HK1004375B - Transdermal system for the simultaneous delivery of a number of active principles - Google Patents

Description

Transdermal system for the simultaneous release of several active ingredients

Technical Field

The present invention relates to transdermal systems for the simultaneous release of a plurality of active ingredients. The system allows for the convenient adjustment of the dosage of one or more active ingredients to be released and reduces the surface area of the system, thereby improving patient safety and comfort in use.

Background

There are many patches (devices) currently used for transdermal delivery of active ingredients.

These patch components are identified in order (i) to ensure good physicochemical stability of the active ingredient over time, and (ii) to obtain an optimal transdermal absorption flux per unit surface area. The dose of active ingredient released during the course of treatment is therefore determined primarily by the surface area of the patch applied to the skin.

The surface area of the patch is not made large because the patch having a large surface area causes discomfort in use, and such a patch is not preferable in terms of size and appearance. In addition, transdermal patches also need to have good adhesive or cohesive properties, be easily torn off and feel uncomfortable when used.

Transdermal patches containing one active ingredient are currently produced that meet these requirements, i.e., are effective, small in area and comfortable, and do not slip or fall off during use.

On the other hand, systems which are capable of effectively releasing two or more active ingredients still present many problems in production and the difficulty of solving these problems increases with the number of active ingredients to be released.

The transdermal systems in the solutions envisaged at the earliest in the prior art consist of a single patch in which all the active ingredients are mixed together. Such systems are described in the patent documents EP-A-0285563, WO-A-92/07589, WO-A-92/07590 and WO-A-94/06383, etc. Although these systems have the advantage of small size, they are generally complex and not perfect.

In fact, the active ingredient contacts the stratum corneum in different ways depending on its species and physicochemical characteristics and generally has a significant influence on the composition of the patch.

The various active ingredients have different absorption fluxes due to the different permeability of the skin to the active ingredients. Thus, the simultaneous release of the desired therapeutic doses of the various active ingredients is essentially impossible to achieve using the same absorption area and formulation.

In addition, it is also not possible to adjust the dosage of at least one active ingredient alone without changing the formulation of the other active ingredient if it is necessary to readjust the released dosage during clinical use.

Also, a single system is often used to transdermally deliver multiple active ingredients at different dosages depending on the condition to be treated by the patient.

Since the dose of active ingredient delivered is proportional to the surface area of the skin with which it is in contact, systems with different surface areas are chosen.

In such systems, which are intended to deliver a plurality of different doses of active ingredients, it is also not possible to achieve different dosage requirements by varying the surface area of the system if at least two active ingredients do not maintain the same dosage ratio for the various doses selected, or if one active ingredient is delivered in a fixed dose, since in this case the doses of the various active ingredients will vary simultaneously with the surface area at a constant dosage ratio.

Neither of the above cases gives good results and it is therefore not possible to obtain a comfortable system with good flux and good physical properties.

The choice of ingredients to form a patch formulation is greatly limited by the increased amount of active ingredient, which creates a conflicting constraint.

In practice, the active ingredient may be partially or completely incompatible with the other ingredients in the formulation (resins, solvents, plasticizers, polymers, skin absorption enhancers, etc.). They may have different solubility and stability temperatures, some of which may crystallize over time, degrade upon application, or be used only in compositions at very low concentrations where the desired therapeutic dosage is not available. Also, none of the universal skin absorption enhancers suitable for all active ingredients can be used to increase their transdermal capacity. Therefore, several promoters or solvents are usually required for the administration of different active ingredients. The introduction of any new substance can cause or create skin irritation or problems with the adhesion or cohesion of the system.

Likewise, these constraints (compatibility, solubility, etc.) can affect various components of the formulation other than the active ingredient, making it difficult to optimize their function and bring about particular advantages in the formulation.

Thus, the first technical solution is not practical and unfeasible, or, due to obvious drawbacks, the patch cannot be used as a medicament.

A second known system for solving the problem of the simultaneous release of several active ingredients consists of several transdermal patches, each containing one active ingredient. Such systems are described in WO-A-94/06383, WO-A-90/06736 and WO-A-94/13354.

This protocol avoids the compatibility, stability problems described above, and allows adjustment of the desired dosage, and then determination of the surface area of each patch to achieve the desired dosage of each active ingredient.

