HK1090844B - Therapeutic patch with polysiloxane matrix comprising capsaicin - Google Patents

Description

Therapeutic patch with polysiloxane matrix containing capsaicin

Background

Neuropathic pain is thought to result from sensitization reactions in the peripheral and central nervous systems. Such pain may be due to peripheral injury or to some systemic diseases such as HIV, herpes zoster, syphilis, diabetes and autoimmune diseases. Neuropathic pain can be severe and often debilitating, and effective methods of reducing neuropathic pain will ameliorate significant pain.

In U.S. Pat. No. 6,248,788(Robbins et al), a topical method of treating neuropathic pain with capsaicin or a substance similar to capsaicin is described. The Robbins et al patent discloses that treatment of the affected body area with a highly concentrated capsaicin preparation, once or at most twice within a few hours, eliminates or significantly reduces pain within weeks. It is believed that the basis for this treatment is that the nerve fibers (C fibers) necessary or responsible for the sensation of pain are desensitized and degenerated by capsaicin (or capsaicin analog). However, this effect is only produced if the concentration of the active compound in the C fibers is sufficiently high. Conventional topical formulations containing capsaicin do not optimally meet these requirements because they release too little capsaicin on the skin and the concentration of the active compound in the C-fibers remains below the effective concentration.

U.S. Pat. No. 6,239,180(Robbins) describes the use of therapeutic patches comprising capsaicin and/or capsaicin analogs at concentrations of greater than 5% to 10% by weight for the treatment of neuropathic pain. Therefore, the objective is to develop a suitable and optimal patch for the topical treatment of neuropathic pain and other conditions.

Brief description of the drawings

FIGS. 1-3 are diagrams showing the construction of a microreservoir system.

Detailed Description

The present invention relates to a drug delivery device suitable for administering capsaicin, a capsaicin analog, or a mixture thereof. For convenience, the term "therapeutic compound" is sometimes used herein below to refer to capsaicin, a capsaicin analog, or a mixture that is administered. In one aspect, the present invention provides a drug delivery device comprising a therapeutic compound-impermeable backing layer, a self-adhesive matrix (typically a silicone-based matrix) comprising individual isolated liquid microreservoir droplets ("microreservoirs") containing capsaicin or a capsaicin analog dissolved in an amphiphilic solvent, and a protective film to be removed prior to use of the device. The term "microreservoir system" as used herein refers to the self-adhesive matrix comprising a plurality of microreservoir droplets microdispersed in the matrix. The active compound (e.g., capsaicin) in the microreservoir droplets is dissolved at a concentration below the saturation concentration (and it is thus present in a fully dissolved form).

In a related aspect, the invention provides a method of treating neuropathic pain in a subject (e.g., human, non-human, primate, or mammal) in need of such treatment by applying the device of the invention.

In another related aspect, the present invention provides a method of making a drug delivery device suitable for use in the treatment of neuropathic pain.

A brief discussion of the architecture of a therapeutic patch will aid in understanding the present invention. Different forms of topical and transdermal patches are known for delivering active compounds (e.g., drugs), most commonly "matrix systems" and "reservoir systems".

The matrix system is characterized (in the simplest case) by a backing layer that is impermeable to the active compound (i.e., the compound to be delivered to the subject), a layer containing the active compound, and a protective layer that is to be removed prior to use. The active compound-containing layer contains the active compound in completely or partially dissolved form and is ideally self-adhesive. In more complex embodiments, the matrix is composed of a number of layers and may include a control membrane. Suitable base polymers for the self-adhesive matrix are, for example, polyacrylates, polysiloxanes, polyurethanes or polyisobutenes.

Reservoir systems are a type of pouch consisting of an impermeable and inert backing layer and an active compound permeable membrane, the active compound being present in a liquid formulation in the pouch. The membrane may be a microporous membrane or a non-porous separator. Typically, the membrane is provided with an adhesive layer for adhering the system to the skin. In this patch design, the skin-facing side is also protected by a membrane that is removed prior to use.

