Elastomeric silicone compositions comprising glycerol, cyclodextrin and octenidine

Abstract

To provide dermal patches and methods of forming dermal patches.SOLUTION: Herein is disclosed an emulsion comprising a silicone pre-elastomer, glycerol, a cyclodextrin, and a metal catalyst suitable for use in the polymerization of the silicone pre-elastomer, a silicone elastomer formed from the emulsion, and dermal patches for release of octenidine formed from the silicone elastomer. Furthermore, disclosed are methods of forming the emulsion, the silicone elastomer and the dermal patch.SELECTED DRAWING: Figure 6

Description

Technical Field

[0001] In the field of silicone elastomers containing glycerol suitable for the release of active substances, a novel composition for releasing an active substance, particularly to mammalian skin, etc., is detailed, which contains at least one cyclodextrin, particularly cyclodextrin, and a hydrophobic active substance, particularly pilthenidine or its derivatives such as octenidine, etc., and particularly contains β-cyclodextrin and octenidine dihydrochloride.

Background Art

[0002] In a series of recent publications and patent applications from the research group of Prof. A. L. Skov, one of the inventors of the present invention, the chemistry of silicone elastomer matrices containing glycerol inclusion compounds has been investigated, including their use in the release of active substances from such matrices. Some relevant publications in this regard include, for example, P. Mazurek et al. J. Appl. Polym. Sci., 2016, 44153, pp. 1 - 8, P. Mazurek et al. Polymer, 2016, v 87, pp. 1 - 7, or P. Mazurek et al., RSC. Adv., 2015, v.5, pp. 15379 - 15386, or Skov et al., WO 2016 / 189117 A1 pamphlet. The silicone elastomer provides a matrix for including at least one inclusion phase of glycerol, and this at least one glycerol phase can exist as discrete droplets or can form a bicontinuous network within the elastomer matrix. The basis of this technique is the mixing of two liquid phases, a silicone pre - elastomer and glycerol, which results in the formation of a glycerol - in - silicone pre - elastomer emulsion, and after cross - linking of the silicone pre - elastomer, this emulsion can form a pressure - sensitive silicone elastomer matrix containing discrete glycerol phases embedded in the silicone elastomer matrix. Studies by several inventors have shown that the embedded glycerol phase can exist as multiple separate globules of glycerol or as a continuous glycerol phase embedded in a partially or fully continuous silicone elastomer (bicontinuous silicone - glycerol elastomer composition).

[0003] From research disclosed by the inventors and their co-workers, it has been shown that glycerol-silicone elastomers are generally stable and can be formed from a wide range of silicone pre-elastomers. This research has shown that when silicone pre-elastomers are (very) hydrophobic, some glycerol-in-silicone pre-elastomer emulsions are less stable than others, and that a small amount of surfactant that functions as a stabilizer and is added to the pre-emulsion mixture of glycerol and silicone pre-elastomer enables the subsequently formed glycerol-in-silicone pre-elastomer emulsion to be stabilized for a sufficient time to enable cross-linking without separating the pre-elastomers to form the resulting silicone elastomer composition containing the embedded glycerol phase.

[0004] In further studies with other co-workers by A.L. Skov and P. Mazurek, two of the inventors, it has been shown that a silicone elastomer matrix containing glycerol, as detailed in WO 2016 / 189117 A1, is an adjustable matrix for the release of active substances, whereby the release kinetics of the active substances contained in the glycerol phase from the elastomer matrix are adjustable between zero-order and first-order release by affecting the form of at least one glycerol phase contained therein. In this further study, first-order, almost zero-order, and zero-order release kinetics have been demonstrated for various hydrophilic active substances.

[0005] Since the two liquids, silicone pre-elastomer and glycerol, are virtually immiscible, mixing them forms a glycerol-in-silicone pre-elastomer emulsion. Cross-linking the silicone phase gives a self-standing silicone-glycerol (adhesive) matrix.

[0006] As is known in the art, depending on the polymerization conditions, the silicone matrix may or may not be an adhesive. In the context of the present invention, one of ordinary skill in the art would be able to prepare a tacky and / or non-tacky silicone elastomer matrix as needed, and thus, the silicone elastomer matrix of the present invention may be an adhesive in some embodiments and non-adhesive in other embodiments depending on their intended use. Similarly, in some embodiments, a combination of a tacky and a non-tacky silicone elastomer can be used to form the silicone elastomer matrix of the present invention.

[0007] Silicone imparts mechanical integrity to the system, while glycerol functions as a liquid filler in the form of micrometer-sized droplets uniformly distributed within the silicone matrix, as shown in FIG. 1. Studies by some of the present inventors have shown that submicron droplets are also possible with the addition of sufficient surfactant. Emulsions derived from silicone pre-elastomers and submicron glycerol droplets have been found to be as stable as emulsions of silicone pre-elastomers and micrometer-sized droplets.

[0008] Glycerol functions as a carrier for the active substance, which is released from the elastomer, for example, upon contact with an aqueous environment. The proposed mechanism for the release of hydrophilic active substances from glycerol-silicone elastomers is shown in FIG. 2. Briefly, the release is considered to be the result of a diffusion process occurring at the interface between glycerol, silicone, and the phase in contact with the outer surface of the elastomer composition (shown by the adjacent aqueous phase in FIG. 2). However, delivery is also affected by the diffusion of the active substance within the glycerol phase and the formed elastomer matrix.

[0009] As reported in the prior art International Publication No. WO 2016 / 189117 pamphlet, the curing of silicone elastomers is carried out using conventional methods known in the art, such as peroxide-based curing, for example, condensation-based curing in the presence of Sn as a catalyst, or addition-based curing in the presence of Pt as a catalyst, for example. During addition-based curing, the Si-H groups of the crosslinking agent react with vinyl groups on the silicone pre-elastomer. Generally, in the context of the present invention, when the catalyst and crosslinking agent are added later, it results in an emulsion that tends to form a non-uniform and lumpy elastomer matrix. Therefore, it is preferable to supply any catalyst and crosslinking agent to the pre-elastomer solution before adding glycerol.

[0010] It is well known in the art that one of the biggest problems when using silicone condensed or addition cured in the presence of a metal catalyst is the vulnerability of the metal catalyst to poisoning. Catalyst poisons include any compound containing, in particular, nitrogen, sulfur, and / or phosphorus. In particular, the platinum catalyst, which is used for its high versatility, such as high conversion efficiency, for example, in the addition-based curing of silicone elastomers, is particularly vulnerable to poisoning by impurities in the substances forming the emulsion prior to polymerization. Platinum is expensive and is irreversibly incorporated into the silicone elastomer matrix formed. Therefore, it is necessary to solve the problem of preventing catalyst poisoning before commercially utilizing this glycerol-silicone elastomer composition.

[0011] In the art, many solutions for solving the above-described problems are known. See, for example, http: / / www.us-tech.com / RelId / 1082642 / pagenum / 2 / ISvars / default / Troubleshooting_Platinum_Catalyzed_Silicones.htm (connected on June 20, 2018). However, while complying with widely generally known preventive measures related to the manufacturing process, some of the above-described problems are reduced for currently studied systems, but in many cases, the active substance may contain accessible active substance molecules and / or functional groups within the active substance molecule, and this molecular group contains in particular one or more of nitrogen, sulfur, and / or phosphorus. Therefore, in the presence of the active substance contained in either the glycerol phase or the silicone phase of the pre-elastomer emulsion, the standard methods in the art have proven to be insufficient for current systems.

[0012] Therefore, there is a need to provide a solution to catalyst poisoning that enables protection of the metal catalyst without inactivating the intended active substance released from the prior art cured elastomer composition.

[0013] Surprisingly, it has been found by some of the inventors that those belonging to the classification of cyclodextrin, particularly β-cyclodextrin, are suitable for use in preventing catalyst poisoning of metal catalysts, particularly platinum catalysts, in compositions containing an emulsion of glycerol-in-silicone pre-elastomer.

[0014] Chinese Patent Application Publication No. 102716104A discloses that β-cyclodextrin can protect a platinum catalyst from catalyst poisoning in the polymerization process of silicone gel in the presence of vegetable oil containing an element selected from N, S, and P. The protection was obtained by preparing insoluble microparticles of vegetable oil and β-cyclodextrin prior to the polymerization of silicone. After polymerization, the microparticles remained intact and non-diffusive in the cured silicone. However, the strong interaction between β-cyclodextrin and the investigated vegetable oils, and the resulting formation of insoluble microparticles, is a significant drawback of the prior art, as it increases the retention capacity of the vegetable oil in the cured silicone and limits the achievable delivery of the investigated vegetable oils.

[0015] Furthermore, with respect to the present invention, in particular with regard to including an emulsion of a glycerol-in-silicone pre-elastomer and at least one active substance containing at least one atom of sulfur, phosphorus, and / or nitrogen, surprisingly, the inventors have noticed that cyclodextrin can be used to prevent catalyst poisoning. The present invention advantageously uses this surprising effect of cyclodextrin in preventing at least platinum catalyst poisoning to propose improving an existing skin patch delivery system of a silicone elastomer containing octenidine for bactericidal wound care.

[0016] In the field of bactericidal wound care, after topical application, a bactericide that does not penetrate, particularly into the body of a mammal, particularly the human body, particularly into the dermis or bloodstream of a mammal, particularly a human, is highly advantageous because it minimizes the potential harm to the person being treated thereby. There is a large list of potent bactericides suitable for use in topical application, such as ethanol and chlorhexidine, for example. However, when considering including a potent bactericide in a wound dressing for long-term release at the wound site during wound healing, the list becomes quite short. Some suitable candidates include silver provided as silver sulfadiazine or silver nanoparticles, and not only these, but also hydrophobic bactericides such as piltanidine and its derivatives, for example octenidine, are widely used.

[0017] In particular, octenidine (basic drug: octenidine dihydrochloride), a cationic surfactant-based bactericide, has attracted wide attention due to its broad effectiveness against Gram-positive and Gram-negative bacteria (Steward et al. Scientific Reports, 2018, 8:895). Octenidine is known in the art to combine a wide range of potential uses such as mouthwash, wound irrigation, topical bactericides, etc., with high biocompatibility and unknown bacterial resistance. Its critical micelle concentration is estimated to be 3.79 mM by Steward et al. The effective concentration of octenidine in suspension is usually more than 0.005% by weight, for example 0.01% by weight, 0.015% by weight, 0.020% by weight, 0.025% by weight, or 0.030% by weight.

[0018]

Table 1

[0019] In the field of wound dressings, formulations include hydrogels formulated with a small amount of glycerol, such as hydrogels containing hydroxyethyl cellulose 4000 (see, for example, US Patent Application Publication No. 2011 / 0091551), and octenidine. Formulations based on various polymers suitable for local drug delivery of active substances contained within a polymer matrix (see, for example, WO 2008 / 008617 pamphlet, WO 2010 / 005680 pamphlet, WO 2014 / 044869 pamphlet), and silicone-derived polymer matrices containing octenidine have also attracted scientific attention (see WO 2007 / 124855 pamphlet, US Patent Application Publication No. 2016 / 0106104). However, while the above-described formulations are suitable for delivering octenidine to the skin of mammals, such as humans, the proposed formulations suffer from problems with delivery kinetics such as burst delivery and rapid octenidine depletion, and thus delivery of octenidine to the wound site under a skin patch is disadvantageous, such as stable delivery and / or delivery for a certain long period of time.

[0020] The present inventors have now presented an improvement of a skin silicone patch containing octenidine, which enables zero-order or nearly zero-order long-term release of octenidine and its derivatives, particularly and preferably, especially, thereby avoiding the burst effect and maintaining an effective concentration of octenidine at the wound site for a long time required for wound healing.

