HK1015281A - Transdermal matrix system - Google Patents
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- HK1015281A HK1015281A HK99100564.8A HK99100564A HK1015281A HK 1015281 A HK1015281 A HK 1015281A HK 99100564 A HK99100564 A HK 99100564A HK 1015281 A HK1015281 A HK 1015281A
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The invention relates to a novel matrix system for the transdermal administration of an estrogenic component and/or a progestin component, consisting of a carrier and an adhesive matrix consisting of an ethylene/vinyl acetate (EVA) copolymer and a specific combination of three compounds, diethyl phthalate, 2-octyldodecyl myristate and N-alkyl-2-pyrrolidone, in which matrix system said estrogen and/or said progestin are dissolved.
The invention also relates to a method for producing said matrix system and to the use thereof in therapy.
Transdermal delivery systems for a variety of hormones, particularly the estrogenic component itself, are now available for the treatment of menopausal and osteoporotic symptoms in what is known as "hormone replacement therapy". These current systems include so-called "reservoir" systems in which the active ingredient is dissolved in a solvent that acts as a vehicle for delivery to the skin through a microporous membrane. This is an example of a 17 β -estradiol based device sold under the trade name ESTRADERM by Ciba-GeigyAnd (5) selling TTS.
Meanwhile, there are so-called "matrix" systems in which the active ingredient is dissolved or dispersed in an adhesive matrix based on polymers (such as EVA copolymers, acrylic copolymers, styrene/isoprene/styrene copolymers, etc.). This is an example based on 17 β -estradiol, a device manufactured by laboratorire sfournier s.c.a. by the trade name oessclimAnd (5) selling.
On the other hand, the production of transdermal delivery systems for the estrogenic component and the progestin component in these matrix systems still presents a number of problems.
Indeed, it is well known that estrogens and progestins are products that have very low solubility in the polymers used to formulate the matrix system. Moreover, each of these active ingredients is partially or totally incompatible with some of the composition's components (resins, solvents, plasticizers, polymers, skin absorption enhancers). They may have different solubility and stability temperatures and one of the two may recrystallize over time and degrade when used or useable in compositions that have only too low a concentration to achieve the desired therapeutic effect. Also, there is no universal skin absorption enhancer that increases the transdermal flux of all active ingredients, and therefore, it is often necessary to use several enhancers and/or solvents when administering different active ingredients. Now, the introduction of any new substances may cause or create new irritation and problems of cohesion and adhesion of the system.
Also, these limitations (compatibility, solubility) combine to affect many other components of the composition in addition to the active ingredient, thereby exacerbating the difficulties to be solved.
Moreover, these requirements relating to skin tolerance, systemic adhesion and cohesion are explained by dose limitations. Generally, the active ingredients have different skin penetration abilities, meaning that each active ingredient has a different absorption capacity. Therefore, it is very complicated to develop a composition that allows each active ingredient to be administered in a desired therapeutic dose. In practice, it is often not possible to develop such compositions, and such development leads to impasse or to rather unsatisfactory and thus economically infeasible systems. This explains why this type of system has not been marketed yet.
Indeed, the only transdermal systems currently available for the administration of two hormones are the 17 β -estradiol and norethisterone acetate based "reservoir" systems, which are sold under the name ESTRAGEST by CIBA-GEIGYAnd (5) selling TTS.
One of ordinary skill in the art also recognizes that estrogens and/or progestins are molecules that cannot readily pass through the skin barrier.
Thus, the amount of active ingredient released to deliver the desired therapeutic effect is generally small compared to the initial amount of active ingredient present in the transdermal device (regardless of its type), and the resulting yield is therefore low.
Although matrix systems for the administration of estrogenic and/or progestinic components, where the matrix is based on ethylene/vinyl acetate (EVA) copolymers have been described for A long time in published patent applications FR-A-2612785, EP-A-0279982, WO-A-92/07589 and EP-A-05560, none of these patent applications discloses or suggests A specific formulation of the invention which makes it possible to overcome the above-mentioned disadvantages.
According to the present invention, it is designed to prepare an EVA-based matrix system for simultaneously administering an estrogenic component and a progestin component in order to solve the above-mentioned problems, and the system also gives excellent productivity.
It is also contemplated to produce matrix systems for administration of the estrogenic component itself or the progestin component itself, which systems provide excellent yields.
According to a second aspect of the invention, a method for preparing these matrix systems is envisaged.
According to another aspect of the invention, it is envisaged to provide a use of such a matrix system for the treatment of menopause and osteoporosis.
The above object is achieved by a new solution in which the matrix of the matrix system containing the estrogenic and/or progestin component consists essentially of a specific combination of EVA and three compounds, namely diethyl phthalate, 2-octyldodecyl myristate and N-alkyl-2-pyrrolidone.
More specifically, according to the present invention, a transdermal matrix system for the transdermal administration of at least one hormone is proposed, the system comprising a carrier and an adhesive matrix, characterized in that the matrix comprises:
(a)39-61 parts by weight of an ethylene/vinyl acetate copolymer,
(b)12-17 parts by weight of 2-octyldodecyl myristate,
(c)5 to 17 parts by weight of diethyl phthalate,
(d)10-16 parts by weight of a compound selected from the group consisting of N-alkyl-2-pyrrolidones wherein alkyl is C4-C15Group), and
(e)1-12 parts by weight of at least one hormone selected from the group consisting of an estrogen component and a progesterone component.