One advantage of reservoir systems is that the saturation solubility of the active compound can be easily adjusted to the specific needs by the choice of the solvent or solvent mixture. For thermodynamic reasons, it is advantageous for the release of the active compound into or onto the skin if the active compound is present in the part of the patch which contains the active compound at a concentration which is not too high below the saturation concentration. With regard to the amount of active compound required, the absorption capacity of the patch can be adjusted within wide limits to suit particular needs by adjusting the amount of active compound solution.

In matrix patches, the active compound is contained in a safe, leak-free form in the adhesive matrix, and the patch can be cut to the desired size with ordinary scissors. On the other hand, it is difficult in some cases to adjust the solubility properties of the matrix for the compound so that the active compound can be dissolved in the matrix in the necessary amount and still be dissolved during storage. In the case of patches for the delivery of capsaicin or an analog, the therapeutic compound is present in the matrix in undissolved form, or it recrystallizes during storage, and therefore does not contribute to the release of the active compound in the skin, since the usual application periods for the treatment of neuropathic pain are short (usually up to several hours).

Surprisingly, it has now been found that another, less well known patch variant "microreservoir system" is particularly suitable for patches intended for high concentration therapy for neuropathic pain treated with capsaicin or capsaicin analogs.

Accordingly, the present invention relates to a topical patch comprising a therapeutic compound impermeable backing layer, a self-adhesive matrix based on silicone comprising at least 1% by weight, preferably at least 2% by weight, more preferably at least 3% by weight, most preferably at least 5% by weight of a capsicum or capsaicin analog, and a protective film to be removed prior to use, wherein

a. Said matrix comprising microreservoirs based on an amphiphilic solvent in which the therapeutically active compound is dissolved

b. The concentration of the therapeutically active compound in the microreservoir system is 20 to 90%, preferably 40 to 70% of the saturation concentration.

In one embodiment, the therapeutic compound is capsaicin.

Suitable amphiphilic solvents include butanediols such as 1, 3-butanediol, dipropylene glycol, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, propylene glycol, dipropylene glycol, carboxylic acid esters of tri-and diethylene glycols, polyethoxylated fatty alcohols having 6 to 18 carbon atoms or 2, 2-dimethyl-4-hydroxymethyl-1, 3-dioxolane(s) (dimethyl ethers, dimethyl) Or mixtures of these solvents. Particular preference is given to dipropylene glycol, 1, 3-butanediol, Diethylene Glycol Monoethyl Ether (DGME) or 2, 2-dimethyl-4-hydroxymethyl-1, 3-dioxolane or mixtures of these solvents.

The solvent or solvent mixture of the microreservoir system can contain viscosity-increasing additives. Examples of viscosity increasing additives include cellulose derivatives (e.g., ethyl cellulose or hydroxypropyl cellulose) and high molecular weight polyacrylic acids or salts and/or derivatives thereof such as esters.

The proportion of microreservoir droplets in the matrix is typically less than about 40% by weight, more often less than about 35% by weight and most often from about 20 to about 30% by weight.

Amine-resistant polysiloxanes may be used in the matrix. Preferably, a mixture of a medium tack silicone and a high tack silicone is used. The polysiloxanes used are synthesized from linear difunctional oligomers and branched multifunctional oligomers. The ratio of the two types of oligomers determines the physical properties of the adhesive. More multifunctional oligomers result in more crosslinked adhesives with higher cohesion and reduced tack, and less multifunctional oligomers result in higher tack and reduced cohesion. The high tack form used in the examples had sufficient tack to adhere to human skin. The medium tack form is almost not tacky at all, but is suitable for compensating the softening effect of other ingredients such as, for example, in the case of capsaicin, and the solvent of the microreservoirs. To increase the adhesion of the matrix, it may comprise from 0.5 to 5% by weight of a silicone oil (e.g. dimethicone).

