Microneedle array containing disinfectant

Abstract

The present invention relates to a microneedle array for use in the intradermal application of an active agent, comprising a plurality of microneedles formed on a support from a formulation containing a biodegradable polymer, an active agent and a bactericide.

Description

Technical Field

[0001] The present invention relates to a microneedle array for intradermal application of an active substance, comprising a plurality of microneedles formed from a formulation containing a biodegradable polymer, an active substance and a bactericide on a support.

Background Art

[0002] Skin, as the most versatile organ in the human and animal organisms, consists of several layers and, in addition to its function as an integumentary organ, fulfills essential functions related to metabolism, thermoregulation, and immune response. The outermost skin layer, the so-called stratum corneum, is known to have a barrier property to prevent foreign substances from entering the body and endogenous substances from exiting the body. The stratum corneum is a complex structure consisting of compacted keratinocyte residues, has a thickness of about 10 - 30 μm, and forms a watertight membrane to protect the body. The natural impermeability of the stratum corneum hinders the administration of most pharmaceuticals and other substances through the skin within the scope of transdermal application.

[0003] Microneedle systems (MNS) consisting of microneedle arrays (MNA) and optionally other components have recently been established as an alternative to classical transdermal applications such as transdermal patches for pharmaceuticals and cosmetics. While a transdermal patch is adhered to the skin and the released active substance is absorbed through the skin, microneedles, also partially referred to as skin penetration systems, are pressed against the skin by the compressive force from the array against the application site to penetrate the stratum corneum, thereby generating fluid channels and, as a result, enabling the application of the active substance intradermally. Such microneedle arrays in microneedle systems, their preparation, and their use for administering several active substances are known in the prior art.

[0004] A recent investigation into developments in the field of microneedles is provided in the paper "Microneedles as an alternative technology for transdermal drug delivery systems: Patent Review" by ML Barreto Queiroz et al., published in "EXPERT OPINION ON THERAPEUTIC PATENTS 2020, Vol. 30, No. 6, pp. 433-452". In particular, various systems are presented, including solid removable microneedles, coated microneedles, self-dissolving microneedles, hollow microneedles, and microneedles that form hydrogels, with the concept of self-dissolving microneedles attracting particular attention recently.

[0005] Accordingly, International Publication No. 2019 / 115815 discloses a microneedle array for use in intradermal application of a drug in salt form, comprising a plurality of microneedles on a support, the microneedles comprising a formulation containing at least one drug in salt form and at least one biodegradable polymer.

[0006] In their paper "Solid lipid nanoparticle-based dissolving microneedles; A promising intradermal lymph targeting drug delivery system with potential for enhanced treatment of lymphatic filariasis," published in the Journal of Controlled Release 316(2019)34-52, ADPermana et al. describe the use of autolytic microneedles for the treatment of lymphatic filariasis.

[0007] International Publication No. 2019 / 092257 describes a microneedle array containing a polyvinylpyrrolidone and HBsAg formulation for use in intradermal application for hepatitis vaccination.

[0008] International Publication No. 2018 / 224559 describes a microneedle array containing a formulation of polyvinylpyrrolidone and at least one glucagon-like peptide analog for use in intradermal application for controlled release.

[0009] International Publication No. 2019 / 202170 relates to a microneedle array containing a fully soluble formulation for use in intradermal application of interferon, in which polyvinylpyrrolidone is the main component of the formulation.

[0010] In particular, for microneedles used for administering protein and nucleic acid drugs, currently approved sterilization methods such as gamma ray sterilization cause degradation of the administered drug, making the provision of sterile products a challenge. Therefore, obtaining sterile products requires expensive and complex sterile manufacturing.

[0011] To address this problem, U.S. Patent Application Publication No. 2017 / 0028184 proposes an in-situ anode and cathode microneedle system achieved by fabricating microneedles from a material having an electrical potential. The metal used to prepare the microneedles has been reported to have bactericidal properties.

[0012] European Patent No. 3669929 describes a microneedle array for plumping the lips, wherein the microneedles may contain a bactericide in addition to a water-soluble polymer.

[0013] U.S. Patent Application Publication No. 2019 / 0358441 describes a microneedle patch comprising a substrate and a microneedle matrix comprising two or more microneedles, each microneedle having a base, a conical sharp end filled with a mixture of a carrier biosoluble material and an active ingredient, and a plurality of wider conical branches geometrically intersecting each other and filled with the biosoluble material between the sharp end and the base, and a base film attached to the substrate on its outer surface, connecting the base and inner surface of the microneedles in the microneedle matrix, wherein the sharp end of the microneedle is positioned over the branch of the microneedle, and the substrate and base film are made of a flexible material.