According to a second aspect of the present invention there is provided a further transdermal system for the transdermal administration of at least one hormone, the system comprising a carrier and an adhesive matrix, characterised in that the matrix comprises:
(a)39-61 parts by weight of an ethylene/vinyl acetate copolymer,
(b)12-17 parts by weight of 2-octyldodecyl myristate,
(c)5 to 17 parts by weight of diethyl phthalate,
(d)10-16 parts by weight of a compound selected from the group consisting of N-alkyl-2-pyrrolidones wherein alkyl is C4-C15A group) of compounds of (a) or (b),
(e)1 to 12 parts by weight of at least one hormone selected from the group consisting of an estrogen component and a progesterone component, and
(f)1 to 10 parts by weight of a vinyl acetate/N-ethylene-2-pyrrolidone (abbreviated to VA/VP) copolymer.
According to the present invention, there is provided a method for preparing the transdermal matrix system, the method being characterized in that it comprises the steps of:
(. alpha.) diethyl phthalate, N-alkyl-2-pyrrolidone, 2-octyldodecyl myristate, a hormone selected from the group consisting of an estrogen component, a progesterone component and mixtures thereof, the VA/VP copolymer (if present in the composition) and the EVA are introduced sequentially into a reactor at a temperature below the boiling point of the solvent or solvent system used, the resulting mixture is stirred,
(β) then adding the solvent or solvent system and stirring all the components still at the same temperature until the EVA has completely dissolved and the mixture is completely homogeneous;
(gamma) coating the homogeneous mixture from the (beta) step on a non-tacky temporary support at a temperature of 50-70 ℃ to obtain 50-300g/m on said support2The deposition amount of (3);
(δ) heating the resulting coating to a temperature of 40-80 ℃, depending on the boiling point of the solvent or solvent system, in order to evaporate the latter; and
(ε) transferring the resulting dry matrix to a final support.
Transdermal matrix systems have also been proposed to provide a medical product for therapeutic use in treating menopausal or osteoporotic symptoms.
In the drawings, FIG. 4 shows the results in μ g/cm2Expressed as amount of released 17 β -estradiol (Q) as a function of time (t) expressed in hours (h), figures 1-3 show the yield of 17 β -estradiol or NETA (norethisterone acetate) (R) in% as a function of time (t) expressed in hours (h).
More specifically, in the drawings:
FIG. 1 shows curves 3, 6 and E relating to the release rate of 17 β -estradiol1Comparison between (R/t system) the curves are obtained using the products of examples 3 and 6 according to the invention and under the trade name ESTRAGESTKnown reference transdermal product of TTS and marketed by Ciba-Jiaji (herein denoted E)1) Obtaining;
fig. 2 shows a comparison of curves 3, 6 relating to the release rate of NETA and E2 (R/t system), which were obtained using the products according to examples 3 and 6 of the invention and the stated ESTRAGESTTTS (referred to herein as E2);
FIG. 3 shows curves 2, 8 and E relating to the release rate of 17 β -estradiol3Comparison of the two products of examples 2 and 8 according to the invention with the product designation OESCIM (R/t system)And marketed by laboratores FOURNIER s.c.a. (herein referred to as E)3) Obtaining; and
FIG. 4 shows curves 3, 6 and E relating to the release of 17 β -estradiol4Comparison (Q/t system) of (A) with the products of examples 3 and 6 according to the invention and OESCIM(referred to herein as E)4) And (4) obtaining the product.
It is preferred to use ethylene/vinyl acetate copolymers having a vinyl acetate content of from 30 to 75% by weight, in particular from 45 to 60% by weight, based on the weight of the ethylene/vinyl acetate copolymer. Mixtures of such EVA's of different molecular weights or different vinyl acetate contents may also be used, if appropriate.
The N-alkyl-2-pyrrolidone herein includes substances in which the alkyl group is composed of 4 to 15 carbon atoms, such as N-dodecyl-2-pyrrolidone and N-octyl-2-pyrrolidone. N-dodecyl-2-pyrrolidone is particularly preferred in the present invention, and within the scope of the present invention hormones are understood to mean an estrogenic component and/or a progestinic component.
Among the estrogenic components suitable for use in the present invention, particular mention should be made of 17 β -estradiol and derivatives of estradiol, in particular estradiol mono-and diesters, such as estradiol 17-acetate, estradiol 3, 17-diacetate, estradiol 3-benzoate and estradiol 17-undecanoate, and estradiol derivatives which are alkylated at the 17-position, such as ethinyl estradiol, ethinyl estradiol 3-isopropyl sulfonate, methyl estradiol, ethinyl estradiol cyclopentyl ether, ethinyl estradiol methyl ester and the like and mixtures thereof, where appropriate.
Among the progesterone components suitable for use in the present invention, mention may be made in particular of progesterone, dimethyldehydroprogesterone and derivatives thereof (in particular 17-hydroxyprogesterone acetate and medroxyprogesterone acetate), norethisterone and derivatives thereof (in particular 17-norethisterone acetate), pregnane (norpregnane), nomegestrol acetate and levonorgestrel.