[0021] Definitions In the present context, the term "silicone elastomer" refers to a polymer containing any inert compound composed of repeating units of siloxanes of the formula -RR'SiO-, where R and R' in the formula are the same or different hydrocarbon groups, and this term is used as a polymer showing rubber-like elasticity according to the IUPAC definition. When polymerized in the presence of a glycerol phase, the silicone elastomer of the present invention forms a matrix of the glycerol phase and embeds the glycerol phase in the silicone elastomer matrix.

[0022] In the present context, the term "polysiloxane" refers to a compound in the form of [RR'SiO]n, where R and R' are the same or different hydrocarbon groups and n is the number of repeating units. The term "polysiloxane" also refers to a compound in the form of [RR'SiO]n, which may be partially functionalized in the sense that a plurality of R and R' groups are replaced or substituted by substituents. Non-limiting examples of such substituents include Cl, CN, F, OH, alkenyl, and alkynyl. Further, the silicone compounds or silicone pre-elastomers or additives used for crosslinking may include functional groups known in the art, including compounds containing SiH, SiOR, Si-oxime, and Si-carboxylate functional groups.

[0023] In the present context, the term "polydimethylsiloxane", abbreviated as "PDMS", has the formula CH 3 [Si(CH 3 ) 2 O] n Si(CH3 ) 3 refers to a compound of 3 (where n is the number of repeating units). The term "polydimethylsiloxane" includes derivatives thereof in which one or more methyl groups in the PDMS are replaced, for example, by SiH, hydroxy groups, vinyl groups, allyl groups at pendant or terminal positions.

[0024] In the context of the present invention, the term silicone pre - elastomer is used to represent any silicone starting composition that, after polymerization and / or cross - linking, forms a silicone elastomer matrix suitable for use in the present invention. Depending on the situation, the term silicone prepolymer is also used, and a silicone prepolymer requires complete polymerization of silicone from related monomers and oligomers suitable for the formation of a silicone elastomer, whereas a pre - elastomer is a subgroup of silicone pre - elastomers in that it includes pre - formed silicone polymers where only cross - linking of the silicone polymer is the next necessary step for forming a silicone elastomer.

[0025] In the context of the present invention and for use in embodiments of the present invention, silicone elastomers suitable for use in the present invention can be formed from silicone monomers, oligomers, and / or polymers according to the teachings of International Publication No. WO 2016 / 189117A1 (incorporated herein by reference in its entirety). Suitable monomers, oligomers, and / or polymers for use in the present invention include, inter alia, monomers, oligomers, and / or polymers as described above herein. Generally, the present invention is not limited by the specific choice of silicone elastomer, whether or not the selected silicone elastomer is an adhesive, as long as the silicone elastomer can form a matrix elastomer of the glycerol phase contained, regardless of whether the silicone elastomer is a micelle or bicontinuous. A simple test for the suitability of a specific silicone pre-elastomer for use in the present invention is to prepare a glycerol-containing silicone elastomer as detailed in International Publication No. WO 2016 / 189117A1, and whether the silicone pre-elastomer forms a silicone elastomer in the presence of 20 phr to 140 phr of glycerol.

[0026] In the context of the present invention, the silicone pre-elastomer can be formulated such that non-tacky and tacky silicone elastomers are obtained after crosslinking.

[0027] In this context, the term "curing" refers to the process of crosslinking of polymer chains.

[0028] In this context, the terms "crosslinker" and "crosslinking agent" are used interchangeably and refer to a compound or group of compounds that promote the crosslinking of polymer chains, particularly silicone polymer chains. No specific limitations on the actual composition of the crosslinker should be inferred or intended by the chosen words. Examples of crosslinkers can be, for example, metals, small molecules, polymeric crosslinkers, or even crosslinking compositions containing two or more active crosslinkers involved in the crosslinking process.

[0029] In this context, the term "phr" used to describe the glycerol content in all compositions corresponds to the weight of glycerol per 100 parts by weight of the silicone pre-elastomer.

[0030] In this context, the term "thin film" refers to an elastomeric film having a typical thickness range of from about 0.01 mm to 20 mm, such as from about 0.05 mm to 10 mm, such as from about 0.1 mm to 5 mm, such as from about 0.5 mm to 2.5 mm, such as about 1 mm.

[0031] In this context, the term "excipient" is used in the sense of a substance added to either the silicone phase or the glycerol phase of the present invention. Thus, in the context of the present disclosure, an excipient is a substance contained in the composition of the present invention in addition to either glycerol or silicone. Excipients can be selected, for example, from the group consisting of active substances, particularly active substances for human or animal use, particularly drugs, and / or catalysts, inhibitors, fluidizing agents, silicone oils, solvents, fillers, foaming agents, strengthening substances, and plasticizers. Other examples of excipients are given below in this specification.

[0032] In the context of the present invention, an active substance is a substance that can be released from the composition of the present invention according to a release rate of zero order or higher, as detailed herein. In particular, it is intended that the active substances include substances that are chemically and / or biologically active on or in the surface or body of a human or animal when released from the composition of the present invention (such as pharmacologically active ingredients and / or drugs, etc.).

[0033] In the context of the present invention, a skin patch or (synonymously) a skin patch is a medicinal patch that delivers an active substance or drug to the skin, for example when placed on the skin of a mammal, particularly when placed on the skin of a human. Thus, in the context of the present invention, the term skin patch is used to distinguish the subject matter of the present invention from a transdermal patch, which is considered to be a skin patch containing a drug or active substance that can deliver the drug or active substance to the bloodstream when the transdermal patch is placed on the skin of a mammal, particularly when placed on the skin of a human.

[0034] Throughout the present disclosure, the term cyclodextrin is used to represent a closed conical molecule formed by 1->4 linkages of 5 or more but less than 10 α-D-glucopyranoside units, such as methylated cyclodextrin, and their derivatives. Preferred cyclodextrins in embodiments of the present invention are α, β, or γ-cyclodextrin (see Figure 3), or their derivatives, such as methylated cyclodextrin. Particularly preferably in embodiments of the present invention, the cyclodextrin is β-cyclodextrin. Throughout the present disclosure, various abbreviations for cyclodextrins may be used, for example βCD for β-cyclodextrin, αCD for α-cyclodextrin, γCD for γ-cyclodextrin, and the like.

[0035] Throughout the present disclosure, pilitenidine is used with respect to N,1-dioctylpyridin-4-imine, and octenidine and octenidine dihydrochloride are used interchangeably with N-octyl-1-[10-(4-octyliminopyridin-1-yl)decyl]pyridin-4-imine dihydrochloride (see Figure 4). While pilitenidine is isolated as an uncharged covalent organic compound, octenidine is (usually) isolated as the dihydrochloride. However, in the compositions of the present invention where the starting material is octenidine dihydrochloride, it is still unclear whether octenidine dihydrochloride loses one or both of its hydrochloride molecules after mixing with glycerol and silicone pre-elastomer. Thus, in the context of the present disclosure, octenidine is to be interpreted as meaning N-octyl-1-[10-(4-octyliminopyridin-1-yl)decyl]pyridin-4-imine and any salts thereof, particularly N-octyl-1-[10-(4-octyliminopyridin-1-yl)decyl]pyridin-4-imine dihydrochloride. When it is intended to emphasize the presence of the hydrochloride, the present disclosure uses the longer term octenidine dihydrochloride. In the context of the present disclosure, octenidine is considered to be a derivative of pilitenidine by the condensation of two pilitenidine molecules, whereby octenidine and two C 3 leaving groups are obtained. Summary of the Invention Means for Solving the Problems

[0036] In a first aspect of the present invention, there is disclosed a glycerol-in-silicone pre-elastomer emulsion containing a silicone pre-elastomer, glycerol, cyclodextrin, and a metal catalyst suitable for use in the polymerization of the silicone pre-elastomer.

[0037] In a second aspect of the present invention, there is disclosed a silicone elastomer containing glycerol and cyclodextrin, preferably a silicone elastomer formed by polymerization of a glycerol-in-silicone pre-elastomer emulsion according to any of the embodiments disclosed herein.

[0038] In a preferred embodiment, the silicone elastomer contains a hydrophobic active substance, preferably a hydrophobic active substance contained in the glycerol phase.

[0039] In a preferred embodiment of the present invention, there is disclosed a glycerol-in-silicone pre-elastomer emulsion containing a silicone pre-elastomer, glycerol, at least one cyclodextrin, and octenidine. In a preferred embodiment, the cyclodextrin is β-cyclodextrin and / or the octenidine is octenidine dihydrochloride.

[0040] In a preferred embodiment of the present invention, there is disclosed a silicone elastomer containing glycerol, octenidine, and at least one cyclodextrin, preferably a silicone elastomer formed by polymerization of a glycerol-in-silicone-pre-elastomer emulsion according to any of the embodiments of the first aspect disclosed herein. Preferably, the silicone elastomer is a silicone elastomer matrix for including glycerol, octenidine, and at least one cyclodextrin.

[0041] In a third aspect of the present invention, there is disclosed a skin patch (1) containing a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin, and the silicone elastomer is according to any of the embodiments of the second aspect.

[0042] In a fourth aspect of the present invention, a method for forming a glycerol-in-silicone pre-elastomer emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin is disclosed, the method comprising: i. mixing glycerol, octenidine, and cyclodextrin; ii. heating the resulting mixture with stirring to a temperature of 50 °C to 90 °C until a clear solution is formed; iii. adding the silicone pre-elastomer; iv. applying shear until an emulsion is formed; and comprising.

[0043] In a preferred embodiment of the fourth aspect of the present invention, the glycerol-in-silicone pre-elastomer emulsion is an emulsion according to any of the embodiments of the first aspect.

[0044] In a fifth aspect of the present invention, a method for forming a silicone elastomer is disclosed, comprising polymerizing a glycerol-in-silicone pre-elastomer emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin. In a preferred embodiment of the fourth aspect of the present invention, the glycerol-in-silicone pre-elastomer emulsion is a glycerol-in-silicone pre-elastomer emulsion according to any of the embodiments of the first aspect.

[0045] In a sixth aspect of the present invention and its embodiments, i. preparing an emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin according to any of the aspects and embodiments described herein; ii. casting the emulsion onto a support layer (2) formed from an inert plastic; iii. coating the emulsion onto the support layer with a coating thickness (t ELforming a coating layer having iv. polymerizing the emulsion at the polymerization temperature for the polymerization time, thereby forming a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin; A method for forming a skin patch (1) according to any of the embodiments of the third aspect, including

[0046] In the seventh aspect and embodiments thereof of the present invention, a method for treating a wound site on the skin of a mammal, including covering the wound site with a skin patch (1) according to any of the embodiments of the third aspect containing octenidine, wherein the skin patch (1) releases octenidine at a certain administration rate, and the skin patch (1) is applied to the wound site for an application time sufficient to release an effective amount of octenidine sufficient to obtain a bactericidal effect against at least one gram-positive or gram-negative bacterium is disclosed. In a preferred embodiment, the mammal is a human.

[0047] In the eighth aspect and embodiments thereof of the present invention, a 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin is disclosed. In a preferred embodiment, the 1:1 complex is solubilized in glycerol. Further, the use of a 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin in an emulsion, a silicone elastomer, and a skin patch according to any of the first to sixth aspects and embodiments thereof is disclosed.

Brief Description of the Drawings

[0048]

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DETAILED DESCRIPTION OF THE INVENTION

[0049] In previous studies reported by some of the inventors and co-researchers, the release of hydrophilic active substances from silicone elastomers has been investigated, and this silicone elastomer contains a micellar glycerol phase that dissolves the hydrophilic active substance.