[0014] International Publication No. 2011 / 127149 discloses a method for controlled release of an effective amount of at least one bioactive or pharmaceutically active agent in a subject, comprising administering a combination biomaterial to the subject, the combination biomaterial comprising a combination biomaterial substrate and a biodegradable polymer, the biodegradable polymer comprising one or more bioactive or pharmaceutically active agents encapsulated by the biodegradable polymer, and the one or more bioactive or pharmaceutically active agents being delivered to the subject over a period of more than one week.

[0015] International Publication No. 2021 / 077119 provides organosilicon quaternary ammonium compounds, as well as formulations thereof for topical medical therapies in humans and animals. [Prior art documents] [Patent Documents]

[0016] [Patent Document 1] International Publication No. 2019 / 115815 [Patent Document 2] International Publication No. 2019 / 092257 [Patent Document 3] International Publication No. 2018 / 224559 [Patent Document 4] International Publication No. 2019 / 202170 [Patent Document 5] U.S. Patent Application Publication No. 2017 / 0028184 [Patent Document 6] European Patent No. 3669929 [Patent Document 7] U.S. Patent Application Publication No. 2019 / 0358441 [Patent Document 8] International Publication No. 2011 / 127149 [Patent Document 9] International Publication No. 2021 / 077119 [Non-patent literature]

[0017] [Non-Patent Document 1] MLBarreto Queiroz et al., "Microneedles as an alternative technology for transdermal drug delivery systems: Patent Review," EXPERT OPINION ON THERAPEUTIC PATENTS 2020, Vol. 30, No. 6, pp. 433-452. [Non-Patent Document 2] ADPermana et al., “Solid lipid nanoparticle-based dissolving microneedles;A promising intradermal lymph targeting drug delivery system with potential for enhanced treatment of lymphatic filariasis,” Journal of Controlled Release 316(2019)34-52 [Overview of the project] [Problems that the invention aims to solve]

[0018] Despite comprehensive efforts made in the prior art, when microneedles are used, there still remains a residual risk of infection by introducing pathogens into the skin. Accordingly, an object of the present invention is to provide a microneedle array that can further reduce this risk and is suitable for administering many active ingredients.

Means for Solving the Problems

[0019] Surprisingly, within the scope of the present invention, it has been found that this object is achieved by a microneedle array in which the microneedles are formed from a blend containing a biodegradable polymer and a bactericide.

Mode for Carrying Out the Invention

[0020] Thus, the present invention relates first to a microneedle array for use in intradermal application, comprising a plurality of microneedles on a support, wherein the microneedles are formed from a blend containing a biodegradable polymer, an active substance, and a bactericide having at least one guanidine group and / or biguanide group. The microneedle array according to the present invention has the advantage of eliminating the expensive aseptic production of microneedles. Rather, the microneedle array according to the present invention has the sterility necessary to further minimize the risk of infection, even though it is produced in a "low bioburden" environment.

[0021] In contrast to the solutions proposed in the prior art, i.e., to accommodate a bactericide in a cavity within the microneedle, the bactericide of the present invention is integrated and / or embedded in the polymer matrix of the microneedle and is immediately available. Further, the solution according to the present invention offers the advantage that the cavity that can be provided within the microneedle can be used to accommodate further active substances rather than being blocked by the bactericide.

[0022] The fungicides are selected from a group of compounds from the guanide and biguanide classes, which exhibit favorable incorporation of biodegradable polymers into polymer matrices, as well as high compatibility with a variety of common drugs.

[0023] Within the scope of the present invention, a bactericide is said to have a guanide group if the corresponding compound has the following structural elements in its chemical structure.

[0024] [ka]

[0025] "Bactericides containing a biguanide group" refers to compounds having the following structural elements:

[0026] [ka]

[0027] Guanides and biguanides are known in the prior art as antimicrobial agents. Guanides and biguanides can be used as monomers, or preferably as polymers, i.e., as polyguanides and / or polybiguanides. In preferred embodiments, guanides and / or biguanides are in the form of water-soluble, physiologically acceptable salts. More preferably, guanides and biguanides are in the form of hydrohalides, such as hydrochlorides or hydrobroms.

