Elastomeric silicone composition containing glycerol, cyclodextrin, and octenidine

Abstract

Disclosed herein is an emulsion containing a silicone preelastomer, glycerol, cyclodextrin, and a metal catalyst suitable for use in polymerizing the silicone preelastomer, a silicone elastomer formed from the emulsion, and a skin patch for octenidine delivery formed from the silicone elastomer. Also disclosed are methods for forming the emulsion, silicone elastomer, and skin patch.

Description

[Technical field]

[0001] Within the field of glycerol-containing silicone elastomers suitable for the release of active substances, novel compositions are described which contain at least one cyclodextrin, in particular a cyclodextrin, and a hydrophobic active substance, in particular pirtenidine or a derivative thereof, such as, for example, octenidine, in particular β-cyclodextrin and octenidine dihydrochloride, for the release of active substances, for example, on the skin of a mammal. [Background technology]

[0002] In a series of recent publications and patent applications from the research group of one of the present inventors, Prof. A. L. Skov, the chemistry of silicone elastomer matrices containing glycerol inclusions has been discussed, including the use of such matrices in the release of active substances. 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. The silicone elastomer provides a matrix for containing at least one inclusion phase of glycerol, which can exist as separate droplets or can form a bicontinuous network in the elastomer matrix. The basis of this technology is the mixing of two liquid phases, silicone pre-elastomer and glycerol, which forms a glycerol-in-silicone pre-elastomer emulsion, which after crosslinking of the silicone pre-elastomer can form a pressure-sensitive silicone elastomer matrix containing a separate glycerol phase embedded in a silicone elastomer matrix. Research by some inventors has shown that the embedded glycerol phase can exist as a plurality of separate globules of glycerol or as a continuous glycerol phase embedded in a partially or completely continuous silicone elastomer (bicontinuous silicone-glycerol elastomer composition).

[0003] The research disclosed by the present inventors and their collaborators shows that glycerol-silicone elastomers are generally stable and can be formed from a wide range of silicone pre-elastomers.The research also shows that some glycerol-in-silicone pre-elastomer emulsions are less stable than others, generally when the silicone pre-elastomer is (very) hydrophobic, and that a small amount of surfactant that acts as a stabilizer and is added to the pre-emulsion mixture of glycerol and silicone pre-elastomer can stabilize the subsequently formed glycerol-in-silicone pre-elastomer emulsion for a sufficient time after emulsification to allow crosslinking without separation of the pre-elastomer to form the resulting silicone elastomer composition containing an embedded glycerol phase.

[0004] Further work by two of the present inventors, A.L.S.kov and P. Mazurek, together with other collaborators, has shown that the glycerol-containing silicone elastomer matrix detailed in WO 2016 / 189117 A1 is a tunable matrix for active substance release, whereby the release kinetics of the active substance contained in the glycerol phase from the elastomer matrix can be tuned between zero-order and first-order release by influencing the morphology of at least one of the glycerol phases contained therein. During this further work, first-order, near-zero-order and zero-order release kinetics were demonstrated for a variety of hydrophilic active substances.

[0005] The two liquids, silicone pre-elastomer and glycerol, are effectively immiscible and when mixed together form a glycerol-in-silicone pre-elastomer emulsion. Cross-linking of the silicone phase results in a free-standing silicone-glycerol (adhesive) matrix.

[0006] As known in the art, depending on the polymerization conditions, the silicone matrix may or may not be a tackifier. In the context of the present invention, it is believed that a person skilled in the art can prepare tacky and / or non-tacky silicone elastomer matrices as needed, and thus the silicone elastomer matrices of the present invention may be tacky in some embodiments and non-tacky in other embodiments depending on their intended use. Similarly, in some embodiments, a combination of tacky and non-tacky silicone elastomers may be used to form the silicone elastomer matrices of the present invention.

[0007] The silicone provides mechanical integrity to the system, while the glycerol acts as a liquid filler in the form of micrometer-sized droplets that are uniformly distributed within the silicone matrix, as shown in Figure 1. Work by some of the inventors has shown that submicron droplets are also possible with sufficient surfactant addition. Emulsions of silicone pre-elastomers and submicron glycerol droplets were found to be as stable as emulsions of silicone pre-elastomers and micrometer-sized droplets.

[0008] The glycerol acts as a carrier for the active agent, which is released from the elastomer upon contact with, for example, an aqueous environment. A presumed mechanism for the release of hydrophilic active agents from glycerol-silicone elastomers is shown in Figure 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 (represented in Figure 2 by the adjacent aqueous phase). However, delivery is also influenced by the diffusion of the active agent within the glycerol phase and the formed elastomer matrix.

[0009] As reported in the prior art WO 2016 / 189117, the curing of silicone elastomers is carried out using conventional methods known in the art, such as peroxide-based curing, condensation-based curing, e.g. in the presence of Sn as catalyst, or addition-based curing, e.g. in the presence of Pt as catalyst, during addition-based curing, the Si-H groups of the crosslinker react with the vinyl groups on the silicone pre-elastomer. Generally, in the context of the present invention, it is preferred to provide any catalyst and crosslinker to the pre-elastomer solution before adding glycerol, since subsequent addition of the catalyst and crosslinker results in an emulsion that tends to form a non-uniform, clumpy elastomer matrix.

[0010] It is well known in the art that one of the biggest problems when using silicones condensation cured or addition cured in the presence of metal catalysts is the vulnerability of metal catalysts to poisoning. Catalyst poisons include any compound that contains, in particular, nitrogen, sulfur, and / or phosphorus. In particular, platinum catalysts, which are used for their high versatility, e.g., high conversion efficiency, in addition-based curing of silicone elastomers, are particularly vulnerable to poisoning by impurities in the materials that form the emulsion before polymerization. Since platinum is expensive and is irreversibly incorporated into the silicone elastomer matrix that is formed, the problem of preventing catalyst poisoning needs to be solved before the present glycerol-silicone elastomer composition can be used commercially.

[0011] Many solutions are known in the art to solve the above mentioned problems, see for example http: / / www.us-tech.com / RelId / 1082642 / pagenum / 2 / ISvars / default / Troubleshooting_Platinum_Catalyzed_Silicones.htm (accessed 20 June 2018). However, while observing the widely known precautions related to the manufacturing process would mitigate some of the above mentioned problems even for the currently studied systems, in the presence of active substances contained in either the glycerol or silicone phase of the pre-elastomer emulsion, the standard methods of the art unfortunately prove insufficient for the current systems, since in many cases the active substances may contain accessible active substance molecules and / or functional groups within the active substance molecules, which molecular groups in particular contain one or more of nitrogen, sulfur and / or phosphorus.

[0012] Therefore, there is a need to provide a solution to catalyst poisoning that allows for protection of metal catalysts without deactivating active materials intended for release from the cured elastomeric compositions of the prior art.

[0013] It has surprisingly been found by some of the present inventors that members of the cyclodextrin class, and in particular β-cyclodextrin, are suitable for use in preventing catalytic poisoning of metal catalysts, and in particular platinum catalysts, in compositions comprising emulsions of glycerol-in-silicone preelastomers.

