阅读说明：本技术 包含甘油、环糊精和奥替尼啶的弹性体硅酮组合物 (Elastomeric silicone compositions comprising glycerin, cyclodextrin, and octenidine ) 是由 A·L·斯科夫 P·S·玛祖瑞卡 V·基奥拉 J·托诺埃 A·C·尼尔森 于 2020-05-13 设计创作，主要内容包括：本文披露了一种包含硅酮预弹性体、甘油、环糊精、以及适合用于所述硅酮预弹性体的聚合中的金属催化剂的乳液、一种由所述乳液所形成的硅酮弹性体和由所述硅酮弹性体所形成的用于释放奥替尼啶的皮肤贴剂。进一步地,披露了形成所述乳液、所述硅酮弹性体和所述皮肤贴剂的方法。(Disclosed herein is an emulsion comprising a silicone pre-elastomer, glycerin, cyclodextrin, and a metal catalyst suitable for use in polymerization of the silicone pre-elastomer, a silicone elastomer formed from the emulsion, and a skin patch formed from the silicone elastomer for release of octenidine. Further, methods of forming the emulsions, the silicone elastomers, and the skin patches are disclosed.)

1. A silicone pre-elastomer in glycerin emulsion comprising a silicone pre-elastomer, glycerin, cyclodextrin, and a metal catalyst suitable for use in polymerization of the silicone pre-elastomer.

2. The silicone pre-elastomer in glycerin emulsion of claim 1, wherein the cyclodextrin is selected from α, β, or γ -cyclodextrin or derivatives thereof.

3. The silicone pre-elastomer in glycerin emulsion of claim 1 or claim 2, wherein the cyclodextrin is β -cyclodextrin.

4. The silicone pre-elastomer-in-glycerin emulsion of any one of claims 1 to 3, wherein the metal catalyst is Sn or Pt.

5. The silicone pre-elastomer in glycerin emulsion of any one of claims 1 to 4, wherein the emulsion further comprises a hydrophobic active.

6. The glycerol-in-silicone pre-elastomer emulsion of any of claims 1 to 5, wherein the hydrophobic active comprises one or more atoms of any of nitrogen, sulfur and/or phosphorus.

7. The glycerol-in-silicone pre-elastomer emulsion of claim 5 or 6, wherein the hydrophobic active is pyritinib or a derivative thereof.

8. The glycerol in silicone pre-elastomer emulsion of any of claims 5 to 7, wherein the hydrophobic active is octenidine.

9. An emulsion comprising a silicone pre-elastomer, glycerin, at least one cyclodextrin, and octenidine.

10. The emulsion of claim 9, wherein the at least one cyclodextrin is selected from at least one of alpha, beta, or gamma-cyclodextrin or derivatives thereof.

11. The emulsion of claim 9 or claim 10, wherein the at least one cyclodextrin is β -cyclodextrin.

12. The emulsion of any one of claims 9 to 11, wherein the silicone pre-elastomer comprises a metal catalyst suitable for polymerization of the silicone pre-elastomer.

13. An emulsion according to claim 12, wherein the metal catalyst is Sn or Pt, preferably Pt.

14. An emulsion according to any one of claims 9 to 13, wherein the cyclodextrin and octenidine are dissolved in glycerol prior to addition of the silicone pre-elastomer.

15. The emulsion according to any one of claims 9 to 14, wherein the concentration of glycerol in the emulsion is from 20phr to 140 phr.

16. An emulsion according to any one of claims 9 to 15 wherein octenidine is octenidine dihydrochloride.

17. An emulsion according to any one of claims 9 to 16, wherein the concentration of octenidine in the emulsion is from 0.1 to 6 wt% based on the total mass of the emulsion.

18. The emulsion of any one of claims 9 to 17, wherein the concentration of the at least one cyclodextrin in the emulsion is from 0.1 wt% to 6 wt% based on the total mass of the emulsion.

19. The emulsion of any one of claims 9 to 18, wherein the molar ratio of octenidine to cyclodextrin is from 3:1 to 1: 1.5.

20. The emulsion of any one of claims 9 to 19, wherein the silicone pre-elastomer is a two-component silicone pre-elastomer.

21. The emulsion of any one of claims 9 to 20, wherein the emulsion is a glycerin-in-silicone pre-elastomer emulsion of any one of claims 1 to 8.

22. A silicone elastomer comprising glycerol and at least one cyclodextrin.

23. The silicone elastomer of claim 22, comprising glycerin and at least one cyclodextrin, wherein the glycerin is present in the silicone elastomer as a discrete phase comprising at least some of the at least one cyclodextrin.

24. A silicone elastomer according to claim 22 or 23, comprising glycerol and at least one cyclodextrin, and further comprising a hydrophobic active.

25. A silicone elastomer according to any of claims 22 to 24, wherein the hydrophobic active substance is pyritinidine or a derivative thereof.

26. A silicone elastomer according to any of claims 22 to 25, wherein the hydrophobic active substance is octenidine or octenidine dihydrochloride.

27. The silicone elastomer of any one of claims 22 to 26 formed by polymerization of the silicone pre-elastomer-in-glycerin emulsion of any one of claims 1 to 8 or the emulsion of any one of claims 9 to 21.

28. The silicone elastomer of claim 27, wherein the polymerization of the emulsion comprises polymerizing the emulsion at a polymerization temperature for a polymerization time suitable to obtain a polymerized emulsion.

29. A silicone elastomer according to claim 27 or 28, wherein the polymerisation of the emulsion comprises polymerising the emulsion for a polymerisation time of from 1 minute to 120 minutes.

30. The silicone elastomer of any of claims 27 to 29, wherein the polymerization of the emulsion comprises polymerizing the emulsion at a polymerization temperature of from 50 ℃ to 90 ℃.

31. A skin patch (1) comprising a silicone elastomer (3) comprising glycerol, octenidine and at least one cyclodextrin, the silicone elastomer being according to any one of claims 22 to 30.

32. A skin patch (1) comprising a silicone elastomer (3) according to claim 31, said silicone elastomer being present at least 0.1 μ g/cm²Octenidine is released at a dose rate per hour.

33. Skin patch (1) comprising a silicone elastomer (3) according to claim 30 or claim 32, wherein the thickness (t) of the silicone elastomer_EL) Is from 0.05mm to 5 mm.

34. A skin patch (1) containing a silicone elastomer (3) according to any of claims 30 to 33, wherein the silicone elastomer is provided with a removable layer (4) formed of an inert plastic.

35. A skin patch (1) comprising a silicone elastomer (3) according to any one of claims 30 to 34, wherein said silicone elastomer is provided with a support layer (2) formed of an inert plastic.

36. Skin patch (1) comprising a silicone elastomer (3) according to any one of claims 30 to 35, wherein said removable layer (4) and said support layer (2) are arranged opposite with respect to said silicone elastomer and are defined by said thickness (t) of said silicone elastomer_EL) Spaced apart.

37. The skin patch (1) comprising a silicone elastomer (3) according to any of claims 30 to 36, wherein the silicone elastomer is present at least 0.1 μ g/cm²Octenidine is released at a dose rate per hour.

38. A method of forming an emulsion comprising a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin, the method comprising:

i. mixing glycerol, octenidine, and cyclodextrin;

heating the resulting mixture to a temperature of from 50 ℃ to 90 ℃ with stirring until a clear solution is formed;

addition of Silicone Pre-Elastomers

Applying shear until an emulsion is formed.

39. A method of forming an emulsion as recited in claim 38 wherein the resulting clear solution is cooled to from 5 ℃ to 50 ℃ prior to the addition of the silicone pre-elastomer.

40. A method of forming an emulsion according to claim 38 or 39, wherein the emulsion is a glycerol-in-silicone pre-elastomer emulsion according to any of claims 1 to 8 or an emulsion according to any of claims 9 to 21.

41. A method of forming a silicone elastomer comprising polymerizing an emulsion comprising a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin.

42. A method of forming a silicone elastomer according to claim 41, wherein the emulsion is a glycerol-in-silicone pre-elastomer emulsion according to any of claims 1 to 8 or an emulsion according to any of claims 9 to 21.

43. A method of forming a silicone elastomer according to claim 41 or 42, wherein the emulsion has been formed according to the method of any of claims 25 to 27.

44. A method of forming a silicone elastomer according to any one of claims 28 to 30, comprising polymerizing the emulsion for from 1 minute to 120 minutes.

45. A method of forming a silicone elastomer according to any one of claims 38 to 40, comprising polymerizing the emulsion at a polymerization temperature of from 50 ℃ to 90 ℃.

46. A method of forming a skin patch (1) according to any one of claims 31 to 37, comprising:

i. providing an emulsion comprising a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin according to any one of claims 1 to 21;

Casting the emulsion onto a support layer (2) formed of an inert plastic;

spreading the emulsion on the support layer to form a layer having a spread thickness (t;)_EL) A spreading layer of (a);

polymerizing the emulsion at a polymerization temperature for a polymerization time to form a silicone elastomer (3) comprising glycerol, octenidine, and at least one cyclodextrin.

47. A method of forming a skin patch (1) according to claim 46, further comprising providing a removable layer (4) formed of an inert plastic onto the silicone elastomer (3) opposite the support layer (2).

48. A method of forming a skin patch (1) according to claim 46 or 47 including polymerizing said emulsion for from 1 minute to 120 minutes.

49. A method of forming a skin patch (1) according to any one of claims 46 to 48 including polymerizing said emulsion at a polymerization temperature of from 50 ℃ to 90 ℃.

50. A method of forming a skin patch (1) according to any one of claims 46 to 49 including cutting the skin patch (1) to 1cm²To 1000cm²The size of (c).

51. A method of treating a wound site on the skin of a mammal, comprising covering the wound site with a skin patch (1) comprising octenidine, the skin patch (1) being according to any one of claims 46 to 49; the skin patch (1) releases octenidine at a dose rate; applying the skin patch (1) to the wound site for an application time sufficient to release an effective dose of octenidine sufficient to obtain an antibacterial effect against at least one gram-positive or gram-negative bacterium.

52. A method of treating a wound site on the skin of a mammal according to claim 51, wherein the mammal is a human.

53. A method of treating a wound site on the skin of a mammal according to claim 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.

