CZ203091A3 - matrix reservoir for a transdermal therapeutic system - Google Patents

Description

The present invention relates to a matrix reservoir for a transdermal therapeutic system intended for continuous transdermal delivery of drugs at a controlled rate.

BACKGROUND OF THE INVENTION

The transdermal therapeutic system (TTS) differs from other topical formulations, for example ointments, mainly in that the rate of delivery of the active ingredient to the bloodstream is controlled by the system and not the skin. The skin itself is not able to act as a barrier to ensure a uniform transfer of substances into and through it. In addition to safe and effective therapy, transdermal therapeutic systems (TTSs) produce and maintain a controllable plasma concentration for drugs that have a short half-life that does not allow a reliable therapeutic effect in other applications. This circumvents both the metabolic degradation of the drug in the body during its first passage through the liver and reduces the incidence of side effects. There is no need to monitor and dose the dosing regimen, as is the case with conventional dosage forms, while maintaining the required drug level without exposing healthy tissues in the body to high drug concentrations, as well as incompatibility in the gastrointestinal tract. There is no need to monitor and follow the dosing regimen.

Although various TTSs are already used in clinical practice, there are data in the literature indicating that some of these TTSs do not guarantee a constant bioavailability of the drug and controlled delivery to the body (Anon .: Drug Cosmet. Ind. 144, 6 (1989)). ).

The development of these preparations to date has been accompanied by efforts to achieve drug release by zero order kinetics (MS A.O. 261.105). Most recently, however, zero-order kinetics is not generally considered to be an optimal solution. This is already contemplated in the formulation of the matrix reservoir of the present invention.

The tools for controlling drug release from TTS are excipients and formulation formulations. A key part of TTS is its drug reservoir reservoir, which ensures a continuous and regular supply of drug to the skin. The amount of drug in the reservoir does not affect the final drug concentration in the blood (Fröming, H .: Pharm. Z tg. 132, 2737 (1989)), but it must be large enough to maintain the concentration gradient required for drug release.

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A number of different types of TTS are described in the patent literature (Eur. Pat. Appl. 250.125; Eur. Pat. 279.982; Ger. Offen. 3,629.304; Eur. Pat. Appl. 328.806), for example membrane, multilamellar, microcompartmental. However, the current trend favors matrix systems whose production can be better standardized. The matrices used vary in composition and structure.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a matrix reservoir for a transdermal therapeutic system for the continuous rate-controlled transdermal delivery of drugs based on crosslinked silicone rubber, which according to the invention contains 5 to 60% by weight of filler. of the hydrogel phase in the dry state, having high swelling in water, drug at a concentration of 0.01 to 50% by weight; and optionally 0.01 to 30 wt. Transdermal absorption accelerators.

According to the invention, the hydrogel phase is preferably a 2-hydroxyethyl methacrylate-co-methacrylic acid copolymer having a content of 10 to 100% by weight. thinly cross-linked methacrylic acid.

The matrix reservoir is based on a matrix made of reticulated silicone rubber having suitable mechanical properties and sufficient durability. The advantage of the matrix reservoir according to the invention is, in addition to the simple preparation, controlled liberation of the transdermally administered drug, provided by excipients used for the formulation of the matrix. These are synthetic hydrogels, which in their swollen state permeate both ions and non-ionic substances, have a three-dimensional polymer network. The powdered hydrogel particles are used to prepare silicone rubber-hydrogel composite materials that have the appearance and properties of conventional silicone rubbers, but are hydrophilic and swell in water and in a variety of organic solvents. These composites are a new type of elastomeric hydrophilic materials that combine the hydrophilicity and permeability of hydrogels on the one hand, with good mechanical properties and processability of silicone rubbers on the other. Hydrophilic silicone composites which are used in the present invention as matrices for the reservoir for TTS medicaments are the subject of patents by J. Šulc, P. Vondráček, P. Lopour: cf. AO 251.890, U.S. Pat. No. 4,696,974, UK Pat. 2,176,194, Germ. U.S. Pat.

3,616.883, MS. pat. (PV 3127-89). The most advantageous properties for the construction of a TTS drug reservoir are composites having a high degree of swelling in water which are filled with a hydrogel filler with an equilibrium swelling of 50 to 95% by weight. water. These composites contain more than 10 wt. (dry-phase) hydrogel phase. An example of such a highly swellable composite are silicone polymers containing powder poles (2 »

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 hydroxyethyl methacrylate-co-methacrylic acid) - (poles (HEMA-coMAA) - containing from 10 to 100% by weight of methacrylic acid) The copolymer content in the matrix is 5 to 60% by weight.

Liberation of various drugs from the matrix reservoir of the invention was determined in vitro using a modified apparatus of Keshary et al. (P.R. Keshary, Y.C. Huang, Chien Y.W .: Drug Develop. Ind. Pharm. 11, 1213 (1985)). The content of drug released from the matrix reservoir into the acceptor medium was determined at 1 to 24 hour intervals. Liberation evaluation was performed by Tornquist hyperbolic function (J. Kučera, J. Henrich, K. Ducková: Pharmazie 45, 635 (1990)).