[0028] When polybiguanides were used as bactericides, particularly favorable results were observed regarding compatibility with other drugs and bactericidal activity. Therefore, embodiments of the present invention in which the aforementioned bactericide is a polybiguanide, preferably chlorhexidine and / or polyhexamethylene biguanide (PHMB), and especially polyhexamethylene biguanide (PHMB), are preferred.

[0029] The microneedle arrays according to the present invention are provided, in particular, for the transdermal administration of cosmetic and pharmaceutically active substances, especially pharmaceutically active substances. They offer the advantage that the aforementioned active substances are present together with a bactericide and a biodegradable polymer as a homogeneous formulation from which the microneedles are made. The active substances and bactericides are released by dissolving the polymer and are therefore directly available at the administration site. Therefore, the aforementioned active substances, particularly drugs, are integrated into or incorporated into the matrix of the microneedle or microarray formulation. Furthermore, at least one active substance, particularly drug, can be applied to the microneedle or support. However, the aforementioned active substances, particularly drug, are components of the microneedle and for that purpose, it is preferable that they be integrated into or incorporated into the microneedle, particularly the tip of the microneedle.

[0030] The active substances used in accordance with the present invention include, in particular, drugs as defined in EU Directive 2001 / 83 / EG (Community Code on Medicinal Products for Human Use).

[0031] Within the scope of the present invention, the microneedle array according to the present invention has been found to be suitable for administering various active substances. Therefore, in the initial experiments, no decrease in drug activity was observed. Preferably, the active substance is a pharmaceutically active substance. Preferably, the active substance is selected from the group consisting of analgesics, anesthetics, anti-asthmatics, antibiotics, antidepressants, antidiabetics, antifungals, antihypertensives, anti-inflammatorys, antineoplastics, anxiolytics, nucleic acids, immunostimulants, immunosuppressants, vitamins, hormones, peptides, proteins, and vaccines. In particular, the aforementioned active substance is a vaccine, an analgesic, or insulin. Even more preferably, the active substance is a vaccine.

[0032] In a more preferred embodiment, the active substance is nucleic acid, particularly mRNA and silencer mRNA.

[0033] In preferred embodiments, the active substance is in the form of lipid nanoparticles. The active substance can be used independently or in combination of several active substances.

[0034] In a preferred embodiment, the microneedle has a multilayer structure, with each layer formed from a biodegradable polymer. Preferably, at least one layer is formed from a formulation containing a biodegradable polymer, an active substance, and a bactericide. In a particularly preferred embodiment, this layer forms the outermost layer of the microneedle. In a preferred embodiment, at least one inner layer is formed from a formulation containing a biodegradable polymer and a bactericide. In this way, sustained release of the bactericide can be achieved.

[0035] In another, alternatively preferred embodiment, the outermost layer of the microneedle is formed from a formulation containing a biodegradable polymer and a bactericide. In this way, the bactericide can exhibit its activity at the administration site even before the active substance is released.

[0036] The microneedles according to the present invention are made from a formulation containing a biodegradable polymer. More preferably, the microneedles are made from a co-compound of a biodegradable polymer, an active substance, and a bactericide. In practical applications, self-dissolving microneedle arrays have proven particularly advantageous. In particular, these are microneedle arrays that remain in the skin after administration and dissolve upon release of the active substance. Because the microneedles remain in the skin, the application time can be shortened, and, for example, irritation of the skin surface by the support material can be avoided. Furthermore, this method allows for the immediate and sustained release of the active substance. For microneedles to be suitable for retention in the skin, the materials used to prepare them must be toxicologically safe on the one hand and self-dissolving on the other hand. This combination of properties is achieved, in particular, when the microneedles are made from a specific biodegradable polymer.

[0037] Therefore, embodiments in which the aforementioned biodegradable polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, cellulose, dextran, glycan, glycosaminoglycan, α-hydroxy acids such as hyaluronic acid, lactic acid and / or glycolic acid, polylactide, polyglycolide, poly(lactide-co-glycolide), and copolymers thereof with polyethylene glycol, polyanhydride, poly(ortho)ester, polyurethane, polybutyric acid, polyvaleric acid, and poly(lactide-co-caprolactone) are preferred. In particularly preferred embodiments, the aforementioned biodegradable polymer is selected from polyvinylpyrrolidone and dextran.

[0038] A microneedle array may have a number of microneedles to deliver a substance through or into the patient's skin, and the aforementioned microneedle array is applied to the patient's skin. Each microneedle in the microneedle array preferably has a long shaft having two ends, one end of which is the base of the microneedle to which the microneedle is attached to a sheet-like support or to which the microneedle is integrated with a sheet-like support. The end of the shaft opposite the base preferably has a tapered design to allow the microneedle to penetrate the skin as easily as possible. A hollow microneedle may have at least one passage or channel or at least one hole extending from the base of the microneedle to the tip of the microneedle or substantially to the tip of the microneedle. The passage preferably has a circular cross-section.