54. A method of treating a wound site on the skin of a mammal as claimed in any of claims 51 to 53, wherein the dosage rate at which octenidine is released is at least 0.1 μ g/cm²In terms of hours.

55. A method of treating a wound site on the skin of a mammal according to any one of claims 51 to 54, wherein the time of administration is at least 1 hour.

56. A method of treating a wound site on the skin of a mammal as claimed in any one of claims 51 to 55, wherein the effective dose of octenidine is at least 0.1 μ g/cm²。

57. A skin patch (1) according to any one of claims 31 to 37, for use in a method according to any one of claims 51 to 55.

58. A molecule 1: 1-complex of octenidine dihydrochloride and beta-cyclodextrin.

59. A molecular 1: 1-complex of octenidine dihydrochloride and β -cyclodextrin in glycerol according to claim 58.

60. Use of a molecular 1: 1-complex of octenidine dihydrochloride and β -cyclodextrin according to claim 58 or 59 in an emulsion according to any one of claims 1 to 21.

61. Octenidine for use in treating a wound site on the skin of a mammal according to any one of claims 51 to 56.

62. Octenidine for use in treating a wound site on the skin of a mammal according to claim 61, wherein octenidine is present in a 1: 1-complex of octenidine dihydrochloride and β -cyclodextrin according to claim 58 or 59.

Technical Field

Within the field of silicone elastomers comprising glycerol suitable for active substance release, novel compositions comprising at least one cyclodextrin, in particular cyclodextrin, and a hydrophobic active substance, in particular pirfenidine or derivatives thereof such as e.g. octenidine, in particular comprising β -cyclodextrin and octenidine dihydrochloride, are detailed for active substance release e.g. to the skin of a mammal.

Background

The chemistry of silicone elastomer matrices containing glycerol inclusions, including the use of such matrices in the release of active substances, has been discussed in a series of recent publications and patent applications from the research group of professor a.l. skov, one of the present inventors. Some relevant publications related thereto include, for example, p.mazurek et al j.appl.polym.sci. [ journal of applied Polymer science ],2016,44153, pages 1-8, p.mazurek et al Polymer [ Polymer ],2016, volume 87, pages 1-7, or p.mazurek et al, rsc.adv. [ evolution of royal chemical society of british ],2015, volume 5, page 15379-15386, or Skov et al, WO2016/189117a 1. The silicone elastomer provides a matrix for an inclusion phase comprising at least one glycerol, wherein the at least one glycerol phase may be present as distinct droplets or form a bicontinuous network in the elastomer matrix. The technology is based on the mixing of two liquid phases of silicone pre-elastomer and glycerol, wherein the mixing results in the formation of a silicone pre-elastomer-glycerol-in-silicone emulsion which, upon cross-linking of the silicone pre-elastomer, can form a pressure-sensitive silicone elastomer matrix comprising a separate glycerol phase embedded in the silicone elastomer matrix. Some studies by the present inventors have shown that the embedded glycerin phase may exist as a plurality of discrete glycerin droplets, or partially or completely as a continuous glycerin phase embedded in a continuous silicone elastomer (bicontinuous silicone-glycerin elastomer composition).

The studies disclosed by the present inventors and their co-workers have shown that glycerin-silicone elastomers are generally stable and can be formed from a wide range of silicone pre-elastomers. This study also shows that some silicone pre-elastomer-in-glycerin emulsions are less stable than other emulsions, typically where the silicone pre-elastomer is (very) hydrophobic, and that a small amount of surfactant (acting as a stabilizer and added to the pre-emulsion mixture of glycerin and silicone pre-elastomer) after emulsification will stabilize the subsequently formed silicone pre-elastomer-in-glycerin emulsion for a sufficient time to allow crosslinking without unmixing the pre-elastomer for forming the resulting silicone elastomer composition comprising an embedded glycerin phase.

In a further work of two of the present inventors, a.l. skov and p.mazurek, among others, with other co-workers, it was shown that the glycerol-containing silicone elastomer matrix detailed in WO 2016/189117 a1 is a tunable matrix for active substance release, wherein the release kinetics of the active substance contained in the glycerol phase from the elastomer matrix becomes tunable between zero order and first order release by influencing the morphology of the at least one glycerol phase contained. In this regard, further work has been documented for a range of hydrophilic actives, first order, near zero order, and zero order release kinetics.

Since the two liquids of silicone pre-elastomer and glycerin are practically immiscible, mixing results in the formation of a silicone pre-elastomer-in-glycerin emulsion. Upon crosslinking the silicone phase, a free-standing silicone-glycerin (tacky) matrix is obtained.

As is known in the art, the silicone matrix may be tacky or non-tacky depending on the polymerization conditions. In the context of the present invention, it is believed that the skilled person is able to prepare tacky and/or non-tacky silicone elastomer matrices as required, 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. Additionally, in some embodiments, a combination of tacky and non-tacky silicone elastomers may be used to form the silicone elastomer matrix of the present invention.

The silicone provides mechanical integrity to the system, while the glycerin acts as a liquid filler in the form of micron-sized droplets uniformly distributed within the silicone matrix, as presented in fig. 1. Studies by some of the present inventors have shown that submicron droplets are also possible by adding sufficient surfactant. Emulsions from silicone pre-elastomer and submicron glycerol droplets were found to be equally stable as emulsions of silicone pre-elastomer and micron sized droplets.

The glycerol acts as a carrier for the active substance released from the elastomer upon contact with, for example, an aqueous environment. A possible release mechanism of the hydrophilic active from the glycerol-silicone elastomer is presented in fig. 2. In short, it is believed that the release is a result of a diffusion process occurring at the interface between the glycerol, the silicone and the phase in contact with the outer surface of the elastomeric composition (illustrated in fig. 2 by the adjacent aqueous phase), whereas the delivery is also affected by the diffusion of the active substance in the glycerol phase and in the formed elastomeric matrix.

As reported in prior art WO 2016/189117, the curing of the silicone elastomer is carried out using conventional methods known in the art, such as peroxide-based curing, condensation-based curing, for example in the presence of Sn as catalyst, or addition-based curing, for example in the presence of Pt as catalyst, wherein during the 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 crosslinking agent to the pre-elastomer solution prior to the addition of glycerol, as the addition of catalyst and crosslinking agent results in an emulsion that tends to form a non-uniform, blocky elastomer matrix.

It is well known in the art that when condensation-or addition-cured silicones are used in the presence of metal catalysts, one of the greatest challenges is the susceptibility of the metal catalysts to poisoning. Poisons for the catalyst include all compounds which contain, in particular, nitrogen, sulfur and/or phosphorus. In particular, platinum catalysts, for example used in addition-based curing of silicone elastomers, for their high versatility, for example high conversion efficiency, are particularly susceptible to poisoning by impurities in the substances forming the emulsion prior to polymerization. Since platinum is expensive and irreversibly incorporated into the formed silicone elastomer matrix, there is a need to solve the problem of preventing catalyst poisoning prior to commercial development of the glycerol-silicone elastomer compositions of the present invention.

In the art, numerous solutions are known to solve the above-mentioned problems, see for examplehttp://www.us- tech.com/RelId/1082642/pagenum/2/ISvars/default/Troubleshooting_Platinum_ Catalyzed_Silicones.htmAnd 20 days 6 and 2018. However, although it is observed that the general and generally known precautions associated with the manufacturing process will also alleviate some of the above-mentioned problems of the systems currently studied, unfortunately, the standard methods in the art have proved to be insufficient with respect to the systems of the present invention in the presence of the active substances contained in the glycerol or silicone phase of the pre-elastomer emulsion, since these active substances may generally comprise accessible molecules and/or functional groups in the molecules of the active substance, wherein the molecular groups comprise one or more of nitrogen, sulphur and/or phosphorus, among others.

Therefore, there is a need to provide a solution to catalytic poisoning which allows to protect the metal catalyst without deactivating the active substances intended to be released from the cured elastomeric compositions of the prior art.

Some of the inventors of the present invention have surprisingly found that members of the cyclodextrin family, in particular β -cyclodextrin, are suitable for preventing catalytic poisoning of metal catalysts, in particular of platinum catalysts, in compositions comprising silicone pre-elastomer glycerol-in-emulsion.

In CN 102716104 a, it was reported that β -cyclodextrin can protect platinum catalyst from catalyst poisoning in the polymerization process of silicone gel in the presence of vegetable oil containing an element selected from N, S and P. This protection is achieved by preparing insoluble microparticles of vegetable oil and β -cyclodextrin prior to polymerization of the silicone. After polymerization, the microparticles remain intact and do not diffuse in the cured silicone. However, by increasing the retention of the vegetable oil by the cured silicone, and limiting the resulting delivery of the vegetable oil of interest, the strong interaction of β -cyclodextrin with the vegetable oil of interest and the resulting formation of insoluble microparticles is a significant disadvantage of the prior art.

Further, in relation to the present invention, the present inventors have surprisingly recognized, in particular, that with regard to emulsions comprising glycerol in a silicone pre-elastomer and at least one active substance, wherein the at least one active substance comprises atoms of at least one of sulfur, phosphorus and/or nitrogen, cyclodextrins can be used to prevent catalytic poisoning. The present invention advantageously uses this surprising effect of cyclodextrins in preventing catalytic poisoning of at least platinum to suggest an improvement over existing skin patch delivery systems for antibacterial wound care comprising octenidine-containing silicone elastomers.

In the field of antimicrobial wound care, antimicrobial agents which do not enter the mammalian body, in particular the human body, in particular the dermis or the bloodstream of a mammal, in particular a human, after topical application are highly advantageous, since their potential for damage to the recipient of the treatment is thereby minimized. The list of potential antimicrobial agents suitable for topical application is long, such as ethanol or chlorhexidine, however this list is significantly shorter when one considers the inclusion of a potential antimicrobial agent in a wound dressing for long term release to the wound site during wound healing. Some suitable candidates comprise silver present as silver sulfadiazine or silver nanoparticles, and hydrophobic antibacterial agents such as pyritinidine and derivatives thereof such as octenidine have been found to be widely used.

