SK203091A3 - Matrix reservoir for transdermal therapeutical system - Google Patents

Description

Technical field

The invention relates to a matrix reservoir for a transdermal therapeutic system intended for the continuous transdermal delivery of medicaments 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 drug delivery to the bloodstream controls the system and not the skin. The skin itself is not able to act as a barrier to ensure uniform transfer of substances to and through it. In addition to safe and effective therapies, 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 upon its first passage through the liver and reduces the occurrence of side effects. There is no need to monitor and maintain the dosage regimen as with conventional dosage forms, while maintaining the required drug level without exposing healthy tissues to undesirable high drug concentrations, as well as incompatibilities in the gastrointestinal tract. There is no need to monitor and follow the dosing regimen.

Although various TTS are already used in clinical practice, there are data in the literature that some TTS are not guaranteed! constant drug bioavailability and controlled delivery (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). Recently, however, the release of zero order kinetics is not considered to be a general optimal solution. This is already contemplated when the matrix reservoir is formulated according to the present invention.

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

In the patent literature (Eur. Pat. Appl. 250.125; Eur. Pat.

279,932; Ger. Offen. 3,629.304; Eur. Pat. Aplle. A number of different types of TTS are described, for example membrane, multilamellar, microcompartment. However, the current trend favors matrix systems whose production can be standardized better. 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, controlled rate transdermal delivery of drugs based on crosslinked silicone rubber, containing 5 to 60% by weight of the hydrogel phase in a dry state having high swelling in water. at a concentration of 0.01 to 50% by weight, and optionally 0.1 to 30% by weight, of a transdermal absorption accelerator.

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

The matrix reservoir is based on a matrix made of reticulated silicone rubber having suitable mechanical properties and sufficient durability. An advantage of the matrix reservoir according to the invention is, besides the simple preparation, the controlled liberation of the transdermal drug administered by the excipients which are used. on a matrix formulation. These are synthetic hydrogels which, in the swollen state, permeate both ions and non-ionic substances, have a three-dimensional polymeric network. The powdered hydrogel particles are used to prepare silicone rubber-hydrogel composites having 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 which combine the hydrophilicity and permeability of hydrogels on the one hand, with good mechanical properties and processability of silicone rubbers on the other. The hydrophilic silicone composites used in the present invention as matrices for the reservoir for TTS medicaments are the subject of a patent by J. Šulc, P. Vondráček, P. Lopour, U.S. Pat. AO 251.890, U.S. Pat. No. 4,696,974, UK Pat. 2,176,194, Germ. pat. 3,616.883, MS. pat. (PV 3127-89). The most advantageous properties for the construction of the TTS drug reservoir are composites having a high degree of swelling in water, which are filled with a hydrogel filler with an equal swelling of 50 to 95% by weight of water. These composites contain more than 10% by weight, in the dry state, of the hydrogel phase. An example of such a highly swellable composite is silicone polymers containing powdered poly (25 hydroxyethyl methacrylate-co-inetacrylic acid) - (poly (HEMA-coMAA)) containing 10 wt% to 100 wt% methacrylic acid. % to 60% by weight.

The 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 hourly intervals of 1 to 24 hours. The evaluation of liberation was performed by Tornquist hyperbolic function (J. Kučera, J. Heinrich, 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 other drugs so as 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 at time t =.

Matrices prepared without the poly (HEMA-co-MAA) filler, regardless of the drug used and its concentration, had a parameter T < 1, confirming that the silicone matrix alone does not allow a hindered drug liberation.

Thus, the results obtained show that the matrix of 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, for example 0.1% by weight, or 1.0% by weight, of glycerol trinitrate, the rate of liberation of the drug concentration does not change. This is evidenced by the parameter T, whose value for the matrix containing 0.1% by weight, glycerine trinitrate was 3.5 h and at a drug concentration of 1.0% by weight. 3.45 h.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

C13 &apos; -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 wt.% Poly (2-hydroxyethyl methacrylate-co-methacrylic acid) (polyHEMA) -co-MAA) containing 22.9% by weight of methacrylic acid (MAA) as the hydrogel filler and 0.1% by weight of glycerin trinitrate as the drug.

After addition of 3% by weight of decaethoxytetrasiloxane as crosslinker and 1% by weight of dibutyltin dilaurane as catalyst, the mixture is poured into a mold where it crosslinks at room temperature over 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 drug is cut. From the matrix reservoir thus prepared, Keshary et al. release 123 / um / ^cm2 / 24 h of glycerol trinitrate.

Example 2

The preparation of the matrix reservoir is as in Example 1, except that 28% by weight, poly (HEMA-co-MAA) containing 33% by weight, is added to the mixture as a hydrogel filler. MAA and drug at a concentration of 0.1% by weight. This matrix reservoir was released in an in vitro experiment by Keshary et al.

n.

yum / cm / 24 hours of drug.

Example 3

The preparation procedure is the same as in Example 1 except that the content of poly (HEMA-co-MAA.) Hydrogel filler in the matrix is 35% by weight, with 50% by weight. MAA and drug concentration of 1% by weight.

This matrix reservoir was released in an in vitro experiment by Keshary et al. 980 / um / ^cm2 / 24 h of 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 wt%, containing 50 wt% MAA, and the drug concentration is 1 wt%. This matrix reservoir was released in an in vitro experiment by Keshary et al. 850 / um / ^cm2 / 24 h of drug.

Example 5

The matrix reservoir is prepared from ο, ω-divinylpolydimethylsiloxane (Petrách Systems Corp.) having a viscosity of 1000 mPas and an approximate molar mass of 28,000 g / mol by mixing with poly (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 dimethylsiloxane-methylhydroxygensiloxane copolymer containing 30% hydrogen-containing groups in an amount of 4% by weight, and a catalyst, a Pt complex and divinyltetramethyldisiloxane dissolved in N2O, N-divinylpolydimethylsiloxane . 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 the matrix reservoir thus prepared, Keshary et al. 120 / ug / ^cm2 / 24 h of drug.

Claims (2)

PATENT CLAIMS A matrix reservoir for a transdermal therapeutic system for continuous controlled rate transdermal drug delivery based on crosslinked silicone rubber, characterized in that it contains as filler 5 to 60% by weight, a hydrogel phase in a dry state having high swelling in water, a medicament at a concentration of 0.01 to 50% by weight, and optionally 0.01 to 30% by weight, of a transdermal absorption accelerator. 2. The matrix reservoir of claim 1, wherein the hydrogel phase is preferably a 2-hydroxyethyl methacrylate-co-methacrylic acid copolymer containing from 10 to 100% by weight of cross-linked methacrylic acid.