According to the invention, it is preferred to use 17 β -estradiol as the estrogenic component and 17-norethisterone acetate (NETA) as the progestinic component.
Vinyl acetate/N-vinyl-2-pyrrolidone copolymers are understood here to mean copolymers having a vinyl acetate content of from 30 to 70% by weight, based on the weight of the copolymer. Such products are known for use as film formers in aerosols, for example sold under the trade name "PVP/VA" by the GAF company, in the form of powders in the case of the PVP/VA-S series, in the form of solutions in ethanol or in isopropanol, respectively, in the case of the PVP/VA-E and PVP/VA-I series, or sold under the trade name Kollidon VA by BASF. Among these products, mention may be made in particular of the VA/VP copolymer containing 40% by weight of vinyl acetate sold under the trade name PVP/VA-S-630 and of the VA/VP copolymer containing 37.7% by weight of vinyl acetate sold under the trade name Kollidon VA 64.
The vehicle for receiving the matrix may be any vehicle that is commonly used in occlusive or non-occlusive transdermal systems and that is impermeable to the components of the matrix. Preferably for example in the form of polyethylene, polypropylene or polyester films, composites of polyethylene and vinyl acetate/ethylene copolymers or foams.
Additional adhesive strips (e.g., circumferential strips in the form of rings) may be added to the system to optimize its adhesive properties, if desired.
In practice, the surface of the substrate that is not bonded to the carrier may be covered with a protective layer or film that may be peeled off prior to use of the article. Such articles may themselves be packaged in a leak-proof protective device such as a polyethylene-aluminum composite.
By being able to provide excellent hormone release rates, the matrix system of the present invention has a number of advantages, which will now be described.
One advantage is the cost price, which is much lower than the price of the products on the market today by using smaller amounts of expensive hormones.
The risk of environmental contamination by these hormones is also reduced when the product is disposed of after the treatment phase.
It is only the composition of the invention in which the EVA copolymer is combined with three specific compounds, namely N-alkyl-2-pyrrolidone, diethyl phthalate and 2-octyldodecyl myristate, that these results are achieved.
Moreover, the use of lower amounts of estrogen and/or progesterone while increasing delivery simplifies the development and manufacture of compositions that form the matrix of the device.
In fact, this reduces or eliminates the problem of solubility of the hormone in EVA and chemical or physical incompatibility with the other components of the matrix. This also solves the problem of hormone crystallization over time and instability of the product, both of which are unacceptable for the utility and marketing of products for therapeutic purposes, such as transdermal systems.
All these advantages thus make it possible to finally obtain an acceptable, commercially acceptable matrix system for the administration of an estrogenic component and a progestinic component, said system giving excellent yields.
If desired, the cohesion of the article can be optimized by using a mixture of EVA's of different molecular weights. Also, the addition of the VA/VP copolymer makes it possible to optimize the coalescence behavior and the solubility of the hormone in the matrix.
Surprisingly, it also makes it possible to reduce the skin irritation that would otherwise occur.
The transdermal systems of the invention are applied by techniques customary to those skilled in the art, i.e. coating in a solvent phase or by the so-called "hot-melt" technique, i.e. in the absence of solvents.
In both cases, in terms of industrial production, large areas are coated and then cut to obtain articles whose size can be adjusted to the dose of active ingredient to be administered in a given time.
In terms of the so-called "solvent phase" technique, a process for the preparation of the adhesive matrix system of the invention is proposed, which comprises the following steps:
(α) adding diethyl phthalate, N-alkyl-2-pyrrolidone, 2-octyldodecyl myristate, a hormone selected from the group consisting of an estrogen component, a progesterone component and mixtures thereof, the VA/VP copolymer (if present in the composition), and EVA sequentially to a mixer at a temperature below the boiling point of the solvent or solvent system used (e.g. ethyl acetate or an ethyl acetate/ethanol mixture), and stirring the resulting mixture;
(β) adding a solvent or solvent system and stirring the whole mixture at the same temperature until the EVA has completely dissolved and the mixture is completely homogeneous;
(gamma) at a temperature of 50-70 ℃ in the range of 50-300g/m2Will be uniformThe mixture is applied to a non-adhesive temporary intermediate support, in particular a siliconized polyester film;
(δ) evaporating the solvent or solvent system by heating to a temperature of 40-80 ℃ (preferably 60-80 ℃), depending on the boiling point of the solvent or solvent system; and
(ε) transferring the dry matrix obtained in step (δ) to a final support of choice.
The novel adhesive matrix preparation according to the invention is particularly suitable for the treatment of osteoporosis, menopause and corresponding cardiovascular diseases in the so-called "hormone replacement therapy" as well as in any treatment based on transdermal administration of estrogens and/or progestins.