Particularly octenidine (base drug: octenidine dihydrochloride), which has received much attention as a cationic surfactant antibacterial agent due to its broad efficacy against gram-positive and gram-negative bacteria (Steward et al Scientific Reports, 2018,8: 895). Octenidine is known in the art to combine high biocompatibility and unknown bacterial resistance with a wide range of potential uses, such as for example in mouth rinses, wound cleansing, topical antiseptics and the like. Steward et al have estimated that the critical micelle concentration is 3.79 mM. An effective concentration of octenidine in the suspension is typically above 0.005 wt%, such as, for example, 0.01 wt%, 0.015 wt%, 0.020 wt%, 0.025 wt%, or 0.030 wt%.

Table 1: the comparison of antibacterial efficacy between octenidine and chlorhexidine was determined by suspension testing after 5 minutes of exposure (source: wikipedia).

In the field of wound care dressings, formulations include hydrogels, such as those containing hydroxyethylcellulose 4000 (see, e.g., US 2011/0091551) and octenidine co-formulated with a small amount of glycerol. Formulations based on various polymers suitable for the topical drug delivery of active substances contained in a polymeric matrix have been described (see for example WO2008/008617, WO 2010/005680, WO 2014/044869), and polymeric matrices derived from octenidine-containing silicones have also received scientific attention (see for example WO2007/124855, US 2016/0106104). However, although the above mentioned formulations are suitable for providing octenidine to the skin of a mammal, e.g. a human, the proposed formulations suffer from drawbacks in terms of delivery kinetics, including burst delivery and rapid depletion of octenidine, whereby delivery of octenidine to the wound site under the skin patch is disadvantageous, such as stable delivery and/or sustained long term delivery.

The present inventors have now presented improvements to a skin silicone patch comprising pirfenidine and derivatives thereof, particularly and preferably octenidine, which may be formulated to allow zero-order or near zero-order release of octenidine over a substantial period of time, thereby avoiding the burst effect and maintaining the active concentration of octenidine at the wound site for a substantial period of time required for wound healing.

Definition of

In the present context, the term "silicone elastomer" refers to a polymer comprising any inert compound consisting of repeating units of a siloxane of the formula-RR 'SiO-, wherein R and R' are identical or different hydrocarbon groups, and wherein the term is used as a polymer exhibiting rubbery elasticity according to its IUPAC definition. When polymerized in the presence of a glycerin phase, the silicone elastomer of the present invention forms a matrix of the glycerin phase, embedding the glycerin phase in the silicone elastomer matrix.

In this context, the term "polysiloxane" refers to a compound of the form [ RR 'SiO ] n, wherein R and R' are identical or different hydrocarbon groups, and wherein n is the number of repeating units. The term "polysiloxane" also refers to a compound of the formula [ RR 'SiO ] n, which may be partially functionalized in the sense that some R, R' groups have been replaced or substituted with substituent groups. Non-limiting examples of such substituent groups include Cl, CN, F, OH, alkenyl, and alkynyl. In addition, the silicone compound or silicone pre-elastomer or additive used for crosslinking may include functional groups known in the art, including compounds containing functional groups of SiH, SiOR, Si-oxime, and Si-carboxylate.

In the present context, the term "polydimethylsiloxane", abbreviated to "PDMS", refers to the formula CH₃[Si(CH₃)₂O]_nSi(CH₃)₃Wherein 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, for example, SiH, hydroxy-, vinyl-, allyl-groups in the pendant or terminal positions.

In the context of the present invention, the term silicone pre-elastomer is used to describe any silicone starting composition which, when polymerized and/or crosslinked, will form a silicone elastomer matrix suitable for use in the present invention. In some cases, the term silicone prepolymer is also used, where a prepolymer of silicone is a subset of a pre-elastomer of silicone, as a prepolymer of silicone requires complete polymerization of silicone from the relevant monomers and oligomers suitable for silicone elastomer formation, while pre-elastomers also include pre-formed silicone polymers where only cross-linking of the silicone polymer is the next necessary step for forming the silicone elastomer.

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 may be formed from silicone monomers, oligomers and/or polymers according to the teachings of WO 2016/189117 a1 (which is incorporated herein by reference in its entirety). Suitable monomers, oligomers and/or polymers for use in the present invention include, inter alia, such monomers, oligomers and/or polymers as mentioned herein above. In general, the invention is not limited to a specific selection of silicone elastomers, whether tacky or not, as long as the selected silicone elastomer can form the matrix elastomer for the included glycerol phase (whether micellar or bicontinuous). A simple test of the suitability of a specific silicone pre-elastomer for use in the present invention is whether the silicone pre-elastomer in the presence of from 20phr to 140phr of glycerol will form a silicone elastomer using the method of preparing a silicone elastomer comprising glycerol as detailed in WO 2016/189117 a 1.

In the context of the present invention, silicone pre-elastomers may be formulated to produce non-tacky as well as tacky silicone elastomers when crosslinked.

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

In the present context, the terms "cross-linker" and "cross-linking agent" are used interchangeably and refer to one or more compounds that facilitate the cross-linking of polymer chains, in particular silicone polymer chains. No particular limitation is imposed on the actual composition of the crosslinking agent (crosslinker) or crosslinking agent (crosslinking agent) and it is inferred from the selected language or intention thereby. Examples of crosslinking agents (crosslinking agents) or crosslinking agents (crosslinking agents) may be, for example, metals, small molecules, polymeric crosslinking agents or even crosslinking compositions comprising more than one reactive crosslinking agent or crosslinking agent involved in the crosslinking process.

In the present context, the term "phr" used to describe the glycerol content in all compositions corresponds to the weight of glycerol per hundred parts by weight of silicone pre-elastomer.

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

In the present context, the term excipient is used to mean an additive substance added to the silicone phase or the glycerin phase of the present invention. Thus, in the context of the present disclosure, an excipient is a substance contained in the composition of the present invention other than glycerin or silicone. The excipient may for example be selected from the group consisting of: active substance, in particular for human or animal use, in particular a medicament, and/or selected from catalysts, inhibitors, flow agents, silicone oils, solvents, fillers, foaming agents, reinforcing substances, and plasticizers. Further examples of excipients are given below.

In the context of the present invention, an active agent is a substance that can be released from the composition of the present invention according to a zero or higher order release rate as detailed herein. In particular, the active substance is intended to comprise substances which are chemically and/or biologically active, such as pharmaceutically active ingredients and/or drugs, on the surface or in the human or animal body when released from the composition of the invention.

In the context of the present invention, a skin patch (dermal patch) or (synonymously) a skin patch (skin patch) is a medicated adhesive patch that delivers an active substance or drug into the skin when placed on e.g. mammalian skin, and in particular when placed on human skin. In the context of the present invention, the term skin patch is therefore used to distinguish the object of the present invention from a transdermal patch, which is considered to be a skin patch containing a drug or active substance, which can deliver the drug or active substance into the bloodstream when the transdermal patch is placed on the skin of a mammal, in particular when the transdermal patch is placed on the skin of a human.

Throughout this disclosure, the term cyclodextrin is used to denote closed-ring and tapered molecules formed by linking 5 or more α -D-glucopyranoside units, but less than 10 α -D-glucopyranoside units, through 1- >4, as well as derivatives thereof, such as, for example, methylated cyclodextrins. Preferred cyclodextrins in embodiments of the present invention are alpha, beta, or gamma-cyclodextrins (see fig. 3) or derivatives thereof, such as methylated cyclodextrins. A particularly preferred cyclodextrin in embodiments of the invention is beta-cyclodextrin. Throughout this disclosure, shorthand notation of various cyclodextrins can be used, such as, for example, β CD of β -cyclodextrin or α CD of α -cyclodextrin or γ CD of γ -cyclodextrin.

Throughout this disclosure, pyritinidine is used interchangeably with N, 1-dioctylpyridin-4-imine, and octenidine dihydrochloride are used with N-octyl-1- [10- (4-octyliminopyridin-1-yl) decyl]Pyridine-4-imine dihydrochloride (see fig. 4) may be used interchangeably. While pyritinidine is isolated as an uncharged covalent organic compound, octenidine is (usually) isolated as the dihydrochloride salt. However, in the compositions of the present invention, where the starting material is octenidine dihydrochloride, it is not clear whether octenidine dihydrochloride loses one or both of its hydrochloride molecules when mixed with glycerol and silicone pre-elastomer. Thus, octenidine is understood to mean, in the context of the present disclosure, N-octyl-1- [10- (4-octyliminopyridin-1-yl) decyl ]Pyridin-4-imines and any salts thereof, in particular N-octyl-1- [10- (4-octyliminopyridin-1-yl) decyl]Pyridine-4-imine dihydrochloride. Where emphasis is intended to be placed on the presence of hydrochloride, the present disclosure will use the longer term octenidine dihydrochloride. In the context of the present disclosure, octenidine is considered to be the generation of octenidine and two cs by condensation of two pirenidine molecules₃-derivatives of pirfenidine as leaving group.

Disclosure of Invention

In a first aspect of the invention, a silicone pre-elastomer-in-glycerin emulsion is disclosed that comprises a silicone pre-elastomer, glycerin, cyclodextrin, and a metal catalyst suitable for use in the polymerization of the silicone pre-elastomer.

In a second aspect of the invention, a silicone elastomer comprising glycerol and cyclodextrin, preferably a silicone elastomer formed by polymerization of a glycerol-in-silicone pre-elastomer emulsion according to any embodiment disclosed herein, is disclosed.

In a preferred embodiment, the silicone elastomer comprises a hydrophobic active, preferably a hydrophobic active in a glycerin phase.

In a preferred embodiment of the present invention, a silicone pre-elastomer glycerin-in-silicone emulsion comprising a silicone pre-elastomer, glycerin, at least one cyclodextrin, and octenidine is disclosed. In a preferred embodiment, the cyclodextrin is β -cyclodextrin and/or octenidine is octenidine dihydrochloride.

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

In a third aspect of the invention, a skin patch (1) is disclosed comprising a silicone elastomer (3) comprising glycerol, octenidine and at least one cyclodextrin, wherein the silicone elastomer is according to any embodiment of the second aspect.