However, the main disadvantage of such systems is that, since they generally have a large total surface area, their size increases with increasing amounts of active ingredient.

Generally, the larger the transdermal system, the more difficult it is to apply. Since the larger the transdermal systems, the more difficult it is to achieve optimal adhesion or cohesion of the entire surface area in contact with the skin.

Thus, the larger the transdermal system, the greater the likelihood of slippage of the adhesive patch, and the more likely it is to stain the garment, pull the skin, be uncomfortable, and even have a noticeable irritating sensation. The adhesive force is interrupted when the patch is removed, and thus the system is not easy to use and acceptable.

In addition, because the dose delivered over time is determined by the patch surface area that contacts the skin, an increase in this surface area increases the likelihood of detachment or wrinkling of part or the entire system. Loss of activity is caused by uneven contact with the skin, especially when applied to curved or constantly moving parts of the body.

Also, in the case of reservoir patches, a non-uniform distribution across the surface area in contact with the skin can alter the delivered dose and fail to achieve the desired therapeutic activity. Thus, for very large reservoir systems, under the force of gravity, the liquid or semisolid (solution or gel) containing the active ingredient will pool in the lower portion of the reservoir, reducing the available surface area and ultimately the effectiveness of the system.

Regardless of its performance, another disadvantage of larger systems is that they are not readily acceptable to patients because they are too large to be easily concealed.

Indeed, the appearance and discontinuity of such transdermal systems can cause discomfort, both of which are important factors in product acceptability and patient compliance with treatment.

All these problems detract from the ease of use of the system and even from the efficacy of the treatment in the patient.

Thus, none of the prior art solutions are satisfactory because they do not successfully reconcile the above two problems of both easy control of the release of each active ingredient and making the transdermal system contact surface area small to allow safe and comfortable use of the system. Object of the Invention

The object of the present invention is to provide a new solution for the simultaneous release of multiple active ingredients, which solution results in an adequate treatment without the above-mentioned disadvantages.

The object proposed by the present invention is achieved by producing a transdermal system which simultaneously delivers at least two active ingredients, which allows simple adjustment of the dosage of the individual active ingredients and simultaneously reduces the total surface area.

Summary of The Invention

The above object is achieved by producing a new industrial product, namely a new system for transdermal delivery of at least two active ingredients, said system consisting of at least two patches placed side by side (or in connection), characterized in that it comprises

A base patch containing a mixture of all active ingredients, wherein at least one first active ingredient (A) is present in an amount effective to deliver a therapeutically effective dose and at least one second active ingredient (B) is present in an amount less than that required to deliver a therapeutically effective dose, and

(ii) one or more additional patches containing a single active ingredient (B) selected from the group consisting of ingredients present in the above-mentioned base patch in an amount less than that required to deliver a therapeutically effective amount, said one or more additional patches serving to replenish the amount of each active ingredient (B) in the system until a therapeutically effective amount is reached. Detailed Description

The term "transdermal system" as used herein refers to a combination of at least two patches for the simultaneous delivery of various active ingredients to the skin.

By "patch" herein is understood any system for transdermal delivery of at least one active ingredient. These systems generally fall into two categories: -a reservoir patch in which one or more active ingredients are dissolved in a solvent that mediates transport of the active ingredients through a tacky or non-tacky microporous membrane; and-a matrix patch in which one or more active ingredients are dissolved or dispersed in a matrix formed by a polymer network, said matrix being adhesive or non-adhesive.

These patches may be single-layered or multi-layered (also called laminated), i.e. stacked from several matrices or reservoirs, with or without one or more active ingredients, which may be separated by microporous membranes.

At least two patches of the invention may be joined using techniques well known to those skilled in the art, such as adhesive bonding to a support, and juxtaposing them to the same support by application of an adhesive or heat sealing. In the above case, the two (or several) patches have the same support, but it is also possible to make a system in which the individual patches have the same or different independent supports, for example by juxtaposing the two patches by heat sealing or by bonding them to another support by the same technique.

The support employed may be any support commonly used in occlusive or non-occlusive transdermal systems of various thicknesses that does not penetrate the components of the patch.

Preferred supports are, for example, polyethylene, polypropylene or polyester films; composite material composed of polyethylene, vinyl acetate/ethylene copolymer and aluminum film; or a foam.

