Microneedle system for applying glucagon-like peptide analogues

Abstract

The present invention relates to a microneedle system (MNS) for the intradermal application of controlled release glucagon-like peptide analogues.

Description

[Technical Field]

[0001] The present invention relates to an intradermally applied microneedle system (MNS) for the controlled release of glucagon-like peptide analogues. [Background technology]

[0002] Glucagon-like peptide GLP-1 (GLP-1) is a gastrointestinal hormone that is formed together with GLP-2 in gastrointestinal cells. GLP-1 is an insulinotropic peptide that regulates blood glucose levels. Its physiological role is to maintain normal glucose homeostasis and energy balance. GLP-1 inhibits glucagon secretion and delays gastric emptying. GLP-1 has an extremely short half-life of approximately 1 minute, making it unsuitable as a therapeutic agent.

[0003] However, slight changes in the structure of GLP-1 prevent it from being affected by the degradative peptidase DDP IV. Even peripheral changes, such as amino acid substitutions, can make the molecule resistant to peptidases. Some GLP-1 analogs developed to date are more potent than endogenous GLP-1 and are used as antidiabetic agents, but they must be applied subcutaneously.

[0004] Such antidiabetic agents of glucagon-like peptide analogues or antagonists, also called incretin mimetics, are specifically exenatide, liraglutide, and lixisenatide (hereinafter referred to as glucagon-like peptide analogues), which bind to GLP-1 receptors. Such glucagon-like peptide analogues have up to 50 amino acids and a molar mass of up to 5 kDa. Their half-life is usually longer than 12 hours.

[0005] Exenatide (C 184 H 282 N 50 O 60 S, Mr=4186.6 Da) is a synthetic peptide consisting of 39 amino acids.

[0006] Liraglutide, or γ-L-glutamoyl(N-α-hexadecanoyl)-Lys26, Arg34-GLP-1(7-37), is a branched peptide consisting of 39 amino acids (C 172 H 265 N 43 O 51 , Mr=3751.2Da).

[0007] Lixisenatide (C 215 H 347 N 61 O 65 S, Mr = 4858.49 Da) is a synthetic peptide consisting of 44 amino acids.

[0008] According to the present invention, exenatide is preferred.

[0009] Skin is composed of several layers. The outermost skin layer, the stratum corneum, has known barrier properties to prevent the entry of foreign substances into the body and the leakage of endogenous substances from the body. For this purpose, the stratum corneum is a complex structure of densified keratinocyte remnants, approximately 10–30 micrometers thick, forming a watertight membrane for protection. The inherent impermeability of the stratum corneum prevents the delivery of many therapeutic drugs and other substances through the skin, except for subcutaneous applications. Proteins, in particular, are difficult to introduce through the skin.

[0010] The microneedle system (MNS) is composed of a microneedle array (MNA) and possibly other components, and when the microneedles (also called main perforation parts) of the array (MNA) are pressed against the application point on the skin by compressive force, they penetrate the stratum corneum, thus forming fluid channels and applying active substances intradermally. Such a microneedle array (MNA) in the microneedle system (MNS) and its manufacture are described in the prior art (Patent Document 1).

[0011] It is also known that MNS can be used for controlled release, and there is a high demand for controlled release, especially for glucagon-like peptide analogs, particularly for controlled release that provides or supports the antidiabetic effect throughout the day, for more than 12 hours (h), or even 24 hours.

[0012] Patent Document 2 describes the controlled release of exenatide by polyvinyl alcohol (PVA)-based MNS (claim 4). Patent Document 2 claims that controlled release based on polyvinylpyrrolidone (PVP) is not possible.

[0013] However, PVP is preferable to PVA in terms of its influence on the release of the active substance and is therefore more suitable for this purpose. [Prior art documents] [Patent documents]

[0014] [Patent Document 1] International Publication No. 2004000389A1 [Patent Document 2] U.S. Patent No. 9320878B2 Summary of the Invention [Problem to be solved by the invention]

[0015] Therefore, the object of the present invention is to enable intradermal application of a glucagon-like peptide analogue in a controlled release manner by means of an MNS containing an MNA based on a suitable formulation. [Means for solving the problem]

[0016] This object is achieved by the present invention by a microneedle system (MNS) containing MNA as set forth in claim 1, wherein the glucagon-like peptide analogue is the subject of formulation of the MNA together with PVP, and thus is inherent in the MNA or forms a unit with the MNA. For this purpose, the MNA may be in an integrated form or in a form as a part thereof. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 shows the in vitro results for formulations F1, F2, and F3. DETAILED DESCRIPTION OF THE INVENTION

[0018] The subject of the present invention is therefore a microneedle system containing an MNA comprising or consisting of a formulation of PVP and at least one glucagon-like peptide analogue for use in controlled release in intradermal applications.