[0050] For the prior art investigation, the release behavior of the hydrophobic active substance was also investigated. However, when a hydrophobic active substance containing at least one of nitrogen, sulfur, or phosphorus in its molecular structure was added to an emulsion of silicone and glycerol, it was observed that the polymerization of the silicone pre-elastomer by metal catalysis was significantly inhibited due to catalyst poisoning. For example, in experiments using piltenidine and derivatives of piltenidine, the active substance contains two or more nitrogen atoms (such as the two nitrogen atoms in piltenidine, see Figure 4), and the catalyst poisoning of a metal catalyst suitable for catalyzing the polymerization of the silicone pre-elastomer, particularly a Pt catalyst, had an adverse effect on the polymerization process. Generally, when a commercially available pre-elastomer solution is used, the silicone pre-elastomer is usually silicone oligomers and polymers, which are crosslinked and cured as defined above to form a silicone matrix. However, in the context of the present invention, as described above, the silicone pre-elastomer may also include silicone monomers that polymerize in addition to curing to form the silicone matrix of the present invention.

[0051] Compared with the specification of Chinese Patent Application Publication No. 102716104A, surprisingly, the inventors have discovered that cyclodextrin may be suitable for masking the tested active substances without interfering with the polymerization process of silicone pre-elastomers in emulsions containing glycerol. Therefore, the present invention describes the dissolution of solid hydrophobic active substances containing at least one element selected from N, S, and P, which form a reversible complex with cyclodextrin, particularly β-cyclodextrin. Thereby, the Pt catalyst present in the emulsion of the present invention for curing the silicone pre-elastomer is protected from catalyst poisoning by the active substance, but does not affect the overall active substance delivery or the active substance delivery rate. Furthermore, in addition to that, surprisingly, cyclodextrin is at least partially distributed at the silicone / glycerol interface, and as a result, functions as a surfactant with respect to the investigated emulsion system containing silicone pre-elastomer and glycerol. In addition to solubilizing and masking active substances containing atoms such as nitrogen, sulfur, or phosphorus that may be involved in catalyst poisoning, surprisingly, it has been observed that the stability of the glycerol-in-silicone pre-elastomer emulsion before polymerization is improved (see Figure 5).

[0052] These observations by the inventors are the subject of a separately filed patent application, are included herein by claim of priority, and according to the present invention, a glycerol-in-silicone pre-elastomer emulsion is disclosed that contains a silicone pre-elastomer, glycerol, cyclodextrin, and a metal catalyst suitable for use in the polymerization of the silicone pre-elastomer. Furthermore, the emulsion may contain an active hydrophobic substance, for example, pillitenidine or a derivative thereof.

[0053] In a preferred embodiment of the present invention, the cyclodextrin can be selected from α, β, or γ-cyclodextrin, or derivatives thereof such as, for example, methylated cyclodextrin (see Figure 3). In a particularly preferred embodiment of the previously filed invention, a glycerol-in-silicone pre-elastomer emulsion according to any of the disclosed embodiments is disclosed, wherein the cyclodextrin is β-cyclodextrin.

[0054] In a further embodiment of the present invention, a glycerol-in-silicone pre-elastomer emulsion according to any of the embodiments disclosed herein is disclosed, wherein the metal catalyst is either Sn or Pt, and preferably, the metal catalyst is Pt.

[0055] Furthermore, in an embodiment of the present invention, a glycerol-in-silicone pre-elastomer emulsion according to any of the embodiments detailed is disclosed, and this glycerol-in-silicone pre-elastomer emulsion further comprises a hydrophobic active substance. In some embodiments, the hydrophobic active substance contains any one or more atoms of nitrogen, sulfur, and / or phosphorus. Preferably, the hydrophobic active substance contains at least one nitrogen atom. Preferably, the active substance is pillitenidine or a derivative thereof.

[0056] Furthermore, in a further aspect of the present invention, a silicone elastomer containing glycerol and cyclodextrin, preferably a silicone elastomer formed by the polymerization of an emulsion according to any of the disclosed embodiments, is disclosed. In a preferred embodiment of the present invention, the hydrophobic active substance contains any one or more atoms of nitrogen, sulfur, and / or phosphorus, and most preferably, the active substance is pillitenidine or a derivative thereof.

[0057] In accordance with the present invention, the inventors investigated whether octenidine, particularly octenidine dihydrochloride (see FIG. 4), can be utilized to release an active substance from a silicone-glycerol elastomer matrix by complex formation with cyclodextrin. As detailed above, octenidine dihydrochloride has several advantages as a skin disinfectant, particularly effectiveness and the advantage of (very) limited skin barrier penetration, but successful formulations in skin patches, particularly those containing silicone elastomers, are not yet available on the market. Some drawbacks of the formulations proposed in the prior art include inappropriate delivery kinetics such as burst delivery and rapid octenidine depletion, and the lack of long-term delivery of octenidine.

[0058] The improvements presented herein by the inventors include, among other things, a silicone skin patch containing octenidine that can be formulated to enable zero-order or nearly zero-order release of octenidine over a fairly long period, thereby avoiding the burst effect and maintaining an effective concentration of octenidine at the wound site for a fairly long period required for wound healing.

[0059] Furthermore, silicone emulsions and silicone polymers suitable for use in forming such skin patches of the present invention, as well as suitable methods for forming the subject matter of the present invention, are detailed herein.

[0060] In one aspect of the present invention, a glycerol-in-silicone pre-elastomer emulsion according to the present invention containing a silicone pre-elastomer, glycerol, at least one cyclodextrin, and octenidine, and embodiments thereof, are described in detail.

[0061] In the context of the present invention, silicone pre-elastomers suitable for use in the present invention may be liquid per se, or they may contain a liquefier such as silicone oil which enables them to be, for example, incorporated into the emulsions of the present invention. In a preferred embodiment of the present invention, the silicone pre-elastomer is a two-component silicone pre-elastomer which forms the silicone elastomer of the present invention upon crosslinking.

[0062] Such two-component silicone pre-elastomers are commercially available from various manufacturers, and two-component silicone pre-elastomers with pre-adjusted properties enable the formation of silicone elastomers which are known to be particularly suitable for the release of active substances, such as for example the release of skin or transdermal active substances, upon crosslinking.

[0063] Thus, in a preferred embodiment of the glycerol-in-silicone pre-elastomer emulsion of the present invention, the silicone pre-elastomer is a two-component silicone pre-elastomer.

[0064] Generally, the actual composition and formulation of the silicone elastomer matrix are considered to be outside the scope of the present invention. As explained above, the silicone pre-elastomer is required to assist in the formation of an emulsion with glycerol and subsequent polymerization to form a glycerol-containing silicone elastomer.

[0065] Non-limiting examples of commercially available silicone pre-elastomers suitable for use in the present invention include, as of the filing date, PDMS pre-elastomers such as Dow Corning's Sylgard® 184 and Wacker Chemie, Germany's Elastosil® RT625, and Dow Corning's two-component pressure-sensitive silicone adhesive MG7-9900, a divinyl-terminated polydimethylsiloxane pre-elastomer containing a crosslinking agent and a Pt catalyst, which is used in the experiments presented herein. In some embodiments, silica is present as a reinforcing agent.

[0066] In multiple embodiments of the present invention, the silicone pre-elastomer can be selected from the group including methyl silicone elastomer, phenyl silicone elastomer, chloroalkyl silicone elastomer, and fluoro silicone elastomer, or a combination thereof.

[0067] In multiple embodiments of the present invention, the silicone pre-elastomer can be selected from the group including polyalkyl siloxane, preferably polydimethylsiloxane (PDMS), and its derivative pre-elastomers. Exemplary PDMS pre-elastomers include vinyl-functional PDMS pre-elastomers that can be crosslinked with hydride-functional crosslinking agents, or hydroxyl-functional PDMS pre-elastomers that can be crosslinked in the presence of Sn or Pt.

[0068] In multiple embodiments of the present invention, the silicone pre-elastomer can be an elastomer composition suitable for use in the present invention.

[0069] In multiple embodiments of the present invention, the silicone pre-elastomer can be an elastomer composition suitable for use in the present invention, and this silicone pre-elastomer is a chlorosilicone pre-elastomer. Non-limiting examples of suitable chlorosilicone pre-elastomers are chloroalkyl-based chlorosilicone pre-elastomers, compositions derived from chloromethyl-terminated polydimethylsiloxane (e.g., Gelest's DMS-L21), or the chlorosilicone elastomers disclosed in WO 2015 / 043792 pamphlet.

[0070] In multiple embodiments of the present invention, the silicone pre-elastomer can be an elastomer composition suitable for use in the present invention, and this silicone pre-elastomer is a fluorosilicone pre-elastomer. Non-limiting examples of commercially available fluorosilicone pre-elastomers are the range of Silastic® F-LSR of Dow Corning's elastomers, the FE / FEA series of ShinEtsu silicones, Krytox of DuPont, or the Elastosil® FLR series of Wacker Chemie.

[0071] In one embodiment of the elastomer composition suitable for use in the present invention, the elastomer composition further contains one or more excipients selected from the group consisting of active substances, particularly active substances for human or animal use, particularly drugs, and / or catalysts, inhibitors, fluidizing agents, silicone oils, solvents, fillers, foaming agents, reinforcing substances, and plasticizers.

[0072] In one embodiment of the elastomer composition suitable for use in the present invention, the one or more excipients can be selected from the group consisting of catalysts (such as Pt complexes (addition curing), Sn (condensation curing), peroxides (peroxide curing), etc.) and inhibitors (such as divinyltetramethyldisiloxane and 1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane, etc.). Examples of commercially available inhibitors are SID4613.0 (1,3-divinyltetramethyldisiloxane) and SIT7900.0 (1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasiloxane) of Gelest Inc.

[0073] In a preferred embodiment of the glycerol-in-silicone pre-elastomer emulsion according to the present invention, the silicone pre-elastomer contains a metal catalyst suitable for use in the polymerization of the silicone pre-elastomer. Preferably, the metal catalyst is either Sn or Pt, and most preferably Pt.

[0074] In one embodiment of the elastomer composition suitable for use in the present invention, the elastomer composition comprises one or more excipients selected from the group consisting of fillers, reinforcing agents, and plasticizers, such as plasticizer oils for reducing the melt viscosity of the elastomer during processing, such as known amounts of active fillers (such as zinc oxide and stearic acid), inert fillers (carbon black, titanium dioxide, silica, carbonates, kaolin, clay, and talc, etc.), or mineral oils containing resins such as Vinyl Q resin of Gelest Inc. Such excipients may be present in commercially available silicone elastomers or may be added individually to the silicone elastomer.

[0075] The amount of excipient required can be varied independently according to the elastomer composition of interest, but is usually in the range of 0 to 40% by weight, such as 5 to 30% by weight, such as 10 to 25% by weight of the elastomer composition.

[0076] In one embodiment of the elastomer composition suitable for use in the present invention, the elastomer composition may further comprise an excipient selected from the group consisting of fluidizing agents, silicone oils, and solvents. Commercially available examples include solvents such as silicone oil WACKER® AK SILICONE FLUID or OS-20 of Dow Corning®. Other suitable examples are, for example, low molecular weight rings such as cyclomethicone (D4 - D6).

[0077] In one embodiment of the elastomer composition suitable for use in the present invention, the elastomer composition contains at least one foaming agent as an excipient.

[0078] In one embodiment of the elastomer composition suitable for use in the present invention, at least one blowing agent is present in an amount in the range of 0.1 to 10 phr, such as 0.2 to 8 phr, such as 0.3 to 6 phr, such as 0.4 to 5 phr, such as 0.5 to 4 phr, such as 0.6 to 3 phr, such as 0.7 to 2 phr, such as 0.8 to 1.5 phr, or such as 0.9 to 1 phr. Preferably, at least one blowing agent is present in an amount of less than 1 phr, such as less than 0.9 phr, such as less than 0.8 phr.