In practice, the entire system or individual patches may be covered with a protective layer or film, which is removed prior to use of the system, or the system may be protected by vacuum sealing using, for example, a polyethylene/aluminum composite.

The patch of the present invention may be prepared using materials well known to those skilled in the art, such as natural or synthetic polymers (e.g., acrylic acid or derivatives thereof, polysiloxanes, block copolymers, vinyl acetate/vinyl copolymers, rubbers and derivatives thereof, etc.), depending on the nature of the active ingredient to be delivered. Other suitable known substances commonly used by those skilled in the art, such as solubilizers, plasticizers, resins, stabilizers, fillers or transdermal enhancers, may also be combined with the active ingredient.

Likewise, films such as those commonly used by those skilled in the art of transdermal systems, for example, ethylene/vinyl acetate copolymer films, may be used.

Where one or more matrix patches are employed in the system of the present invention, the matrix patches may be made using coating techniques well known to those skilled in the art, either with solvent or hot melt (solvent-free).

Also, in the case of a reservoir type patch, the patch can be produced by a technique well known to those skilled in the art, for example, a reservoir is formed by heat-sealing a support to a membrane and filling the reservoir at the same time or at different times.

In both cases, the patch is of a suitable size in industrial production, based on the amount of active ingredient or ingredients contained per surface area, so that the system can deliver a selected dose of active ingredient in a given time.

The transdermal systems of the present invention may have any geometry: square, rectangular, circular or oval. The individual patches may be arranged side-by-side or concentrically (each patch surrounding a patch), or any other geometry may be used. The patch may be separated or surrounded by one or more additional films, which may be adhered together if desired.

For active ingredients which are administered transdermally and act locally or systemically, any combination of several active ingredients can be used within the scope of the present invention.

Among these combinations, the following combinations are possible:

a) natural or synthetic estrogen or estrogens in combination with progestin or progestins for contraceptive purposes or for treating menopause symptoms, such as estradiol, ethinyl estradiol, estriol and their derivatives in combination with norethindrone acetate, norethisterone, levonorgestrel, desogestrel, norgestimate, lynestrenol, gestodene, nomegestrol acetate or dienogest;

b) beta-blockers in combination with diuretic compounds, especially for cardiovascular diseases, such as timolol, indolol, bufuraline (bufradol), indolol or nilpdiole in combination with amiloride (amilonide) or hydrochlorothiazide;

c) corticoids and antihistamine compounds, especially for the treatment of allergies, such as methylprednisolone, prednisolone, hydrocortisone, beclomethasone or triamcinolone in combination with astemizole, dexchlorpheniramine, cetirizine, diphenylhydramine chloride or chlorpheniramine;

d) analgesics and anti-inflammatory compounds, especially for the treatment of pain, such as acetylsalicylic acid, paracetamol or noraminopyrine in combination with mefenamic acid, flufenamic acid, diclofenac, oxybuprazone, buconazole, naxoprene or bibutyric acid; and

e) antibiotics and antibiotic compounds, which are used exclusively for the treatment of infections, such as amoxicillin and clavulanic acid, sulfamethoxazole and trimethoprim, erythromycin and acesulfame-soxazole or erythromycin and tetracycline in combination.

The system in which the active ingredients are released simultaneously is preferably one selected from estrogenic compounds, while another is particularly preferably selected from progestogenic compounds. Best mode

The best mode for carrying out the invention consists of a system for transdermal delivery of two active principles (A and B), characterized in that it comprises

A basic matrix patch comprising in its body an active ingredient A and an active ingredient B, said active ingredient A being present in a therapeutically effective amount to be delivered, said active ingredient B being present in an amount which is less than that required to deliver a therapeutically effective amount, and

(ii) an additional matrix patch comprising an active ingredient B in a quantity sufficient to replenish said base patch until a therapeutically effective dose is reached.

In other words, the proposed system consists of two juxtaposed (or connected) matrices, which is a system whose first matrix contains a mixture of two active principles, one of which is released at a dose lower than its effective therapeutic dose, and whose second matrix, associated with the first matrix, contains the same active principle as the one released at the effective therapeutic dose.

This regimen is very advantageous for the simultaneous release of estrogen and progestin, especially for the simultaneous release of 17- β -estradiol and 17- β -norethindrone acetate in a dose ratio of 1/4 and 1/8 for different doses of 17- β -estradiol (25-100 μ g released per 24 hours) and for different doses of 17- β -norethindrone acetate (800 μ g released per 24 hours), respectively, which are effective in the treatment of amenorrhea and cardiovascular diseases.

