BR-112020003314-B1 - A transdermal therapeutic system for transdermal administration of an active agent, its manufacturing method, uses of emulsifier, and method for stabilizing a biphasic coating mixture.

BR112020003314B1BR 112020003314 B1BR112020003314 B1BR 112020003314B1BR-112020003314-B1

Abstract

The present invention relates to a transdermal therapeutic system (TTS) comprising a layered structure containing an active agent, comprising: A) a support layer, and B) a biphasic matrix layer, the biphasic matrix layer having a) an outer, continuous phase, with a composition comprising 70 to 100% by weight of at least one polymer, b) an inner, discontinuous phase, having a composition comprising the active agent and a solvent of the active agent, in sufficient quantity for the active agent to form a solution with the solvent in the inner phase, and c) an emulsifier in an amount of 0.1 to 20% by weight, based on the biphasic matrix layer; manufacturing processes and uses thereof, corresponding methods of treatments with the same.

Inventors

Gabriel Wauer
Frank Seibertz

Assignees

LTS LOHMANN THERAPIE-SYSTEME AG

Dates

Publication Date: 20260317
Application Date: 20180831
Priority Date: 20170904

Claims (20)

1. A transdermal therapeutic system for transdermal administration of an active agent, characterized in that it comprises a layer structure containing the active agent, wherein the layer structure containing the active agent comprises: (a) a support layer, and (b) a biphasic matrix layer, wherein the biphasic matrix layer has: (c) a continuous outer phase, with a composition comprising 70 to 100% by weight of at least one polymer, (d) a discontinuous inner phase, having a composition comprising the active agent and a solvent of the active agent, in sufficient quantity for the active agent to form a solution with the solvent in the inner phase, wherein the discontinuous inner phase forms dispersed deposits in the continuous outer phase, and (e) an emulsifier in an amount of 0.1 to 20% by weight, based on the biphasic matrix layer, wherein the emulsifier is selected from a group consisting of emulsifiers that, When mixed at about 500 to 1500 rpm, with an equal weight of the continuous external phase composition, for about 1 hour in a test tube, it provides a mixture with the composition of the continuous and external phases, exhibiting less than 20% phase separation after storage for about 24 hours at about 20°C, determined by comparing the height of the separated phase in the test tube and the height of the total contents in the test tube; the emulsifier being based on a mixture of PEG-12 dimethicone and PEG/PPG-19/19 dimethicone.
2. Transdermal therapeutic system, according to claim 1, characterized in that the biphasic matrix layer contains 0.1 to less than 20%, or 0.5 to 10%, or 0.5 to 5% by weight of emulsifier.
3. Transdermal therapeutic system, according to claim 1 or 2, characterized in that at least one polymer in the external, continuous phase is polysiloxane or polyisobutylene.
4. Transdermal therapeutic system, according to any one of claims 1 to 3, characterized in that at least one polymer in the external, continuous phase is a pressure-sensitive adhesive polymer.
5. Transdermal therapeutic system, according to any one of claims 1 to 4, characterized in that the active agent is contained in an amount of 1 to 30% by weight, based on the biphasic matrix layer and/or the active agent is contained in an amount of 0.1 to 5 mg/cm2, based on the biphasic matrix layer.
6. Transdermal therapeutic system, according to any one of claims 1 to 5, characterized in that the active agent is selected from the group consisting of buprenorphine and diclofenac.
7. Transdermal therapeutic system, according to any one of claims 1 to 6, characterized in that the biphasic matrix layer has an area weight greater than 60 g/m2.
8. Transdermal therapeutic system, according to any one of claims 1 to 7, characterized in that the solvent for the active agent is selected from the group consisting of carboxylic acids, long-chain alcohols with more than four carbon atoms, fatty alcohols, polyoxyethylene ethers of fatty alcohols, long-chain esters with more than four carbon atoms, fatty acid esters or mixtures thereof.
9. Transdermal therapeutic system, according to claim 8, characterized in that the active agent is in solution in a carboxylic acid to form a carboxylic acid-active agent mixture in the internal, discontinuous phase of the biphasic matrix layer.
10. Transdermal therapeutic system, according to any one of claims 1 to 9, characterized in that the biphasic matrix layer further comprises a viscosity-increasing substance, preferably in an amount of about 0.1% to about 8% by weight of the biphasic matrix layer.
11. Transdermal therapeutic system, according to any one of claims 1 to 10, characterized in that the solvent for the active agent is a carboxylic acid and the carboxylic acid is contained in an amount of 2 to 20%, or 5 to 15%, or 6 to 12%, by weight, based on the biphasic matrix layer.
12. Transdermal therapeutic system, according to any one of claims 1 to 11, characterized in that the active agent-containing layer structure is a self-adhesive active agent-containing layer structure and preferably the biphasic matrix layer is the skin contact layer.
13. Transdermal therapeutic system, according to any one of claims 1 to 12, characterized in that the active agent is buprenorphine, for use in a method of treating pain, preferably for use in a method of treating pain wherein the transdermal therapeutic system is applied for 7 days to the skin of a patient.
14. Transdermal therapeutic system, according to any one of claims 1 to 12, characterized in that the active agent is diclofenac, for use in a method to treat patients suffering from pain/inflammation, such as osteoarthritis, shoulder periarthritis, muscle pain, back pain, rheumatism, contusions, muscle strain, lumbago, arthrosis, sweat gland abscess or multiple system atrophy.
15. Transdermal therapeutic system, according to any one of claims 1 to 12, characterized in that a therapeutically effective amount of diclofenac is provided for approximately 24 hours by said transdermal therapeutic system during a period of administration on the skin of a human patient for approximately 24 hours.
16. Use of an emulsifier, as defined in claim 1, characterized in that it reduces the maximum size of dispersed deposits in a biphasic coating mixture during the preparation process of a transdermal therapeutic system, as defined in any one of claims 1 to 15.
17. Use of an emulsifier, as defined in claim 1, characterized in that it reduces the maximum size of the dispersed deposits in the biphasic matrix layer of a transdermal therapeutic system, as defined in any one of claims 1 to 15.
18. Use of an emulsifier based on a mixture of PEG-12 dimethicone and PEG/PPG-19/19 dimethicone, characterized by the fact that it is in a transdermal therapeutic system with a biphasic matrix layer containing active agent featuring a discontinuous inner phase and a continuous outer phase to control the maximum sphere size of the inner discontinuous phase of the biphasic matrix layer.
19. Method for stabilizing a two-phase coating mixture, comprising a discontinuous inner phase having a composition comprising an active agent and a solvent for the active agent, in sufficient quantity for the active agent to form a solution with the solvent in the inner phase, the inner phase forming dispersed deposits in a continuous outer phase comprising a polymer, said method being characterized in that it comprises mixing the two-phase coating mixture with an emulsifier, which is selected from a group consisting of emulsifiers that, when mixed at about 500 to 1500 rpm with an equal weight of the continuous outer phase composition for about 1 hour in a test tube, provides a mixture with the continuous outer phase composition exhibiting less than 20% phase separation after storage for about 24 hours at about 20°C, determined by comparing the height of the separated phase in the test tube and the height of the total contents in the test tube; the emulsifier being based on a mixture of PEG-12 dimethicone and PEG/PPG-19/19 dimethicone.
20. Method for manufacturing a two-phase matrix layer, characterized in that it comprises the steps of: (1) preparing a stabilized two-phase coating mixture, as defined in claim 19; (2) coating the stabilized two-phase coating mixture onto a film in an amount to provide a desired area weight; and (3) evaporating the solvents to provide a two-phase matrix layer with the desired area weight.