[0079] In one embodiment of the elastomer composition suitable for use in the present invention, the blowing agent is a base. Non-limiting examples thereof include inorganic bases such as NaOH, KOH, and LiOH; amine-based compounds such as triethanolamine, ethanolamine, triethylamine, ethylamine, methylamine, polyetheramine (such as JeffAmines (registered trademark) commercially available from Huntsman); and phosphazene bases such as BEMP (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorin) and P1-t-Bu (N,N,N’,N’,N’’,N’’-hexamethyl-N’’’-(2-methyl-2-propanil)phosphorimidic acid triamide).

[0080] In a preferred embodiment of the present invention, a glycerol-in-silicone pre-elastomer emulsion is disclosed in which at least one cyclodextrin is selected from at least one of α, β, γ-cyclodextrin, or derivatives thereof. In a particularly preferred embodiment, at least one cyclodextrin contained in the emulsion is β-cyclodextrin. In a plurality of embodiments, at least one cyclodextrin is hydroxy-propyl cyclodextrin (HPCD).

[0081] In a further preferred embodiment of the present invention, there is disclosed a silicone elastomer containing glycerol and cyclodextrin, preferably a silicone elastomer formed by the polymerization of a glycerol-in-silicone pre-elastomer emulsion according to any of the embodiments disclosed herein.

[0082] In a preferred embodiment, the hydrophobic active substance contains any one or more atoms of nitrogen, sulfur, and / or phosphorus, and most preferably, the active substance is pilthenidine or a derivative thereof, preferably octenidine.

[0083] In a preferred embodiment of the present invention, there is disclosed a glycerol-in-silicone pre-elastomer emulsion in which octenidine is octenidine dihydrochloride.

[0084] In a particularly preferred embodiment of the present invention, and according to the experiments presented, octenidine is octenidine dihydrochloride and cyclodextrin is β-cyclodextrin.

[0085] As detailed in the experiments (see Example 3 and Figure 7), octenidine dihydrochloride forms a complex with β-cyclodextrin, which, based on the data, is consistent with the complex being a 1:1 molecular complex.

[0086] As disclosed in the experimental section and the methods detailed hereinafter in this specification, the 1:1 complex of octenidine dihydrochloride and β-cyclodextrin can be formed, for example, by heating octenidine dihydrochloride and β-cyclodextrin in a glycerol solution to a temperature of 50 °C to 90 °C while stirring until a clear solution is obtained. Preferably, the temperature is 80 °C.

[0087] As far as the inventors are aware, such a 1:1 complex of octenidine dihydrochloride and β-cyclodextrin has not been described in the prior art. Since the form of complexation with octenidine dihydrochloride is still unknown, the inventors tentatively propose that other salts of octenidine, in particular halide salts such as HF, HBr, or HI, are also suitable for forming the observed 1:1 complex with β-cyclodextrin. Accordingly, such other salts of octenidine, in particular such other halide salts, are also considered to be included in the present invention. However, preferably, octenidine is present as octenidine dihydrochloride in the glycerol-in-silicone pre-elastomer emulsion of the present invention.

[0088] Accordingly, the present invention further relates to a 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin, in particular a 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin in glycerol. The present invention further relates to the use of such molecular complexes in the glycerol-in-silicone pre-elastomer emulsion, elastomer, and skin patch of the present invention.

[0089] Thus, in a preferred embodiment of the glycerol-in-silicone pre-elastomer emulsion of the present invention, cyclodextrin and octenidine are dissolved in glycerol before the silicone pre-elastomer is added. Preferably, cyclodextrin and octenidine are present as a 1:1 molecular complex in glycerol, more preferably β-cyclodextrin and octenidine are present as a 1:1 molecular complex in glycerol, and even more preferably β-cyclodextrin and octenidine dihydrochloride are present as a 1:1 molecular complex in glycerol.

[0090] In a preferred embodiment of the glycerol-in-silicone pre-elastomer emulsion according to the present invention, the concentration of glycerol in the emulsion is 20 phr to 150 phr, preferably 30 to 140 phr, 40 phr to 130 phr, 50 phr to 120 phr, 60 phr to 110 phr, 70 phr to 100 phr, or 80 phr to 90 phr.

[0091] From the research of some of the present inventors, when the concentration of glycerol is less than about 100 phr, glycerol exists as separate small spheres (see Figure 5), while when the concentration of glycerol exceeds about 100 phr, a bicontinuous emulsion of silicone pre-elastomer and glycerol is known to be formed. After polymerization, the silicone elastomer containing glycerol formed from the bicontinuous emulsion exhibits zero-order active substance release. When the concentration of glycerol is about 70 phr to about 100 phr, the release kinetics are nearly zero-order for small active substances, and when the concentration of glycerol is about 20 phr to about 70 phr, the release kinetics follow a first-order release mechanism. In the experiments presented herein, various emulsions, silicone elastomers, and skin patches were formulated to exhibit first-order release and thus had glycerol contents of 20 phr to 70 phr, particularly 40 phr and 60 phr.

[0092] Thus, in multiple embodiments of the present invention, the glycerol-in-silicone pre-elastomer emulsion contains a glycerol component of 20 phr to 70 phr, preferably 30 phr to 60 phr, or 40 phr to 50 phr for use in the formation of a silicone elastomer in which octenidine release follows a first-order release kinetics.

[0093] Thus, in multiple embodiments of the present invention, the glycerol-in-silicone pre-elastomer emulsion contains a glycerol component of 70 phr to 100 phr, preferably 75 phr to 95 phr, or 80 phr to 85 phr for use in the formation of a silicone elastomer in which octenidine release follows a nearly zero-order release kinetics.

[0094] Thus, in multiple embodiments of the present invention, the glycerol-in-silicone pre-elastomer emulsion contains a glycerol component of 100 phr to 150 phr, preferably 110 phr to 140 phr, or 120 phr to 130 phr for use in the formation of a silicone elastomer in which octenidine release follows zero-order release kinetics.

[0095] In multiple embodiments of the glycerol-in-silicone pre-elastomer emulsion of the present invention, the concentration of octenidine in the emulsion is 0.1 wt% to 6 wt% based on the total mass of the emulsion. Preferably, the concentration of octenidine in the emulsion is 0.3 wt% to 5.5 wt%, 0.6 wt% to 5 wt%, 1 wt% to 4.5 wt%, 1.5 wt% to 4 wt%, 2 wt% to 3.5 wt%, or 2.5 wt% to 3 wt% based on the total mass of the emulsion.

[0096] In a preferred embodiment of the glycerol-in-silicone pre-elastomer emulsion of the present invention, octenidine is octenidine dihydrochloride, and the concentration of octenidine dihydrochloride in the emulsion is 0.1 wt% to 6 wt% based on the total mass of the emulsion. Preferably, the concentration of octenidine in the emulsion is 0.3 wt% to 5.5 wt%, 0.6 wt% to 5 wt%, 1 wt% to 4.5 wt%, 1.5 wt% to 4 wt%, 2 wt% to 3.5 wt%, or 2.5 wt% to 3 wt% based on the total mass of the emulsion.

[0097] Furthermore, in multiple embodiments of the present invention, the concentration of at least one cyclodextrin in the glycerol-in-silicone pre-elastomer emulsion is 0.1 wt% to 6 wt% based on the total mass of the emulsion. Preferably, the concentration of cyclodextrin in the emulsion is 0.3 wt% to 5.5 wt%, 0.6 wt% to 5 wt%, 1 wt% to 4.5 wt%, 1.5 wt% to 4 wt%, 2 wt% to 3.5 wt%, or 2.5 wt% to 3 wt% based on the total mass of the emulsion.

[0098] In a preferred embodiment of the glycerol-in-silicone-pre-elastomer emulsion of the present invention, at least one cyclodextrin is β-cyclodextrin, and the concentration of β-cyclodextrin in the emulsion is 0.1 wt% to 6 wt% based on the total mass of the emulsion. Preferably, the concentration of octenidine in the emulsion is 0.3 wt% to 5.5 wt%, 0.6 wt% to 5 wt%, 1 wt% to 4.5 wt%, 1.5 wt% to 4 wt%, 2 wt% to 3.5 wt%, or 2.5 wt% to 3 wt% based on the total mass of the emulsion.

[0099] In addition, in multiple embodiments of the glycerol-in-silicone-pre-elastomer emulsion of the present invention, the molar ratio of octenidine to cyclodextrin in the emulsion, preferably the molar ratio of octenidine dihydrochloride to β-cyclodextrin, is 4:1 to 1:1.5, preferably 3:1 to 1:1.5. Preferably, the molar ratio of octenidine to cyclodextrin in the emulsion is 4:1 to 3:1, 2.5:1 to 1:1.4, 2:1 to 1:1.3, 1.5:1 to 1:1.2, 1.3:1 to 1:1.1, or 1:1.

[0100] In a preferred embodiment of the glycerol-in-silicone pre-elastomer emulsion of the present invention, the emulsion contains a silicone pre-elastomer, 20 phr to 150 phr of glycerol based on the mass of the silicone pre-elastomer, 0.1 wt% to 6 wt% of octenidine based on the total mass of the emulsion, and 0.1 wt% to 6 wt% of cyclodextrin.

[0101] In a further aspect of the present invention, a silicone elastomer containing glycerol, octenidine, and at least one cyclodextrin is disclosed. Preferably, the silicone elastomer is a silicone elastomer matrix for including glycerol in the form of a glycerol phase according to the prior art, preferably for including a glycerol phase containing octenidine and at least one cyclodextrin. According to the prior art, the glycerol phase can exist as discontinuous droplets or as a bicontinuous phase.

[0102] Preferably, the silicone elastomer according to this further aspect of the present invention is formed by polymerization of a glycerol-in-silicone-pre-elastomer emulsion according to any of the embodiments detailed in the present disclosure. As demonstrated by the presented experiments, the silicone elastomer formed from the emulsion disclosed herein reliably releases octenidine and further forms a silicone elastomer matrix suitable for forming a skin patch according to the objects and goals of the present invention.

[0103] According to the present invention, the silicone elastomer of the present invention can be formed from the glycerol-in-silicone pre-elastomer emulsion of the present invention by polymerizing the emulsion at a polymerization temperature and for a polymerization time suitable for obtaining a polymerized emulsion. Preferably, the polymerization time is 1 minute to 120 minutes, preferably 2 minutes to 90 minutes, 3 minutes to 60 minutes, 4 minutes to 50 minutes, 5 minutes to 40 minutes, 6 minutes to 30 minutes, 7 minutes to 20 minutes, 8 minutes to 17 minutes, 9 minutes to 15 minutes, or 10 minutes to 12 minutes.

[0104] In one embodiment, the polymerization temperature is 50°C to 90°C. Obtaining an appropriate combination of polymerization time and temperature for a given silicone pre-elastomer contained in the emulsion of the present invention is within the skill of those in the art. In alternative embodiments, the emulsion contains a low-temperature polymerization inhibitor, whereby polymerization and / or curing can be carried out at temperatures above 90°C, such as above 100°C, above 110°C, or even above 120°C. This can be advantageous when rapid silicone matrix formation is desired. If necessary, detailed guidelines for the polymerization conditions can be obtained from WO 2016 / 189117A1 pamphlet.

[0105] In a further aspect of the present invention, there is disclosed a skin patch (1) comprising a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin. Preferably, the silicone elastomer is a silicone elastomer matrix for containing glycerol, octenidine, and at least one cyclodextrin. An exemplary non-limiting drawing of the skin patch (1) according to the present invention is shown in FIG. 9.

[0106] Skin patches are well known in the art, and the structure of skin patches according to the art is not part of the present invention. Rather, it is contemplated that those skilled in the art can manufacture skin patches according to various requirements when in possession of the information disclosed herein.

[0107] In a plurality of embodiments, the skin patch is a wound care article such as a wound dressing.