[0014] It is reported in CN102716104A that β-cyclodextrin can protect platinum catalyst from catalyst poisoning in the polymerization process of silicone gel in the presence of vegetable oil containing elements selected from N, S and P. The protection is obtained by preparing insoluble microparticles of vegetable oil and β-cyclodextrin before the polymerization of silicone. After polymerization, the microparticles remain intact and non-diffusible in the cured silicone. However, the strong interaction of β-cyclodextrin with the investigated vegetable oil and the resulting formation of insoluble microparticles is a significant drawback of the prior art by increasing the retention capacity of the cured silicone for the vegetable oil and limiting the resulting delivery of the investigated vegetable oil.

[0015] Furthermore, with regard to the present invention, particularly with regard to the inclusion of an emulsion of glycerol-in-silicone pre-elastomer and at least one active agent containing at least one atom of sulfur, phosphorus, and / or nitrogen, the inventors have surprisingly found that cyclodextrin can be used to prevent catalyst poisoning.The present invention proposes to advantageously use this surprising effect of cyclodextrin in preventing catalyst poisoning of at least platinum to improve the existing skin patch delivery system of silicone elastomer containing octenidine for antiseptic wound care.

[0016] In the field of antiseptic wound care, it is very advantageous for antiseptics that do not enter the mammalian body, especially the human body, especially the mammalian, especially the human dermis or bloodstream after topical application, because they minimize the possibility of harming the person being treated.There is a long list of potential antiseptics suitable for use in topical application, such as ethanol and chlorhexidine.However, when considering the inclusion of potential antiseptics in wound dressings for long-term release at the wound site during wound healing, the list becomes much shorter.Some suitable candidates include silver sulfadiazine or silver provided as silver nanoparticles, as well as hydrophobic antiseptics such as pirtenidine and its derivatives, such as octenidine, are widely used.

[0017] In particular, octenidine (basic drug: octenidine dihydrochloride), a cationic surfactant-based bactericide, has attracted widespread 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 applications, such as mouthwash, wound wash, and topical bactericide, with high biocompatibility and unknown bacterial resistance. Its critical micelle concentration is estimated by Steward et al. to be 3.79 mM. The effective concentration of octenidine in suspension is usually greater than 0.005% by weight, such as 0.01%, 0.015%, 0.020%, 0.025%, or 0.030% by weight.

[0018] [Table 1]

[0019] In the field of wound dressings, formulations include hydrogels formulated with small amounts of glycerol, such as hydrogels containing hydroxyethylcellulose 4000 (see, for example, US Patent Application Publication No. 2011 / 0091551), and octenidine. Various polymer-based formulations suitable for local drug delivery of active substances contained within a polymer matrix (see, for example, WO 2008 / 008617, WO 2010 / 005680, WO 2014 / 044869), and silicone-derived polymer matrices containing octenidine have also attracted scientific attention (see, for example, WO 2007 / 124855, US Patent Application Publication No. 2016 / 0106104). However, while the above-mentioned formulations are suitable for delivering octenidine to the skin of mammals, e.g., humans, the proposed formulations suffer from shortcomings in delivery kinetics, such as burst delivery and fast octenidine depletion, and therefore, the delivery of octenidine to a wound site under a skin patch is disadvantageous, such as stable and / or constant long-term delivery.

[0020] The inventors have now presented an improved skin silicone patch containing octenidine and its derivatives, particularly and preferably octenidine, which can be formulated to allow zero order or near zero order extended release of octenidine, thereby avoiding the burst effect and maintaining an effective concentration of octenidine at the wound site for the extended period required for wound healing.

[0021] definition In the present context, the term "silicone elastomer" refers to a polymer comprising any inert compound composed of siloxane repeating units of the formula -RR'SiO-, where R and R' are the same or different hydrocarbon radicals, and the term is used according to the IUPAC definition as a polymer that exhibits rubber-like elasticity. 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 this context, the term "polysiloxane" refers to a compound of the form [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 of the form [RR'SiO]n, which may be partially functionalized in the sense that multiple R, R' groups are replaced or substituted by substituents. Non-limiting examples of such substituents include Cl, CN, F, OH, alkenyl, and alkynyl. Furthermore, the silicone compounds or silicone pre-elastomers or additives used for crosslinking may contain 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 CH3[Si(CH3)2O] nIt refers to the compound Si(CH3)3, where n is the number of repeating units. The term "polydimethylsiloxane" includes derivatives thereof in which one or more methyl groups in PDMS are replaced by SiH, hydroxy, vinyl, or allyl groups, for example, in pendant or terminal positions.

[0024] In the context of the present invention, the term silicone preelastomer is used to describe any silicone starting composition which, after polymerization and / or crosslinking, forms a silicone elastomer matrix suitable for use in the present invention. In some contexts, the term silicone prepolymer is also used, which is a subgroup of silicone preelastomers in that preelastomers also include preformed silicone polymers where only crosslinking of the silicone polymer is the next necessary step to form a silicone elastomer, whereas silicone prepolymers require complete polymerization of silicone from related monomers and oligomers suitable 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 WO 2016 / 189117 A1 (hereby incorporated by reference in its entirety). Monomers, oligomers, and / or polymers suitable for use in the present invention include, among others, monomers, oligomers, and / or polymers as described hereinabove. In general, the present invention is not limited by the specific selection of silicone elastomers, whether or not they are adhesives, so long as the selected silicone elastomers, whether micellar or bicontinuous, are capable of forming a matrix elastomer of the included glycerol phase. A simple test for the suitability of a specific silicone pre-elastomer for use in the present invention is whether the silicone pre-elastomer forms a silicone elastomer in the presence of 20 phr to 140 phr of glycerol using the method of preparing glycerol-containing silicone elastomers as detailed in WO 2016 / 189117 A1.

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

[0027] In the present context, the term "curing" refers to the process of cross-linking of polymer chains.

[0028] In this context, the term "crosslinker, crosslinking agent" is used interchangeably and refers to a compound or group of compounds that promotes 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 selected words. Examples of crosslinkers may be, for example, metal, small molecule, polymeric crosslinkers, or even crosslinking compositions that contain two or more active crosslinkers that participate in the crosslinking process.

[0029] In the present 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 silicone pre-elastomer.

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

[0031] In this context, the term excipient is used to mean a substance that is added to either the silicone phase or the glycerol phase of the present invention.Therefore, in the context of this disclosure, excipient is a substance that is included in the composition of the present invention in addition to either glycerol or silicone.Excipient can be selected, for example, from the group consisting of active substances, particularly active substances for humans or animals, particularly drugs, and / or from catalysts, inhibitors, flow agents, silicone oils, solvents, fillers, foaming agents, reinforcing agents, and plasticizers.Other examples of excipients are given below in this specification.

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

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

[0034] Throughout this disclosure, the term cyclodextrin is used to refer to closed ring cone-shaped molecules formed by 1->4 linking 5 or more but less than 10 α-D-glucopyranoside units and their derivatives, such as methylated cyclodextrin. Preferred cyclodextrins in embodiments of the invention are α, β, or γ-cyclodextrin (see FIG. 3), or derivatives thereof, such as methylated cyclodextrin. Particularly preferred in embodiments of the invention is the cyclodextrin β-cyclodextrin. Throughout this disclosure, various abbreviations of cyclodextrin may be used, such as βCD for β-cyclodextrin, αCD for α-cyclodextrin, γCD for γ-cyclodextrin, etc.

