, wherein the matrix system comprises a total of 100 parts by weight of the matrix (a) 60 parts by weight of a solution of a self-curing adhesive acrylate copolymer in the form of a solution containing about 47.7% by weight of (2-ethylhexyl) acrylate / vinyl acetate / butyl acrylate / acrylic acid and aluminum acetylacetonate as the crosslinking agent. the glass transition temperature of the adhesive copolymer is -60 ° C, (b) 10 parts by weight of a cationic acrylate copolymer of butyl methacrylate / [2- (dimethylamino) ethyl] methacrylate / methyl methacrylate having a glass transition temperature of + 50 ° C, c) 10 parts by weight of ibuprofen in the form of the free acid as a racemic mixture of S (+) - ibuprofen and R (-) - ibuprofen; and d) 20 parts by weight of diethyl phthalate. 11. Methods 1-10. A transdermal matrix system according to any one of claims 1 to 6, characterized in that: a) the cationic acrylate copolymer, ibuprofen and diethyl phthalate, having a glass transition temperature of 20 to 80 ° C, are solubilized in an organic solvent with homogeneity; β) introducing into the resulting homogeneous mixture between -70 and -10 ° C - a solution of an adhesive acrylate copolymer having a glass transition temperature of 28 in the form of a solution in an organic solvent or a mixture of organic solvents, and the resulting mixture is homogenized and degassed; γ) applying the resulting homogeneous mixture to a non-adhesive, temporary carrier, which is coated with 50 to 300 g / m; δ) removing the solvents from the resulting coating by drying and, if desired, crosslinking the adhesive acrylate copolymer with gradual heating to 40 to 130 ° C; and ε) transferring the resulting coating onto a final substrate.