In a fourth aspect of the invention, a method of forming a silicone pre-elastomer glycerin-in-silicone emulsion comprising a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin, the method comprising:

i. mixing glycerol, octenidine, and cyclodextrin;

heating the resulting mixture to a temperature of from 50 ℃ to 90 ℃ with stirring until a clear solution is formed;

addition of Silicone Pre-Elastomers

Applying shear until an emulsion is formed.

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

In a fifth aspect of the invention, a method of forming a silicone elastomer is disclosed that includes emulsion polymerizing a silicone pre-elastomer-in-glycerin emulsion comprising a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin. In a preferred embodiment of the fourth aspect of the invention, the silicone pre-elastomer in glycerol emulsion is a silicone pre-elastomer in glycerol emulsion according to any embodiment of the first aspect.

In a sixth aspect of the invention and its embodiments, a method of forming a skin patch (1) according to any of the embodiments of the third aspect is disclosed, comprising:

i. providing an emulsion comprising a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin according to any of the aspects and embodiments mentioned herein;

casting the emulsion onto a support layer (2) formed of an inert plastic;

spreading the emulsion on the support layer to form a layer having a spread thickness (t;)_EL) A spreading layer of (a);

polymerizing the emulsion at a polymerization temperature for a polymerization time to form a silicone elastomer (3) comprising glycerol, octenidine, and at least one cyclodextrin.

In a seventh aspect of the invention and its embodiments, 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) comprising octenidine, the skin patch (1) being in accordance with any embodiment of the third aspect; the skin patch (1) releases octenidine at a dose rate; applying the skin patch (1) to the wound site for an application time sufficient to release an effective dose of octenidine sufficient to obtain an antibacterial effect against at least one gram-positive or gram-negative bacterium. In a preferred embodiment, the mammal is a human.

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

Drawings

FIG. 1: SEM image of cross-section of prior art-cured glycerin-silicone elastomer.

FIG. 2: a mechanism for releasing a substance from a glycerin-silicone elastomer.

FIG. 3: alpha, beta, and gamma-cyclodextrin as structural and space filling models.

FIG. 4: (A) molecular structures of pirtinidine and (B) octenidine dihydrochloride.

FIG. 5: a silicone pre-elastomer glycerin-in-silicone pre-elastomer emulsion comprising a silicone pre-elastomer and glycerin without (a) and with (B) β -cyclodextrin and octenidine.

FIG. 6: a graph showing the amount of octenidine released as a function of the octenidine content in the skin patch.

FIG. 7: a graph showing the released octenidine as a function of the beta-cyclodextrin content in a skin patch.

FIG. 8: a graph showing the released octenidine as a function of the glycerol content in the skin patch.

FIG. 9: an exemplary skin patch.

Detailed Description

In prior studies reported by some of the inventors and co-workers of the present invention, the release of hydrophilic actives from silicone elastomers comprising a micellar glycerol phase that solubilizes the hydrophilic actives has been studied.

In the studies of the prior art, the release behavior of hydrophobic active substances was also investigated. However, it was observed that when a hydrophobic active substance is added to an emulsion of silicone and glycerol, which active substance contains at least one of nitrogen, sulphur or phosphorus in its molecular structure, the polymerization of the silicone pre-elastomer catalyzed by the metal is severely inhibited due to catalyst poisoning. For example, in experiments with pyritinib and derivatives of pyritinib, the active species contains two nitrogen atoms (such as two nitrogen atoms in pyritinib, see fig. 4) or more, and catalyst poisoning of metal catalysts, in particular Pt-catalysts suitable for catalyzing the polymerization of silicone pre-elastomers, adversely affects the polymerization process. Typically, when commercial pre-elastomer solutions are used, the silicone pre-elastomers are typically silicone oligomers and polymers that crosslink by curing as defined above to form a silicone matrix. However, in the context of the present invention, as discussed above, the silicone pre-elastomer may also comprise silicone monomers which, in addition to curing, undergo polymerization to form the silicone matrix of the present invention.

In contrast to CN 102716104 a, the present inventors have surprisingly found that cyclodextrins may in some cases be suitable for masking the active substances tested without interfering with the polymerization process of the silicone pre-elastomer in the emulsion with glycerol. Thus, in the present invention we describe the dissolution of a solid hydrophobic active comprising at least one element selected from N, S and P, which forms a reversible complex with cyclodextrins, in particular β -cyclodextrin, thereby protecting the Pt catalyst present in the emulsion of the invention for curing silicone pre-elastomers from catalytic poisoning by the active, but without affecting the total active delivery or active delivery rate. Further, it has additionally and unexpectedly been observed that cyclodextrins partition at least partially at the silicone/glycerol interface, thus unexpectedly providing an improvement in the stability of silicone pre-elastomer glycerol-in-silicone emulsions prior to polymerization (see fig. 5) relative to the investigated use of an emulsifying system comprising a silicone pre-elastomer and glycerol as a surfactant; in addition to compatibilization and masking of active species containing atoms such as nitrogen, sulfur or phosphorus that may participate in catalyst poisoning.

These observations by the inventors of the present invention are the subject of a separately filed patent application and consist herein of the priority claims, wherein according to the present invention there is disclosed a silicone pre-elastomer-in-glycerol emulsion comprising a silicone pre-elastomer, glycerol, cyclodextrin, and a metal catalyst suitable for use in the polymerization of the silicone pre-elastomer. Further, the emulsion may comprise an active hydrophobic substance comprising e.g. pyritinib or derivatives thereof.

In a preferred embodiment of the invention, the cyclodextrin may be selected from alpha, beta, or gamma-cyclodextrin or derivatives thereof, such as for example methylated cyclodextrin (see fig. 3). In a particularly preferred embodiment of the previously filed invention, there is disclosed a silicone pre-elastomer glycerin-in-silicone emulsion according to any of the disclosed embodiments, wherein the cyclodextrin is β -cyclodextrin.

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

Further, in an embodiment of the present disclosure, a silicone pre-elastomer in glycerin emulsion according to any detailed embodiment is disclosed, wherein the silicone pre-elastomer in glycerin emulsion further comprises a hydrophobic active. In some embodiments, the hydrophobic active comprises one or more atoms of any of nitrogen, sulfur, and/or phosphorus. Preferably, the hydrophobic active substance comprises at least one nitrogen atom. Preferably, the active substance is pyritinib or a derivative thereof.

In a further aspect of the invention, a silicone elastomer comprising glycerol and cyclodextrin, preferably a silicone elastomer formed by polymerization of an emulsion according to any of the embodiments disclosed, is disclosed. In a preferred embodiment of the invention, the hydrophobic active substance comprises one or more atoms of any of nitrogen, sulphur and/or phosphorus, and most preferably the active substance is pyritinib or a derivative thereof.

According to the present invention, the inventors have investigated whether octenidine, notably octenidine dihydrochloride (see fig. 4), can be used to release an active substance from a silicone-glycerol elastomer matrix by complexing with cyclodextrin. As detailed previously above, octenidine dihydrochloride has several advantages as a skin antiseptic, in particular efficacy and (very) limited skin access hindrance, however, successful formulations in skin patches, and in particular in skin patches comprising silicone elastomers, have not been available on the market. Some of the disadvantages of the formulations proposed in the prior art include insufficient delivery kinetics, including burst delivery and rapid depletion of octenidine, lack of long-term delivery of octenidine, and the like.

The improvements proposed herein by the present inventors include dermal silicone patches comprising octenidine which may be formulated, inter alia, to allow zero-order or near zero-order release of octenidine over a significant period of time, avoiding the burst effect and maintaining an active concentration of octenidine at the wound site for a significant period of time required for wound healing.

Further, silicone emulsions and silicone polymers suitable for use in forming such skin patches of the present invention and suitable methods for forming the purposes of the present invention are detailed herein.

In one aspect of the invention, detailing a glycerin-in-silicone pre-elastomer emulsion and embodiments thereof, a glycerin-in-silicone pre-elastomer emulsion according to the invention comprises a silicone pre-elastomer, glycerin, at least one cyclodextrin, and octenidine.

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

Such two-component silicone pre-elastomers are commercially available from various manufacturers, having pre-tailored properties which, when cross-linked, allow the formation of silicone elastomers known to be particularly suitable for active substance release, such as, for example, for dermal or transdermal active substance release.

Thus, in a preferred embodiment of the glycerin-in-silicone pre-elastomer emulsion of the present invention, the silicone pre-elastomer is a two-component silicone pre-elastomer.

In general, the actual composition and formulation of the silicone elastomer matrix is considered to be outside the scope of the present invention. As discussed above, it is necessary that the silicone pre-elastomer support be formed with an emulsion of glycerin and subsequently polymerized to form a silicone elastomer comprising glycerin.

Non-limiting examples of commercially available silicone pre-elastomers suitable for use in the present invention include PDMS pre-elastomers as of filing date, including those from Dow Corning184 and from Wacker Chemie, GermanyRT625, and two-component pressure sensitive silicone adhesive MG7-9900 from Dow Corning, which is a divinyl-terminated polydimethylsiloxane pre-elastomer containing a crosslinker and a Pt catalyst as used in the experiments presented herein. In some embodiments, silica is present as the reinforcing agent.

In embodiments of the present invention, the silicone pre-elastomer may be selected from the group consisting of pre-elastomers of methyl silicone elastomer, phenyl silicone elastomer, chloroalkyl silicone elastomer, and fluorosilicone elastomer, or combinations thereof.

In embodiments of the present invention, the silicone pre-elastomer may be selected from the group of pre-elastomers comprising polyalkylsiloxanes, preferably Polydimethylsiloxane (PDMS), and derivatives thereof. Exemplary PDMS pre-elastomers include vinyl functional PDMS pre-elastomers that are crosslinkable with hydride functional crosslinkers, or hydroxy functional PDMS pre-elastomers that are crosslinkable in the presence of Sn or Pt.

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

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

In embodiments of the present invention, the silicone pre-elastomer may be an elastomer composition suitable for use in the present invention, wherein the silicone pre-elastomer is a fluorosilicone pre-elastomer. A non-limiting example of a commercially available fluorosilicone pre-elastomer is available from Dow Corning corporationF-LSR series elastomers, FE/FEA series from shinEtsu silicones, Krytox from DuPont, or Wacker ChemieFLR series.

