NZ291449A

NZ291449A - Transdermal systems comprising estradiol with a water-binding additive containing matrix

Info

Publication number: NZ291449A
Application number: NZ291449A
Authority: NZ
Inventors: Walter Muller; Hanshermann Franke; Thomas Pontzen; Michael Horstmann
Original assignee: Lohmann Therapie Syst Lts
Priority date: 1994-08-20
Filing date: 1995-08-12
Publication date: 1998-09-24
Also published as: CA2197865C; MX9701301A; PL180943B1; KR100374476B1; CN1155836A; FI970702A; IL114948A0; AU700119B2; JPH10504314A; NO970553L; FI118721B; CZ50897A3; SK280299B6; ATE173163T1; KR970705380A; CN1073413C; SK21997A3; FI970702A0; CA2197865A1; EP0776197A1

Abstract

The invention concerns a transdermal therapeutic system which contains oestradiol as active substance and optionally further active substances as well as a hydrophylic additive. The therapeutic system has a layered structure comprising a backing which is impervious to the active substances and moisture, an active substance-containing matrix layer and, depending on the case, a separable protective layer. The system is characterized in that the hydrophylic additive is a component of the matrix.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £91449 New Zealand No. 291449 International No. PCT/EP95/03202 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 20.08.1994; Complete Specification Filed: 12.08.1995 Classification: (6) A61K9/70; A61L15/60; A61K31/565; A61K47/04 Publication date: 24 September 1998 Journal No.: 1432 Title of Invention: Oestradiol-containing transdermal therapeutic system comprising hydrophylic additives Name, address and nationality of applicant(s) as in international application form: LTS LOHMANN THERAPIE-SYSTEME GMBH, Irlicher Str. 55, 56567 Neuwied, Germany new zealand patents act 1953 COMPLETE SPECIFICATION 29 1 4 4 9 Estradiol-TTS having water-binding additives SPECIFICATION The present invention relates to a transdermal therapeutic system with the active substance estradiol and, optionally, additional active substances as well as a water-binding additive substance, and with a layered structure of a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, in case of need, a removable protective layer covering the matrix layer. In the pharmaceutical therapy of several diseases, Transdermal Therapeutic Systems (TTS) have bean introduced on the market for some time now. In the following the term "estradiol" is to be understood as the anhydrous substance of 17-p-estradiol in dissolved or crystalline (anhydrate) form. In the meantime, TTSs comprising the active substance estradiol have been on the market as therapeutic agent for climacteric complaints, and, since a short time ago, also against osteoporosis; they have proved successful in therapy. A disadvantage of prior art systems is the insufficient capability of the active substance to permeate through the skin. This cannot be increased beyond a certain limit, the so-called "saturation flow", although several galenic measures with respect to the TTS-con-struction have been taken (use of multilayer systems, use of controlling membranes, variation of the active substance i 18 FEB 1397 i received 2 29 1 4 4 9 concentration, modification of the base polymer, and the like). This finding, i.e., that the transdermal flow of an active substance from the solid, finely dispersed phase cannot be increased further in principle, even if high-dissolving vehicles are used, can already be found in the trailblazing works of Higuchi, e.g., T. Higuchi: Physical Chemical Analysis of percutaneous process from creams and ointments. J. Soc. Cosmetic Chem. 11, p. 85-97 (1960). The systems described in EP 0 421 454 comprise estradiol in an acrylate polymer under addition of "crystallization inhibitors" and tackifying resins. Swelling agents are contained to give protection against premature loss of adhesive force. With a lot of active substances, so-called "enhancers" may be added to the TTS during production. These are usually liquid admixtures improving the absorption properties of human skin; for this reason, they allow the absorption of the active substance from a sufficiently small TTS-surface. In particular readily volatile enhancers, e.g., ethanol used for the active substance estradiol, involve the problem of softening the TTS's adhesive layers to a great extent; above all they require additional bulky compartments in the system, rendering the TTS unacceptably thick. Finally, any additional non-polymeric additive involves the risk of incompatibility reactions on the skin, possibly even that of sensitization. The addition of certain less volatile, however, mostly less active enhancers (e.g., glycerol esters, cyclic amides, eucalyptol) allows the production of matrix systems comprising the active substance and the absorption-promoting component in one or several monolithic layers. US 4 863 738 represents one of many examples claiming the application of active substances, e.g., estradiol, together with a certain enhancer (in this case glycerol monooleate) in an optional TTS-matrix and in an optional concentration. According to the art, these TTSs do not permit a satisfactory therapy either. The reason is that either the active enhancers are 29 14 49 poorly tolerated by the skin or that the systems require unac-ceptably large surfaces owing to the still insufficient flow through the skin. Another possibility of increasing the active substance flow through the skin is that an amount of active substance is dissolved molecularly disperse in the TTS, which exceeds that corresponding to the saturation solubility. With supersaturation of these systems the permeation rate of the skin increases to the same extent. However, since such states are thermodynamicaliy unstable, these forms of administration are not stable in storage; unforeseeable recrystallization of active substance particles will take place so that the flow rate through the skin gradually decreases to the saturation flow level; depending on the starting concentration, this results in losing a great portion of the initially existent therapeutic activity. This process is a characteristic of estradiol. At room temperature and normal relative air humidity (20-60% relative humidity), estradiol is not present in one of the two known anhydric modifications (I and II) but as a semihydrate (Busetti and Hospital, Acta Cryst. 