[0019] The present invention therefore includes an article having a microneedle array comprising or consisting of a formulation of PVP and at least one glucagon-like peptide analogue for use in controlled release in intradermal applications.

[0020] Such a product is, for example, a pharmaceutical product or antidiabetic agent comprising a protruding microneedle array for the controlled release of at least one glucagon-like peptide analogue in intradermal application, which is used for the prevention and treatment of diabetes, type 2 diabetes, insulin resistance, high blood pressure, obesity, and metabolic syndrome.

[0021] The term "intradermal application" (synonymously referred to as "intracutaneous application") according to the present invention describes the administration of a substance (herein: glucagon-like peptide analogue) from an MNA to the skin and requires piercing the skin with a microneedle.

[0022] The term "controlled release" within the scope of the present invention means that the active substance (herein: glucagon-like peptide analogue) is released or dispensed continuously over a period of more than 2 hours, preferably more than 12 hours, in particular 24 hours. The active substance is not released suddenly or immediately (immediate release).

[0023] The present invention therefore relates to a product for use in controlled release in intradermal applications, wherein the time period for controlled release is greater than 2 hours, preferably 12 hours, in particular 24 hours.

[0024] Doses of glucagon-like peptide analogues up to 50 μg / MNA may be particularly advantageous for human applications.

[0025] This advantageously allows for a single application of a daily dose of glucagon-like peptide analogue.

[0026] Another object of the present invention is a method for the controlled release of at least one glucagon-like peptide analogue in intradermal application, comprising a microneedle array comprising or consisting of a formulation of PVP and at least one glucagon-like peptide analogue.

[0027] Another subject of the present invention is a method for carrying out an intradermal application for the controlled release of at least one glucagon-like peptide analogue, comprising: a) fixing a microneedle system according to the present invention to the skin; b) penetrating the skin with a microneedle array containing a formulation of PVP and at least one glucagon-like peptide analogue; The method includes:

[0028] In another embodiment, the formulation may comprise any PVP having a relative molecular mass greater than 10,000 Da. The proportion (wt%) of PVP in the formulation may be 50-99%, particularly 70-90%, and preferably 75-80%. In particular, the PVP content depends on the residual moisture content. Typical residual moisture contents may be 5-20%, particularly 12-18%. At a residual moisture content of 16%, the PVP content will be approximately 76% or possibly less.

[0029] In addition, the formulation may contain auxiliary substances and additives such as: a.) Binders or emulsifiers, such as carboxymethylcellulose, alginates, gelatin b.) Humectants, such as glycerin, urea, and trehalose c.) Humectants, such as cetyl alcohol, glyceryl monostearate d.) Antioxidants such as ascorbic acid and vitamin E However, preferred are poloxamers, alginates, and polysorbates (Tween).

[0030] The proportion of poloxamer in the formulation may be 2 to 7%, the proportion of alginate in the formulation may be 2 to 7%, and the proportion of polysorbate in the formulation may be 0.1 to 1%.

[0031] In another embodiment of the present invention, the applicator system can be used to apply a microneedle array (MNA) that can cause sudden skin stress. In another more preferred embodiment, the applicator is configured as a microneedle system containing a microneedle array. Such an applicator can advantageously activate a pressure mechanism to penetrate the microneedle array into the skin or stratum corneum (see, for example, WO2008091602A2, WO2016162449A1).

[0032] In another embodiment, the applicator system containing the microneedle array can be configured with conventional functional items that allow it to be fixed on the skin as well as being easily handled to apply pressure to the skin, and in particular can contain at least one fixing means.