In embodiments of elastomeric compositions suitable for use in the present invention, the elastomeric composition further comprises one or more excipients selected from the group consisting of: active substance, in particular for human or animal use, in particular a medicament, and/or selected from catalysts, inhibitors, flow agents, silicone oils, solvents, fillers, foaming agents, reinforcing substances, and plasticizers.

In embodiments suitable for use in the elastomeric compositions of 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.

In a preferred embodiment of the glycerol emulsion in silicone pre-elastomer according to the invention, the silicone pre-elastomer comprises a metal catalyst suitable for the polymerization of the silicone pre-elastomer. Preferably, the metal catalyst is Sn or Pt, most preferably Pt.

In embodiments of elastomeric compositions 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 substances, and plasticizers such as, for example, plasticizer oils for reducing the melt viscosity of the elastomer during its processing, for example, mineral oils containing known amounts of active fillers (e.g., zinc oxide and stearic acid), inactive fillers (such as carbon black, titanium dioxide, silica, carbonates, kaolin, clay, and talc), or resins such as vinyl Q resins from Gelest corporation. Such excipients may be present in commercially available silicone elastomers or may be added separately to the silicone elastomer.

The amount of necessary excipients may vary independently depending on the elastomeric composition in question, but typically ranges from 0 to 40 wt% of the elastomeric composition, such as from 5 to 30 wt%, such as from 10 to 25 wt%.

In embodiments suitable for use in the elastomeric composition of the present invention, the elastomeric composition may further comprise an excipient selected from the group consisting of a flow agent, a silicone oil, and a solvent. Commercially available examples thereof include silicone oilsAK SILICONE FLUID or solvent such as those from Dow Corning) OS-20 of (1). Other suitable examples are, for example, low molecular weight cyclic compounds such as, for example, cyclomethicone (D4-D6).

In an embodiment of the elastomeric composition suitable for use in the present invention, the elastomeric composition comprises at least one foaming agent as an excipient.

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

In an embodiment of the elastomeric composition suitable for use in the present invention, the blowing agent is a base. Non-limiting examples thereof include inorganic bases such as NaOH, KOH, and LiOH; amine-based compounds, such as triethanolamine, ethanolamine, triethylamine, ethylamine, methylamine, polyetheramines (such as those commercially available from Huntsman corporation) ) (ii) a And phosphazene bases such as BEMP (2-tert-butylimino-2-diethylamino-1, 3-dimethylperhydro-1, 3, 2-diazaphosphine) and P1-t-Bu (N, N ', N "-hexamethyl-N'" - (2-methyl-2-propyl) imidophosphoric triamide).

In preferred embodiments of the present invention, a silicone pre-elastomer glycerol-in-silicone emulsion is disclosed, wherein the at least one cyclodextrin is selected from at least one of alpha, beta, gamma-cyclodextrin or derivatives thereof. In a particularly preferred embodiment, the at least one cyclodextrin comprised in the emulsion is β -cyclodextrin. In an embodiment, the at least one cyclodextrin is hydroxypropyl cyclodextrin (HPCD).

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

In a preferred embodiment, the hydrophobic active substance comprises one or more atoms of any of nitrogen, sulphur and/or phosphorus, and most preferably the active substance is pyritinidine or a derivative thereof, preferably octenidine.

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

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

As detailed in the experiments, referring to example 3 and fig. 7, octenidine dihydrochloride formed a complex with β -cyclodextrin, which is consistent with the complex being a 1:1 molecular complex based on the data.

As disclosed in the experimental section and in the methods detailed herein below, a 1:1 complex of octenidine dihydrochloride and β -cyclodextrin may be formed, for example, by heating octenidine dihydrochloride and β -cyclodextrin in glycerol solution to a temperature of from 50 ℃ to 90 ℃ with stirring until a clear solution is obtained. Preferably, the temperature is 80 ℃.

To the knowledge of the inventors of the present invention, such 1:1 complexes of octenidine dihydrochloride with β -cyclodextrin have not been described so far in the prior art. Since the mode of complexation between octenidine dihydrochloride is not yet known, the inventors of the present invention have temporarily suggested that other salts of octenidine, in particular halide salts such as, for example, HF, HBr, or HI, are also suitable for forming the observed 1:1 complex with β -cyclodextrin. Accordingly, such further salts of octenidine, in particular such further halide salts, are also considered to be encompassed by the present invention. However, it is preferred that octenidine is present as octenidine dihydrochloride in the glycerin-in-silicone pre-elastomer emulsion of the present invention.

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

Thus, in a preferred embodiment of the silicone pre-elastomer-in-glycerin emulsion of the present invention, the cyclodextrin and octenidine are dissolved in glycerin prior to addition of the silicone pre-elastomer. 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.

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

From studies by some of the inventors of the present invention, it was known that when the concentration of glycerol is below about 100phr, glycerol is present as discrete droplets (see fig. 5), and when the concentration of glycerol is increased above about 100phr, a bicontinuous emulsion of silicone pre-elastomer and glycerol is formed. Upon polymerization, the silicone elastomer containing glycerin formed from the bicontinuous emulsion exhibits zero order active release. The release kinetics of small active substances approach near zero order when the concentration of glycerol is from about 70phr to about 100phr, and follow a first order release mechanism when the concentration of glycerol is from about 20phr to about 70 phr. In the experiments shown herein, various emulsions, silicone elastomers and skin patches were formulated to show a first order release and thus have a glycerol content of from 20phr to 70phr, notably 40phr and 60 phr.

Thus, in embodiments of the invention, the silicone pre-elastomer-in-glycerin emulsion comprises from 20phr to 70phr, preferably from 30phr to 60phr, or from 40phr to 50phr, of glycerin content for forming a silicone elastomer in which octenidine release follows a first order release kinetics.

Thus, in embodiments of the invention, the silicone pre-elastomer-in-glycerin emulsion comprises from 70phr to 100phr, preferably from 75phr to 95phr, or from 80phr to 85phr, of glycerin content for forming a silicone elastomer in which octenidine release follows near zero order release kinetics.

Thus, in embodiments of the invention, the silicone pre-elastomer-in-glycerin emulsion comprises a glycerin content of from 100phr to 150phr, preferably from 110phr to 140phr, or from 120phr to 130phr, for forming a silicone elastomer in which octenidine release follows zero order release kinetics.

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

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

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

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

Even further, in embodiments of the silicone pre-elastomer in glycerin emulsion of the present invention, the molar ratio of octenidine to cyclodextrin, preferably octenidine dihydrochloride to β -cyclodextrin, in the emulsion is from 4:1 to 1:1.5, preferably from 3:1 to 1: 1.5. Preferably, the molar ratio of octenidine to cyclodextrin in the emulsion is from 4:1 to 3:1, from 2.5:1 to 1:1.4, from 2:1 to 1:1.3, from 1.5:1 to 1:1.2, from 1.3:1 to 1:1.1, or 1:1.

In a preferred embodiment of the glycerin-in-silicone pre-elastomer emulsion of the present invention, the emulsion comprises a silicone pre-elastomer, from 20phr to 150phr of glycerin, based on the mass of the silicone pre-elastomer, and from 0.1 wt% to 6 wt% octenidine and from 0.1 wt% to 6 wt% cyclodextrin, based on the total mass of the emulsion.

In a further aspect of the invention, a silicone elastomer comprising glycerin, octenidine, and at least one cyclodextrin is disclosed. Preferably, the silicone elastomer is a silicone elastomer matrix for containing glycerol in the form of a glycerol phase according to the prior art, preferably for containing a glycerol phase containing octenidine and at least one cyclodextrin. According to the prior art, the glycerol phase may be present as discrete droplets or as a bicontinuous phase.

Preferably, the silicone elastomer according to this further aspect of the invention is formed by polymerisation of a glycerol-in-silicone pre-elastomer emulsion according to any of the embodiments detailed in the present disclosure. As documented in the presented experiments, the silicone elastomer formed from the emulsion disclosed herein forms a silicone elastomer matrix that reliably releases octenidine and is further suitable for use in forming skin patches in accordance with the objects and objectives of the present invention.

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

In an embodiment, the polymerization temperature is from 50 ℃ to 90 ℃. For a given silicone pre-elastomer to be included in the emulsion of the present invention, it is within the skill of the person skilled in the art to obtain a suitable combination of polymerization time and temperature. In alternative embodiments, the emulsion comprises a low temperature polymerization inhibitor, whereby the polymerization and/or curing may be performed at a temperature above 90 ℃, such as above 100 ℃, above 110 ℃, or even above 120 ℃. This may be advantageous where rapid formation of the silicone matrix is desired. Further guidance on the conditions of the polymerization can be obtained, if necessary, from WO 2016/189117A 1.

In a further aspect of the invention, a skin patch (1) comprising a silicone elastomer (3) comprising glycerin, octenidine, and at least one cyclodextrin is disclosed. Preferably, the silicone elastomer is a silicone elastomer matrix comprising glycerol, octenidine and at least one cyclodextrin. An illustrative, non-limiting drawing of a skin patch (1) according to the invention is shown in fig. 9.

Skin patches are well known in the art, and the construction of skin patches according to the art is not part of the present invention. Rather, it is believed that the skilled artisan, in possession of the information disclosed herein, can prepare skin patches according to their various needs.

In an embodiment, the skin patch is a wound care device, such as a wound dressing.

According to the present invention, a skin patch (1) comprising a silicone elastomer (3) comprising glycerol, octenidine and at least one cyclodextrin is disclosed, wherein the silicone elastomer is according to any of the aspects and embodiments detailed in the present disclosure. In particular, a skin patch (1) comprising a silicone elastomer (3) comprising glycerol, octenidine and at least one cyclodextrin is disclosed, wherein the silicone elastomer is formed from a silicone pre-elastomer in glycerol emulsion according to any aspect and embodiment detailed herein.