1972, B28, 560). Owing to the layered structure stabilized via hydrogen bridges, and because of the dif-fusional compactness of the crystal compound, the semihydrate can be subjected to a short-term heat treatment to temperatures of about 170°C without decomposition thereof (Kuhnert-Brand-statter and Winkler (1976) Scientia Pharmaceutica 44 (3), 177-190). However, the anhydrous form can quantitatively be obtained already at about 120°C by way of enlarging the crystal surface by means of micronizing. According to own observations, the transformation already takes place at about 90°C if heating is conducted very slowly (0.2-1 K/min) and in case of a particularly fine-crystalline substance. I i 18 FEB iS37 RjC&VS3 4 29 14 49 With decreasing partial water vapor pressure, on the other hand, estradiol has a higher solubility in some polymers, particularly in polyacrylates. According to Fick's law, higher concentrations with otherwise same conditions increase the diffusion flow through the skin; for this reason such a concentration increase is very desirable in transdermal therapeutic systems. However, the water introduced with the estradiol-semihydrate is already sufficient to initiate gradual recrystallization from the solution as estradiol-semihydrate (Kuhnert-Brandstatter and Winkler (1976) Scientia Phar-maceutica 44 (3), 177-190). After crystallization, the flow rate from the system to the skin considerably decreases with the diminishing concentration. Taking into account these circumstances, transdermal therapeutic systems are known that offer a pharmacotherapeutically satisfying solution by exactly regulating the concentration to little less than the saturation solubility of the estradiol-anhydrate (DE-PS 42 37 453) or by using partially undissolved, disperse estradiol-anhydrate (DE-PS 42 23 360). Even in consideration of this state of the art, it is important to maintain a sufficiently low atmospheric humidity during production and storage of an estradiol-TTS in order to avoid large-area precipitation of the poorly soluble estradiol-semihydrate. To this end, a waterproof package having a low water-vapor permeability can be used in principle. However, owing to the low estradiol concentration contained in today's TTSs, very small amounts of humidity are sufficient to cause precipitation of the estradiol-semihydrate. If, for example, 2 mg of anEstradiol (anhydrous) are present in a TTS in dissolved form, an amount of only 66.1 //g of water can cause complete precipitation. Using conventional packaging means, it is therefore very difficult to exclude entry of such small quantities of moisture over storage periods of several years. 5 'I H • DE 42 3? 453 already proposes to use desiccants in the ready-for-storage package; however, there are no indications with respect to using the water-binding additive as a component of the matrix. Accordingly, it is the object of the present invention to provide a transdermal therapeutic system comprising estradiol, that protects i the system in the package during storage against precipitation of the estradiol-semihydrate, and which, if required, is suitable for a matrix which comprises more active substance in a moleculariy disperse dissolved form than corresponds to the saturation solubility. In a transdermal therapeutic system of the kind mentioned in the introductory part of claim 1, this object is achieved with the present invention by the fact that the water-binding additive substance is a constituent of the matrix. Integrating water-binding mineral components in the substance of the matrix according to the present invention can be realized in a TTS in different manners: the most simple form is a single-layer matrix system the matrix of which simultaneously has a pressure-sensitive adhesive function, rendering an additional adhesive layer superf! Alternatively, the transdermal therapeutic system can be multilayered, and that at least one of these layers comprises a pharmaceutically acceptable water-binding mineral additive. The mineral components that are contained in the matrix in dissolved form or which are usually dispersed in solid phase, ensure an equilibrium-moisture content over the storage period that is low enough to render precipitation of the estradiol-semihydrate impossible. If direct contact of the skin with the mineral particles is to be avoided, only the matrix is provided with water-binding mineral components and an adhesive layer which faces the skin and is free from particulate estradiol is applied by lamination. Preferably, the proportion of the mineral water-binding additive in the total matrix material amounts to between 1 and 40%-wt, and preferably to 20%-wt. INTELLECTUAL PROPERTY OFFICE OF N.Z / H " i:\io i L jJL IJJO 1 t RFpcu/cn I 291419 if a