Description

TECHNICAL FIELD OF THE INVENTION [0001] The present invention relates to a transdermal therapeutic system (TTS) comprising a biphasic structure, including an internal, discontinuous phase dispersed in a continuous external phase, processes for manufacturing and using this system, as well as corresponding methods of treatment with this system. BACKGROUND OF THE INVENTION [0002] Transdermal therapeutic systems (TTS) can be distinguished primarily into two types of TTS for active agent delivery, the so-called matrix-type TTS and the so-called reservoir-type TTS. [0003] In a matrix-type TTS, the active agent is homogeneously dissolved and/or dispersed within a polymeric carrier, i.e., the matrix, which forms a matrix layer with the active agent and optionally remaining ingredients. In this system, the matrix layer controls the release of the active agent from the TTS. [0004] In a reservoir-type TTS, the active agent is present in a liquid reservoir. In such a system, the release of the active agent is preferably controlled by a rate-controlling membrane. In particular, the reservoir is sealed between the support layer and the rate-controlling membrane. Furthermore, the reservoir-type TTS typically includes a skin contact layer, where the reservoir layer and the skin contact layer may be separated by the rate-controlling membrane. An advantage of the reservoir-type TTS is the high utilization of the active agent due to the often supersaturated reservoir. However, in case of reservoir damage, dose spillage may occur. [0005] A microreservoir TTS is considered in the art to be a mixed form of matrix-type TTS and reservoir-type TTS and differs from a homogeneous single-phase matrix TTS and a reservoir-type TTS in the concept of active agent transport and active agent release. A microreservoir TTS comprises at least two phases, namely, an internal phase dispersed and an external phase surrounding the internal phase deposits. Limited solubility of the internal phase in the external phase is a prerequisite for providing such a biphasic structure. Microreservoir TTS is generally characterized by improved active agent utilization compared to matrix-type TTS, since the active agent contained in the internal phase only dissolves slightly in the external phase, thus supporting the tendency to move from the microreservoir system to the skin. A current problem with microreservoir TTS is insufficient stabilization of the biphasic structure, particularly during the TTS manufacturing process. [0006] For example, a two-phase composition to be coated is generally prepared in batches and then stored for as long as the coater is ready to coat the composition. The time between composition preparation and coating in a normal production routine can be almost zero if, after mixing, the composition is transferred to the coating station and coated directly, and can be as long as several days, for example, four to six days, to store the composition during a painter's failure or a weekend or other reasons for interrupting the coating process. After the two-phase composition is prepared in the mixing stage, the system tends towards phase separation. The internal phase deposits tend to coalesce and the larger deposits formed may sediment during storage. [0007] Furthermore, during the coating process, shear forces act on the two-phase coating composition, resulting in strong coalescence of the internal phase and an uncontrolled distribution of molten internal phase deposits within the coating composition and in the final two-phase matrix layer. [0008] Without wanting to be tied to any theory, it is believed that the size and size distribution of the depots influence the release of the active agent from the TTS. Large depots release the active agent too quickly and predict an undesirable delivery of the active agent at the beginning of the dosing period (also known as "drug burst") and a failure of the system for longer dosing periods, since the loss of the active agent at the beginning will lead to a loss of driving force later in the dosing period. The permeation of the active agent is then unpredictable and may be too fast, not long enough, and not continuous enough. [0009] There is therefore a need to sufficiently control the size and size distribution of the deposits. The deposits must especially be prevented from merging during the storage time between mixing and coating and during the coating process. [0010] To reduce the initial size of the deposits (droplets) in the two-phase coating composition, the composition can be homogenized. However, coalescence of the internal phase can still be observed during storage of the two-phase coating composition and, especially, under shear stress during the coating process. [0011] WO 2014/195352 refers to a TTS microreservoir for the transdermal administration of buprenorphine and shows that the fusion of the deposits and the corresponding increase in size of the deposits can be controlled by the use