[0039] A microneedle may have a shaft with a circular cross-section or a non-circular cross-section, such as a triangular, square, or polygonal cross-section. The shaft may have a passage or several passages extending from the needle base to the needle tip, or substantially to the needle tip. A microneedle may be formed as a hook (or barb), and one or more such microneedles may have one or more such hooks. Furthermore, a microneedle may have a helical shape and a rotatable mount that facilitates penetration into the skin when rotational motion is applied, as described, for example, in German Patent Application Publication No. 10353629, and can be fixed in the skin at a desired penetration depth in the epidermis.

[0040] The diameter of the microneedles is typically 1 μm to 500 μm, preferably 10 μm to 100 μm. The diameter of the passages is typically 3 μm to 80 μm, preferably suitable for the passage of liquid materials, solutions, and preparations. The length of the microneedles is typically 10 μm to 1000 μm, particularly 100 μm to 500 μm.

[0041] The microneedles are attached to or integrated with a sheet-like support via their base. The microneedles are preferably provided to stand essentially perpendicular to the surface of the support. The microneedles may have a regular or irregular arrangement. Several arrays of microneedles may have microneedles with different cross-sectional shapes, different diameters, and / or different lengths. Some of the aforementioned arrays of microneedles may have only hollow microneedles. The arrays may both include solid microneedles and may have partially solid composite materials, such as solid microneedles impregnated with a liquid encapsulant.

[0042] The microneedle array may have a sheet-like support, which essentially has a disc-shaped, plate-shaped, or sheet-like basic shape. The support may have circular, elliptical, triangular, quadrilateral, or polygonal basic regions. The support may be made from different materials, such as metals, ceramic materials, semiconductors, organic materials, polymers, or composite materials. Suitable materials for preparing the support are preferably sheets or sheet-like materials, such as microporous membranes made preferably from polyethylene (PE) or polypropylene (PP), or diffusion membranes made preferably from ethylene / vinyl acetate copolymer (EVA) or polyurethane (PU). Suitable materials for preparing the support can be selected from the group consisting of polyesters such as polyethylene terephthalate (PET), polycarbonate (PC), polyetherketone (PEK), polyethylene naphthalate (PEN), polybutylene terephthalate (PBT), polyurethane (PU), polystyrene (PS), polyamide (PA), polyoxymethylene (POM), polyolefins such as polyethylene (PE) and polypropylene (PP), polytetrafluoroethylene (PTFE), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), polylactic acid (PLA), and cellulosic polymers such as hydrated cellulose or cellulose acetate. Suitable materials for preparing the support can also be selected from the group consisting of metals such as aluminum, iron, copper, gold, silver, platinum, alloys of the above metals, and other pharmaceutically acceptable metal foils or sheets coated with vapor-deposited metals.

[0043] Preferably, the support is made of a flexible material, such as plastic. A support made of a flexible material can conform better to the skin surface and its curvature compared to a support made of a non-flexible material. This achieves better contact between the microneedle array and the skin, improving the reliability of the microneedle array.

[0044] In a preferred embodiment, a disinfectant can also be provided on the support.

[0045] The present invention further relates to a process for preparing the aforementioned microneedle array according to the present invention, characterized in that the microneedles are made from a biodegradable polymer, and more particularly comprised thereof, and a bactericide is embedded in the polymer matrix.

[0046] The process according to the present invention consists of the following steps: a) To provide a liquid formulation comprising a biodegradable polymer, an active substance, and a bactericide having at least one guanide group and / or a biguanide group, b) Fill a flexible mold corresponding to the negative print of the prepared microneedle array with this formulation. c) Dry this mixture in the mold, and d) Including demolding the dried microneedle array.

[0047] In a preferred embodiment, the biodegradable polymer and / or bactericide is in the form of its monomer in the provided liquid formulation.

[0048] The aforementioned drying of the formulation in a flexible mold for forming the microneedle array can be carried out by methods known to those skilled in the art, preferably by heating and / or ventilation.

[0049] The amount of bactericide in the formulation is preferably such that it allows for incorporation into the polymer matrix, while achieving a sufficient bactericidal effect to minimize the risk of infection by the microneedles. In preferred embodiments, the amount of bactericide in the liquid formulation is 100 to 600 μg, preferably 150 to 550 μg, and particularly 200 μg or 400 μg, based on 1 ml of the liquid formulation.