The advantages and features of the present invention will be apparent from the following examples of the production of the system of the present invention and its comparison with the systems described in the prior art in this field. Of course, these details do not constitute any limitation on the overall invention, but merely illustrate it. The systems of the present invention and the comparative systems are formed from matrix patches in various combinations, as described below.

Example 1 (Patch 1)

47.0g LEVAPREN^450P (ethylene/vinyl acetate copolymer (hereinafter abbreviated as EVA) produced by Bayer), 48g of crotamiton [ N-ethyl-2-N- (2-tolyl) -2-butenamide [ ]](BOEHRINGERINGGELHEIM), 0.2g IRGANOX^B215 (an antioxidant from Ciba-Geigy) and 115.53g of ethyl acetate were placed in a container. The mixture was heated for 5 hours until the EVA was completely dissolved. After stirring at room temperature for 1 hour, 4g of norethindrone acetate (hereinafter abbreviated as NETA) dissolved in 20g of tetrahydrofuran in advance was added. The resulting mixture was stirred for another 30 minutes until it was completely homogeneous; it was then left until the bubbles completely disappeared. The substrate was coated on a silicone-coated polyester film at room temperature (15-25 ℃ C.) to give (100. + -. 10) g/m²Deposited material ofAnd (5) feeding. The resulting article was heated at 70 ℃ for 30 minutes and then transferred to a polyethylene support. The resulting product is then cut to the appropriate size. The cut product is packaged in bags, envelopes or vacuum seals if desired.

Example 2 (Patch 2)

Analogously to the procedure described above in example 1, 49.8g LEVAPREN were used^450P、44gcrotamiton、0.2g IRGANOX^B215, 116.2g of ethyl acetate, 2g of 17-beta-estradiol and 4g of norethindrone acetate (added simultaneously with the addition of 17-beta-estradiol), these two hormones being dissolved together in 30g of tetrahydrofuran.

Example 3 (Patch 3)

20.7g of ELVAX^46L and 6.9g ELVAX^46 (DuPont ethylene/vinyl acetate copolymer) and 6g ETHOCEL^(ethyl cellulose from DOW CHEM IC AL) was placed in a vessel, stirred and heated to about 130 ℃. Then 1.2g of 17-. beta. -estradiol and 18.9g of EUTANOL were added gradually at 130 ℃ with continued stirring^G (2-octyldodecanol commercially available from HENKE), the mixture was stirred further until it was completely homogeneous. Then 6.3g of SURFADONE was added at 100-^LP300 (N-dodecyl-2-pyrrolidone commercially available from GAF) and stirring was continued until the mixture was completely homogeneous. The resulting mixture was heated at 100 ℃ and 140 ℃ to a temperature of (100. + -. 10) g/m²The thickness is applied to a temporary support that is resistant to adhesion, in particular a silicone-coated polyester film. The resulting matrix was transferred to a polyethylene support.

Example 4 (Patch 4)

Except that 11g of ELVAX was used^46L、11g ELVAX^46、5g ETHOCEL、15gEUTANOL^G、5g SURFADONE^LP300, 1g of 17-. beta. -estradiol and 2g of norethindrone acetate, the same procedure as in example 3 was followed.

Example 5 (Patch 5)

The same procedure as in example 3 was followed except that 37.75g of ELVAX46L, 11.25g of ELVAX46, 10g of ETHOCEL, 30.5g of EUTANOLG, 4g of norethindrone acetate and 10.5g of SURFADONE LP300 were used.