[0035] Throughout this disclosure, pirtenidine is used for N,1-dioctylpyridin-4-imine, and octenidine and octenidine dihydrochloride are used interchangeably for N-octyl-1-[10-(4-octyliminopyridin-1-yl)decyl]pyridin-4-imine dihydrochloride (see FIG. 4). Pirtenidine is isolated as an uncharged covalent organic compound, while octenidine is (usually) isolated as a dihydrochloride salt. However, in the composition of the present invention in which 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 preelastomer. Therefore, in the context of this disclosure, octenidine shall be understood to mean N-octyl-1-[10-(4-octyliminopyridin-1-yl)decyl]pyridin-4-imine and any salt thereof, in particular N-octyl-1-[10-(4-octyliminopyridin-1-yl)decyl]pyridin-4-imine dihydrochloride. When it is intended to emphasize the presence of hydrochloride, this disclosure uses the longer term octenidine dihydrochloride. In the context of this disclosure, octenidine is considered to be a derivative of pirtenidine by condensation of two pirtenidine molecules, which gives octenidine and two C3 leaving groups. Summary of the Invention [Means for solving the problem]

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

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

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

[0039] In a preferred embodiment of the present invention, a glycerol-in-silicone preelastomer emulsion is disclosed, which contains a silicone preelastomer, 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, a silicone elastomer containing glycerol, octenidine and at least one cyclodextrin is disclosed, preferably formed by polymerization of a glycerol-in-silicone-preelastomer emulsion according to any embodiment of the first aspect disclosed herein.Preferably, the silicone elastomer is a silicone elastomer matrix for containing glycerol, octenidine and at least one cyclodextrin.

[0041] In a third aspect of the present invention, a skin patch (1) is disclosed comprising a silicone elastomer (3) containing glycerol, octenidine and at least one cyclodextrin, the silicone elastomer being 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 preelastomer emulsion containing a silicone preelastomer, 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 a silicone pre-elastomer; iv. applying shear until an emulsion is formed; Includes.

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

[0045] In a sixth aspect of the present invention and an embodiment thereof, i. providing 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. The emulsion is applied onto the support layer, and the applied thickness (t EL forming a coating layer having a iv. polymerizing the emulsion at a polymerization temperature for a 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 embodiments of the third aspect is disclosed, comprising:

[0046] In a seventh aspect of the present invention and embodiments thereof, a method of treating a wound site on the skin of a mammal is disclosed, comprising covering the wound site with a skin patch (1) according to any of the embodiments of the third aspect comprising octenidine, the skin patch (1) releasing octenidine at a dosage rate and 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 bacteria. In a preferred embodiment, the mammal is a human.

[0047] In an eighth aspect of the present invention and its embodiments, 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 disclosed is the use of the 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin in emulsions, silicone elastomers, and skin patches according to any of the first to sixth aspects and their embodiments. [Brief description of the drawings]

[0048] [Figure 1] 1 is a prior art SEM image of a cross section of a cured glycerol-silicone elastomer. [Diagram 2] This is the mechanism by which substances are released from glycerol-silicone elastomers. [Diagram 3] α, β, and γ-cyclodextrins as structural and space-filling models. [Figure 4] Molecular structures of (A) pirtenidine and (B) octenidine dihydrochloride. [Diagram 5] The glycerol-in-silicone preelastomer emulsions contain a silicone preelastomer and glycerol, and do not contain (A) β-cyclodextrin and octenidine, and do contain (B) β-cyclodextrin and octenidine. [Figure 6] 1 is a graph showing released octenidine as a function of octenidine content in skin patches. [Figure 7]1 is a graph showing octenidine released as a function of β-cyclodextrin content in skin patches. [Figure 8] FIG. 1 is a graph showing released octenidine as a function of glycerol content in skin patches. [Figure 9] 1 is an exemplary skin patch. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] Previous studies reported by the present inventors and some of their collaborators have investigated the release of hydrophilic actives from silicone elastomers that contain a micellar glycerol phase that dissolves the hydrophilic actives.

[0050] For the prior art survey, the release behavior of hydrophobic active substances was also investigated. However, it was observed that when hydrophobic active substances containing at least one of nitrogen, sulfur, or phosphorus in the molecular structure were added to the silicone and glycerol emulsion, the polymerization of silicone pre-elastomers by metal catalysis was significantly inhibited due to catalyst poisoning. For example, in the experiments with pirtenidine and derivatives of pirtenidine, the active substances contained two or more nitrogen atoms (such as two nitrogen atoms in pirtenidine, see FIG. 4), and the catalyst poisoning of metal catalysts suitable for catalyzing the polymerization of silicone pre-elastomers, especially Pt catalysts, had a negative effect on the polymerization process. In general, when a commercially available pre-elastomer solution is used, the silicone pre-elastomers are usually silicone oligomers and polymers, which are crosslinked to form a silicone matrix by curing as defined above. However, in the context of the present invention, as mentioned above, the silicone pre-elastomers may also contain silicone monomers that, in addition to curing, polymerize to form the silicone matrix of the present invention.

[0051] Compared with CN102716104A, the present inventors have surprisingly found that cyclodextrin may be suitable in some circumstances to mask the tested active substance without interfering with the polymerization process of silicone pre-elastomer in emulsion with glycerol.Therefore, the present invention describes the dissolution of solid hydrophobic active substance comprising at least one element selected from N, S and P, which forms a reversible complex with cyclodextrin, especially β-cyclodextrin, so that the Pt catalyst present in the emulsion of the present invention for curing 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, it has been surprisingly observed that cyclodextrin at least partially partitions at the silicone / glycerol interface, thereby functioning as a surfactant for the investigated emulsion systems comprising silicone preelastomer and glycerol, and surprisingly improving the stability of the glycerol-in-silicone preelastomer emulsion prior to polymerization (see FIG. 5), in addition to solubilizing and masking active substances containing atoms such as nitrogen, sulfur, or phosphorus that may be involved in catalyst poisoning.

[0052] These observations by the inventors are the subject of a separately filed patent application, which is incorporated herein by claim of priority, and in accordance with the present invention, a glycerol-in-silicone preelastomer emulsion is disclosed, which contains a silicone preelastomer, glycerol, a cyclodextrin, and a metal catalyst suitable for use in the polymerization of the silicone preelastomer. Additionally, the emulsion may contain an active hydrophobic material, including, for example, pyrtenidine or a derivative thereof.

[0053] In preferred embodiments 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 FIG. 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 is disclosed according to any of the embodiments disclosed herein, wherein the metal catalyst is either Sn or Pt, preferably the metal catalyst is Pt.

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

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

[0057] According to the present invention, the inventors have investigated whether octenidine, especially octenidine dihydrochloride (see FIG. 4), can be used to release active substances from silicone-glycerol elastomer matrices by complexation with cyclodextrin.As detailed above, octenidine dihydrochloride has several advantages as a skin bactericide, especially its effectiveness and (very) limited skin barrier penetration, but successful formulations in skin patches, especially those containing silicone elastomers, are not yet available on the market.Some disadvantages of the formulations proposed in the prior art include inadequate delivery kinetics, such as burst delivery and fast octenidine depletion, lack of long-term delivery of octenidine, etc.