In a preferred embodiment of the topical patch preparation of the present invention, said base comprises at least 5% to about 10% by weight of capsaicin or capsaicin analog, 10-25% by weight of diethylene glycol monoethyl ether, 0-2% by weight of ethylcellulose, 0-5% by weight of silicone oil and 58-85% by weight of self-adhesive pressure-sensitive polysiloxane. The coating weight of the substrate is generally from 30 to 200g/m²Preferably 50 to 120g/m². Suitable materials for the backing layer include, for example, polyester films (e.g., 10-20 μm thick), ethylene-vinyl acetate copolymers, and the like.

Suitable capsaicin analogs for use in the patches of the present invention include naturally occurring and synthetic capsaicin derivatives and analogs ("capsaicinoids"), such as those described, for example, in U.S. patent 5,762,963, which is incorporated herein by reference.

In microreservoir systems, a liquid formulation of an active compound is dispersed in the form of droplets ("microreservoirs") in an adhesive matrix. The appearance of microreservoir systems is similar to that of classical matrix systems and, because only small microreservoirs can be recognized under a microscope, microreservoir systems can only be distinguished from classical matrix systems with great effort. Thus, in the preceding and following sections, the active compound-containing portion of the patch is also described as a "matrix". The size of the resulting droplets depends on the stirring conditions and the shear forces used during stirring. The size is very consistent and reproducible using the same mixture conditions.

However, it is to be noted that, unlike classical matrix systems, in microreservoir systems the active compound is mainly dissolved in the microreservoirs (and only to a small extent in the polymer). In this sense, microreservoir systems can be considered a hybrid type of matrix patch and reservoir patch, and combine the advantages of both patch variants. As in classical reservoir systems, the saturation solubility can easily be adjusted by choice of solvent to a sufficient value (value) to adequately meet the specific needs, and as in classical matrix systems, the patch can be divided into smaller patches with scissors without leakage.

The microreservoir system can also include a control membrane that controls the release of the active compound and excipients. However, for certain applications in the context of the present invention (i.e. having a short application time, requiring the active compound to be released as soon as possible upon application), there is generally no control membrane present.

Microreservoir systems are disclosed in U.S. patents 3,946,106, 4,053,580, 4,814,184, and 5,145,682, each of which is incorporated herein by reference. A particular microreservoir system is described in International patent publication WO-A-01/01, 967, the disclosure of which is incorporated herein by reference. These microreservoir systems comprise a polysiloxane as the base polymer and an amphiphilic solvent for the microreservoir droplets. It has now been found that such microreservoir systems are particularly suitable for topical high concentration therapies using these active compounds, on the basis of the good solubility of capsaicin and capsaicin analogs in amphiphilic solvents such as, for example, diethylene glycol monoethyl ether, 1, 3-butanediol, dipropylene glycol and Solketal.

One solvent which has proven particularly suitable is diethylene glycol monoethyl ether (DGME, also known by the trade nameTo refer to it). The solubility of capsaicin in DGME is about 50% by weight, and the solubility of capsaicin analogs that are structurally similar to capsaicin is comparable. This means that in order to incorporate sufficient active compound into the matrix, the therapeutic compound does not necessarily have to be dissolved in DGME at a concentration close to the saturation limit. The result is that the patch itself does not recrystallize the therapeutic compound (e.g., capsaicin) even under adverse conditions such as, for example, loss of some of the solvent or low temperature. In practice, solutions of about 20-35% by weight capsaicin in DGME have proven particularly suitable. Since the saturated concentration of capsaicin in DGME is 50% by weight, this solution is 40-70% by weight of the saturated solubility. In this regard, the concentration is calculated according to the following formula:

weight of therapeutic compound x 100/(weight of therapeutic compound + weight of solvent)