[0108] According to the present invention, there is disclosed a skin patch (1) comprising a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin, and this silicone elastomer is according to any of the aspects and embodiments detailed in the present disclosure. In particular, there is disclosed a skin patch (1) comprising a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin, and this silicone elastomer is formed from a glycerol-in-silicone-preelastomer emulsion according to any of the aspects and embodiments detailed herein.

[0109] In a preferred aspect of the present invention, there is disclosed a skin patch (1) comprising a silicone elastomer (3) according to any of the aspects and embodiments detailed in the present disclosure, and this silicone elastomer releases octenidine at a dosing rate of at least 0.1 μg / cm 2 / hour. Preferably, the silicone elastomer of the present invention releases octenidine at a rate of at least 0.3 μg / cm 2 / hour, at least 0.5 μg / cm 2 / hour, at least 0.8 μg / cm 2 / hour, at least 1 μg / cm 2 / hour, at least 1.3 μg / cm 2 / hour, at least 1.5 μg / cm 2 / hour, at least 1.8 μg / cm 2 / hour, at least 2 μg / cm 2 / hour, at least 2.3 μg / cm 2 / hour, at least 2.5 μg / cm 2 / hour, at least 2.8 μg / cm 2 / hour, at least 3 μg / cm 2 / hour, at least 3.3 μg / cm 2 / hour, at least 3.5 μg / cm 2 / hour, at least 3.8 μg / cm 2 / hour, at least 4 μg / cm 2 / hour, at least 4.3 μg / cm 2 / hour, at least 4.5 μg / cm 2 / hour, at least 4.8 μg / cm2 / hour, at least 5 μg / cm 2 / hour, at least 5.3 μg / cm 2 / hour, at least 5.5 μg / cm 2 / hour, at least 5.8 μg / cm 2 / hour, at least 6 μg / cm 2 / hour, at least 6.3 μg / cm 2 / hour, at least 6.5 μg / cm 2 / hour, at least 6.8 μg / cm 2 / hour, at least 7 μg / cm 2 / hour, at least 7.3 μg / cm 2 / hour, at least 7.5 μg / cm 2 / hour, at least 7.8 μg / cm 2 / hour, at least 8 μg / cm 2 / hour, at least 8.3 μg / cm 2 / hour, at least 8.5 μg / cm 2 / hour, at least 8.8 μg / cm 2 / hour, at least 9 μg / cm 2 / hour, at least 9.3 μg / cm 2 / hour, at least 9.5 μg / cm 2 / hour, at least 9.8 μg / cm 2 / hour, or at least 10 μg / cm 2 Octenidine is released at a dosing rate of / hour.

[0110] In the experiments reported below, the skin patches tested released octenidine at a rate of approximately 0.2 μg / cm 2 / hour (0.3 wt% octenidine dihydrochloride, 2:1 molar ratio of OCT:βCD) to approximately 4.1 μg / cm 2 / hour (3 wt% octenidine dihydrochloride, 2:1 molar ratio of OCT:βCD) during the first constant release phase of the transdermal patches tested (see Figures 6 - 8). Overall, the total amount of octenidine observed for all skin patches tested was an amount sufficient to obtain the bactericidal effect against the common bacteria shown in Table 1.

[0111] As described in the experimental section, due to the molecular association with β-cyclodextrin, it is unclear to the inventors how octenidine dihydrochloride is released from the silicone elastomer matrix of the present invention. However, the inventors, without being bound by this theory, believe that octenidine dihydrochloride remains as the dihydrochloride in the emulsions, elastomers, and skin patches of the present invention. However, since the biological effectiveness of octenidine is not related to the association with the dihydrochloride, but rather the salt formation of octenidine is related to the compatibility of aqueous delivery, this aspect is not very important. As demonstrated in this experiment, octenidine is reliably released from the skin patches of the present invention, thereby achieving biological effectiveness.

[0112] In a preferred embodiment of the skin patch (1) of the present invention, the silicone elastomer is present in the skin patch as a layer (3) of silicone elastomer having a thickness (t EL ) of 0.05 mm to 5 mm. Preferably, the thickness (t EL ) is the thickness of the silicone elastomer measured perpendicular to the intended application direction in accordance with known practice in the art of skin patches. The skin patches prepared for the investigations in the experiments reported hereinafter have a thickness (t EL ) of 0.35 mm, which is a thickness common to many patches in transdermal drug delivery. As is well known in the art, the thickness (t EL ) is varied as defined by those skilled in the art to adjust the reservoir content of the active substance and is generally considered not to be relevant to the present invention. Preferably, the thickness (t EL ) is 0.05 mm to 2 mm, 0.1 mm to 1.5 mm, 0.2 mm to 1.3 mm, 0.3 mm to 1 mm, 0.4 mm to 0.9 mm, 0.5 mm to 0.8 mm, or 0.6 mm to 0.7 mm.

[0113] In a preferred embodiment of the skin patch (1) of the present invention, the silicone elastomer (3) comprises a removable layer (4) formed of an inert plastic. In a further preferred embodiment of the skin patch (1) of the present invention, the silicone elastomer (3) comprises a support layer (2) formed of an inert plastic. Preferably, the removable layer (4) and the support layer (2) are arranged on opposite sides of the silicone elastomer and are separated by the thickness (t EL ) of the silicone elastomer, as is customary in the field of skin patches.

[0114] In some embodiments of the present invention, for example when the silicone elastomer is not a pressure-sensitive silicone elastomer, the support layer (2) may include an adhesive layer for contacting and adhering the silicone elastomer (3) to the support layer (2). In many applications, when the elements of the skin patch containing the active substance are themselves adhesives, this can be disadvantageous, for example, it may be disadvantageous for the wound healing of open wounds. These aspects of skin patches are well known to those skilled in the art and are considered outside the scope of the present invention. Usually, the silicone elastomers of the present invention may be pressure-sensitive or non-pressure-sensitive to mammalian skin, particularly human skin, depending on the circumstances of their use.

[0115] In a further aspect and embodiments of the present invention, a method of forming a glycerol-in-silicone pre-elastomer emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin is disclosed. This method comprises i. mixing glycerol, octenidine, and cyclodextrin; ii. heating the resulting mixture with stirring to a temperature of 50 °C to 90 °C until a clear solution is formed; iii. adding the silicone pre-elastomer; iv. applying shear until an emulsion is formed; and includes.

[0116] By following the method of the present invention, particularly when octenidine is octenidine dihydrochloride and cyclodextrin is β-cyclodextrin, octenidine and cyclodextrin are completely associated (see Examples 3 and Figure 7), thereby ensuring that they are optimally available for release from the silicone elastomer and skin patch of the present invention.

[0117] ii. The optimal temperature range for forming the complex of octenidine and cyclodextrin is 50°C to 90°C, and 80°C is optimal. Below 50°C, the formation of the complex of octenidine and cyclodextrin is slow. As detailed in the above method, it is usually preferable to mix the components before heating, but if necessary, it is also possible to directly add octenidine and cyclodextrin to hot glycerol.

[0118] As detailed in WO 2016 / 189117 A1 pamphlet, it is necessary to apply shear (iv.) to form an emulsion of silicone pre-elastomer and glycerol. Usually, it is recommended in WO 2016 / 189117 A1 pamphlet to apply shear at 1500 rpm to 5000 rpm until the emulsion is formed, but other methods of applying shear known to those skilled in the art are also considered suitable for use in the method of the present invention.

[0119] In one embodiment of the method for forming a glycerol-in-silicone pre-elastomer emulsion according to the present invention, the resulting transparent solution in (ii.) is cooled to 5°C to 50°C before adding the silicone pre-elastomer. Usually, when the glycerol content is moderately low, this step can be omitted. However, when the glycerol content is high, for example, when a mixing temperature of 80°C is used, polymerization initiated by the undesired heat of the silicone pre-elastomer may occur, which can be avoided by pre-cooling. In an alternative embodiment, the emulsion contains a low-temperature polymerization inhibitor, whereby polymerization and / or curing can be carried out at temperatures above 90°C, such as above 100°C, above 110°C, or even above 120°C. This can be advantageous when rapid silicone matrix formation is desired.

[0120] In a particularly preferred embodiment of the method for forming a glycerol-in-silicone pre-elastomer emulsion according to the present invention, the emulsion is an emulsion according to any of the aspects and embodiments of the present invention detailed herein.

[0121] A method for forming a silicone elastomer is disclosed, which includes polymerizing a glycerol-in-silicone pre-elastomer emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin. Preferably, the silicone elastomer is a silicone elastomer matrix for containing glycerol, octenidine, and at least one cyclodextrin.

[0122] In a preferred embodiment of the method for forming a silicone elastomer according to the present invention, the glycerol-in-silicone pre-elastomer emulsion is an emulsion according to any of the aspects and embodiments of the present invention detailed herein.

[0123] In a preferred embodiment of the method for forming a silicone elastomer according to the present invention, the glycerol-in-silicone pre-elastomer emulsion is formed according to the method according to any of the aspects and embodiments of the present invention detailed herein.

[0124] In one embodiment of the method for forming a silicone elastomer according to the present invention, the polymerization of the glycerol-in-silicone pre-elastomer emulsion is carried out for 1 minute to 120 minutes, preferably 2 minutes to 90 minutes, 3 minutes to 60 minutes, 4 minutes to 50 minutes, 5 minutes to 40 minutes, 6 minutes to 30 minutes, 7 minutes to 20 minutes, 8 minutes to 17 minutes, 9 minutes to 15 minutes, or 10 minutes to 12 minutes.

[0125] In a further method for forming a silicone elastomer according to the present invention, the polymerization of the glycerol-in-silicone pre-elastomer emulsion is carried out at a polymerization temperature of 50°C to 90°C. In an alternative embodiment, the emulsion contains a low-temperature polymerization inhibitor, whereby the polymerization and / or curing can be carried out at a temperature above 90°C, such as above 100°C, above 110°C, or even above 120°C. This can be advantageous when rapid silicone matrix formation is desired.

[0126] In a further aspect of the present invention and its embodiments, i. preparing a glycerol-in-silicone emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin according to any of the aspects and embodiments described herein; ii. casting the emulsion onto a support layer (2) formed from an inert plastic; iii. coating the emulsion onto the support layer to form a coating layer having a coating thickness (t EL ); iv. polymerizing the emulsion at the polymerization temperature for the polymerization time, thereby forming a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin; A method of forming a skin patch (1) according to any of the aspects and embodiments described herein, including

[0127] In one embodiment of the method of forming a skin patch (1), the method further comprises providing a removable layer (4) formed from an inert plastic on top of a silicone elastomer (3) on the opposite side of the support layer (2).

[0128] In one embodiment of the method of forming a skin patch (1), the method further comprises polymerizing a glycerol-in-silicone pre-elastomer emulsion for 1 minute to 120 minutes, preferably 2 minutes to 90 minutes, 3 minutes to 60 minutes, 4 minutes to 50 minutes, 5 minutes to 40 minutes, 6 minutes to 30 minutes, 7 minutes to 20 minutes, 8 minutes to 17 minutes, 9 minutes to 15 minutes, or 10 minutes to 12 minutes.

[0129] In one embodiment of the method of forming a skin patch (1), the method further comprises polymerizing a glycerol-in-silicone pre-elastomer emulsion at a polymerization temperature of 50 °C to 90 °C, preferably 80 °C. In an alternative embodiment, the emulsion contains a low-temperature polymerization inhibitor, whereby polymerization and / or curing can be carried out at a temperature above 90 °C, such as above 100 °C, above 110 °C, or even above 120 °C. This can be advantageous when rapid silicone matrix formation is desired.

[0130] In one embodiment of the method of forming a skin patch (1), the method further comprises cutting the skin patch (1) to a size of 1 cm 2 ~1000 cm 2 of.