[0058] The improvements presented herein by the inventors include, inter alia, silicone skin patches containing octenidine that can be formulated to allow for zero order or near zero order release of octenidine over a significant period of time, thereby avoiding the burst effect and maintaining an effective concentration of octenidine at the wound site for a significant period of time required for wound healing.

[0059] Additionally, 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 preelastomer emulsion and embodiments thereof, a glycerol-in-silicone preelastomer emulsion according to the present invention containing a silicone preelastomer, glycerol, at least one cyclodextrin, and octenidine, is described in detail.

[0061] In the context of the present invention, the silicone pre-elastomer suitable for use in the present invention may be liquid itself or it may contain a liquefying agent, such as, for example, a silicone oil, which allows it to become included in the emulsion of the present invention. In a preferred embodiment of the present invention, the silicone pre-elastomer is a two-component silicone pre-elastomer, which when crosslinked forms the silicone elastomer of the present invention.

[0062] Such two-component silicone pre-elastomers are commercially available from a variety of manufacturers and have pre-tailored properties that upon crosslinking allow the formation of silicone elastomers that are known to be particularly suitable for active agent release, e.g., dermal or transdermal active agent release.

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

[0064] Generally, the actual composition and formulation of the silicone elastomer matrix is ​​considered outside the scope of the present invention. As explained above, a silicone pre-elastomer is required to aid 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 Sylgard® 184 from Dow Corning and Elastosil® RT625 from Wacker Chemie, Germany, as well as Dow Corning's two-component pressure-sensitive silicone adhesive MG7-9900, a divinyl-terminated polydimethylsiloxane pre-elastomer containing a crosslinker and a Pt catalyst, which is used in the experiments presented herein. In some embodiments, silica is present as a reinforcing agent.

[0066] In embodiments of the present invention, the silicone pre-elastomer may be selected from the group including pre-elastomers of methylsilicone elastomers, phenylsilicone elastomers, chloroalkylsilicone elastomers, and fluorosilicone elastomers, or combinations thereof.

[0067] In embodiments of the present invention, the silicone pre-elastomer can be selected from the group including polyalkylsiloxanes, preferably polydimethylsiloxanes (PDMS), and pre-elastomers of its derivatives. Exemplary PDMS pre-elastomers include vinyl-functional PDMS pre-elastomers crosslinkable with hydride-functional crosslinkers, or hydroxyl-functional PDMS pre-elastomers crosslinkable in the presence of Sn or Pt.

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

[0069] In some embodiments of the present invention, the silicone pre-elastomer may be an elastomer composition suitable for use in the present invention, the silicone pre-elastomer being a chlorosilicone pre-elastomer.Non-limiting examples of suitable chlorosilicone pre-elastomers are chloroalkyl-based chlorosilicone pre-elastomers, compositions derived from chloromethyl-terminated polydimethylsiloxanes (e.g., DMS-L21 from Gelest), or chlorosilicone elastomers as disclosed in WO 2015 / 043792.

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

[0071] In one embodiment of an elastomeric composition suitable for use in the present invention, the elastomeric composition further comprises one or more excipients selected from the group consisting of active substances, in particular human or veterinary active substances, in particular drugs, and / or catalysts, inhibitors, flow agents, silicone oils, solvents, fillers, blowing agents, reinforcing substances, and plasticizers.

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

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

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

[0075] The amount of excipient required can vary independently depending on the elastomer composition in question, but typically ranges from 0 to 40% by weight of the elastomer composition, such as 5 to 30% by weight, for example 10 to 25% by weight.

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

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

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

[0079] In one embodiment of the elastomeric composition suitable for use in the present invention, the blowing agent is a base, non-limiting examples of which include inorganic bases such as NaOH, KOH, and LiOH, amine-based compounds such as triethanolamine, ethanolamine, triethylamine, ethylamine, methylamine, polyetheramines (such as JeffAmines® available from Huntsman), and phosphazene bases such as BEMP (2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine) and P1-t-Bu (N,N,N',N',N'',N''-hexamethyl-N'''-(2-methyl-2-propanyl) phosphorimidic triamide).

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

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

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

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

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

[0085] As detailed in the experiments (see Example 3 and FIG. 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 in the methods detailed hereinafter, a 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. with stirring until a clear solution is obtained. Preferably, the temperature is 80° C.

[0087] To the best of the inventors' knowledge, such a 1:1 complex between octenidine dihydrochloride and β-cyclodextrin has not been described in the prior art.Since the form of complexation between octenidine dihydrochloride and β-cyclodextrin is still unknown, the inventors tentatively propose that other salts of octenidine, particularly halide salts such as HF, HBr, or HI, are also suitable for forming the observed 1:1 complex with β-cyclodextrin.Therefore, such other salts of octenidine, particularly 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 preelastomer emulsion of the present invention.

[0088] The present invention therefore further relates to a 1:1 molecular complex of octenidine dihydrochloride with β-cyclodextrin, in particular a 1:1 molecular complex of octenidine dihydrochloride with β-cyclodextrin in glycerol.The present invention further relates to the use of such molecular complex in the glycerol-in-silicone pre-elastomer emulsions, elastomers and skin patches of the present invention.

[0089] Thus, in a preferred embodiment of the glycerol-in-silicone preelastomer emulsion of the present invention, cyclodextrin and octenidine are dissolved in glycerol before the silicone preelastomer is added. Preferably, the cyclodextrin and octenidine are present as a 1:1 molecular complex in glycerol, more preferably, the β-cyclodextrin and octenidine are present as a 1:1 molecular complex in glycerol, and even more preferably, the 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 from 20 phr to 150 phr, preferably from 30 to 140 phr, from 40 phr to 130 phr, from 50 phr to 120 phr, from 60 phr to 110 phr, from 70 phr to 100 phr, or from 80 phr to 90 phr.

[0091] From the work of some of the inventors, it is known that when the concentration of glycerol is less than about 100 phr, the glycerol exists as separate globules (see FIG. 5), while when the concentration of glycerol is more than about 100 phr, a bicontinuous emulsion of silicone pre-elastomer and glycerol is formed. After polymerization, the silicone elastomer containing glycerol formed from the bicontinuous emulsion shows zero-order active release. When the concentration of glycerol is about 70 phr to about 100 phr, the release kinetics approaches zero-order for small actives, and when the concentration of glycerol is about 20 phr to about 70 phr, the release kinetics follows a first-order release mechanism. In the experiments presented herein, various emulsions, silicone elastomers, and skin patches were formulated to show first-order release, and therefore had glycerol contents of 20 phr to 70 phr, particularly 40 phr and 60 phr.

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

[0093] Thus, in embodiments of the present invention, the glycerol-in-silicone pre-elastomer emulsion comprises from 70 phr to 100 phr, preferably from 75 phr to 95 phr, or from 80 phr to 85 phr of glycerol component for use in forming silicone elastomers in which octenidine release follows near zero order release kinetics.

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

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

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

[0097] Further, in some embodiments of the present invention, the concentration of the at least one cyclodextrin in the glycerol-in-silicone preelastomer emulsion is from 0.1% to 6% by weight based on the total weight of the emulsion. Preferably, the concentration of the cyclodextrin in the emulsion is from 0.3% to 5.5% by weight based on the total weight of the emulsion, from 0.6% to 5% by weight, from 1% to 4.5% by weight, from 1.5% to 4% by weight, from 2% to 3.5% by weight, or from 2.5% to 3% by weight based on the total weight of the emulsion.