In addition to the high saturation limit of capsaicin in this compound, one advantage of using DGME is that DGME acts as a penetration enhancer. It is therefore advantageous that DGME is released with capsaicin or the like after application of the patch to the skin. The simultaneous release of DGME allows the concentration of the therapeutic compound in the microreservoir system and thus also its thermodynamic activity to remain high despite the release. As demonstrated by the results of the permeation experiments on human epidermis shown in table 2, the flux of active compound from such systems is about twice as high as from a matrix supersaturated with crystalline capsaicin. This indicates that the active compound concentration in the microreservoir system increases even above the saturation solubility and that the system becomes supersaturated with even dissolved capsaicin. However, because of the short application time, the therapeutic compound has no opportunity to recrystallize, thereby allowing the active compound to flow into the skin or disperse into the skin very effectively. The rapid increase in the concentration of active compound in the active compound reservoir after application of the patch, due to the rapid release of DGME, is the ultimate reason why the initial concentration of the compound can be well below the saturation concentration without adversely affecting the flux of active compound. Further contribution is made to the absorption of water from the skin. Because the polysiloxane has a very low water absorption capacity, moisture migrates only into the microreservoirs. Water is a poor solvent for capsaicin and most capsaicin analogs. As a result, the saturation concentration of the therapeutic compound in the microreservoir is reduced and thus the thermodynamic activity of the therapeutic compound is increased.

In order for these mechanisms to be effective, it is important that diffusible materials in the polymer have a high diffusion coefficient. For this reason, polysiloxanes are preferred as base polymers compared to all other polymers now used in microreservoir systems.

The polysiloxanes can be prepared from solvent-free two-component systems or solutions in organic solvents. For the preparation of the patch, self-adhesive polysiloxanes dissolved in solvents are preferred.

These exist in two fundamentally different polysiloxane variants: normal polysiloxanes with free silanol groups as shown in formula I,

and said "amine-resistant variant" which differs in that the free silanol groups are derivatized with trimethylsilyl groups. Such amine-resistant polysiloxanes have also proven suitable for use in therapeutic compound-containing patches without active compounds and/or excipients which all have no basic groups. Due to the absence of free silanol groups, the solubility of the active compound in the polymer is further reduced and for many therapeutic compounds the diffusion coefficient is further increased due to interaction with polar free silanol groups, which is not possible. Formula I shows the structure of a linear polysiloxane molecule prepared from dimethylsiloxane by polycondensation. Three-dimensional crosslinking can be achieved by the additional use of methylsiloxanes.

In another polysiloxane of the invention, the methyl groups may be replaced in whole or in part by other alkyl groups or alternatively by phenyl groups.

Without limiting the invention thereto, the base matrix composition of an embodiment of a patch of the present invention comprising the therapeutic compound capsaicin can be seen in Table 1 below.

Table 1:

matrix composition for microreservoir system for topical high dose therapy of capsaicin

The thickness of the matrix is generally from about 30 to about 200 μm (equivalent to about 30 to about 200 g/m)²Coating weight) but different values may be used depending on the nature of the particular formulation. In practice, a matrix thickness of 50 to 100 μm has proven to be particularly suitable.

The backing layer of the patch should ideally be as impermeable or inert as possible for the therapeutic compound and DGME or the chosen amphiphilic solvent. Polyester fulfills this condition, but other materials such as, for example, ethylene-vinyl acetate copolymers and polyamides are also suitable. In practice, polyester films about 20 μm thick have proven to be very suitable. In order to improve the adhesion of the substrate to the backing layer, the contact surface of the backing layer with the substrate is advantageously siliconized. Polyacrylate-based adhesives do not adhere to such siliconized films or adhere only poorly, however, polysiloxane-based adhesives adhere very well due to chemical similarity.

As protective films to be removed before use, it is advantageous to use polyester films which, owing to a special surface treatment, repel adhesives based on polysiloxanes. Suitable films are available from a number of manufacturers and are most well known to those skilled in the art.

The self-adhesive silicone matrix may be an adhesive mixture with different adhesion behavior in order to optimize the adhesion behavior of the patch to the skin. To further improve the adhesion behavior, silicone oils of suitable viscosity or molecular weight can additionally be added in concentrations of up to about 5% by weight.

The invention also relates to a method of making the topical patch of the invention comprising dissolving the therapeutic compound in an amphiphilic solvent, adding this solution to a solution of the polysiloxane or matrix component and dispersing under agitation, applying the resulting dispersion to a removable protective layer and removing the solvent for the polysiloxane at elevated temperature and laminating the backing layer to the dried layer.