The best mode for carrying out the invention consists in using a transdermal matrix system, the matrix of which comprises the following components, based on 100 parts by weight:
(a)54 parts by weight of an ethylene/vinyl acetate copolymer,
(b)17 parts by weight of 2-octyldodecyl myristate,
(c)5 parts by weight of diethyl phthalate,
(d)16 parts by weight of N-dodecyl-2-pyrrolidone,
(e1)2 parts by weight of 17 beta-estradiol,
(e2)5 parts by weight of norethisterone acetate, and
(f)1 part by weight of a vinyl acetate/N-vinyl-2-pyrrolidone (VA/VP) copolymer,
on the one hand, or
(a)62 parts by weight of an ethylene/vinyl acetate copolymer,
(b)13 parts by weight of 2-octyldodecyl myristate,
(c)10 parts by weight of diethyl phthalate,
(d)10 parts by weight of N-dodecyl-2-pyrrolidone,
(e)3 parts by weight of 17 beta-estradiol, and
(f)2 parts by weight of a vinyl acetate/N-vinyl-2-pyrrolidone (VA/VP) copolymer,
on the other hand, or
(a)53 parts by weight of an ethylene/vinyl acetate copolymer,
(b)17 parts by weight of 2-octyldodecyl myristate,
(c)10 parts by weight of diethyl phthalate,
(d)13 parts by weight of N-dodecyl-2-pyrrolidone,
(e)6 parts by weight of norethisterone acetate, and
(f)1 part by weight of a vinyl acetate N/-vinyl-2-pyrrolidone (VA/VP) copolymer.
In these compositions, a useful vinyl acetate content of the EVA used is 60% by weight (based on the weight of the EVA copolymer). Useful vinyl acetate contents of the VA/VP copolymers are from 35 to 40% by weight, based on the weight of the VA/VP copolymer.
Other advantages and features of the present invention will be more clearly understood from the following description of examples and comparative tests.
Of course, these details as a whole are in no way meant to be limiting and are given by way of illustration only.
The following abbreviations are used for convenience below:
EVA: ethylene/vinyl acetate copolymer
Es; 17 beta-estradiol
NETA: nossesterone acetate
VA/VP; vinyl acetate/N-vinyl-2-pyrrolidone copolymer example 1
0.62 g of 17 beta-estradiol, 1.2 g of NETA, 3 g of SURFADONELP300 (N-dodecyl sold by GAF corporation)2-pyrrolidone), 3.9 g of 2-octyl-dodeca myristate (hereinafter abbreviated as "ODM") sold by GATTEFOSSE, 3 g of diethyl phthalate and 40.5 g of ethyl acetate were added in this order to a 250 ml beaker. The resulting mixture was heated to a temperature of 65-75 ℃ with stirring. Then 18.3 grams of LEVAPREN was added600HV (EVA copolymer sold by BAYER having a content of vinyl acetate units of 60% by weight) is added in portions, the resulting mixture is stirred for about 50 minutes, and heating is continued at a temperature of 65-75 ℃ until the EVA copolymer has completely dissolved. The dry extract was readjusted to 50% by weight and the resulting mixture was degassed. Coating onto a temporary siliconized polyester support at a temperature of 65-75 ℃ to form (100 + -10) g/m2Of (2) a deposit of (a). The resulting coating was heated to 70 ℃ for at least 15 minutes to evaporate the solvent. The resulting matrix was then transferred to a final polyester support. After cutting to the desired size, the product is packaged in heat sealable sachets. Example 2
In this example, the procedure is similar to that of example 1, except that 0.83 grams Es, 1.6 grams NETA, 4 grams SURFADONE are usedLP300, 6 grams ODM, 6 grams diethyl phthalate, 54 grams ethyl acetate and 21.6 grams LEVAPREN600HV (EVA copolymer sold by BAYER having a vinyl acetate unit content of 60% by weight). Example 3
In this example, the procedure is similar to example 1, except that 0.62 grams Es, 1.2 grams NETA, 4.8 grams SURFADONE are usedLP300, 5.1 grams ODM, 3 grams diethyl phthalate, 40.5 grams ethyl acetate and 15.3 grams LEVAPREN600 HV. Example 4
In this example, the procedure is similar to that of example 1, except that a mixture of EVA copolymers is used. Adding 0.62 g Es, 1.5 g NETA, 3 g SURFADONELP300, 4.5 grams ODM, 3 grams diethyl phthalate, 40.5 grams ethyl acetate and 14.4 grams LEVAPREN600HV and 3 gram LEVAPREN400 (EVA copolymer with a content of vinyl acetate units of 40% sold by BAYER). Example 5
Mixing 201.6 g of the mixtureDiethyl phthalate, 101.3 g SURFADONELP300, 100.8 grams ODM, 20.7 grams Es, 40 grams NETA and 539.9 grams LEVAPREN500HV (EVA copolymer sold by BAYER with a content of vinyl acetate units of 50%) was added to the reactor at room temperature, and the whole reaction was stirred. 1003.7 grams of ethyl acetate were then added and the mixture was heated at about 75 ℃ with stirring until the EVA copolymer had completely dissolved. The resulting mixture was degassed. Coated onto a temporary siliconized polyester support at a temperature of 50 ℃ to form a (100 ± 10) g/m 2 deposit. The coated product was then placed in a drying tunnel at a temperature of 60-80 ℃ to evaporate the solvent and the resulting matrix was transferred to the final polyester support. After cutting to the desired size, the product is packaged in heat sealable sachets. Example 6