In a preferred aspect of the present invention, a skin patch (1) is disclosed, comprising any of the patches detailed in accordance with the present disclosureThe silicone elastomer (3) of aspects and embodiments, wherein the silicone elastomer is present at a level of at least 0.1 μ g/cm²Octenidine is released at a dose rate per hour. Preferably, the silicone elastomer of the invention is present at a level of at least 0.3. mu.g/cm²At least 0.5. mu.g/cm per hour²At least 0.8 mug/cm per hour²At least 1 mug/cm per hour²At least 1.3. mu.g/cm per hour²At least 1.5. mu.g/cm per hour²At least 1.8. mu.g/cm per hour²At least 2. mu.g/cm per hour²At least 2.3. mu.g/cm per hour²At least 2.5. mu.g/cm per hour²At least 2.8. mu.g/cm per hour²At least 3 mug/cm per hour²At least 3.3. mu.g/cm per hour²At least 3.5. mu.g/cm per hour²At least 3.8. mu.g/cm per hour²At least 4 mug/cm per hour²At least 4.3. mu.g/cm per hour²At least 4.5. mu.g/cm per hour²At least 4.8. mu.g/cm per hour²At least 5 mug/cm per hour²At least 5.3. mu.g/cm per hour²At least 5.5. mu.g/cm per hour²At least 5.8. mu.g/cm per hour²At least 6 mug/cm per hour²At least 6.3. mu.g/cm per hour²At least 6.5. mu.g/cm per hour²At least 6.8 mug/cm per hour²At least 7 mug/cm per hour²At least 7.3. mu.g/cm per hour²At least 7.5. mu.g/cm per hour ²At least 7.8. mu.g/cm per hour²At least 8 mug/cm per hour²At least 8.3. mu.g/cm per hour²At least 8.5. mu.g/cm per hour²At least 8.8. mu.g/cm per hour²At least 9 mug/cm per hour²At least 9.3. mu.g/cm per hour²At least 9.5. mu.g/cm per hour²At least 9.8. mu.g/cm per hour²Per hour, or at least 10. mu.g/cm²Octenidine is released at a dose rate per hour.

In the experiments reported below, the skin patch examined was measured at a rate of from about 0.2 μ g/cm when measured during the initial constant release phase of the skin patch examined²(0.3 wt% octenidine dihydrochloride, 2:1 molar ratio OCT: β CD) to about 4.1 μ g/cm²Release rate between/hr (3 wt% octenidine dihydrochloride, 2:1 molar ratio OCT: β CD)Tinidine (see FIGS. 6-8). Generally, for all observed skin patches, the total release of octenidine observed is in a sufficient amount to obtain an antibacterial effect against the common bacteria given in table 1.

As mentioned in the experimental section, the inventors are not aware of what form octenidine dihydrochloride is released from the silicone elastomer matrix of the present invention due to the association of the molecule with β -cyclodextrin. However, the inventors believe, without being bound by this theory, octenidine dihydrochloride remains dihydrochloride in the emulsions, elastomers and skin patches of the present invention. However, this aspect is not important, since the biological efficacy of octenidine is not associated with association of the dihydrochloride, but rather salt formation in octenidine is associated with suitability for aqueous delivery. As documented in this experiment, octenidine is reliably released from the skin patch of the present invention, thereby achieving biological efficacy.

In a preferred embodiment of the skin patch (1) of the invention, the silicone elastomer as such has a thickness (t) of from 0.05mm to 5mm_EL) The layer (3) of silicone elastomer of (a) is present in a skin patch. Preferably, the thickness (t)_EL) Is the thickness of the silicone elastomer measured perpendicular to the direction of intended application according to known practice in the field of skin patches. The skin patches prepared for study in the experiments reported below have a thickness (t) of 0.35mm_EL) This is a common thickness for many patches in dermal drug delivery. Thickness (t) as is well known in the art_EL) Are routinely varied by the skilled person to adjust the reserve (reservoir) content of the active substance and are generally considered to be outside the context of the present invention. Preferably, the thickness (t)_EL) Is from 0.05mm to 2mm, from 0.1mm to 1.5mm, from 0.2mm to 1.3mm, from 0.3mm to 1mm, from 0.4mm to 0.9mm, from 0.5mm to 0.8mm or from 0.6mm to 0.7 mm.

In a preferred embodiment of the skin patch (1) of the invention, the silicone elastomer (3) is provided with a removable layer (4) formed of an inert plastic. In a further preferred embodiment of the skin patch (1) of the invention, the silicone elastomer (3) is provided with a branch formed of an inert plasticA support layer (2). Preferably, the removable layer (4) and the support layer (2) are arranged opposite with respect to the silicone elastomer and are defined by a thickness (t) of the silicone elastomer _EL) Spaced apart as is customary in the field of skin patches.

In some embodiments of the invention, the support layer (2) may comprise an adhesive layer for contacting and adhering the silicone elastomer (3) to the support layer (2), for example in the case where the silicone elastomer is not a tacky silicone elastomer. In many applications it is disadvantageous if the element of the skin patch containing the active substance is itself an adhesive, since this may be disadvantageous for wound healing of e.g. open wounds. These aspects of skin patches are well known to the skilled person and are considered outside the present invention. In general, the silicone elastomers of the present invention can be tacky as well as non-tacky to mammalian skin, particularly human skin, as required by their environment of use.

In further aspects of the invention and embodiments thereof, a method of forming a silicone pre-elastomer glycerin-in-silicone emulsion comprising a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin is disclosed, the method comprising:

i. mixing glycerol, octenidine, and cyclodextrin;

heating the resulting mixture to a temperature of from 50 ℃ to 90 ℃ with stirring until a clear solution is formed;

Addition of Silicone Pre-Elastomers

Applying shear until an emulsion is formed.

After the method of the present invention, especially when octenidine is octenidine dihydrochloride and the cyclodextrin is β -cyclodextrin, it is ensured that octenidine and cyclodextrin become fully associated and (see example 3 and fig. 7) are thus optimally available for release from the silicone elastomers and skin patches of the present invention.

The optimal temperature range for octenidine complexation with cyclodextrin is from 50 ℃ to 90 ℃, with 80 ℃ being optimal. The octenidine and the cyclodextrin are slowly compounded at the temperature lower than 50 ℃. It is generally preferred to mix the components prior to heating as detailed in the above method, however, octenidine and cyclodextrin may be added directly to the hot glycerol if desired.

As detailed in WO 2016/189117 a1, it is necessary to apply shear (iv) for forming an emulsion of silicone pre-elastomer and glycerol. Generally, it is recommended in WO 2016/189117 a1 to apply shear from 1500rpm to 5000rpm until an emulsion is formed, but other methods of applying shear known to the skilled person are also considered suitable for use in the process of the present invention.

In an embodiment of the method of forming a glycerin-in-silicone pre-elastomer emulsion according to the present disclosure, the resulting clear solution of (ii) is cooled to from 5 ℃ to 50 ℃ prior to addition of the silicone pre-elastomer. In general, this step can be omitted when the glycerol content is reasonably low, whereas when the glycerol content is high and a mixing temperature of 80 ℃ has been used, for example, some unwanted heat-initiated polymerization of the silicone pre-elastomer may occur, which is avoided by pre-cooling. In alternative embodiments, the emulsion comprises a low temperature polymerization inhibitor, whereby the polymerization and/or curing may be performed at a temperature above 90 ℃, such as above 100 ℃, above 110 ℃, or even above 120 ℃. This may be advantageous where rapid formation of the silicone matrix is desired.

In a particularly preferred embodiment of the method of forming a glycerin-in-silicone pre-elastomer emulsion according to the present invention, the emulsion is an emulsion according to any aspect and embodiment of the present invention detailed herein.

In further aspects of the invention and embodiments thereof, a method of forming a silicone elastomer is disclosed that includes emulsion polymerizing a silicone pre-elastomer including a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin in glycerin. Preferably, the silicone elastomer is a silicone elastomer matrix comprising glycerol, octenidine and at least one cyclodextrin.

In a preferred embodiment of the method of forming a silicone elastomer according to the invention, the silicone pre-elastomer-in-glycerin emulsion is an emulsion according to any aspect and embodiment of the invention detailed herein.

In a preferred embodiment of the method of forming a silicone elastomer according to the present invention, the silicone pre-elastomer in glycerol emulsion has been formed according to a method according to any aspect and embodiment of the present invention detailed herein.

In an embodiment of the method of forming a silicone elastomer according to the invention, the polymerization of the silicone pre-elastomer-in-glycerin emulsion is from 1 minute to 120 minutes, preferably from 2 minutes to 90 minutes, from 3 minutes to 60 minutes, from 4 minutes to 50 minutes, from 5 minutes to 40 minutes, from 6 minutes to 30 minutes, from 7 minutes to 20 minutes, from 8 minutes to 17 minutes, from 9 minutes to 15 minutes, or from 10 minutes to 12 minutes.

In a further method of forming a silicone elastomer according to the invention, the polymerization of the silicone pre-elastomer-in-glycerin emulsion is carried out at a polymerization temperature of from 50 ℃ to 90 ℃. In alternative embodiments, the emulsion comprises a low temperature polymerization inhibitor, whereby the polymerization and/or curing may be performed at a temperature above 90 ℃, such as above 100 ℃, above 110 ℃, or even above 120 ℃. This may be advantageous where rapid formation of the silicone matrix is desired.

In further aspects of the invention and embodiments thereof, a method of forming a skin patch (1) according to any of the herein mentioned aspects and embodiments is disclosed, comprising:

i. providing a silicone pre-elastomer glycerin-in-silicone emulsion comprising a silicone pre-elastomer, glycerin, octenidine, and at least one cyclodextrin according to any of the aspects and embodiments mentioned herein;

casting the emulsion onto a support layer (2) formed of an inert plastic;

spreading the emulsion on a support layer to form a layer having a spread thickness (t)_EL) A spreading layer of (a);

polymerizing the emulsion for a polymerization time at a polymerization temperature to form a silicone elastomer (3) comprising glycerol, octenidine, and at least one cyclodextrin.

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

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

In an embodiment of the method of forming a skin patch (1), the method further comprises polymerizing the silicone pre-elastomer-in-glycerin emulsion at a polymerization temperature of from 50 ℃ to 90 ℃, preferably 80 ℃. In alternative embodiments, the emulsion comprises a low temperature polymerization inhibitor, whereby the polymerization and/or curing may be performed at a temperature above 90 ℃, such as above 100 ℃, above 110 ℃, or even above 120 ℃. This may be advantageous where rapid formation of the silicone matrix is desired.