[0131] In a further aspect and embodiment of the present invention, there is provided a method of treating a wound site on the skin of a mammal, comprising covering the wound site with an octenidine-containing skin patch (1) according to any of the aspects and embodiments detailed herein, wherein the skin patch (1) releases octenidine at a certain administration rate, and the skin patch (1) is applied to the wound site for an application time sufficient to release an effective amount of octenidine sufficient to obtain a bactericidal effect against at least one gram-positive or gram-negative bacterium.

[0132] In one embodiment of the method of treating a wound site on the skin of a mammal disclosed herein, the mammal is a human.

[0133] In one embodiment of the method of treating a wound site on the skin of a mammal disclosed herein, at least one gram-positive or gram-negative bacterium is selected from Staphylococcus aureus, Escherichia coli, Proteus mirabilis, Candida albicans, or Pseudomonas aeruginosa.

[0134] In one embodiment of the method of treating a wound site on the skin of a mammal disclosed herein, the administration rate of octenidine release is at least 0.1 μg / cm 2 / hour. Preferably, the administration rate of octenidine release is at least 0.3 μg / cm 2 / hour, at least 0.5 μg / cm 2 / hour, at least 0.8 μg / cm 2 / hour, at least 1 μg / cm 2 / hour, at least 1.3 μg / cm 2 / hour, at least 1.5 μg / cm 2 / hour, at least 1.8 μg / cm 2 / hour, at least 2 μg / cm 2 / hour, at least 2.3 μg / cm 2 / hour, at least 2.5 μg / cm2 / hour, at least 2.8 μg / cm 2 / hour, at least 3 μg / cm 2 / hour, at least 3.3 μg / cm 2 / hour, at least 3.5 μg / cm 2 / hour, at least 3.8 μg / cm 2 / hour, at least 4 μg / cm 2 / hour, at least 4.3 μg / cm 2 / hour, at least 4.5 μg / cm 2 / hour, at least 4.8 μg / cm 2 / hour, at least 5 μg / cm 2 / hour, at least 5.3 μg / cm 2 / hour, at least 5.5 μg / cm 2 / hour, at least 5.8 μg / cm 2 / hour, at least 6 μg / cm 2 / hour, at least 6.3 μg / cm 2 / hour, at least 6.5 μg / cm 2 / hour, at least 6.8 μg / cm 2 / hour, at least 7 μg / cm 2 / hour, at least 7.3 μg / cm 2 / hour, at least 7.5 μg / cm 2 / hour, at least 7.8 μg / cm 2 / hour, at least 8 μg / cm 2 / hour, at least 8.3 μg / cm 2 / hour, at least 8.5 μg / cm 2 / hour, at least 8.8 μg / cm 2 / hour, at least 9 μg / cm 2 / hour, at least 9.3 μg / cm 2 / hour, at least 9.5 μg / cm 2 / hour, at least 9.8 μg / cm 2 / hour, or at least 10 μg / cm 2 / hour.

[0135] In one embodiment of the method for treating a wound site on the skin of a mammal disclosed herein, the application time is at least 1 hour.

[0136] In an embodiment of the method for treating a wound site on the skin of a mammal disclosed in this specification, the effective dosage of octenidine is at least 0.1 μg / cm 2 is. Preferably, the effective dosage of octenidine is at least 0.3 μg / cm 2 , at least 0.5 μg / cm 2 , at least 0.8 μg / cm 2 , at least 1 μg / cm 2 , at least 1.3 μg / cm 2 , at least 1.5 μg / cm 2 , at least 1.8 μg / cm 2 , at least 2 μg / cm 2 , at least 2.3 μg / cm 2 , at least 2.5 μg / cm 2 , at least 2.8 μg / cm 2 , at least 3 μg / cm 2 , at least 3.3 μg / cm 2 , at least 3.5 μg / cm 2 , at least 3.8 μg / cm 2 , at least 4 μg / cm 2 , at least 4.3 μg / cm 2 , at least 4.5 μg / cm 2 , at least 4.8 μg / cm 2 , at least 5 μg / cm 2 , at least 5.3 μg / cm 2 , at least 5.5 μg / cm 2 , at least 5.8 μg / cm 2 , at least 6 μg / cm 2 , at least 6.3 μg / cm 2 , at least 6.5 μg / cm 2 , at least 6.8 μg / cm 2 , at least 7 μg / cm 2 , at least 7.3 μg / cm 2 , at least 7.5 μg / cm 2 , at least 7.8 μg / cm 2 , at least 8 μg / cm 2 , at least 8.3 μg / cm 2 , at least 8.5 μg / cm2 、at least 8.8 μg / cm 2 、at least 9 μg / cm 2 、at least 9.3 μg / cm 2 、at least 9.5 μg / cm 2 、at least 9.8 μg / cm 2 、or at least 10 μg / cm 2 is.

[0137] In a preferred embodiment of the method for treating a wound site on the skin of a mammal disclosed herein, octenidine is octenidine dihydrochloride.

[0138] In a further aspect of the invention and its embodiments, a skin patch (1) according to any of the detailed aspects and embodiments herein is disclosed for use in a method according to any of the detailed aspects and embodiments herein, preferably, octenidine is octenidine dihydrochloride and cyclodextrin is β-cyclodextrin.

Example

[0139] Materials The two-component pressure-sensitive silicone adhesive MG7-9900, i.e., divinyl-terminated polydimethylsiloxane containing a crosslinking agent and a Pt catalyst, was purchased from Dow Corning. Glycerol (food grade, maximum 0.5% water), a by-product of biodiesel production, was provided by Emmelev A / S and used as received while avoiding excessive contact with air. β-cyclodextrin from Wacker Chemie was purchased from Sigma Aldrich. Octenidine dihydrochloride was purchased from Dishman Group. All chemicals were used as received.

[0140] Equipment A dual asymmetric centrifugal mixer SpeedMixer DAC 150FVZ-K was used for mixing all compounds. A Leica DM LB optical microscope was utilized to examine the glycerol in silicone emulsion form.

[0141] Method All silicone compositions containing a glycerol phase were prepared according to steps i. - v. of WO 2016 / 189117A1 Pamphlet. The obtained glycerol-in-silicone pre-elastomer emulsion and silicone elastomer were characterized according to prior art methods, in particular by visual inspection using an optical microscope.

[0142] The two-component MG7-9900 silicone kit was mixed at a weight ratio of 1:1 as recommended by the manufacturer. Subsequently, the desired amount of glycerol, and where applicable β-cyclodextrin and octenidine, were added to the silicone pre-elastomer and stirred with a speed mixer at 3500 rpm for 5 minutes until a stable emulsion was formed, unless otherwise stated. In some cases, after the mixing step, the composition was cast onto a metal mold with a 1 mm spacer and cured at 80 °C for 1 hour. Thereafter, the obtained film was left at room temperature for at least 2 days for final post-curing.

[0143] Prior to mixing with the silicone pre-elastomer, it was advantageously observed that a clear solution was obtained by mixing glycerol, β-cyclodextrin, and octenidine with stirring at a temperature in the range of 50 °C to 90 °C, preferably 80 °C. This suggests complete complexation of octenidine by β-cyclodextrin and complete solubilization of the formed complex in glycerol. In that case, the resulting glycerol-in-silicone-pre-elastomer emulsion of silicone pre-elastomer and glycerol containing a complex of octenidine and β-cyclodextrin will be free of precipitates within the accuracy of the optical microscope.

[0144] A list of all examined samples is shown in Table 2 together with details regarding the appropriate sample name and composition.

[0145] [Table 2]

[0146] Sample G40_1%Oct_2:1(Oct:CD)_MG7-9900 is selected as the model sample and used to show the sample preparation procedure in more detail. The masses of the individual compounds are shown in Table 3.

[0147]

Table 3

[0148] Stability of Glycerol-in-Silicone Pre-Elastomer Emulsion Emulsion 1: Continuous phase of glycerol-in-silicone pre-elastomer emulsion - uncured pressure-sensitive silicone adhesive MG7-9900 from Dow Corning. Dispersed phase - glycerol (40 phr).

[0149] Emulsion 2: Continuous phase of glycerol-in-silicone pre-elastomer emulsion - uncured pressure-sensitive silicone adhesive MG7-9900 from Dow Corning. Dispersed phase - glycerol (40 phr) containing 3 wt% β-cyclodextrin and 3 wt% piltanidine derivative (weight percent based on the total composition).

[0150] The stability of glycerol-in-silicone pre-elastomer emulsions with or without β-cyclodextrin-piltanidine derivative complex was investigated.

[0151] The average droplet size was calculated based on the analysis of at least 100 adjacent glycerol domains in both emulsions. From the experiment (Figure 4), it was revealed that the average droplet diameters after 10 minutes from mixing were 16.0 μm (±4.9 μm) and 9.3 μm (±2.4 μm) for Emulsion 1 and Emulsion 2, respectively. The data indicates that cyclodextrin, especially β-cyclodextrin, partitions itself also at the interface between glycerol and silicone pre-elastomer and thus functions as a stabilizing surfactant for the emulsion obtained by mixing the components with respect to this composition.

[0152] In the presence of β-cyclodextrin, polymerization of Emulsion 2 was possible despite the presence of nitrogen in the pilltenidine derivative. It was observed that complexation of the poison of the platinum catalyst by cyclodextrin significantly reduced the inhibition of the addition-curing system. The pilltenidine derivative is thought to be unable to participate in platinum poisoning because it orients itself (at least partially) to the nitrogen groups in the cavity of β-cyclodextrin.

[0153] Solubilization of octenidine in glycerol Since octenidine is an amphiphilic substance, its solubility in glycerol is very low, but it can form micelles to increase solubility. In this investigation, β-cyclodextrin (βCD) was used as a tool to dissolve a large amount of hydrophobic substances in a hydrophilic medium such as glycerol. Cyclodextrin as a cyclic oligosaccharide that forms a host-guest complex with a hydrophobic molecule, thereby enabling a number of potential applications. Here, octenidine (0.35 g) and β-cyclodextrin (0.3182 g) were added to glycerol. The molar ratio between octenidine and β-cyclodextrin in this example was 2:1. The mixture was heated to 80 °C and stirred using a magnetic stirrer (usually within 30 minutes) until a clear solution was obtained. The fact that a clear mixture was obtained indicates the successful preparation of the βCD-octenidine complex.

[0154] Preparation of Functional Adhesive A mixture containing glycerol and βCD-octenidine complex was placed in a plastic container. Subsequently, 12.5 g of MG7-9900 as Liquid A and 12.5 g of MG7-9900 as Liquid B were added. The composition was mixed at 3500 revolutions per minute (rpm) for 5 minutes using a dual asymmetric centrifugal mixer SpeedMixer Dac 150 FVZ-K. In this way, a glycerol-in-silicone-pre-elastomer emulsion was prepared. The emulsion was cast onto an inert plastic support and spread using a commercially available knife to form a film (t EL ) with a thickness of 350 μm. Subsequently, the material was placed in an oven at 80 °C for 1 hour. Thereafter, the resulting polymerized skin patch was cut into 25 cm 2 square samples while still attached to the support. The resulting skin patches exhibited excellent surface adhesiveness with respect to adhesiveness over time and ease of release from the surface after use.

[0155] Investigation of Release The release behavior of octenidine from the polymerized skin patch was determined by immersing the sample in 200 ml of deionized water. The progress of octenidine release was observed by measuring the change in the concentration of octenidine in an aqueous environment. For the test, a UV-vis spectrophotometer, the POLARstar Omega microplate reader from BMG LabTech was used. The results were compared with the calibration curve of the βCD-octenidine complex in the aqueous solution. Each release behavior curve represents the average of three separate experiments. To avoid evaporation of water, the samples were tested in a sealed container (placed on a rotary shaker). The release profiles of various samples are represented as plots of the released octenidine in μg / cm 2 units as a function of time.