Example 6 (Patch 6)

13.35g KRATONG^1657 (Poly (styrene/ethylene/butylene/styrene) triblock copolymer marketed by SHELL), 0.1g IRGANOX^565 (an antioxidant commercially available from Ciba-Geigy) and 12.5g ZONATACL^105L (an adhesive resin commercially available from ARIZNA CHEM ICAL), 10.25g of PARAPOL 950 (a butene/isobutylene copolymer commercially available from EXXON CHEMICAL), 10.25g of RUTANOL^G (2-octyldodecanol commercially available from HENKEL), 3G SURFADONE^LP300 (N-dodecyl-2-pyrrolidone commercially available from the GAF company) and 25.6g cyclohexane were placed in a 250ml beaker and the mixture was stirred for 6 hours while heating at 60 ℃ until the components were completely dissolved. Then, 0.55g of norethindrone acetate, previously dissolved in 2.75g of tetrahydrofuran, was added, the resulting mixture was stirred for 30 minutes until complete homogenization, and then it was left until the bubbles completely disappeared. The resulting mixture was stirred at room temperature (15-25 ℃) to (100. + -. 10) g/m²The amount of (a) is coated on a silicone coated polyester film. After heating at 70 ℃ for 0.5 hour, the resulting matrix was transferred to a polyethylene support. The product is then cut to size and packaged in bags, if desired.

Example 7 (Patch 7)

13.8g VECTOR^4211D [ a ternary block copolymer of polystyrene/isoprene/styrene ]]、23.85g ECR^3385 (a tackifying resin commercially available from EXXON CHEM ICAL) 0.1g IRGANOX^565 (an antioxidant commercially available from Ciba-Geigy) and 3.5g of SURFADONE^LP300 (N-dodecyl-2-pyrrolidone commercially available from BOEHRINGAR INGELHEIM), 7.5g LAUROGLYCOL^(a mixture of propylene glycol monolaurate and dilaurate, commercially available from GATTEFOSSE) and 19.8g of ethyl acetate were placed in a 2500ml beaker. The mixture was stirred while it was heated at 60 ℃ until the compound was completely dissolved. Then a solution of 1.25g norethindrone acetate, previously dissolved in 6.25g tetrahydrofuran, was added. The resulting mixture was stirred for about 30 minutesUntil completely homogeneous. And cooling until the bubbles disappear completely. At room temperature (15-20 ℃) in the range of (100. + -. 10) g/m²The amount of (b) is coated on a silicone polyester film. The coating was transferred to a polyethylene support after heating at 50 ℃ for at least 30 minutes. The product is cut to size.

The advantages of the present invention can be demonstrated by an in vitro (exvivo) permeation test of the abdominal skin of male nude mice performed according to the following protocol:

the surface area previously cut with a hollow punch was 2.54cm²The transdermal patch of (1), placed at 3.14cm²The amount of hormone (i.e., steroid hormone) released was measured on the skin of the belly of a round nude mouse using a glass tube kept at a constant temperature of 37 c. The glass tube was provided with a receiving chamber having a volume of 11.5ml and containing a receiving phase consisting of an isotonic solution/PEG 400 mixture (75/25; v/v).

Samples of the receiving solution were taken at 2, 4, 6, 8, 12, 16, 20 and 24 hours and analyzed by liquid chromatography. To obtain the different results caused by the intrinsic permeability of these skin samples, permeation experiments of transdermal patch samples were performed on a minimum of 3 to 5 skin samples. The results presented are the average values obtained from each patch of these experiments.

The following is 17-. beta. -estradiol (F) obtained in the case of patches 1-7_ES) And/or norethindrone acetate (F)_NETA) Average skin absorption flux of (1):

patch 1: F_NETA=0.35±0.16μg/cm²/h

Patch 2: F_ES=0.2±0.07μg/cm²/h

F_NETA=0.39±0.1μg/cm²/h

Patch 3: F_Es=0.61±0.08μg/cm²/h

Patch 4: F_ES=0.57±0.13μg/cm²/h

F_NETA=0.57±0.17μg/cm²/h

Patch 5: F_NETA=0.5±0.03μg/cm²/h

Patch 6: F_NETA=0.47±0.05μg/cm²/h

Patch 7: F_NETA=0.89±0.12μg/cm²/h

Tables I to V illustrate the reduction in surface area of the systems of the invention in the case of simultaneous transdermal delivery of 17-beta-estradiol and norethindrone acetate, relative to the comparative system formed by two side-by-side patches of a single active ingredient.

Table I compares inventive System I, consisting of Patches 4 and 5, with comparative System Ia, consisting of Patches 3 and 5.

Table II compares inventive System II consisting of Patches 2 and 1 with comparative System IIa consisting of Patches 3 and 1.

Table iii compares the inventive system iii consisting of patches 4 and 1 with the comparative system iiia consisting of patches 3 and 1.