[0050] In a preferred embodiment, further formulations can be incorporated into a flexible mold to form a multilayer structure.

[0051] The present invention further relates to the use of formulations containing biodegradable polymers, active substances, and bactericides having at least one guanide group and / or biguanide group for preparing microneedle arrays, particularly microneedle arrays for transdermal application.

[0052] The present invention will be further illustrated by the following embodiments, but these should not be understood as limiting the concept of the present invention. [Examples]

[0053] The antimicrobial activity of the microneedle array according to the present invention was tested by an inhibitory area test. A microneedle array was prepared from a formulation containing dextran as a biodegradable polymer and 200 μg / ml of PHMB, and then spread onto an agar plate containing bacteria. After a 24-hour incubation period, the formation of inhibitory areas, as a measure of reduced bacterial growth around the microneedle array, was clearly observed, with each contact site of the microneedle array marked as a white dot. Surprisingly, the same results were obtained even with microneedle arrays that had already been stored for one month. [Brief explanation of the drawing]

[0054] [Figure 1] This figure shows the antibacterial effect of the microneedle array according to the present invention against Pseudomonas aeruginosa. [Figure 2] This figure shows the antibacterial effect of the microneedle array according to the present invention against Staphylococcus aureus.

[0055] Furthermore, using hepatitis B S antigen (HBsAg) as an exemplary active substance and PHMB as a bactericide, the effect of the bactericide on other active substances in the formulation was tested. Since adverse effects of the bactericide on the integrity of HBsAg are expected to manifest as a decrease in drug binding in HBsAg-specific ELISA, microneedle arrays according to the present invention were prepared and measured from formulations of dextran, 200 μg / ml or 400 μg / ml of PHMB, and 20 μmol of HBsAg per microarray. The HBsAg ELISA kit from Alpha Diagnostics was used as the ELISA. The results are summarized in Figure 3, which shows two microarrays according to the present invention containing 200 μg / ml and 400 μg / ml of PHMB, respectively, and a control series without PHMB. A lower amount found in the ELISA indicates a greater effect of the bactericide on the active substance. As can be seen from the data in Figure 3, no significant difference in antigen binding was observed between the control and the PHMB-containing samples.

Claims

1. A microneedle array for use in intradermal application, comprising a plurality of microneedles on a support, wherein the microneedles are formed from a co-compound containing a biodegradable polymer, an active substance, and a bactericide having at least one guanide group and / or a biguanide group, The active substance and the bactericide are incorporated into the polymer matrix of the microneedle. The aforementioned active substance is a vaccine, in a microneedle array.

2. The microneedle array for use according to claim 1, characterized in that the disinfectant is a polybiguanide, preferably chlorhexidine and / or polyhexamethylene biguanide (PHMB), particularly polyhexamethylene biguanide (PHMB).

3. The microneedle array for use according to at least one of claims 1 to 2, characterized in that the active substance is selected from the group consisting of nucleic acids, peptides, and proteins.

4. The microneedle array for use according to at least one of claims 1 to 2, characterized in that the biodegradable polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, cellulose, dextran, glycan, glycosaminoglycan, α-hydroxy acids such as hyaluronic acid, lactic acid and / or glycolic acid, polylactide, polyglycolide, poly(lactide-co-glycolide), and copolymers thereof with polyethylene glycol, polyanhydride, poly(ortho)ester, polyurethane, polybutyric acid, polyvaleric acid, and poly(lactide-cocaprolactone).

5. The following steps a) To provide a liquid formulation comprising a biodegradable polymer, an active substance, and a bactericide having at least one guanide group and / or a biguanide group, b) Filling a flexible mold corresponding to the negative print of the prepared microneedle array with the aforementioned compound. c) Drying the compound in the mold, and d) A process for preparing a microneedle array for use according to at least one of claims 1 to 2, comprising demolding a dried microneedle array.

6. The process according to claim 5, characterized in that the amount of disinfectant in the liquid formulation is 100 to 600 μg, preferably 150 to 550 μg, and particularly 200 μg or 400 μg, based on 1 ml of the formulation.

7. The use of a formulation for preparing a microneedle array that includes a biodegradable polymer, an active substance, and a bactericide containing at least one guanide group and / or a biguanide group, The active substance and the bactericide are incorporated into the polymer matrix of the microneedle. The use of the formulation, wherein the active substance is a vaccine.

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