[0156] Example 1 Stability of Glycerol-in-Silicone Emulsion Containing Octenidine Emulsion 1: Continuous phase of the emulsion - Dow Corning uncured pressure - sensitive silicone adhesive MG7 - 9900. Dispersed phase - glycerol (40 phr).

[0157] Emulsion 2: Continuous phase of the emulsion - Dow Corning uncured pressure - sensitive silicone adhesive MG7 - 9900. Dispersed phase - glycerol (40 phr) containing 3 wt% β - cyclodextrin and 3 wt% octenidine (weight percent based on the whole composition).

[0158] The stability of glycerol - in - silicone pre - elastomer emulsions with or without β - cyclodextrin - octenidine derivative complexes was investigated.

[0159] The average droplet size was calculated based on the analysis of at least 100 adjacent glycerol domains in both emulsions. From the experiment (Figure 5), it was revealed that the average droplet diameters 10 minutes after mixing were 16.0 μm (±4.9 μm) and 9.3 μm (±2.4 μm) for Emulsion 1 and Emulsion 2, respectively. The data indicate that β - cyclodextrin distributes itself at the interface between the glycerol phase and the glycerol - silicone pre - elastomer and thus functions as a stabilizing surfactant for the emulsion obtained by mixing the components with respect to this composition.

[0160] In the presence of β - cyclodextrin, polymerization of Emulsion 2 was possible despite the presence of nitrogen in octenidine. It was observed that the complexation of the poison of the platinum catalyst by cyclodextrin significantly reduced the inhibition of the addition - curing system. Octenidine is thought to be unable to participate in platinum poisoning because it orients itself (at least partially) to the nitrogen groups in the cavity of β - cyclodextrin.

[0161] Example 2 Effect of octenidine content on the release of octenidine from silicone skin patches Skin patches containing 0.3, 1, and 3 wt% octenidine were investigated. The molar ratio of octenidine to β-CD was kept constant at 2:1 (2 molecules of octenidine per 1 molecule of β-CD). The release behavior shown in Figure 6 clearly shows that the drug dosage delivered from different skin patches increases as expected with the increase in the octenidine content.

[0162] After 24 hours, the samples containing 0.3, 1, and 3 wt% octenidine released approximately 3, 12, and 39 μg of octenidine per 1 cm of the membrane 2 respectively. Within the accuracy of the experiment, the dose release appears to be linearly proportional to the octenidine content (1:3:10) in the skin patch and the doses released (1:4:13) respectively. The inventors, while not being bound by this theory, believe that the observed excess release is likely related to the secondary release mechanism as discussed below for Example 3.

[0163] All three patches released octenidine in an amount sufficient to obtain a bactericidal effect against the common bacteria shown in Table 1.

[0164] Example 3 Effect of β-cyclodextrin content on the release of octenidine from silicone skin patches In a further example, the effect of the molar ratio of octenidine to β-cyclodextrin on the release of octenidine from the formed skin patches was investigated. In this study, samples containing 2 molecules (molar ratio 2:1) and 1 molecule (molar ratio 1:1) of octenidine per 1 molecule of β-cyclodextrin were investigated. The release behavior of both membranes is shown in Figure 7.

[0165] As can be observed from the graph, the release of octenidine into water from the skin patch containing octenidine and β-cyclodextrin in a 2:1 ratio is slightly faster than that from the 1:1 composition, and there is not much change in the release kinetics between the two compositions. The data appears to be consistent with the hypothesis that octenidine and β-cyclodextrin form a 1:1 complex and that the 1:1 complex governs the diffusion and release characteristics of the silicone elastomer as a whole.

[0166] In particular, the data appears to be consistent with the model shown in Figure 2, where the release of the active substance occurs mainly via release from the active substance reservoir contained in the glycerol phase, which maintains a (substantially) constant concentration of the active substance in the silicone elastomer matrix.

[0167] In this model, the release of the hydrophobic active substance is inhibited by insufficient absorption of water. Octenidine, a surfactant with a moderately high CMC value (estimated to be 3.79 mM in water by Steward et al. and likely higher in glycerol), dissolves to some extent in water and glycerol, which is significantly enhanced in the presence of cyclodextrin. Therefore, although not bound by this theory, the inventors believe that the release of octenidine is governed by the release rate of the 1:1 octenidine-βCD-complex and that there is likely a partial contribution from (micellar) octenidine dissolved directly in glycerol and (subsequently) water.

[0168] When the molar ratio of octenidine to β-cyclodextrin was 2:1, only an increase in delivery efficiency of about 25% to 30% was obtained compared to a molar ratio of 1:1. The optimal formulation of octenidine to β-cyclodextrin (when only considering the release rate) needs to be formulated such that the molar ratio of these two components is 1:1 or less, preferably close to 1:1.1, 1:1.2, 1:1.3, 1:1.4, and even 1:1.5. Thereby, substantially all octenidine forms a complex with β-cyclodextrin (the latter being in excess), such that substantially all octenidine becomes available for release via a faster octenidine-βCD-complex release mechanism compared to the slower release rate of octenidine that is not part of the octenidine-βCD-complex.

[0169] However, using an excess of octenidine relative to β-cyclodextrin, for example, molar ratios of excess 3:1, 2.5:1, 2:1, and even 1.5:1, has the advantage that the overall release of octenidine from the skin patch increases due to the availability of octenidine for release by the secondary release mechanism.

[0170] Example 4 Effect of glycerol addition amount on the release of octenidine from a silicone skin patch Samples containing 40 and 60 phr (parts by weight per 100 parts by weight of silicone rubber) of glycerol were prepared and investigated. The amounts of octenidine and β-cyclodextrin in the membrane were kept constant at 1 wt%, and octenidine and β-cyclodextrin were present in a molar ratio of 2:1.

[0171] The results shown in Figure 8 are consistent with the release model shown in Figure 2, in which the release rate of the active substance increases as the amount of glycerol added to the membrane increases.

[0172] In the first part of the drug delivery process, the release rates appear to be equal, but the difference becomes significant after about 5 hours. After about 24 hours, the sample containing 40 phr of glycerol was 1 cm 2While releasing approximately 12 μg of octenidine per centimeter, the sample containing 60 phr of glycerol 2 released approximately 18 μg of octenidine per centimeter.

[0173] In relation to the release model shown in detail in Figure 2, the observed data is explainable. First, the reservoir near the surface of the skin patch containing octenidine and the octenidine-β-cyclodextrin 1:1-complex is depleted, resulting in an almost equal delivery rate between the two different samples. Subsequently, the delivery rate comes to be governed by the exchange rate between the reservoir at a deeper position and the drug release reservoir at the surface, and the reservoir structure of 60 phr of glycerol enables a faster reservoir exchange than that of 40 phr of glycerol.

[0174] Although not bound by this theory, the inventors believe this is due to the thinning of the wall in the polymeric silicone matrix where the passage of the silicone matrix wall by octenidine and / or the octenidine-β-cyclodextrin complex is rate-limiting.

[0175] Conclusion In conclusion, the formation of the complex of octenidine and β-cyclodextrin in the composition and elastomeric matrix of the present invention enables a wide range (easily) adjustable delivery rate of octenidine from the silicone elastomer skin patch.

[0176] In some embodiments, octenidine is in excess compared to cyclodextrin, thereby increasing the delivery rate and octenidine does not form a complex with cyclodextrin that functions as a long-term reservoir of sustained-release octenidine from the skin patch. In another embodiment, cyclodextrin becomes excessive due to the rapid delivery of octenidine and the rapid depletion of the skin patch of octenidine.

[0177] According to the research of the present inventors, a silicone elastomer matrix containing 40 phr or 60 phr of glycerol has a micelle structure (compare FIGS. 1 and 5), while a silicone elastomer matrix containing more than 100 phr of glycerol is bicontinuous in both the silicone elastomer phase and the glycerol phase. According to the research of the present inventors, the delivery rate of small hydrophilic active substances from individual micelle structures of glycerol of less than about 70 phr follows first-order release behavior, and from about 70 phr to about 100 phr of glycerol, the delivery of small hydrophilic active substances follows almost zero-order release behavior. For glycerol exceeding about 100 phr, such as 120 phr, the release of small hydrophilic active substances follows zero-order release behavior.

[0178] The release data shown here is consistent with previous observations in that the release data shows first-order release kinetics expected for glycerol contents of less than about 70 phr.

[0179] Thus, in some embodiments, the initial emulsion is prepared with a glycerol content of less than 70 phr, thereby forming micelle structures of glycerol in the polymerized silicone elastomer. In another embodiment, the glycerol content is greater than 100 phr, thereby forming a bicontinuous emulsion and a polymerized silicone elastomer.

[0180] Embodiments where octenidine is in excess relative to cyclodextrin and / or the glycerol content is less than 70 phr can be beneficially applied, for example, to locations where skin patches cannot be easily replaced. Embodiments where octenidine is present at a lower molar ratio than cyclodextrin and / or the glycerol content is greater than 100 phr can be beneficially applied when the skin patch is intended for short-term use only, or in combination with frequent replacement, or when only one-time skin coverage by the skin patch is intended during early wound healing.

[0181] Thereby, a wide range of easily adjustable skin patches for the delivery of octenidine to a wound site where, for example, the release of a bactericide is desired are shown, whereby the release amount and release rate can be adjusted by a simple manipulation of the concentration of the components of the initial composition for forming the resulting skin patch and the composition and emulsion prepared prior to the polymerization of the resulting emulsion.