130.5 g of ODM, 130.9 g of diethyl phthalate and 100.9 g of SURFADONELP300, 20.7 grams Es, 40 grams NETA, 570.3 grams LEVAPREN600HV and 10.1 g of PVP/VA-S-630 (a vinyl acetate/N-vinyl-2-pyrrolidone copolymer containing 40% by weight of vinyl acetate sold by the GAF company) were charged to a reactor at 75 ℃ and the whole reaction was heated for 5 minutes. 989.9 g of vinyl acetate and 10.1 g of ethanol were then added. The whole is stirred at 75 ℃ until the EVA copolymer has completely dissolved and the resulting mixture is degassed. The mixture was coated on a temporary siliconized polyester support at a temperature of 50 ℃ to form (100. + -. 10) g/m2Of (2) a deposit of (a). The coated product is then placed in a drying tunnel at a temperature of 60-80 ℃ to evaporate the solvent and the resulting substrate is transferred to a final polyester support. After cutting to the desired size, the product is packaged in heat sealable sachets. Example 7
201.4 g diethyl phthalate, 201.1 g SURFADONELP300, 340.1 grams ODM, 40 grams Es, 80 grams NETA, 60 grams PVP/VA-S-630, and 1080.2 grams LEVAPREN500HV was added to a reactor at 75 ℃. The resulting mixture was stirred. 1999.8 grams of ethyl acetate were then added and the mixture was stirred for about 4 hours while still at about 75 ℃ until the EVA copolymer was completely dissolved. Subjecting the obtainedThe mixture is degassed. The mixture was coated on a temporary siliconized polyester support at a temperature of 50 ℃ to form (100. + -. 10) g/m2Of (2) a deposit of (a). The coated product is then placed in a drying tunnel at a temperature of 60-80 ℃ to evaporate the solvent and transfer the resulting substrate to a final polyester support. After cutting to the desired size, the product is packaged in heat sealable sachets. Example 8
0.62 g Es, 1.5 g NETA, 3 g SURFADONELP300, 4.5 g ODM, 3 g diethyl phthalate, 0.3 g PVP/VA-S-630, 10 g ethanol and 40.5 g ethyl acetate were added to a 250 ml beaker. The resulting mixture is heated at a temperature of 65-75 ℃ with stirring until the VA/VP copolymer has completely dissolved. Then 17.1 grams of LEVAPREN was added600HV was added in portions and the resulting mixture was stirred at 65-75 ℃ for about 50 minutes with continued heating until the EVA copolymer had completely dissolved. The dry extract was readjusted to 50% by weight, and the resulting mixture was degassed. The mixture was coated onto a temporary siliconized polyester temporary at 65-75 ℃ to form (100 + -10) g/m2Of (2) a deposit of (a). The resulting coating was heated at 70 ℃ for at least 15 minutes to evaporate the solvent and the resulting substrate was transferred to the final polyester support. After cutting to the desired size, the product is packaged in heat sealable sachets. Example 9
In this example, the procedure is similar to example 1, except that only one hormone, i.e. NETA, is added. Thus, 1.2 grams of NETA and 3 grams of SURFADONE are used hereinLP300, 7.5 grams ODM, 1.5 grams diethyl phthalate, 40.5 grams ethyl acetate and 16.8 grams LEVAPREN500 HV. Example 10
In this example, the procedure is similar to example 9, except that 4.8 g of NETA, 19.2 g of SURFADONE are usedLP300, 20.4 grams ODM, 6 grams diethyl phthalate, 162 grams ethyl acetate and 69.6 grams LEVAPREN600 HV. Example 11
1.8 g of NETA, 4.8 g of SURFADONELP300, 5.1 g ODM, 3 g diethyl phthalate and 40.5 g ethyl acetate were added to 250 mmThe beaker was raised and the entire mass was heated to about 75 ℃ with stirring. Then 12 grams of LEVAPREN were added in small batches600HV and 3 gram LEVAPREN400 and the mixture is stirred for about 1 hour, still at 75 c, until the EVA copolymer has completely dissolved. The dry extract was readjusted to 50% by weight, and 0.6 g of PVP/VA-S-630 in 50% by weight ethanol solution was added. The entire reaction was stirred and the resulting mixture was degassed. Coating the mixture onto a temporary siliconized polyester support at a temperature of 65-75 ℃ to form (100 + -10) g/m2Of (2) a deposit of (a). The resulting coating was heated at 70 ℃ for at least 15 minutes to evaporate the solvent. The resulting substrate is then transferred to a final polyester support. After cutting to the desired size, the product is packaged in heat sealable sachets. Example 12
0.93 g Es and 3 g SURFADONELP300, 3.9 g ODM, 3 g diethyl phthalate, 0.6 g KOLLIDON VA-64 (a vinyl acetate/N-vinyl-2-pyrrolidone copolymer containing 37.7% by weight vinyl acetate sold by BASF), 37.5 g ethyl acetate and 3 g ethanol were added to a 250 ml beaker. The entire reaction was heated at 75 ℃ with stirring until KOLLIDON VA-64 had completely dissolved. Then 18.6 grams of LEVAPREN were added in small batches600HV and the mixture was stirred for about 1 hour until the EVA copolymer had completely dissolved. The dry extract was readjusted to 50% by weight and the resulting mixture was degassed. Applying the mixture to a temporary siliconized polyester support at a temperature of 65-75 ℃ to form (100 + -10) g/m2Of (2) a deposit of (a). The resulting coating was then heated at 75 ℃ for at least 15 minutes to evaporate the solvent. The resulting substrate is then transferred to a final polyester support. After cutting to the desired size, the product is packaged in heat sealable sachets. Example 13
In this example, the procedure is similar to example 12, except that the second hormone (i.e., NETA) is added. Thus, 1.5 grams of NETA, 0.62 grams of Es, 4.8 grams of SURFADONE were used hereinLP300, 5.1 grams ODM, 1.5 grams diethyl phthalate, 0.3 grams KOLLIDON VA-64, 37.5 grams ethyl acetate, 3 grams ethanol, and 16.2 grams LEVAPREN600. Example 14
In this example, the procedure is similar to example 11, except that only one solvent, ethyl acetate; 1.8 g of NETA and 3.9 g of SURFADONE were usedLP300, 5.1 grams ODM, 3 grams diethyl phthalate, 40.5 grams ethyl acetate, 15.9 grams LEVAPREN600HV and 0.6 g PVP/VA-S-630.