The solvent for the therapeutic compound is not necessarily, or may only to a small extent, be mixed with the solvent for the adhesive. Suitable solvents for the adhesive are, for example, petroleum ether or alkanes such as n-hexane and n-heptane. It has been shown that dispersion of a therapeutic compound solution can be more easily achieved if the viscosity of the therapeutic compound solution is increased by the addition of a suitable substance, such as, for example, a cellulose derivative, such as ethyl cellulose or hydroxypropyl cellulose. The dispersion is now applied to a removable protective film in a thickness which, after removal of the solvent of the adhesive, results in a matrix layer of the desired thickness. The dried layer is now laminated with the backing layer to obtain the finished patch laminate.

Patches of the desired shape and size can now be punched out of this laminate and packaged into suitable pouches in a primary package. Very suitable primary packages have proven to be based on paper/glue/aluminium foil/glue/as described in U.S. Pat. No. RE37,934A layer product is formed.Is a heat-sealable polymer based on rubber-modified acrylonitrile copolymers, which is distinguished by a low absorption of volatile constituents of the patch.

It is an object of the present invention to develop a patch with an optimal flux of a therapeutic compound into the human skin. Since the microreservoir system within the meaning of the present invention has no membrane controlling the release of the therapeutic compound and the matrix itself is not able to exert a kinetic control of the release of the therapeutic compound due to the high diffusion coefficient of the therapeutic compound in the polysiloxane, the only element controlling the release of the therapeutic compound into the deeper skin layers is the skin or the uppermost layer of the skin, the stratum corneum. Optimization of the matrix composition was therefore consistently performed by in vitro permeation studies using human skin and Franz diffusion cells for experimental procedures well known to those skilled in the art.

In the first study, the effect of DGME on permeation rate was studied. The results are shown in table 2.

Table 2:

effect of DGME on the permeation Rate of capsaicin through human epidermis (1)

(1) Epidermis, female mammary gland, 37 years old

(2) Average of 3 individual measurements each

(3) 8% by weight of capsaicin and 21% by weight of DGME in an amine-resistant silicone matrix

(4) Matrix supersaturated with crystalline capsaicin

In formulation 2, the therapeutic compound capsaicin is mostly (> 95% by weight) undissolved in the matrix in the form of small crystals. This means that the matrix is saturated with dissolved capsaicin and the thermodynamic activity of the therapeutic compound is greatest for a stable matrix that is not supersaturated. Formulation 1 exhibited an approximately 2-fold higher permeation rate.

Ignoring the small amounts of capsaicin that are dissolved in the polysiloxane itself, the concentration of the capsaicin in the microreservoir droplets in formulation 1 is about 28% by weight. This is well below the saturation concentration of 50% by weight and ensures that there is no risk of recrystallization in the matrix even with partial loss of DGME or reduced temperature. This means that the patch is physically stable prior to use and will only reach a higher saturated or supersaturated state after use, associated with a greatly increased permeation rate.

In the second series, the effect of capsaicin concentration on permeation rate was studied. The results are shown in table 3.

Table 3:

effect of capsaicin concentration on permeation Rate through human epidermis (1)

(1) Epidermis, female mammary gland, 47 years old

(2) Mean value from 3 individual measurements

(3) DGME concentration of 21% by weight

The permeation rate shows a significant dependence on the capsaicin concentration, i.e. the release rate of the patch can easily be adjusted to the value necessary for capsaicin or capsaicin analog by the concentration in DGME (or the solvent intended for the microreservoirs).

A capsaicin concentration of about 8% by weight (e.g., about 5% to about 10% by weight, usually 7% to 9% by weight) in combination with a DGME concentration of about 15 to about 25% by weight has proven particularly suitable.