membrane which is hardly permeable to estradiol is introduced between such a matri>c which comprises estradiol and water-binding mineral constituents, and the adhesive layer, a modified active substance release is achieved. Preferably, the transdermal therapeutic system has a matrix base material selected from polymers which, under water-free conditions have a solubility for the active substance estradiol of between 0.4 and 3.0%(w/w). In addition to the wide-spread acrylic-acid ester copolymers suitable for the use with estradiol, other polymers may also be used as base material, for example, polyisobutylene, polyvinyl acetate, and copolymers, synthetic rubber, silicones. Preferably, the matrix base material is a polyacrylate polymer. In any case, the characterizing feature of transdermal therapeutic systems according to the present invention is the presence of water-binding mineral components in the matrix. In this connection, the exact amount of said additives in the matrix must be sufficiently large since this increases the total moisture-binding capacity in the system. The exact amount of added substances will result for the skilled artisan in a comprehensible manner from the component's binding power for water. Since the water-binding capacity of most of the following exemplary substances generally lies above that of estradiol, an addition in the range of the estradiol contained - about 1 to 2 percent - may be considered as minimum amount. The upper limit is determined by mechanical values, such as flowability of the matrix, adhesive force, and processibility. In general, a proportion of 10 to 50 percent by weight, preferably between 20 and 35 percent by weight is desired. The following substances may be used as water-binding mineral components, e.g., zinc oxide, silicon dioxide, silica gel (also in modified, e.g., hydrophobized form), talc, phosphorus pentaoxide, alumina, aluminum phosphate, magnesium oxide and hydroxide, calcium oxide and hydroxide, kaolin, molecular sieves, sodium oxide, calcium and magnesium carbonate, magnesium sulfate, fi 14 calcium sulfate, copper sulfate, manganese oxides, silicates, alu-minates, or magnesium perchlorate. In this connection, it must be considered that both chemico-reac-tive processes, such as the reaction of magnesium oxide to magnesium hydroxide, and the physical changes, e.g., inclusion of crystal water into initially anhydrous sodium sulfate, calcium sulfate, or calcium chloride, or also pure, nonstoichiometric hygro-scopy or adsorptivity can be utilized; these are commonly known as such to the skilled artisan. Substances having a high water-binding capacity in case of low humidity (in the range of below about 5% relative humidity) are preferably used. In addition, a high degree of physiological compatibility is desired. Fortunately, many hydrates of salts of the alkaline earth metals and alkali metals comply with these conditions, for example, calcium and magnesium carbonate, calcium, sodium, and magnesium sulfate, or many silicates, aluminates, borates, and phosphates of the alkali metals (preferably sodium, potassium, lithium) and alkaline earth metals (calcium and magnesium). There is also provided a process for the production of the transdermal therapeutic siystem characterized by the steps: - preparing a suspension of estradiol-semihydrate and water-binding mineral additive in a solution, dispersion, or melt of the matrix base material, - using this suspension to apply a layer on a sheet-like substrate, - carrying out a conversion of estradiol-semihydrate into anhydrous estradiol in the layer by heating to a temperature of between 90 to 175°C. Additional embodiments of the present invention are provided according to the subclaims. Examples: Example 1: Production of a system according to the present invention. 2.0 g of 1 7-13-estradioi-semihydrate, micronized 60.0 g of HanflpyR 1107 {gtymnp-isoprene-styrene block copolymer) | jhijpert>' OFFICE| 2 C JJL HECEI'VEL s r~ A f 1% I *i 120.0 g of Staybeiite Ester 5E {thermoplastic ester gum of colophony derivatives) 50 g of viscous paraffin 50 g of calcium sulfate dihydrate are molten in an evacuatable kneader at 130°C and brought into an externally homogeneous form by means of kneading within ten hours. Under vacuum {less than 0.02 bar) heating to 165°C is effected for one hour, while doing so crystal water is driven off the active substance and calcium sulfate by means of kneading. The melt is cooled down to 120°C; in a continuous coating line it is subsequently coated onto a siliconized polyester film of 100 pm thickness in such a manner that the weight per unit area of the layer amounts to 200 g/m2. Afterwards a polyester film 15 jjm thick is applied (laminated) under roll pressure on the still hot layer, avoiding the formation of air bubbles. Transdermal systems of 16 cm2 are obtained by punching using a wad punch. The moisture proof package may additionally comprise a desiccant. Example 2: Production of a system according to the present invention 3.0 g of 17-P-estradiol-semihydrate, micronized 400.0 g of acrylic-acid ester copolymer solution (solids content 50% w/w) 70.0 g of calcium sulfate, anhydrous ("anhydrite") are stirred at room temperature in a cylindrical glass vessel until a homogeneous suspension is obtained. Afterwards coating is effected at a slit width of 500 pm onto a 100^/m siliconized polyester film. The coating is diied at25.°Cf at 50°Cf at SCC and at 95°C, each tins.for 10 minutes. A 15 pm polyester film is immediately applied intellectual property office Of- N.2. </div>