Depending on the concentration of the drug, the composition and the hydrogel phase content, it is possible to regulate the release of glycerol trinitrate, but also of other drugs, to release the drug from 40 to 600 µg / cm ² / 24h as needed to achieve a therapeutic effect. The qualitative differences of the prepared matrices based on the evaluation of drug liberation versus time best resulted from the mathematical interpretation of the Tornquist function by comparing the parameter T (ie, the time taken for half of the cumulative drug fraction to be released at t =.

Matrices prepared without HEMA-co-MAA, regardless of the drug used and its concentration, had a parameter T <1,

confirming that the silicone matrix alone does not allow controlled drug liberation.

The results thus show that the matrix according to the invention releases the drug at a controlled rate, which is also confirmed by the parameter T, which ranged from 3.1 to 6.5 hours. Also in the presence of the same filler content and composition and different drug concentrations, e.g. %, 1 wt. or 1.0 wt. trinitrate glycerol, the rate of liberation of drug concentrations does not change. This is evidenced by the parameter T, whose value for a matrix containing 0.1 wt. glycerine trinitrate was 3.5 h and at a drug concentration of 1.0 wt. 3.45 h.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 6-C, -dihydroxydimethylsiloxane (Lukopren N 1000 type silicone rubber) having a viscosity of 2000 mPas and an approximate molecular weight of 40,000 g / mol is mixed with 16.7% by weight at room temperature. % poly (2-hydroxyethyl methacrylate-co-methacrylic acid) copolymer (polyHEMA-co-MAA) containing 22.9 wt. % methacrylic acid (MAA) as a hydrogel filler and 0.1 wt.

glycerin trinitrate as a medicament.

After addition of 3 wt. % decaethoxytetrasiloxane as crosslinker and 1 wt. The dibutyltin dilaurane catalyst is poured into a mold where it crosslinks at room temperature for 24 hours. The vulcanizate is prepared in the form of about 0.05 to 0.6 mm thin plates, from which a circular matrix reservoir with the drug is cut. From the matrix reservoir thus prepared, an in vitro experiment according to Keshary et al. vacant 123 / um / ^cm2 / 24 hours glycerine trinitrate.

Example 2

The preparation of the matrix reservoir was carried out as in Example 1, except that 28% by weight of hydrogel filler was added to the mixture. % (HEMA-co-MAA) containing 33 wt. MAA and drug at a concentration of 0.1 wt. This matrix reservoir was released in an in vitro experiment according to Keshary et al. 97 / um / ^cm2 / 24 hr drug.

Example 3

The preparation procedure is the same as in Example 1 except that the content of the hydrogel filler poles (HEMA-co-MAA) in the matrix is 35% by weight. containing 50 wt. MAA and drug concentration of 1 wt.

This matrix reservoir was released in an in vitro experiment according to Keshary et al. 980 yum / ^cm2 / 24 hr drug.

Example 4

The procedure for preparing the matrix reservoir is the same as in Example 1, except that the poly (HEMA-co-MAA) hydrogel filler content is 16.7% by weight. containing 50% by weight MAA and a drug concentration of 1% by weight. This matrix reservoir was released in an in vitro experiment according to Keshary et al. 850 / um / ^cm2 / 24 hr drug.

Example 5

The matrix reservoir was prepared from α, ω-divinylpolydimethylsiloxane (Petrá Systems Corp.) having a viscosity of 1000 rPas and an approximate molecular weight of 28,000 g / mol by mixing with a hydrogel filler pole (HEMA-co-MAA) in an amount of 16.7% by weight. (MAA content in the filler 22.9 wt.%) and drug (glycerin trinitrate) in an amount of 0.1 wt. at room temperature. This mixture is further mixed with a crosslinker, a copolymer of dimethylsiloxane and methylhydroxygensiloxane containing 30% hydrogen-containing groups in an amount of 4% by weight. and a catalyst, a Pt complex and a divinyltetramethyldisiloxane dissolved in N, N-divinylpolydimethylsiloxane containing 3% Pt in an amount of 200 ppm. This mixture is vulcanized in the mold at room temperature for 48 hours. From the vulcanizate with a thickness of approx. 0.6 mm, a circular reservoir with medicine is cut. From as follows

the prepared matrix reservoir was released in an in vivo experiment according to Keshary et al. 120 ~ g / ^cm2 / 24 hr drug.

Claims (1)

A matrix reservoir for a transdermal therapeutic system intended for continuous rate-controlled transdermal drug delivery based on cross-linked silicone rubber, characterized in that it contains from 5 to 60% by weight of filler. of the hydrogel phase in the dry state, having high swellability in water, drug at a concentration of 0.01 to 50% by weight and optionally 0.01 to 30 wt. Transdermal absorption accelerators. 1. The matrix reservoir of claim 1 wherein the drug phase is a 2-hydroxyethyl methacrylate-co-methacrylic acid copolymer having a content of 10 to 100% by weight. thinly cross-linked methacrylic acid. 1 O f r 1 * 1> o / o 7 ^ ^c · / I N>. (.C-3 1 - * C r · v J