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

[0099] Additionally, in some 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 preelastomer emulsion of the present invention, the emulsion contains a silicone preelastomer, 20 phr to 150 phr of glycerol based on the weight of the silicone preelastomer, 0.1% to 6% by weight of octenidine, and 0.1% to 6% by weight of cyclodextrin based on the total weight of the emulsion.

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

[0102] Preferably, the silicone elastomer according to this further aspect of the invention is formed by polymerization of a glycerol-in-silicone pre-elastomer emulsion according to any of the embodiments detailed in this disclosure. As demonstrated by the experiments presented, 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 in accordance with 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 preelastomer emulsion of the present invention by polymerizing the emulsion at a polymerization temperature and for a polymerization time suitable to obtain a polymerized emulsion. Preferably, the polymerization time is from 1 to 120 minutes, preferably from 2 to 90 minutes, 3 to 60 minutes, 4 to 50 minutes, 5 to 40 minutes, 6 to 30 minutes, 7 to 20 minutes, 8 to 17 minutes, 9 to 15 minutes, or 10 to 12 minutes.

[0104] In one embodiment, the polymerization temperature is between 50°C and 90°C. It is within the skill of one of ordinary skill in the art to obtain the appropriate combination of polymerization time and temperature for a given silicone pre-elastomer contained in the emulsion of the present invention. In an alternative embodiment, the emulsion includes 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 guidance on polymerization conditions can be obtained from WO 2016 / 189117 A1.

[0105] In a further aspect of the present invention, a skin patch (1) is disclosed that comprises 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 diagram 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 construction of a skin patch according to the art is not a part of the present invention, rather it is believed that one skilled in the art, when armed with the information disclosed herein, would be able to manufacture a skin patch according to various requirements.

[0107] In some embodiments, the skin patch is a wound care product, such as a wound dressing.

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

[0109] In a preferred aspect of the present invention, a skin patch (1) is disclosed comprising a silicone elastomer (3) according to any of the aspects and embodiments detailed in this disclosure, the silicone elastomer having a molecular weight of at least 0.1 μg / cm 2 Preferably, the silicone elastomer of the present invention releases octenidine at a dosage 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 Releases octenidine at a dosage rate of 100 mg / hr.

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

[0111] As described in the experimental section, the inventors are not sure in what form octenidine dihydrochloride is released from the silicone elastomer matrix of the present invention due to molecular association with β-cyclodextrin.However, the inventors believe, without being bound by this theory, that octenidine dihydrochloride remains as dihydrochloride in the emulsion, elastomer, and skin patch of the present invention.However, this aspect is not very important, since the biological effectiveness of octenidine is not related to the association with dihydrochloride, but the salt formation of octenidine is related to the compatibility of aqueous delivery.As demonstrated in this experiment, octenidine is reliably released from the skin patch 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 has a thickness (t EL ) is present in the skin patch as a layer (3) of silicone elastomer having a thickness (t EL ) is the thickness of the silicone elastomer measured perpendicular to the intended direction of application, according to known practices in the art of skin patches. The skin patches prepared for investigation in the experiments reported hereinafter had a thickness (t EL ), which is a common thickness for many patches in transdermal drug delivery. As is well known in the art, the thickness (t EL ) may be routinely varied by those skilled in the art to adjust the reservoir content of active material and is generally not considered relevant to the present invention. 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) made of 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) made of 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 a thickness (t) of the silicone elastomer, as is customary in the field of skin patches. EL ) are used to separate the

[0114] In some embodiments of the present invention, for example when the silicone elastomer is not an adhesive silicone elastomer, the support layer (2) may include an adhesive layer for contacting and attaching the silicone elastomer (3) to the support layer (2). In many applications, it is disadvantageous if the element of the skin patch containing the active substance is itself an adhesive, as this may be disadvantageous for example for wound healing of open wounds. These aspects of skin patches are well known to those skilled in the art and are considered to be outside the scope of the present invention. In general, the silicone elastomers of the present invention may be adhesive or non-adhesive to mammalian skin, particularly human skin, as required by the context of their use.

[0115] In a further aspect and embodiment thereof, the present invention discloses a method for forming a glycerol-in-silicone preelastomer emulsion containing a silicone preelastomer, glycerol, octenidine, and at least one cyclodextrin, 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 a silicone pre-elastomer; iv. applying shear until an emulsion is formed; Includes.

[0116] By following the methods of the present invention, particularly when the octenidine is octenidine dihydrochloride and the cyclodextrin is β-cyclodextrin, it is ensured that the octenidine and cyclodextrin are fully associated (see Example 3 and FIG. 7), thereby making them optimally available for release from the silicone elastomers and skin patches of the present invention.

[0117] The optimum temperature for the formation of the complex between octenidine and cyclodextrin in ii. is in the range of 50°C to 90°C, with 80°C being the optimum. Below 50°C, the complex formation between octenidine and cyclodextrin is slow. As detailed in the above method, it is usually preferred to mix the ingredients before heating, but if necessary, octenidine and cyclodextrin can be added directly to hot glycerol.

[0118] As detailed in WO 2016 / 189117 A1, application of shear (iv.) is necessary to form an emulsion of the silicone preelastomer and glycerol. Typically, application of shear at 1500 rpm to 5000 rpm until an emulsion is formed is recommended in WO 2016 / 189117 A1, although other methods of applying shear known to those skilled in the art are also contemplated as suitable for use in the methods of the present invention.

[0119] In one embodiment of the method of forming the glycerol-in-silicone pre-elastomer emulsion according to the invention, the resulting clear solution of (ii.) is cooled to 5°C-50°C before adding the silicone pre-elastomer. Typically, if the glycerol content is reasonably low, this step can be omitted, but if the glycerol content is high, e.g. if a mixing temperature of 80°C is used, undesirable thermally initiated polymerization of the silicone pre-elastomer may occur, which is 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 of 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 invention detailed herein.

[0121] In a further aspect and embodiment of the present invention, a method of forming a silicone elastomer is disclosed which comprises polymerizing a glycerol-in-silicone preelastomer emulsion containing a silicone preelastomer, glycerol, octenidine, and at least one cyclodextrin. Preferably, the silicone elastomer is a silicone elastomer matrix containing glycerol, octenidine, and at least one cyclodextrin.

[0122] In a preferred embodiment of the method of 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 invention detailed herein.

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

[0124] In one embodiment of the method of forming a silicone elastomer according to the present invention, polymerization of the glycerol-in-silicone pre-elastomer emulsion is 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 of forming a silicone elastomer according to the present invention, polymerization of the glycerol-in-silicone pre-elastomer emulsion is carried out at a polymerization temperature of from 50° C. to 90° C. In an alternative embodiment, the emulsion includes 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.

[0126] Further aspects and embodiments of the present invention comprise: i. preparing a glycerol-in-silicone emulsion containing a silicone preelastomer, 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. The emulsion is applied onto the support layer, and the applied thickness (t EL forming a coating layer having a iv. polymerizing the emulsion at a polymerization temperature for a polymerization time, thereby forming a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin; Disclosed is a method of forming a skin patch (1) according to any of the aspects and embodiments described herein, comprising:

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

[0128] In one embodiment of the method of forming the skin patch (1), the method further comprises polymerizing the 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 the skin patch (1), the method further comprises polymerizing the glycerol-in-silicone pre-elastomer emulsion at a polymerization temperature between 50° C. and 90° C., preferably 80° C. In an alternative embodiment, the emulsion comprises 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 may be advantageous when rapid silicone matrix formation is desired.