A matrix containing therapeutic compounds optimized for adhesion behavior to skin and other physical properties has the following composition:

table 4:

optimal composition of matrix for microreservoir system for topical high dose therapy with capsaicin

Components	Weight percent of
		Capsaicin and its preparation method	8
DGME	20
		Ethyl cellulose	0.8
High-adhesion amine-resistant polysiloxane BIO-PSA 4301, Dow Corning	21
		Medium adhesion amine-resistant polysiloxane BIO-PSA 4201, Dow Corning	49
Silicone oil, 12,500 cSt	2
		Coating weight	80g/m

Patches containing the therapeutic compound capsaicin within the meaning of the present invention have proven to be quite effective in appropriate clinical studies. Even one hour treatment of the affected area significantly reduced the sensation of pain, with effects lasting weeks. The patch in this case proved to be highly tolerated and well accepted by the patient. In summary, it can therefore be said that the patch in the meaning of the present invention is most suitable for the treatment of neuropathic pain using high concentrations of capsaicin or capsaicin analogs as described in U.S. Pat. No. 6,248,788.

Thus, the present invention also relates to the use of the topical patch of the present invention for the treatment of neuropathic pain and other conditions.

Use of capsaicin or capsaicin analog patch

This section describes the application of the present invention. It is to be understood, however, that the examples in this section are provided for purposes of illustration and not limitation. Capsaicin use has a number of therapeutic benefits, each of which can be effectively treated with the methods of the present invention. Conditions that may be amenable to treatment with capsaicin or capsaicin analog include neuropathic pain (including pain associated with diabetic neuropathy, postherpetic neuralgia, HIV/AIDS, traumatic injury, complex regional pain syndrome, trigeminal neuralgia, erythromelalgia, and phantom pain), pain resulting from mixed nociceptive and/or neuropathic mixed etiologies (e.g., cancer, osteoarthritis, fibromyalgia, and low back pain), inflammatory hyperalgesia, interstitial cystitis, dermatitis, pruritus (pruritis), itch, psoriasis, warts, and headache. In general, any condition for which topical application of capsaicin is beneficial can be treated with a patch containing capsaicin or a capsaicin analog.

Examples

The following examples serve to illustrate the invention without restricting it.

Example 1: production of a Patch comprising capsaicin

250g of DGME were first thickened with 4.5g of ethylcellulose under stirring. 97g of capsaicin was then added and allowed to dissolve completely with stirring. 286g of the above therapeutic compound solution are added to 1000g of a solution of a polysiloxane or a mixture of polysiloxanes in n-heptane having a solids content of 70% by weight and dispersed in the adhesive solution with vigorous stirring.

Subsequently, the dispersion is applied to a removable protective film in a suitable coating process to a certain thickness and is suitable for use in silicone adhesives such as those from 3M1022 to give a coating weight of 80g/m after removal of n-heptane². The dried film is then laminated with a backing layer, for example a polyester film 20 μm thick, and the finished patch is punched out of the finished laminate. The punched patches are then sealed into a pouch of a suitable primary packaging laminate.

The temperature of the n-heptane, which removes the solvent of the adhesive, should ideally not exceed 40 ℃. There is more DGME in the final pine (bulk) mixture than in the final composition due to loss of DGME during drying.

Example 2:

196g of DGME were first thickened with stirring with 4g of ethylcellulose. Then 30g of nonivamide (vanillylnonanoate amide) are added and dissolved completely with stirring.

The solution is then added to 1000g of a solution of a polysiloxane or a mixture of polysiloxanes in n-heptane having a solids content of 70% by weight and dispersed in the adhesive solution with vigorous stirring.

Subsequently, the dispersion is applied to a removable protective film, for example from 3M, in a suitable coating process, in a certain thickness1022 to give a coating weight after removal of n-heptane of 100g/m². The dried film is then laminated with a backing layer, for example a polyester film 20 μm thick, and the finished patch is punched out of the finished laminate. The punched patches are then sealed into a suitable primary-packaged pouch.

Example 3:

200g of dipropylene glycol were thickened with 2g of hydroxyethyl cellulose with stirring. Then 60g of capsaicin was added and allowed to dissolve completely with stirring.

The solution is then added to 1000g of a solution of a polysiloxane or a mixture of polysiloxanes in n-heptane having a solids content of 70% by weight and dispersed in the adhesive solution with vigorous stirring.