Table IV compares the inventive system IV consisting of patches 4 and 6 with a comparative system IVa consisting of patches 3 and 6.

Table v compares inventive system v, consisting of patches 4 and 7, with comparative system va, consisting of patches 3 and 7.

The abbreviations used in these tables have the following meanings:

SD1 denotes the surface area of the base patch in cm²And (4) showing.

SD2 denotes the surface area of the patch in cm²And (4) showing.

S represents the total surface area in cm of a system formed by two patches arranged side by side²And (4) showing.

G represents the reduced surface area, expressed in percentage, of the system of the invention (represented in the second row of the table) compared with a system formed by two patches, each containing one active ingredient, juxtaposed (represented in the first row of the table).

In the system of the present invention, the base patch contains a mixture of 17- β -estradiol and norethindrone acetate, whereas in the comparative system, it contains only 17- β -estradiol.

The patch contains norethindrone acetate only. TABLE I

	SD1	SD2	S	G
					Comparative System Ia	3.4	20.8	24.2
System I	3.6	16.7	20.3	16.1

TABLE II

	SD1	SD2	S	G
					Comparative System IIa	3.4	29.8	33.2
System II	10.4	18.1	28.5	14.1

TABLE III

	SD1	SD2	S	G
					Comparative System IIIa	3.4	29.8	33.2
System III	3.6	23.8	27.4	17.3

TABLE IV

	SD1	SD2	S	G
					Comparative System IVa	3.4	22.2	25.6
System IV	3.6	17.7	21.3	16.8

TABLE V

	SD1	SD2	S	G
					Comparative System Va	3.4	11.7	15.1
System V	3.6	9.4	13	13.9

In the context of the present invention, it is desirable to deliver the following therapeutically effective doses:

-release of 50 μ g17- β -estradiol every 24 hours, and

-release of 250 μ g norethindrone acetate every 24 hours.

If it is desired to release both hormones simultaneously in a single patch, the difference in skin permeability (i.e., skin absorption flux) between norethindrone acetate and 17- β -estradiol must be 5. Such a difference is theoretically attainable, but in practice it is difficult to attain, and it is impossible to attain such a difference if marketing constraints such as stability, comfort, and adhesive performance of such patches are taken into consideration.

Therefore, patches 2 and 4 having good physicochemical properties and a pleasant feeling also do not make it possible to adjust the required dose.

Without increasing the release dose of 17- β -estradiol by 2.5-fold or 5-fold, respectively, it is not possible to achieve the desired effective dose of norethindrone acetate. Another solution is to use a system of 2 juxtaposed matrix patches (one containing 17- β -estradiol and the other containing norethindrone acetate), but this solution is not as effective as the one of the present invention. While the concentration of norethindrone acetate in the patch did not reach the desired 250 μ g dose over 24 hours due to the reduced surface area associated with the base matrix patch containing the mixture of the two hormones, the additional patch contained only norethindrone acetate, which provided a supplemental dose for adjustment to the desired 250 μ g over 24 hours.

Thus, the skin was used to absorb a flux of 0.61. mu.g/cm as compared to comparative system Ia in Table I²The patch 3, for releasing 50. mu.g of 17-. beta. -estradiol in 24 hours, requires the use of a surface area of 3.4cm²The patch of (1).

Also, the flux absorbed by the skin was 0.5. mu.g/cm²The patch 5/h released 250 μ g of norethindrone acetate in 24 hours, using a surface area of 20.8cm²The patch of (1). Thus, the total surface area of comparative system Ia reached 24.2cm²。

In contrast, we have found that the skin absorption flux for norethindrone acetate and 17- β -estradiol using patch 4 of system I of the invention is 0.57 μ g/cm²In the case of the reaction, 50. mu.g of 17-beta-estradiol were released in 24 hours using a surface area of 3.6cm²The patch of (1). The 3.6cm²The patch of (a) can simultaneously release 49.2g norethindrone acetate in 24 hours. Thus, 200.8g of norethindrone acetate is still required to be released to achieve a 250 μ g dose. The amount can be achieved by the patch 5, the surface area of the patch 5 being 16.7cm²The skin absorption flux is 0.5 mu g/cm²/h。

The surface area of the entire system I was therefore 20.3cm²This was 16.1% less than the comparative system Ia of patches 3 and 5 above.