In an embodiment of the method of forming a skin patch (1), the method further comprises cutting the skin patch (1) from 1cm ²To 1000cm²The size of (c).

In further aspects of the 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) comprising octenidine, the skin patch (1) according to any of the aspects and embodiments detailed herein; the skin patch (1) releases octenidine at a dose rate; the skin patch (1) is applied to a wound site for an application time sufficient to release an effective dose of octenidine sufficient to obtain an antibacterial effect against at least one gram-positive or gram-negative bacterium.

In embodiments of the methods of treating a wound site on the skin of a mammal disclosed herein, the mammal is a human.

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

In embodiments of the methods of treating a wound site on the skin of a mammal disclosed herein, the dosage rate at which octenidine is released is at least 0.1 μ g/cm ²In terms of hours. Preferably, the dosage rate at which octenidine is released is at least 0.3 μ g/cm²At least 0.5. mu.g/cm per hour²At least 0.8 mug/cm per hour²At least 1 mug/cm per hour²At least 1.3. mu.g/cm per hour²At least 1.5. mu.g/cm per hour²At least 1.8. mu.g/cm per hour²At least 2. mu.g/cm per hour²At least 2.3. mu.g/cm per hour²At least 2.5. mu.g/cm per hour²At least 2.8. mu.g/cm per hour²At least 3 mug/cm per hour²At least 3.3. mu.g/cm per hour²At least 3.5. mu.g/cm per hour²At least 3.8. mu.g/cm per hour²At least 4 mug/cm per hour²At least 4.3. mu.g/cm per hour²At least 4.5. mu.g/cm per hour²At least 4.8. mu.g/cm per hour²At least 5 mug/cm per hour²At least 5.3. mu.g/cm per hour²At least 5.5. mu.g/cm per hour²At least 5.8. mu.g/cm per hour²At least 6 mug/cm per hour²At least 6.3. mu.g/cm per hour²At least 6.5. mu.g/cm per hour²At least 6.8 mug/cm per hour²At least 7 mug/cm per hour²At least 7.3. mu.g/cm per hour²At least 7.5. mu.g/cm per hour²At least 7.8. mu.g/cm per hour²At least 8 mug/cm per hour²At least 8.3. mu.g/cm per hour²At least 8.5. mu.g/cm per hour²At least 8.8. mu.g/cm per hour²At least 9 mug/cm per hour²At least 9.3. mu.g/cm per hour²At least 9.5. mu.g/cm per hour²At least 9.8. mu.g/cm per hour ²Per hour, or at least 10. mu.g/cm²In terms of hours.

In embodiments of the methods of treating a wound site on the skin of a mammal disclosed herein, the time of administration is at least 1 hour.

In embodiments of the methods of treating a wound site on skin of a mammal disclosed herein, the effectiveness of octenidineThe dosage is at least 0.1 μ g/cm². Preferably, the effective dose rate of octenidine is at least 0.3 μ g/cm²At least 0.5. mu.g/cm²At least 0.8. mu.g/cm²At least 1. mu.g/cm²At least 1.3. mu.g/cm²At least 1.5. mu.g/cm²At least 1.8. mu.g/cm²At least 2. mu.g/cm²At least 2.3. mu.g/cm²At least 2.5. mu.g/cm²At least 2.8. mu.g/cm²At least 3. mu.g/cm²At least 3.3. mu.g/cm²At least 3.5. mu.g/cm²At least 3.8. mu.g/cm²At least 4. mu.g/cm²At least 4.3. mu.g/cm²At least 4.5. mu.g/cm²At least 4.8. mu.g/cm²At least 5. mu.g/cm²At least 5.3. mu.g/cm²At least 5.5. mu.g/cm²At least 5.8. mu.g/cm²At least 6. mu.g/cm²At least 6.3. mu.g/cm²At least 6.5. mu.g/cm²At least 6.8. mu.g/cm²At least 7. mu.g/cm²At least 7.3. mu.g/cm²At least 7.5. mu.g/cm²At least 7.8. mu.g/cm²At least 8. mu.g/cm²At least 8.3. mu.g/cm²At least 8.5. mu.g/cm²At least 8.8. mu.g/cm²At least 9. mu.g/cm²At least 9.3. mu.g/cm ²At least 9.5. mu.g/cm²At least 9.8. mu.g/cm²Or at least 10. mu.g/cm²。

In a preferred embodiment of the methods of treating a wound site on the skin of a mammal disclosed herein, octenidine is octenidine dihydrochloride.

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

Examples of the invention

Material

Two-component pressure sensitive silicone adhesive MG7-9900, a divinyl-terminated polydimethylsiloxane containing a crosslinker and a Pt catalyst, was available from Dow Corning. Glycerol (food grade, up to 0.5% water) as a by-product from biodiesel production was provided by Emmelev a/S and used as such to avoid prolonged contact with air. Beta-cyclodextrin from Wacker Chemie (Wacker Chemie) was purchased from Sigma Aldrich (Sigma Aldrich). Octenidine dihydrochloride is available from Dishman Group. All chemicals were used as received.

Device

A double asymmetric centrifuge speedMixer DAC 150FVZ-K was used to mix all compounds. A Leica DM LB light microscope was used to study the morphology of glycerol in silicone emulsions.

Method

All silicone compositions comprising a glycerin phase were prepared as per steps i.v. of WO 2016/189117 a 1. The resulting silicone pre-elastomer-in-glycerin emulsion and silicone elastomer were characterized according to prior art methods, in particular by visual inspection using an optical microscope.

Two-component MG7-9900 silicone kit was mixed in a 1:1 weight ratio as recommended by the manufacturer. Subsequently, the desired amount of glycerol and related β -cyclodextrin and octenidine was added to the silicone pre-elastomer and stirred with the aid of a speed mixer at 3500rpm for 5 minutes, unless otherwise stated, until a stable emulsion had been formed. In some cases, after the mixing step, the composition was cast onto a metal mold with 1mm spacers and cured at 80 ℃ for 1 hour. The obtained film was then left at room temperature for at least two days for final post-curing.

It was advantageously observed that prior to mixing with the silicone pre-elastomer, glycerol, β -cyclodextrin and octenidine can be mixed under stirring at a temperature ranging from 50 ℃ to 90 ℃, preferably 80 ℃, to obtain a clear solution, indicating that octenidine is completely complexed by β -cyclodextrin and that the complex formed is completely dissolved in glycerol. The resulting silicone pre-elastomer and silicone pre-elastomer-in-glycerin emulsion of glycerin complex with octenidine and β -cyclodextrin will then be free of precipitates within the precision of an optical microscope.

A list of all study samples with appropriate sample names and details on the compositions is presented in table 2.

^aParts by weight per hundred parts by weight of silicone rubber

^bWeight amount of octenidine compared to total mass of glycerin-silicone membrane

Table 2. list of study samples.

Sample G40_ 1% octenidine _2:1 (octenidine: CD) _ MG7-9900 was selected as a model sample and will be used to present the sample preparation procedure in more detail. The mass amounts of the respective compounds are shown in table 3.

Material	Quality of
		MG7-9900 part A	12.5g
MG7-9900 part B	12.5g
		Glycerol	10g
Octenidine	0.35g
		Beta-cyclodextrin	0.3182

TABLE 3 Mass amounts of the respective compounds used to prepare sample G40_ 1% octenidine _2:1 (octenidine: CD) _ MG 7-9900.

Stability of Silicone Pre-elastomer Glycerol-in-Silicone emulsions

Emulsion 1: continuous phase silicone pre-elastomer-in-glycerin emulsion-uncured pressure sensitive silicone adhesive MG7-9900 from Dow Corning corporation. Disperse phase-glycerol (40 phr).

Emulsion 2: continuous phase silicone pre-elastomer-in-glycerin emulsion-uncured pressure sensitive silicone adhesive MG7-9900 from Dow Corning corporation. Dispersed phase-glycerol with 3 wt% of beta-cyclodextrin and 3 wt% of pyritinidine-derivative (40phr) (weight-percentage based on total composition).

The stability of the glycerol-in-silicone pre-elastomer emulsions with and without the β -cyclodextrin-pyrinidine-derivative complex was investigated.

The average droplet size was calculated based on analysis of at least 100 adjacent glycerol domains in both emulsions. The experiment (FIG. 4) shows that the mean droplet diameters of emulsion 1 and emulsion 2 at 10 minutes after mixing are 16.0 μm (+ -4.9 μm) and 9.3 μm (+ -2.4 μm), respectively. The data show that cyclodextrins, in particular β -cyclodextrin, also partition themselves at the interface between glycerol and silicone pre-elastomer, and thus act as stabilizing surfactants on the emulsion resulting from the mixing of the components with respect to the composition of the present invention.

Polymerization of the emulsion 2 is possible in the presence of β -cyclodextrin, despite the presence of nitrogen in the pyritinidine-derivative. It was observed that complexation of poisons to platinum catalysts by cyclodextrins significantly reduced inhibition of addition cure systems. It is believed that the pyritinidine-derivative itself is (at least partially) oriented with the nitrogen group within the cavity of its β -cyclodextrin and therefore cannot participate in platinum poisoning.

Solubilization of octenidine in Glycerol

Octenidine is an amphiphilic substance, and thus its solubility in glycerol is negligible, but micelles of higher solubility can be formed. In this study, beta-cyclodextrin (β CD) was used as a tool to allow significant amounts of hydrophobic substances to be dissolved in hydrophilic media such as glycerol. Cyclodextrins serve as cyclic oligosaccharides that form host-guest complexes with hydrophobic molecules, thereby achieving a variety of potential uses. Octenidine (0.35g) and β -cyclodextrin (0.3182g) were added to glycerol here. The molar ratio between octenidine and β -cyclodextrin in the examples was 2: 1. The mixture was heated to 80 ℃ and stirred using a magnetic stirrer until a clear solution was obtained (typically no more than 30 minutes). The clear mixture obtained indicates the successful preparation of the β CD-octenidine complex.