The productivity of the device of the invention is determined based on measuring the amount of hormone released within 24 hours of an in vitro skin model.
This test was performed by performing an in vitro permeation test on the abdominal skin of male nude mice according to the following principle.
The surface area of the sample was 2.54cm as measured in a static glass cell temperature controlled at 37 ℃ and having a receiving chamber with a volume of 11.5 ml2The transdermal device of (2) releases the hormone (originally perforated and placed at 3.14cm2On a dish of the abdominal skin of a male nude mouse), the receiving chamber contained an isotonic solution/PEG 400 mixture (75/25 vol/vol) as the receiving phase.
Each penetration test of the transdermal article samples was performed on a minimum number of 3-5 skin samples, taking into account the variability of results associated with the intrinsic permeability of the skin samples.
The results obtained are based on the average of each article obtained in these tests. The ratio of the mean value of the amount of hormone released after 24 hours of exercise to the initial amount of hormone contained in the product makes it possible to evaluate the 24-hour yield of the transdermal system of the invention.
For comparison, the only currently available product containing estrogen and progestin (i.e., marketed under the trademark ESTRAGEST by Ciba-Geigy) was measured in the same mannerTTS marketed) the amount of hormone released over a 24 hour period. Moreover, this article is the only commercially available transdermal system containing a progesterone component.
ESTRAGESTThe TTS product consists of two adjacent layers containing 17 beta-estradiol, 10mg, and neta, 30mgReservoirs were formed, each reservoir containing a mixture of 5mg of 17 β -estradiol and 15mg of NETA.
Placing at 3.14cm according to the same method2Skin permeation measurements were made on only one of the two reservoirs on the skin sample. The initial amount of hormone contained in the reservoir is converted to an initial amount of hormone per unit surface area in μ g/cm2And (4) showing.
The ratio of the average of the amount of 17 β -estradiol or NETA released in 24 hours to the initial amount contained in the reservoir makes it possible to obtain a 24-hour yield of Es or NETA.
The results obtained for the estrogen and progesterone containing formulations of the present invention are collected in table I and the results for the progesterone only formulations are listed in table II.
The yield of 17 beta-estradiol obtained in 24 hours with the article according to the invention was compared with the only currently commercially available substrate article based on EVA copolymers, i.e. OESCLIMThe yields of (a) were compared. This is generally done according to the same method by using 2.54cm2OESCIM ofThe samples were tested in vitro by permeation on the abdominal skin of male nude mice. Several tests carried out with the matrix article showed that the mean initial value of 17 beta-estradiol per unit surface area was 452.7 mug/cm2And the amount of 17 beta-estradiol released in the skin model after 24 hours is 14.2 mug/cm2。
Table III shows the products and products OESCIM of examples 1, 2, 3, 6 and 12 of the present invention considering 17 β -estradiol aloneCalculated yield.
In the case of matrices containing 17 β -estradiol and NETA, Table I shows that the system of the invention is superior to the above-mentioned product ESTRAGESTThe benefits of TTS. As can be seen from this example, as shown by curves 3 and 6 of FIGS. 1 and 2, the product of the invention for 17 β -estradiol and NETA generally has a yield ratio of ESTRAGESTThe TTS system yields are significantly high, with starting amounts that are respectively 8 and 12 (a factor) smaller.
Furthermore, Table I shows that the yield ratio for 17 β -estradiol is ESTRAGESTTTS is 25-80 times higher on average, and the yield is ESTRAGEST times higher than that of NETATTS is 20-50 times higher.