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

[0131] In a further aspect and embodiment thereof of the present invention, there is disclosed a method of treating a wound site on mammalian skin 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 dosage rate, and wherein the skin patch (1) is applied to the wound site for an application time sufficient to release an effective amount of octenidine sufficient to provide a bactericidal effect against at least one gram-positive or gram-negative bacteria.

[0132] In one embodiment of the methods 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 mammalian skin disclosed herein, the 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 mammalian skin disclosed herein, the administration rate of octenidine release is at least 0.1 μg / cm 2 Preferably, the dosage 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 / o'clock.

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

[0136] In embodiments of the methods of treating a wound site on mammalian skin disclosed herein, the effective dosage of octenidine is at least 0.1 μg / cm 2 Preferably, the effective dose 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 It is.

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

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

[0139] material Two-component pressure-sensitive silicone adhesive MG7-9900, a divinyl-terminated polydimethylsiloxane containing a crosslinker and Pt catalyst, was purchased from Dow Corning. Glycerol (food grade, max. 0.5% water), a by-product of biodiesel production, was provided by Emmelev A / S and used as received, avoiding excessively long 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] Device A dual asymmetric centrifuge SpeedMixer DAC 150FVZ-K was used for mixing all compounds. A Leica DM LB light 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. to v. of WO 2016 / 189117 A1. The resulting glycerol-in-silicone pre-elastomer emulsions and silicone elastomers were characterized according to the methods of the prior art, in particular by visual inspection using an optical microscope.

[0142] The two-component MG7-9900 silicone kit was mixed in a 1:1 weight ratio as recommended by the manufacturer. The desired amount of glycerol, and β-cyclodextrin and octenidine, if applicable, were then added to the silicone pre-elastomer and mixed 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. The resulting film was then left at room temperature for at least 2 days for final post-curing.

[0143] It has been advantageously observed that mixing glycerol, β-cyclodextrin and octenidine with stirring at temperatures ranging from 50° C. to 90° C., preferably 80° C., prior to mixing with the silicone preelastomer results in a clear solution. This indicates complete complexation of octenidine with β-cyclodextrin and complete solubilization of the formed complex in glycerol. The resulting glycerol-in-silicone-preelastomer emulsion of silicone preelastomer and glycerol containing the complex of octenidine with β-cyclodextrin will then be free of precipitates within the accuracy of an optical microscope.

[0144] A list of all samples examined is provided in Table 2, along with pertinent sample names and compositional details.

[0145] [Table 2]

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

[0147] [Table 3]

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

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

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

[0151] The average droplet size was calculated based on the analysis of at least 100 adjacent glycerol domains in both emulsions. The experiment (FIG. 4) revealed that the average droplet diameter after 10 minutes of mixing was 16.0 μm (±4.9 μm) and 9.3 μm (±2.4 μm) for emulsion 1 and emulsion 2, respectively. The data show that cyclodextrin, especially β-cyclodextrin, also distributes itself at the interface between glycerol and the silicone pre-elastomer, and therefore acts as a stabilizing surfactant for the emulsion obtained by mixing the components for this composition.

[0152] In the presence of β-cyclodextrin, polymerization of emulsion 2 was possible despite the presence of nitrogen in the pyrutenidine derivative. It was observed that complexation of the platinum catalyst poison with cyclodextrin significantly reduced the inhibition of the addition cure system. It is believed that the pyrutenidine derivative orients itself (at least in part) to the nitrogen group in the cavity of β-cyclodextrin and therefore cannot participate in platinum poisoning.

[0153] Solubilization of Octenidine in Glycerol Octenidine is an amphiphilic substance, so it has negligible solubility in glycerol, but can form micelles to enhance solubility. In this study, β-cyclodextrin (βCD) was used as a tool to dissolve large amounts of hydrophobic substances in hydrophilic media such as glycerol. Cyclodextrin as a cyclic oligosaccharide can form host-guest complexes with hydrophobic molecules, thereby enabling numerous 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 until a clear solution was obtained (usually within 30 min). The obtaining of a clear mixture indicates the successful preparation of βCD-octenidine complex.

[0154] Preparation of functional adhesive The mixture containing glycerol and βCD-octenidine complex was placed in a plastic container. Then, 12.5 g of MG7-9900, which is part A, and 12.5 g of MG7-9900, which is part B, were placed in the container. The composition was mixed for 5 minutes at 3500 revolutions per minute (rpm) using a dual asymmetric centrifuge SpeedMixer Dac 150 FVZ-K. Thus, a glycerol-in-silicone-pre-elastomer emulsion was prepared. The emulsion was cast on an inert plastic support and spread using a commercial knife to obtain a 350 μm thick film (t EL The material was then placed in an oven at 80° C. for 1 hour. The resulting polymerized skin patch was then cut into 25 cm pieces while still attached to the support. 2 The resulting skin patches showed excellent surface adhesion in terms of adhesion over time and ease of release from the surface after use.

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

[0156] Example 1 Stability of glycerol-in-silicone emulsions 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 percentage based on total composition).

[0158] The stability of glycerol-in-silicone pre-elastomer emulsions with and 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. The experiment (FIG. 5) revealed that the average droplet diameter after 10 minutes of mixing was 16.0 μm (±4.9 μm) and 9.3 μm (±2.4 μm) for emulsion 1 and emulsion 2, respectively. The data show that β-cyclodextrin also distributes itself in the glycerol phase and at the interface between glycerol and the silicone pre-elastomer, and therefore acts as a stabilizing surfactant for the emulsion obtained by mixing the components of 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 complexation of the platinum catalyst poison with cyclodextrin significantly reduced the inhibition of the addition cure system. It is believed that octenidine orients itself (at least in part) to the nitrogen groups in the cavity of β-cyclodextrin and is therefore unable to participate in platinum poisoning.

[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 βCD was kept constant at 2:1 (2 molecules of octenidine per molecule of βCD). The release behavior shown in Figure 6 clearly indicates that the drug dose delivered from the different skin patches increases with increasing octenidine content, as expected.

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

[0163] All three patches released octenidine in sufficient quantities to produce bactericidal effects 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 patch was investigated. In this study, samples containing 2 molecules of octenidine per molecule of β-cyclodextrin (molar ratio 2:1) and 1 molecule of octenidine per molecule of β-cyclodextrin (molar ratio 1:1) were investigated. The release behavior of both films is shown in Figure 7.

[0165] As can be observed from the graph, the release of octenidine into water from skin patches containing octenidine and β-cyclodextrin in a 2:1 ratio is slightly faster than the release from the 1:1 composition, with little change in release kinetics between the two compositions. The data appears to be consistent with the assumption that octenidine and β-cyclodextrin form a 1:1 complex, and that the 1:1 complex dominates the diffusion and release characteristics of the entire silicone elastomer.

[0166] In particular, the data appear to be consistent with the model depicted in FIG. 2, in which release of the active agent occurs primarily via release from an active agent reservoir contained in the glycerol phase, which maintains a (substantially) constant concentration of active agent in the silicone elastomer matrix.