[0182] Annotation The term "comprising" as used in the claims does not exclude other elements or steps. The terms "a" or "an" as used in the claims do not exclude a plurality. The present invention has been described in detail for purposes of illustration, but such details are for that purpose only and it is understood that those skilled in the art may make modifications without departing from the scope of the present invention. The present disclosure further includes the following aspects: <<Aspect 1>> A glycerol-in-silicone pre-elastomer emulsion containing a silicone pre-elastomer, glycerol, cyclodextrin, and a metal catalyst suitable for use in the polymerization of the silicone pre-elastomer. <<Aspect 2>> The glycerol-in-silicone pre-elastomer emulsion according to Aspect 1, wherein the cyclodextrin is selected from α, β, or γ-cyclodextrin or derivatives thereof. <<Aspect 3>> The glycerol-in-silicone pre-elastomer emulsion according to any one of Aspect 1 or Aspect 2, wherein the cyclodextrin is β-cyclodextrin. <<Aspect 4>> The glycerol-in-silicone pre-elastomer emulsion according to any one of Aspects 1 to 3, wherein the metal catalyst is either Sn or Pt. <<Aspect 5>> The glycerol-in-silicone pre-elastomer emulsion according to any one of Aspects 1 to 4, wherein the emulsion further contains a hydrophobic active substance. <<Aspect 6>> The glycerol-in-silicone pre-elastomer emulsion according to any one of Aspects 1 to 5, wherein the hydrophobic active substance contains any one or more atoms of nitrogen, sulfur, and / or phosphorus. 《Aspect 7》 The glycerol-in-silicone pre-elastomer emulsion according to Aspect 5 or 6, wherein the hydrophobic active substance is piltanidine or a derivative thereof. 《Aspect 8》 The glycerol-in-silicone pre-elastomer emulsion according to any one of Aspects 5 to 7, wherein the hydrophobic active substance is octenidine. 《Aspect 9》 An emulsion containing a silicone pre-elastomer, glycerol, at least one cyclodextrin, and octenidine. 《Aspect 10》 The emulsion according to Aspect 9, wherein the at least one cyclodextrin is selected from at least one of α, β, γ-cyclodextrin or a derivative thereof. 《Aspect 11》 The emulsion according to Aspect 9 or 10, wherein the at least one cyclodextrin is β-cyclodextrin. 《Aspect 12》 The emulsion according to any one of Aspects 9 to 11, wherein the silicone pre-elastomer contains a metal catalyst suitable for use in the polymerization of the silicone pre-elastomer. 《Aspect 13》 The emulsion according to Aspect 12, wherein the metal catalyst is either Sn or Pt, preferably Pt. 《Aspect 14》 The emulsion according to any one of Aspects 9 to 13, wherein the cyclodextrin and octenidine are dissolved in glycerol before the silicone pre-elastomer is added. 《Aspect 15》 The emulsion according to any one of Aspects 9 to 14, wherein the concentration of glycerol in the emulsion is 20 phr to 140 phr. 《Aspect 16》 The emulsion according to any one of Aspects 9 to 15, wherein octenidine is octenidine dihydrochloride. 《Aspect 17》 The emulsion according to any one of Aspects 9 to 16, wherein the concentration of octenidine in the emulsion is 0.1% by weight to 6% by weight based on the total mass of the emulsion. 《Aspect 18》 The emulsion according to any one of Aspects 9 to 17, wherein the concentration of at least one cyclodextrin in the emulsion is 0.1% by weight to 6% by weight based on the total mass of the emulsion. 《Aspect 19》 The emulsion according to any one of Aspects 9 to 18, wherein the molar ratio of octenidine to cyclodextrin is 3:1 to 1:1.5. 《Aspect 20》 The emulsion according to any one of Aspects 9 to 19, wherein the silicone pre-elastomer is a two-component silicone pre-elastomer. 《Aspect 21》 The emulsion according to any one of Aspects 9 to 20, wherein the emulsion is the glycerol-in-silicone pre-elastomer emulsion according to any one of Aspects 1 to 8. 《Aspect 22》 A silicone elastomer containing glycerol and at least one cyclodextrin. 《Aspect 23》 The silicone elastomer according to Aspect 22, which contains glycerol and at least one cyclodextrin, wherein the glycerol exists in the silicone elastomer as a separate phase containing at least a part of at least one cyclodextrin. 《Aspect 24》 The silicone elastomer according to any one of Aspects 22 or 23, which contains glycerol and at least one cyclodextrin and further contains a hydrophobic active substance. 《Aspect 25》 The silicone elastomer according to any one of Aspects 22 to 24, wherein the hydrophobic active substance is pillitenidine or a derivative thereof. Aspect 26 The silicone elastomer according to any one of Aspects 22 to 25, wherein the hydrophobic active substance is octenidine or octenidine dihydrochloride. Aspect 27 The silicone elastomer according to any one of Aspects 22 to 26, which is formed by polymerizing the glycerol-in-silicone pre-elastomer emulsion according to any one of Aspects 1 to 8 or the emulsion according to any one of Aspects 9 to 21. Aspect 28 The silicone elastomer according to Aspect 27, wherein the polymerization of the emulsion includes polymerizing the emulsion at a polymerization temperature and for a polymerization time suitable for obtaining a polymerized emulsion. Aspect 29 The silicone elastomer according to Aspect 27 or 28, wherein the polymerization of the emulsion includes polymerizing the emulsion for a polymerization time of 1 minute to 120 minutes. Aspect 30 The silicone elastomer according to any one of Aspects 27 to 29, wherein the polymerization of the emulsion includes polymerizing the emulsion at a polymerization temperature of 50°C to 90°C. Aspect 31 A skin patch (1) comprising the silicone elastomer (3) according to any one of Aspects 22 to 30, which contains glycerol, octenidine, and at least one cyclodextrin. Aspect 32 The skin patch (1) containing the silicone elastomer (3) according to Aspect 31, wherein the silicone elastomer releases octenidine at a dosing rate of at least 0.1 μg / cm 2 / hour. Aspect 33 The skin patch (1) containing the silicone elastomer (3) according to Aspect 30 or 32, wherein the thickness (t EL ) of the silicone elastomer is 0.05 mm to 5 mm. Aspect 34 The silicone elastomer-containing skin patch (1) according to any one of aspects 30 to 33, wherein the silicone elastomer comprises a removable layer (4) formed of an inert plastic. 《Aspect 35》 The silicone elastomer-containing skin patch (1) according to any one of aspects 30 to 34, wherein the silicone elastomer comprises a support layer (2) formed of an inert plastic. 《Aspect 36》 The removable layer (4) and the support layer (2) are arranged on the side opposite to the silicone elastomer, and are separated by the thickness (t EL ) of the silicone elastomer. The silicone elastomer-containing skin patch (1) according to any one of aspects 30 to 35. 《Aspect 37》 The silicone elastomer releases octenidine at a dosing rate of at least 0.1 μg / cm 2 / hour. The silicone elastomer-containing skin patch (1) according to any one of aspects 30 to 36. 《Aspect 38》 A method for forming an emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin, comprising: i. Mixing glycerol, octenidine, and cyclodextrin; ii. Heating the resulting mixture with stirring to a temperature of 50°C to 90°C until a clear solution is formed; iii. Adding the silicone pre-elastomer; iv. Applying shear until an emulsion is formed; A method comprising the above steps. 《Aspect 39》 The method for forming an emulsion according to aspect 38, wherein the resulting clear solution is cooled to 5°C to 50°C before adding the silicone pre-elastomer. 《Aspect 40》 The method for forming the emulsion according to aspect 38 or 39, wherein the emulsion is the glycerol-in-silicone pre-elastomer emulsion according to any one of aspects 1 to 8, or the emulsion according to any one of aspects 9 to 21. 《Aspect 41》 A method for forming a silicone elastomer, comprising polymerizing an emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin. 《Aspect 42》 The method for forming a silicone elastomer according to aspect 41, wherein the emulsion is the glycerol-in-silicone pre-elastomer emulsion according to any one of aspects 1 to 8, or the emulsion according to any one of aspects 9 to 21. 《Aspect 43》 The method for forming a silicone elastomer according to aspect 41 or 42, wherein the emulsion is formed according to the method described in any one of aspects 25 to 27. 《Aspect 44》 The method for forming a silicone elastomer according to any one of aspects 28 to 30, comprising polymerizing the emulsion for 1 minute to 120 minutes. 《Aspect 45》 The method for forming a silicone elastomer according to any one of aspects 38 to 40, comprising polymerizing the emulsion at a polymerization temperature of 50°C to 90°C. 《Aspect 46》 i. Preparing an emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin according to any one of aspects 1 to 21; ii. Casting the emulsion onto a support layer (2) formed from an inert plastic; iii. Coating the emulsion onto the support layer to form a coating layer having a coating thickness (t EL ); iv. Polymerize the emulsion at the polymerization temperature for the polymerization time, thereby forming a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin; The method for forming the skin patch (1) according to any one of Aspects 31 to 37, including this. 《Aspect 47》 The method for forming the skin patch (1) according to Aspect 46, further including providing a removable layer (4) formed of an inert plastic on the silicone elastomer (3) on the opposite side of the support layer (2). 《Aspect 48》 The method for forming the skin patch (1) according to Aspect 46 or 47, including polymerizing the emulsion for 1 minute to 120 minutes. 《Aspect 49》 The method for forming the skin patch (1) according to any one of Aspects 46 to 48, including polymerizing the emulsion at a polymerization temperature of 50°C to 90°C. 《Aspect 50》 Cut the skin patch (1) into a size of 1 cm 2 ~1000 cm 2 The method for forming the skin patch (1) according to any one of Aspects 46 to 49, including this. 《Aspect 51》 A method for treating a wound site on the skin of a mammal, including covering the wound site with the skin patch (1) according to any one of Aspects 46 to 49 containing octenidine, wherein the skin patch (1) releases octenidine at a certain administration rate, and the skin patch (1) is applied to the wound site for an application time sufficient to release an effective amount of octenidine sufficient to obtain a bactericidal effect against at least one gram-positive bacterium or gram-negative bacterium. 《Aspect 52》 The method for treating a wound site on the skin of a mammal according to Aspect 51, wherein the mammal is a human. 《Aspect 53》 The method for treating a wound site on the skin of a mammal according to aspect 51 or 52, wherein the at least one Gram-positive bacterium or Gram-negative bacterium is selected from Staphylococcus aureus, Escherichia coli, Proteus mirabilis, Candida albicans, or Pseudomonas aeruginosa. 《Aspect 54》 The method for treating a wound site on the skin of a mammal according to any one of aspects 51 to 53, wherein the administration rate of the octenidine release is at least 0.1 μg / cm 2 / hour. 《Aspect 55》 The method for treating a wound site on the skin of a mammal according to any one of aspects 51 to 54, wherein the application time is at least 1 hour. 《Aspect 56》 The method for treating a wound site on the skin of a mammal according to any one of aspects 51 to 55, wherein the effective amount of octenidine is at least 0.1 μg / cm 2 . 《Aspect 57》 The skin patch (1) according to any one of aspects 31 to 37 for use in the method according to any one of aspects 51 to 55. 《Aspect 58》 A 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin. 《Aspect 59》 The 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin according to aspect 58 in glycerol. 《Aspect 60》 Use of the 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin according to aspect 58 or 59 in the emulsion according to any one of aspects 1 to 21. 《Aspect 61》 Octenidine for use in treating a wound site on the skin of a mammal according to any one of aspects 51 to 56. 《Aspect 62》 Octenidine for use in the treatment of a wound site on the skin of a mammal according to embodiment 61, wherein the octenidine is present in a 1:1 complex of octenidine dihydrochloride and β-cyclodextrin according to embodiment 58 or 59.

Claims

1. A glycerol-in-silicone preelastomer emulsion comprising a silicone preelastomer, glycerol, β-cyclodextrin, and a metal catalyst suitable for use in the polymerization of said silicone preelastomer, said emulsion further comprising octenidine; The molar ratio of the octenidine to the β-cyclodextrin in the emulsion is from 4:1 to 1:1.5; Glycerol-in-silicone pre-elastomer emulsion.

2. 2. The glycerol-in-silicone preelastomer emulsion of claim 1, wherein the metal catalyst is either Sn or Pt.

3. The composition contains glycerol and β-cyclodextrin, and further contains octenidine or octenidine dihydrochloride, the molar ratio of octenidine or octenidine dihydrochloride to β-cyclodextrin in the emulsion is from 4:1 to 1:1.5; further comprising a metal catalyst suitable for use in the polymerization of the silicone preelastomer. Silicone elastomer.

4. A skin patch (1) comprising the silicone elastomer (3) according to claim 3, which contains glycerol, octenidine and β-cyclodextrin.

5. The silicone elastomer has a viscosity of at least 0.1 μg / cm ２ A skin patch (1) comprising the silicone elastomer (3) according to claim 4, which releases octenidine at a dosage rate of 100 mg / kg / hour.

6. 1. A method of forming an emulsion containing a silicone pre-elastomer, glycerol, octenidine, β-cyclodextrin, and a metal catalyst suitable for use in polymerizing said silicone pre-elastomer, comprising the steps of: the molar ratio of octenidine to β-cyclodextrin in the emulsion is from 4:1 to 1:1.5; i. mixing glycerol, octenidine, β-cyclodextrin, and the metal catalyst; ii. Heating the resulting mixture to a temperature of 50° C. to 90° C. with stirring until a clear solution is formed; iii. Adding a silicone pre-elastomer; iv. applying shear until an emulsion is formed; The method includes:

7. polymerizing an emulsion containing a silicone pre-elastomer, glycerol, octenidine, β-cyclodextrin, and a metal catalyst suitable for use in polymerizing said silicone pre-elastomer; The molar ratio of octenidine to β-cyclodextrin in the emulsion is 4:1 to 1:1.5; A method for forming a silicone elastomer.

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