Preparation of functional adhesive

The mixture containing glycerol and the beta CD-octenidine complex is placed in a plastic container. 12.5g of MG7-9900 part A and 12.5g of MG7-9900 part B were subsequently added. The composition was mixed using a double asymmetric centrifuge SpeedMixer Dac 150FVZ-K at 3500 revolutions per minute (rpm) for 5 minutes. A silicone pre-elastomer in glycerin emulsion was prepared in this manner. The emulsion was cast onto an inert plastic support and spread using a commercial knife to form a 350 μm thick film (t)_EL). The material was then placed in an oven at 80 ℃ for 1 hour. The resulting polymerized skin patch was then cut into 25cm pieces²While still attached to the support. The resulting skin patch showed good surface adhesion with respect to tack time variation and ease of release from the surface after use.

Release study

The release profile of octenidine from the polymeric skin patch was determined by immersing the sample in 200ml of deionized water. The progress of octenidine release is monitored by measuring changes in the concentration of octenidine in an aqueous environment. Using a UV-visible spectrophotometer, a POLARstar Omega microplate reader from BMG LabTech was used for the test and the results were compared to a calibration curve for the beta CD-octenidine-complex in aqueous solution. Each release profile represents the average of three independent experiments. Testing samples in tightly sealed containers (placed on a rotary shaker) In order to avoid water evaporation. The release profile of the various samples is expressed in μ g/cm as a function of time²Graph of the released octenidine.

Example 1

Stability of glycerin-in-silicone emulsions comprising octenidine

Emulsion 1: emulsion of continuous phase-uncured pressure sensitive silicone adhesive MG7-9900 from Dow Corning Corp. Disperse phase-glycerol (40 phr).

Emulsion 2: emulsion of continuous phase-uncured pressure sensitive silicone adhesive MG7-9900 from Dow Corning Corp. Dispersed phase-glycerin (40phr) with 3 wt% beta-cyclodextrin and 3 wt% octenidine (weight-percent based on total composition).

The stability of the glycerin-in-silicone pre-elastomer emulsion with and without the β -cyclodextrin-octenidine complex was investigated.

The average droplet size was calculated based on analysis of at least 100 adjacent glycerol domains in both emulsions. The experiment (FIG. 5) shows that the mean droplet diameters of emulsion 1 and emulsion 2 at 10 minutes after mixing are 16.0 μm (+ -4.9 μm) and 9.3 μm (+ -2.4 μm), respectively. The data show that β -cyclodextrin partitions itself in the glycerol phase and also at the interface between glycerol and silicone pre-elastomer, and thus acts as a stabilizing surfactant on the emulsion resulting from the mixing of the components with respect to the composition of the present invention.

Polymerization of emulsion 2 is possible in the presence of beta-cyclodextrin despite the presence of nitrogen in octenidine. It was observed that complexation of poisons to platinum catalysts by cyclodextrins significantly reduced inhibition of addition cure systems. Octenidine is believed to orient itself (at least in part) with the nitrogen groups within the cavity of its β -cyclodextrin, and thus cannot participate in platinum poisoning.

Example 2

Effect of octenidine content on the Release of octenidine from Silicone skin Patches

Skin patches containing octenidine at 0.3 wt%, 1 wt% and 3 wt% were studied. The molar ratio between octenidine and β CD was kept constant at 2:1(2 molecules of octenidine/one molecule of β CD). The release profiles presented in fig. 6 clearly demonstrate that the drug dose delivered from the different skin patches increased as expected with increasing octenidine content.

After 24 hours, samples with 0.3 wt%, 1 wt%, and 3 wt% octenidine released approximately 3 μ g, 12 μ g, and 39 μ g octenidine/cm, respectively²The film of (1). Within the accuracy of the experiment, the dose release appeared to be linearly proportional to the octenidine content (1:3:10) and the release dose (1:4:13), respectively, in the skin patch. The present inventors believe, without being bound by this theory, that the observed excess release may be related to a secondary release mechanism as discussed below for example 3.

All three patches released enough octenidine to obtain an antibacterial effect against the common bacteria given in table 1.

Example 3

Effect of beta-Cyclodextrin content on Octenidine Release 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 formed skin patches was investigated. In this study, samples of octenidine having two molecules (molar ratio 2:1) and one molecule (molar ratio 1:1) per molecule of β -cyclodextrin were studied. The release profiles for the two membranes are presented in figure 7.

As can be seen from the figure, octenidine was released from a skin patch containing octenidine and β -cyclodextrin in a 2:1 ratio to water slightly faster than from the 1:1 composition, and there was no significant change in the release kinetics between the two compositions. The data appear to be consistent with the hypothesis that octenidine and β -cyclodextrin form a 1:1 complex, where the 1:1 complex dominates the diffusion and release characteristics of the entire silicone elastomer.

In particular, the data appear to be consistent with the model presented in fig. 2, wherein the active release is mainly via release from an active reservoir contained in the glycerol phase, which maintains a (substantially) constant concentration of active in the silicone elastomer matrix.

In this model, the release of the hydrophobic active will be inhibited by insufficient water absorption. Octenidine, a surfactant with a reasonably high CMC-value (estimated by Steward et al to be 3.79mM in water and possibly higher in glycerol), will have some solubility in water and glycerol, which is significantly enhanced in the presence of cyclodextrin. Thus, the inventors believe, without being bound by this theory, that the release of octenidine may be governed by the release rate of the 1:1 octenidine- β CD-complex, where octenidine directly solubilized (micellar) in glycerol and (subsequently) water has a partial contribution.

Given that a molar ratio of octenidine to β -cyclodextrin of 2:1 only results in an increased delivery efficacy of about 25% to 30% over a 1:1 molar ratio, an optimal formulation of octenidine to β -cyclodextrin (when considering only the release rate) should be formulated with a molar ratio of these two components approaching 1:1 or lower, preferably 1:1.1, 1:1.2, 1:1.3, 1:1.4 or even 1: 1.5. Thus, substantially all octenidine will complex with β -cyclodextrin (the latter being in excess), whereby substantially all octenidine will be available for release via a faster octenidine- β CD-complex release mechanism as compared to the slower release rate of octenidine that is not part of the octenidine- β CD-complex.

However, using an excess of octenidine over β -cyclodextrin, such as for example in a molar ratio of 3:1, 2.5:1, 2:1, or even 1.5:1, has the following advantages: as octenidine is available for release via a secondary release mechanism, the overall release of octenidine from the skin patch is increased.

Example 4

Effect of Glycerol loading on Octenidine Release from Silicone skin Patches

Samples with 40phr and 60phr (parts by weight per hundred parts by weight of silicone rubber) of glycerol were prepared and studied. The amounts of octenidine and β -cyclodextrin in the membrane were kept constant at 1 wt%, wherein octenidine and β -cyclodextrin were present in a 2:1 molar ratio.

The results presented in fig. 8 are consistent with the release model presented in fig. 2, where the release rate of the active substance increases with increasing loading of glycerol in the membrane.

In the first part of the drug delivery process, the release rates appeared comparable, however after about 5 hours the difference became significant. After about 24 hours, the sample with 40phr of glycerin released about 12 μ g of octenidine/cm²Whereas a sample with 60phr of glycerol released about 18 μ g of octenidine/cm²。

In the context of the release model detailed in fig. 2, the observed data is interpretable. Initially, the reservoir near the surface of the skin patch containing octenidine and the octenidine- β -cyclodextrin 1:1 complex is depleted, thus resulting in approximately equal delivery rates between the two different samples. Subsequently, the delivery rate is dominated by the exchange rate between deeper located reservoirs and drug release reservoirs at the surface, with a reservoir structure of 60phr glycerol allowing faster reservoir exchange than 40phr glycerol.

The present inventors believe, without being bound by this theory, that this is due to wall thinning in the polymerized silicone matrix, wherein the passage of the silicone matrix wall by octenidine and/or octenidine- β -cyclodextrin-complex is rate limiting.

Conclusion

In summary, complexation of octenidine with β -cyclodextrin in the compositions and elastomer matrices of the present invention allows for a wide range of (easily) adaptable delivery rates of octenidine from silicone elastomer skin patches.

In some embodiments, the octenidine will be in excess compared to the cyclodextrin, thereby increasing the rate of delivery, wherein the octenidine not complexed with the cyclodextrin is used as a long-term reservoir for slow release of octenidine from the skin patch. In other embodiments, the cyclodextrin is redundant for rapid delivery of octenidine and rapid depletion of the skin patch of octenidine.

According to the studies of the inventors of the present invention, the silicone elastomer matrix containing 40phr or 60phr of glycerol has a micellar structure (compare figures 1 and 5), whereas the silicone elastomer matrix containing more than 100phr of glycerol is bicontinuous in both the silicone elastomer phase and the glycerol phase. According to the present inventors' studies, the delivery rate of small hydrophilic actives from discrete micellar structures below about 70phr glycerol follows first order release kinetics, from about 70phr glycerol to about 100phr glycerol, the delivery of small hydrophilic actives follows near zero release kinetics, and above about 100phr glycerol, such as at 120phr, the release of small active hydrophilic actives follows zero order release kinetics.

The release data presented so far are consistent with the observations made previously, as the release data show first order release kinetics as expected for glycerol contents below about 70 phr.

Thus, in some embodiments, an initial emulsion will be prepared having a glycerin content of less than 70phr, thereby creating a micellar structure of glycerin in the polymerized silicone elastomer; in other embodiments, the glycerol content will be greater than 100phr, thereby producing a bicontinuous emulsion and a polymerized silicone elastomer.

Embodiments in which octenidine is in excess relative to cyclodextrin and/or in which the glycerol content is below 70phr are advantageously applicable, for example, in cases where skin patches cannot be easily replaced. Embodiments in which octenidine is present in a lower molar ratio than cyclodextrin and/or in which the glycerol content is higher than 100phr are beneficially applicable, for example where the skin patch is intended for short-term use only, or in combination with frequent replacement, or where one skin coverage of the skin patch is intended only during early wound healing.

Thus, a wide range of easily adjustable skin patches for delivering octenidine to, for example, a wound site where release of an antibacterial agent is desired are exemplified, whereby the amount and rate of release can be adjusted by simply manipulating the concentrations of the components of the compositions and emulsions prepared prior to polymerization of the initial compositions and emulsions used to form the resulting skin patch.

End comment

The term "comprising" as used in the claims does not exclude other elements or steps. The term "a/an" as used in the claims does not exclude a plurality. Although the invention has been described in detail for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the scope of the invention.