More precisely, ESTRAGESTThe TTS was compared as follows:
in example 1, the yield of Es was 47 times greater and the yield of NETA was 29 times greater;
in example 2, the yield of Es was 55 times greater and the yield of NETA was 32 times greater;
in example 3, the yield of Es was 81 times greater and the yield of NETA was 52 times greater;
in example 4, the yield of Es was 36 times greater and the yield of NETA was 29 times greater;
in example 5, the yield of Es was 26 times greater and the yield of NETA was 18 times greater;
in example 6, the yield of Es was 48 times greater and the yield of NETA was 31 times greater;
in example 7, the yield of Es was 29 times greater and the yield of NETA was 18 times greater;
in example 8, the yield of Es was 38 times greater and the yield of NETA was 23 times greater;
in example 13, the yield of Es was 75 times greater and the yield of NETA was 50 times greater.
These greater differences again demonstrate the advantages of the present invention, namely the use of less product for the desired therapeutic purpose, thereby achieving considerable cost savings, avoiding possible crystallization problems and incompatibility problems with the matrix, thus simplifying the development and manufacture of systems, particularly highly efficient and commercially acceptable matrix systems for the administration of estrogen and progestin components.
The VA/VP copolymers used in examples 6-8 and 13 are useful, as the case may be, for improving the adhesion of the article, improving the solubility of the hormone in the matrix, and surprisingly improving the skin discomfort phenomena that may occur during use. According to the invention, the presence of the VA/VP copolymers does not affect the good yields obtained, taking into account the amounts used.
Similarly, the same good results are generally obtained also in the case of a mixture of two EVA's with different vinyl acetate contents (example 4).
Similarly, similar results were obtained in the case of systems containing Es alone or NETA alone, as shown in fig. 3 and 4 on the one hand and in tables II and III on the other hand.
The results in table II show that despite a 12-fold lower concentration, the amount of released NETA is generally greater than ESTRAGESTThe released amount of TTS is large.
The yield analysis in Table II shows that the NETA yields of the products of examples 9, 10, 11 and 14 are respectively higher than ESTRAGESTThe yields of TTS products were 26-fold, 39-fold, 25-fold, and 48-fold greater.
The results in Table III also show that the articles of the invention containing 17 beta-estradiol are superior to OESCIMThe product has the advantages of simple process and low cost. And OESCIMComparison of the products (which are the only EVA-based matrix systems currently on the market), it was again found that the products according to the invention were produced in yields, whether in examples 1, 2, 3 and 6 containing 17 β -estradiol and NETA or as OESCIMExample 12, which contains only 17 β -estradiol, gives the product of the invention in the best case in yields which are typically 3-5 times greater. The results are also shown by curves 2 and 8 in fig. 3 (corresponding to examples 2 and 8).
Similarly, curves 3 and 6 in FIG. 4 show that the amount of 17 β -estradiol released by the article of the invention is generally significantly greater than OESCIMThe amount of product released (this amount is 2.3 times smaller) is significantly larger.
The conclusions from table I are also evident for the advantages of the device of the invention in the case of administration of two hormones and are the same as in the case of administration of only one hormone.
TABLE I
| Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 | Example 7 | Example 8 | Example 13 | ESTRAGESTTTS | ||
| Es | Q0 | 212.6 | 200.8 | 192.9 | 192.9 | 200.6 | 192.9 | 212.6 | 204.7 | 181 | 1570 |
| Q24 | 19.9 | 22 | 31.1 | 14.1 | 10.5 | 18.7 | 12.5 | 15.5 | 273 | 3.1 | |
| R | 9.4 | 11 | 16.2 | 7.3 | 5.2 | 9.7 | 5.9 | 7.6 | 15 | 0.2 | |
| NETA | Q0 | 421.2 | 401.6 | 385.8 | 484.2 | 404.4 | 385.8 | 429.1 | 511.8 | 449 | 4790 |
| Q24 | 20.9 | 21.9 | 34.2 | 24 | 12.6 | 20.2 | 13.2 | 20 | 38.2 | 8.2 | |
| R | 5 | 5.5 | 8.9 | 5 | 3.1 | 5.2 | 3.1 | 3.9 | 8.5 | 0.17 | |
| Q24: the amount of Es or NETA released in 24 hours, in μ g/cm2To represent | |||||||||||
| Q0: initial amount of Es or NETA, in μ g/cm2To represent | |||||||||||
| R: yield in percent (R ═ 100Q)24/Q0) | |||||||||||
TABLE II
| Example 9 | Example 10 | Example 11 | Example 14 | ESTRAGESTTTS | ||
| NETA | Q0 | 397.6 | 413.3 | 586.7 | 590 | 4790 |
| Q24 | 17.8 | 27.9 | 24.8 | 47.8 | 8.2 | |
| R | 4.5 | 6.7 | 4.2 | 8.1 | 0.17 | |
| Q24: the amount of NETA released in 24 hours, in μ g/cm2To represent | ||||||
| Q0: initial amount of NETA in μ g/cm2To represent | ||||||
| R: yield in percent (R ═ 100Q)24/Q0) | ||||||
TABLE III
| Example 1 | Example 2 | Example 3 | Example 6 | Example 12 | OESCLIM | ||
| Es | Q0 | 212.6 | 200.8 | 192.9 | 192.9 | 295 | 452.7 |
| Q24 | 19.9 | 22 | 31.3 | 18.7 | 27.5 | 14.2 | |
| R | 9.4 | 11 | 16.2 | 9.7 | 9.3 | 3.1 | |
| Q24: the amount of Es released in 24 hours, in μ g/cm2To represent | |||||||
| Q0: initial amount of Es in μ g/cm2To represent | |||||||
| R: yield in percent (R ═ 100Q)24/Q0) | |||||||
Claims (13)
1. A transdermal matrix system for the transdermal administration of at least one hormone, the system comprising a carrier and an adhesive, characterized in that the matrix comprises:
(a)39-61 parts by weight of an ethylene/vinyl acetate copolymer,
(b)12-17 parts by weight of 2-octyldodecyl myristate,
(c)5 to 17 parts by weight of diethyl phthalate,
(d)10-16 parts by weight of a compound selected from the group consisting of N-alkyl-2-pyrrolidones, wherein alkyl is C4-C15The radical(s) is (are),and
(e)1-12 parts by weight of at least one hormone selected from the group consisting of an estrogen component and a progesterone component.