[0167] In this model, the release of hydrophobic active substances is inhibited by insufficient absorption in water.Octenidine, a surfactant with a moderately high CMC value (estimated by Steward et al. to be 3.79 mM in water, and likely to be higher in glycerol), dissolves to some extent in water and glycerol, which is greatly enhanced in the presence of cyclodextrin.Therefore, without being bound by this theory, the inventors believe that the release of octenidine is dominated by the release rate of 1:1 octenidine-βCD-complex, with a likely partial contribution from (micellar) octenidine directly dissolved in glycerol and (then) water.

[0168] A molar ratio of octenidine to β-cyclodextrin of 2:1 only results in an increase in delivery efficiency of about 25% to 30% compared to a molar ratio of 1:1. The optimal formulation of octenidine to β-cyclodextrin (when only considering release rate) requires 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, or even 1:1.5. This ensures that substantially all of the octenidine is complexed with β-cyclodextrin (the latter being in excess), thereby making substantially all of the octenidine available for release via the 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 to β-cyclodextrin, for example a molar ratio of 3:1, 2.5:1, 2:1 or even 1.5:1 excess, has the advantage that the overall release of octenidine from the skin patch is increased due to the availability of octenidine for release by a secondary release mechanism.

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

[0171] The results shown in FIG. 8 are consistent with the release model shown in FIG. 2, where the release rate of the active increases with increasing glycerol loading in the membrane.

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

[0173] The observed data can be explained in relation to the release model detailed in Figure 2. First, the near-surface reservoir of the skin patch containing octenidine and octenidine-β-cyclodextrin 1:1-complex is depleted, resulting in approximately equal delivery rates between the two different samples. The delivery rate then becomes dominated by the exchange rate between the deeper reservoir and the superficial drug release reservoir, with the 60 phr glycerol reservoir structure allowing faster reservoir exchange than the 40 phr glycerol one.

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

[0175] conclusion In conclusion, the composition of the present invention and the formation of a complex of octenidine with β-cyclodextrin in an elastomer matrix allows a wide range of (easily) tunable delivery rates of octenidine from silicone elastomer skin patches.

[0176] In some embodiments, the octenidine is in excess relative to the cyclodextrin, thereby increasing the rate of delivery and the octenidine is not complexed with the cyclodextrin, which acts as a long-term reservoir for sustained release of octenidine from the skin patch. In another embodiment, the cyclodextrin is in excess for rapid delivery of octenidine and rapid depletion of the skin patch of octenidine.

[0177] According to our studies, silicone elastomer matrices containing 40 or 60 phr of glycerol have a micellar structure (compare Figures 1 and 5), while silicone elastomer matrices containing more than 100 phr of glycerol are bicontinuous in both the silicone elastomer and glycerol phases. According to our studies, the delivery rate of small hydrophilic actives from the discrete micellar structures of less than about 70 phr of glycerol follows a first order release behavior, from about 70 phr of glycerol to about 100 phr of glycerol, the delivery of small hydrophilic actives follows an approximately zero order release behavior, and above about 100 phr of glycerol, such as 120 phr, the release of small hydrophilic actives follows a zero order release behavior.

[0178] The release data presented here is consistent with previous observations in that the release data exhibits the expected first order release kinetics for glycerol contents below about 70 phr.

[0179] Thus, in some embodiments, the initial emulsion is prepared with a glycerol content of less than 70 phr, which results in the formation of micellar structures of glycerol in the polymerized silicone elastomer, while in other embodiments the glycerol content is greater than 100 phr, which results in the formation of a bicontinuous emulsion and a polymerized silicone elastomer.

[0180] Embodiments in which octenidine is in excess relative to cyclodextrin and / or the glycerol content is less than 70 phr can be beneficially applied, for example, where the skin patch cannot be easily replaced.Embodiments in which octenidine is present in 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 the skin patch is intended for one-time skin coverage during early wound healing.