A similar analysis, as shown in Table II, shows a 14.1% reduction in surface area for system II of the present invention. This result is very interesting because in this case the system II of the invention contained the 17-. beta. -estradiol absorption flux of the patch 2 of the two hormones (0.2. + -. 0.07. mu.g/cm)²H) comparison17-beta-estradiol-only patch 3 (F) of comparative system IIa_Es=0.61μg/cm²H) low, which indicates that the patch 2 in the system of the invention must have a large surface area (10.4 cm)²). Nevertheless, the surface area of the inventive system II is significantly reduced compared to the comparative system IIa. This result was significant because patch 2 also had a very low norethindrone acetate uptake flux of 0.39 μ g/cm²This means that the dose of norethindrone acetate delivered by the patch 1 is very large.

In this case, it should also be noted that patch 1 had a very low absorption flux of norethindrone acetate in both systems: f_NETA=0.35μg/cm²/h。

It was also found that, in the case of patch 1, system II according to the invention reduced the surface area more than comparative system IIa, i.e. from 29.8cm²Reduced to 18.1cm²And the reduction is 40 percent.

One of the conclusions in this case is to increase the number of formulations available, since even though they have a lower skin permeation flux, it does not necessarily mean that an excessively large surface area has to be used.

In Table V, patch 7 exhibited a high norethindrone acetate uptake flux (0.89. mu.g/cm) in both systems, as compared to the previous case²H), a lower total surface area of 15.1cm was obtained compared to the comparative system Va (each patch containing a hormone)²The reduction in surface area of the inventive system V was found to be about 14%.

The same results were obtained in tables III and IV, which had a reduction in surface area of 17.3% and 16.8%, respectively.

These two tables and Table V also highlight another advantage of the present invention, namely that different types of patches can be used to produce a transdermal system.

The patch 4 based on ethylene/vinyl acetate copolymer can be associated with a patch 1 based on the same copolymer but with a different formulation (table iii) or with a patch 6 based on a poly (styrene/ethylene/butylene/styrene) block copolymer (table iv) or with a patch 7 based on a poly (styrene/isoprene/styrene) block copolymer (table v).

Further selection of compounds that can be used in the patch composition and use of the above-described patch with low absorption flux allows for convenient adjustment of the dosage of the various active ingredients required, thus greatly broadening the scope of development and application, providing transdermal systems with several different dosages, appropriate size and ease of use for simultaneous delivery of at least two active ingredients.

The estrogen/progestin systems listed here have a 15-20% reduction in surface area due to the permeability of the active ingredient used, which is clearly a further advantage.

Claims (8)

1. A system for the transdermal delivery of at least two active ingredients, consisting of at least two juxtaposed patches, characterized in that it comprises

A base patch comprising a mixture of all active ingredients, wherein at least one first active ingredient (A) is present in an amount effective to deliver a therapeutically effective amount and at least one second active ingredient (B) is present in an amount less than that required to deliver a therapeutically effective amount, and

(ii) one or more additional patches containing a single active ingredient (B) selected from the group consisting of ingredients present in the above-mentioned base patch in an amount less than that required to deliver a therapeutically effective amount, said one or more additional patches serving to replenish the amount of each active ingredient (B) in the system until a therapeutically effective amount is reached.

2. System according to claim 1, characterized in that the patches of the system are of the depot or matrix type.

3. System according to claim 2, characterized in that the patches of the system are single-layered, multi-layered or laminated.

4. A system according to any of claims 1-3, characterized in that all patches in the system share a support.

5. A system according to any of claims 1-3, characterized in that each patch in the system has a separate support.

6. System for the release of two active principles (A and B) according to claim 1, characterized in that it comprises

A basic matrix patch, the body of the matrix comprising an active ingredient A and an active ingredient B, said active ingredient A being present in a therapeutically effective releasable amount, the active ingredient B being present in an amount less than that required to release a therapeutically effective amount, and

(ii) an additional matrix patch, the body of matrix of which contains active ingredient B in an amount to supplement said base patch until a therapeutically effective dose is reached.

7. A system according to any of claims 1-6, characterized in that the active ingredients released simultaneously are selected from estrogenic compounds on the one hand and progestogenic compounds on the other hand.

8. A regimen according to claim 7, characterized in that it comprises the estrogenic compound 17- β -estradiol and the progestogenic compound norethindrone acetate.