2. Transdermal matrix system according to claim 1, characterized in that the adhesive matrix further comprises 1 to 10 parts by weight of a vinyl acetate/N-vinyl-2-pyrrolidone (VA/VP) copolymer.
3. Transdermal matrix system according to claim 2, characterized in that the vinyl acetate/N-vinyl-2-pyrrolidone copolymer has a vinyl acetate content of 30 to 70% by weight, based on the weight of the copolymer.
4. A transdermal matrix system according to any one of claims 1 to 3, characterized in that the N-alkyl-2-pyrrolidone is N-dodecyl-2-pyrrolidone.
5. A transdermal matrix system according to any one of claims 1 to 3, characterized in that the ethylene/vinyl acetate copolymer has a vinyl acetate content of 30 to 75% by weight, preferably 60% by weight, based on the weight of the copolymer.
6. Transdermal matrix system according to any one of claims 1 to 3, characterized in that the hormone is an estrogenic component, preferably 17 β -estradiol.
7. A transdermal matrix system according to any one of claims 1 to 3, characterized in that the hormone is a progesterone component, preferably norethisterone acetate.
8. A transdermal matrix system according to any one of claims 1 to 3, characterized in that the system comprises a mixture of an estrogenic component and a progestin component, preferably a mixture of 17 β -estradiol and norethisterone acetate.
9. A process for the preparation of a transdermal matrix system according to any one of claims 1 to 8, characterized in that it comprises the following steps:
(α) adding diethyl phthalate, N-alkyl-2-pyrrolidone, 2-octyldodecyl myristate, at least one hormone selected from the group consisting of an estrogen component, a progesterone component and mixtures thereof, VA/VP copolymer (if present in the composition), and EVA sequentially to a reactor at a temperature below the boiling point of the solvent or solvent system used, and stirring the resulting mixture;
(β) adding a solvent or solvent system and stirring the whole mixture, still at the same temperature, until the EVA has completely dissolved and the mixture is completely homogeneous;
(γ) coating the resulting homogeneous mixture on a non-tacky temporary support at a temperature of 50-70 ℃ to obtain 50-300g/m2The coating of (1);
(δ) heating the resulting coating to a temperature of 40-80 ℃ to evaporate the solvent or solvent system, depending on the boiling point of the solvent or solvent system; and
(ε) transferring the resulting dry matrix to a final support.
10. Use of a transdermal matrix system according to any one of claims 1 to 8 for the preparation of a medical product for the treatment of menopause or osteoporosis.
11. The system according to claim 2, characterized in that the matrix contains the following in total 100 parts by weight:
(a)54 parts by weight of an ethylene/vinyl acetate copolymer,
(b)17 parts by weight of 2-octyldodecyl myristate,
(c)5 parts by weight of diethyl phthalate,
(d)16 parts by weight of N-dodecyl-2-pyrrolidone,
(e1)2 parts by weight of 17 beta-estradiol,
(e2)5 parts by weight of norethisterone acetate, and
(f)1 part by weight of a vinyl acetate/N-vinyl-2-pyrrolidone (VA/VP) copolymer.
12. The system according to claim 2, characterized in that the matrix contains the following in total 100 parts by weight:
(a)62 parts by weight of an ethylene/vinyl acetate copolymer,
(b)13 parts by weight of 2-octyldodecyl myristate,
(c)10 parts by weight of diethyl phthalate,
(d)10 parts by weight of N-dodecyl-2-pyrrolidone,
(e)3 parts by weight of 17 beta-estradiol, and
(f)2 parts by weight of a vinyl acetate/N-vinyl-2-pyrrolidone (VA/VP) copolymer.
13. The system according to claim 2, characterized in that the matrix contains the following in total 100 parts by weight:
(a)53 parts by weight of an ethylene/vinyl acetate copolymer,
(b)17 parts by weight of 2-octyldodecyl myristate,
(c)10 parts by weight of diethyl phthalate,
(d)13 parts by weight of N-dodecyl-2-pyrrolidone,
(e)6 parts by weight of norethisterone acetate, and
(f)1 part by weight of a vinyl acetate/N-vinyl-2-pyrrolidone (VA/VP) copolymer.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR95/11326 | 1995-09-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1015281A true HK1015281A (en) | 1999-10-15 |
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