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

[0182] Note The term "comprising" when used in the claims does not exclude other elements or steps. The terms "a" or "an" when used in the claims do not exclude a plurality. Although the invention has been described in detail for purposes of illustration, it will be understood that such details are for the purpose only and changes may be made by one skilled in the art without departing from the scope of the invention. The present disclosure further includes the following aspects: Aspect 1 A glycerol-in-silicone preelastomer emulsion comprising a silicone preelastomer, glycerol, a cyclodextrin, and a metal catalyst suitable for use in the polymerization of said silicone preelastomer. Aspect 2 2. The glycerol-in-silicone preelastomer emulsion of embodiment 1, wherein the cyclodextrin is selected from α, β, or γ-cyclodextrin or derivatives thereof. Aspect 3 3. The glycerol-in-silicone preelastomer emulsion of either of the preceding claims, wherein the cyclodextrin is a β-cyclodextrin. Aspect 4 4. The glycerol-in-silicone preelastomer emulsion according to any one of aspects 1 to 3, wherein the metal catalyst is either Sn or Pt. Aspect 5 5. The glycerol-in-silicone preelastomer emulsion of any one of the preceding claims, wherein the emulsion further comprises a hydrophobic active. Aspect 6 A glycerol-in-silicone preelastomer emulsion according to any one of the preceding aspects, wherein the hydrophobic active material comprises one or more atoms of nitrogen, sulfur, and / or phosphorus. Aspect 7 7. The glycerol-in-silicone preelastomer emulsion of any one of claims 5 to 6, wherein the hydrophobic active agent is pirtenidine or a derivative thereof. Aspect 8 8. The glycerol-in-silicone preelastomer emulsion of any one of aspects 5 to 7, wherein the hydrophobic active agent is octenidine. Aspect 9: An emulsion comprising a silicone pre-elastomer, glycerol, at least one cyclodextrin, and octenidine. Aspect 10 10. The emulsion according to embodiment 9, wherein the at least one cyclodextrin is selected from at least one of α, β, γ-cyclodextrin or derivatives thereof. Aspect 11 11. The emulsion of embodiment 9 or embodiment 10, wherein the at least one cyclodextrin is a β-cyclodextrin. Aspect 12 12. The emulsion of any one of aspects 9-11, wherein the silicone preelastomer comprises a metal catalyst suitable for use in polymerizing the silicone preelastomer. Aspect 13 13. The emulsion according to embodiment 12, wherein the metal catalyst is either Sn or Pt, preferably Pt. Aspect 14 14. The emulsion of any one of aspects 9 to 13, wherein the cyclodextrin and octenidine are dissolved in glycerol before the silicone preelastomer is added. Aspect 15 15. The emulsion according to any one of aspects 9 to 14, wherein the concentration of glycerol in the emulsion is from 20 phr to 140 phr. Aspect 16 16. The emulsion according to any one of aspects 9 to 15, wherein the octenidine is octenidine dihydrochloride. Aspect 17 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 weight of the emulsion. Aspect 18 18. The emulsion according to any one of aspects 9 to 17, wherein the concentration of the at least one cyclodextrin in the emulsion is from 0.1% to 6% by weight, based on the total weight of the emulsion. Aspect 19 19. The emulsion according to any one of aspects 9 to 18, wherein the molar ratio of octenidine to cyclodextrin is from 3:1 to 1:1.5. Aspect 20 20. The emulsion of any one of aspects 9 to 19, wherein the silicone preelastomer is a two-component silicone preelastomer. Aspect 21 21. The emulsion of any one of aspects 9 to 20, wherein the emulsion is a glycerol-in-silicone preelastomer emulsion of any one of aspects 1 to 8. Aspect 22 A silicone elastomer containing glycerol and at least one cyclodextrin. Aspect 23 23. The silicone elastomer according to embodiment 22 containing glycerol and at least one cyclodextrin, wherein the glycerol is present in the silicone elastomer as a separate phase with at least a portion of the at least one cyclodextrin. Aspect 24 24. The silicone elastomer according to any one of claims 22 or 23, comprising glycerol and at least one cyclodextrin, and further comprising a hydrophobic active agent. Aspect 25 25. The silicone elastomer according to any one of aspects 22 to 24, wherein the hydrophobic active substance is pirtenidine or a derivative thereof. Aspect 26 26. The silicone elastomer according to any one of aspects 22 to 25, wherein the hydrophobic active agent is octenidine or octenidine dihydrochloride. Aspect 27 27. The silicone elastomer of any one of claims 22 to 26, formed by polymerization of the glycerol-in-silicone preelastomer emulsion of any one of claims 1 to 8, or the emulsion of any one of claims 9 to 21. Aspect 28 28. The silicone elastomer according to embodiment 27, wherein polymerizing the emulsion comprises polymerizing the emulsion at a polymerization temperature and for a polymerization time suitable to obtain a polymerized emulsion. Aspect 29 29. The silicone elastomer of any one of claims 27 to 28, wherein polymerizing the emulsion comprises polymerizing the emulsion for a polymerization time between 1 minute and 120 minutes. Aspect 30 30. The silicone elastomer of any one of aspects 27 to 29, wherein polymerizing the emulsion comprises polymerizing the emulsion at a polymerization temperature from 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 type of cyclodextrin. Aspect 32 The silicone elastomer has a density of at least 0.1 μg / cm 2 32. A skin patch (1) containing a silicone elastomer (3) according to embodiment 31, which releases octenidine at an administration rate of 1 / hour. Aspect 33 The thickness of the silicone elastomer (t EL 33. The skin patch (1) containing a silicone elastomer (3) according to claim 30 or 32, wherein the thickness of the skin patch (1) is 0.05 mm to 5 mm. Aspect 34 A skin patch (1) containing a silicone elastomer (3) according to any one of aspects 30 to 33, wherein the silicone elastomer has a removable layer (4) formed by an inert plastic. Aspect 35 A skin patch (1) containing a silicone elastomer (3) according to any one of aspects 30 to 34, wherein the silicone elastomer has a support layer (2) formed by an inert plastic. Aspect 36 The removable layer (4) and the support layer (2) are disposed on opposite sides of the silicone elastomer, and the thickness (t EL 36. The skin patch (1) containing a silicone elastomer (3) according to any one of embodiments 30 to 35, wherein the skin patch (1) is separated by a Aspect 37 The silicone elastomer has a density of at least 0.1 μg / cm 2 The skin patch (1) containing a silicone elastomer (3) according to any one of aspects 30 to 36, which releases octenidine at an administration rate of 1 / hour. Aspect 38 1. A method of forming an emulsion containing a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin, comprising the steps of: 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 a silicone pre-elastomer; iv. applying shear until an emulsion is formed; The method includes: Aspect 39 39. The method of forming an emulsion according to embodiment 38, wherein the resulting clear solution is cooled to 5° C. to 50° C. before adding the silicone preelastomer. Aspect 40 A method of forming an emulsion according to aspect 38 or 39, wherein the emulsion is a glycerol-in-silicone preelastomer emulsion according to any one of aspects 1 to 8, or an 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 preelastomer, glycerol, octenidine, and at least one cyclodextrin. Aspect 42 A method of forming a silicone elastomer according to embodiment 41, wherein the emulsion is a glycerol-in-silicone preelastomer emulsion according to any one of embodiments 1 to 8, or an emulsion according to any one of embodiments 9 to 21. Aspect 43 A method of forming a silicone elastomer according to any one of Aspects 25 to 27. Aspect 44 A method of 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 A method for forming a silicone elastomer according to any one of aspects 38 to 40, comprising polymerizing the emulsion at a polymerization temperature of from 50° C. to 90° C. Aspect 46 i. preparing an emulsion comprising a silicone pre-elastomer, glycerol, octenidine, and at least one cyclodextrin according to any one of aspects 1-21; ii. casting the emulsion onto a support layer (2) made of an inert plastic; iii. The emulsion is applied onto a support layer to a coating thickness (t EL forming a coating layer having a iv. polymerizing the emulsion at a polymerization temperature for a polymerization time, thereby forming a silicone elastomer (3) containing glycerol, octenidine, and at least one cyclodextrin; A method for forming the skin patch (1) according to any one of aspects 31 to 37, comprising: Aspect 47 A method for forming a skin patch (1) as described in embodiment 46, further comprising providing a removable layer (4) formed from an inert plastic on the silicone elastomer (3) opposite the support layer (2). Aspect 48 48. A method for forming a skin patch (1) according to any one of claims 46 to 47, comprising polymerizing the emulsion for 1 minute to 120 minutes. Aspect 49 A method for forming a skin patch (1) according to any one of aspects 46 to 48, comprising polymerizing the emulsion at a polymerization temperature of 50°C to 90°C. Aspect 50 The skin patch (1) is 1 cm 2 ~1000cm 2 50. A method for forming a skin patch (1) according to any one of aspects 46 to 49, comprising cutting the patch to size. Aspect 51 50. A method for treating a wound site on the skin of a mammal, comprising covering the wound site with a skin patch (1) containing octenidine according to any one of aspects 46 to 49, wherein the skin patch (1) releases octenidine at a dosage 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 bacteria. Aspect 52 52. A method of treating a wound site on the skin of a mammal according to aspect 51, wherein the mammal is a human. Aspect 53 53. The method of treating a wound site on the skin of a mammal according to aspect 51 or 52, wherein the at least one gram positive or gram negative bacterium is selected from Staphylococcus aureus, Escherichia coli, Proteus mirabilis, Candida albicans, or Pseudomonas aeruginosa. Aspect 54 The dosage rate of octenidine release is at least 0.1 μg / cm 2 54. A method for treating a wound site on the skin of a mammal according to any one of aspects 51 to 53, wherein the treatment is performed for 1 hour / hour. Aspect 55 55. A method of treating a wound site on mammalian skin according to any one of aspects 51 to 54, wherein the application time is at least 1 hour. Aspect 56 The effective amount of octenidine is at least 0.1 μg / cm 2 56. A method for treating a wound site on mammalian skin according to any one of aspects 51 to 55, Aspect 57 A skin patch (1) according to any one of aspects 31 to 37, for use in a method according to any one of aspects 51 to 55. Aspect 58 A 1:1 molecular complex of octenidine dihydrochloride with β-cyclodextrin. Aspect 59 59. A 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin according to embodiment 58 in glycerol. Aspect 60 60. Use of a 1:1 molecular complex of octenidine dihydrochloride and β-cyclodextrin according to embodiment 58 or 59 in an emulsion according to any one of embodiments 1 to 21. Aspect 61 57. Octenidine for use in treating a wound site on mammalian skin according to any one of aspects 51 to 56. Aspect 62 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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