Subsequently, the dispersion is applied to a removable protective film, for example from 3M, in a suitable coating process, in a certain thickness1022 to give a coating weight after removal of n-heptane of 100g/m². The dried film is then laminated with a backing layer, for example a polyester film 20 μm thick, and the finished patch is punched out of the finished laminate. The punched patches are then sealed into a suitable primary-packaged pouch.

Example 4:

the same procedure as described in example 1 was used, except that olvanil (oleoyl vanillylamide) was used instead of capsaicin.

Example 5:

36g of nonivamide were dissolved in 164g of Solketal with stirring. The solution is then added to 1000g of a solution of the polysiloxane or polysiloxane mixture in n-heptane having a solids content of 70% by weight and dispersed in the adhesive solution with vigorous stirring.

Subsequently, the dispersion is applied to a removable protective film, for example from 3M, in a suitable coating process, in a certain thickness1022 to give a coating weight after removal of n-heptane of 100g/m². The dried film is then laminated with a backing layer, for example a polyester film 20 μm thick, and the finished patch is punched out of the finished laminate. The punched patches are then sealed into a suitable primary-packaged pouch.

Claims (13)

1. A topical patch for the treatment of neuropathic pain comprising a therapeutic compound-impermeable backing layer, a self-adhesive silicone-based matrix containing from 7% to 9% by weight of the therapeutic compound, and a protective film to be removed prior to use, wherein the protective film is applied to the backing layer

The matrix contains a liquid microreservoir droplet comprising diethylene glycol monoethyl ether as an amphiphilic solvent in a concentration of 15% to 25% by weight, in which the therapeutic compound is dissolved, and

the concentration of the therapeutic compound in the microreservoir droplet is from 40% to 70% by weight of the saturation concentration,

wherein the therapeutic compound is capsaicin.

2. The topical patch of claim 1, wherein said microreservoir droplets comprise a viscosity increasing additive dissolved in a solvent.

3. The topical patch preparation of claim 2, wherein said viscosity increasing additive is a cellulose derivative or a high molecular weight polyacrylic acid.

4. The topical patch preparation of claim 3, wherein said viscosity increasing additive is ethyl cellulose or hydroxypropyl cellulose.

5. The topical patch preparation of claim 1 wherein said microreservoir droplets are present in the matrix in a proportion of less than 40% by weight.

6. The topical patch preparation of claim 1, wherein said self-adhesive matrix comprises an amine-resistant polysiloxane.

7. The topical patch preparation of claim 6, wherein said self-adhesive matrix comprises a mixture of a medium-adhesive polysiloxane and a high-adhesive polysiloxane.

8. The topical patch preparation of claim 6, wherein said base includes 0.5% to 5% by weight of silicone oil.

9. The topical patch of claim 1, wherein said matrix comprises

7-9% by weight of capsaicin,

15-25% by weight of diethylene glycol monoethyl ether,

0-2% by weight of ethyl cellulose,

0 to 5% by weight of a silicone oil, and

58-85% by weight of a self-adhesive polysiloxane and a coating weight of the substrate of 30 to 200g/m²。

10. The topical patch preparation of claim 1, wherein said matrix is formed from

7-9% by weight of capsaicin,

15-25% by weight of diethylene glycol monoethyl ether,

0-2% by weight of ethyl cellulose,

0 to 5% by weight of a silicone oil, and

58-85% by weight of a self-adhesive polysiloxane and the coating weight of the substrate is 30 to 200g/m²。

11. The patch of claim 1, wherein the backing layer consists of a polyester film 10-20 μm thick.

12. The topical patch preparation of claim 1, wherein said backing layer is comprised of ethylene-vinyl acetate copolymer.

13. A method of making a topical patch preparation according to any one of claims 1 to 12, comprising dissolving the therapeutic compound in an amphiphilic solvent, adding and dispersing the solution to a solution of the polysiloxane or matrix component, applying the resulting dispersion to a removable protective layer and removing the solvent for the polysiloxane and laminating the backing layer to the dried matrix layer.