Claims

(laminated) on the dry layer under roller pressure, avoiding the formation of air bubbles. Transdermal systems of 10 cm2 are obtained by punching using a wad punch. These are packed into a composite packaging material of paper/aluminum foil/hot-sealing layer under addition of a desiccant tablet comprising 0.3 g of calcium sulfate (previously predried at 1 805 C). The moisture proof package may additionally comprise a desiccant. CLAIMS

1. A transdermal therapeutic system with the active substance estradiol and, optionally, further active substances and, optionally, water-binding additives, having a layered structure comprising a backing layer which is impermeable to active substances and moisture, an active substance-containing matrix layer, and, optionally, a removable protective layer, characterised in that the matrix contains the active substance as water-free estradiol, together with a water-binding additive, said water-binding additive ensuring an equilibrium moisture which prevents the precipitation of estradiol semihydrate.

2. The transdermal therapeutic system according to claim 1 characterized by a multilayered matrix and that at least one of these layers comprises a pharmaceutically acceptable, water-binding mineral additive.

3. The transdermal therapeutic system according to claim 1 or 2 characterized in that the matrix material comprises the water-binding additive substance in finely dispersed suspension.

4. The transdermal therapeutic system according to one or several of claims 1 to 3 characterized in that the water-binding additive substance is a mineral.

5. The transdermal therapeutic system according to one or several of claims 1 to 4 characterized in that the water-binding additive is the anhydrate of an alkaline-earth or alkali metal salt.

6. The transdermal therapeutic system according to one or several of claims 1 to 4 characterized in that the water-binding additive is the semihydrate or anhydrate ("anhydrite") of calcium sulfate intellectual property office of n.z. 2 0 J'JL 1998 L received f> f m A

7. The transdermal therapeutic system according to one or several 'of. _ ;j m,J claims 1 to 6 characterized in that anhydrous estradiol is present in a dispersed crystalline form.

8. The transdermal therapeutic system according to one or several of claims 1 to 7 characterized in that estradiol is comprised in the matrix base material in a molecuiarly disperse supersaturated form. i

9. The transdermal therapeutic system according to one or several of claims 1 to 8 characterized in that the proportion of the mineral water-binding additive in the total matrix material amounts to between 1 and 40%-wt., and preferably to 20%-wt.

10. The transdermal therapeutic system according to one or several of claims 1 to 9 characterized in that the matrix base material being selected from polymers which, under water-free conditions, have a solubility for the active substance estradiol of between 0.4 and 3.0% (w/w).

11. The transdermal therapeutic system according to claim 10 characterized in that the matrix base material is a polyacrylate polymer.

12. A process for the production of the transdermal therapeutic system according to one or several of the preceding claims, characterized by the steps: - preparing a suspension of estradiol-semihydrate and water-bind-ing mineral additive in a solution, dispersion, or melt of the matrix base material, - using this suspension to apply a layer on a sheet-like substrate, - carrying out a conversion of estradiol-semihydrate into anhydrous estradiol in the layer by heating to a temperature of between 90 to 175°C.

13. The process according to claim 12 characterized in that the heating is carried out to a temperature of 90 to 200°C until a further conversion of the mineral water-binding additive, at first present in the hydrous form, into its anyhdrous form has taken place.

14/ The process according to any one of claims 12 or 13 characterized in that the transdermal therapeutic system is packed into a moistureproof package which comprises a desiccant, if required. 1 5. A transdermal therapeutic system, according to any one of claims 1 to 11 substantially as herein described and with reference to Example 1 or Example 2. 1 6. A process for the production of the transdermal therapeutic system according to any one of claims 12 to 14, substantially as herein described and with reference to Example 1 or Example 2. END OF CLAIMS