[0033] Within the scope of the present invention, an applicator system is a system containing a device for placing a microneedle array on the skin and applying it intradermally for administration of a glucagon-like peptide analogue.

[0034] In an advantageous and preferred embodiment, the applicator system may include an electrically or mechanically controlled trigger device, and may have, for example, a plunger for positioning or applying the microneedle array on / to the skin so that the microneedles penetrate the skin.

[0035] The trigger device can include, for example, a pump, syringe, or spring to impact the plunger with sufficient energy. The plunger can be of any shape and nature, and must first reliably deliver the microneedle array from a first location to a second location on the skin for administration of the active substance.

[0036] The applicator system may also include a push button or a thread.

[0037] According to another embodiment, the microneedle array can contain a fixation means, preferably for fastening to the patient's or subject's skin using an adhesive strip or patch (also called a needle patch). Highly viscous substances that stick to the skin after a short period of light pressure (known as pressure-sensitive adhesives or PSAs) are suitable as adhesives. They have high cohesive and adhesive strength. For example, poly(meth)acrylate-based, polyisobutylene-based, or silicone-based adhesives can be used. In another embodiment, the fixation means can consist of a band, elastic band, rubber, or belt. Such fixation means can be used to ensure secure fixation to the body.

[0038] Such an applicator system allows the MNA according to the present invention to be reliably positioned for controlled release of the glucagon-like peptide analogue.

[0039] The following examples and figures are intended to explain the invention in more detail, without limiting it in any way.

[0040] Figure 1 shows in vitro results for formulations F1, F2, and F3, which demonstrate slowed and time-controlled release of the active agent exenatide over a period of up to 24 hours. The formulations are identified in Table 1.

[0041] [Table 1] [Example]

[0042] The microneedle composition contained the following ingredients / pharmaceutical adjuvants: - Polyvinylpyrrolidone (PVP) Type 1: MW 20-60kDa; Type 2: >1000kDa - Poloxamer (Pluronic F-68) - Sodium alginate - Glycerin - Polyoxyethylene sorbitan monooleate (polysorbate, Tween-80)

[0043] After drying, some of the water was left behind in the array to form a matrix structure with the polymer (PVP).

[0044] For the active substance exenatide with 50 μg, one preferred embodiment of the formulation was as follows:

[0045] [Table 2]

Claims

1. A microneedle array for use in controlled release in intradermal applications, comprising a formulation comprising 50-99% by weight of polyvinylpyrrolidone and at least one glucagon-like peptide analogue, and further adjuvants and additives; The glucagon-like peptide analogue is selected from the following group: exenatide, liraglutide, lixisenatide; The adjuvant and the additive are a.) a binder or emulsifier selected from carboxymethylcellulose, alginate, and gelatin; b.) a humectant selected from glycerin, urea, and trehalose; c.) a humectant selected from cetyl alcohol and glyceryl monostearate; d.) an antioxidant selected from ascorbic acid and vitamin E; e.) Polysorbate or Poloxamer The microneedle array is characterized in that it contains at least the alginate, the glycerin, and the polysorbate selected from the above, and forms a matrix structure together with the polyvinylpyrrolidone with residual moisture such that the residual moisture content is 5 to 20%.

2. A product for use in controlled release in intradermal application, comprising the microneedle array of claim 1, which comprises a formulation comprising 50 to 99% by weight of polyvinylpyrrolidone and at least one glucagon-like peptide analogue, and further adjuvants and additives; The product, characterized in that the glucagon-like peptide analogue is selected from the following group: exenatide, liraglutide, lixisenatide.

3. 10. The product of claim 2 for use in controlled release in intradermal application for the prevention and treatment of diabetes, type 2 diabetes, insulin resistance, hypertension, obesity, and metabolic syndrome.

4. A microneedle array or product for use in controlled release in intradermal application according to any one of claims 1 to 3, characterized in that the time period for controlled release is greater than 2 hours, greater than 12 hours or 24 hours.

5. A microneedle array or product for use in controlled release in intradermal application according to any one of claims 1 to 4, characterized in that the formulation contains an emulsifier.

6. 6. A microneedle array or product for use in controlled release in intradermal application according to claim 5, characterized in that the formulation contains 2-7% poloxamer, or 2-7% alginate, or 0.1-1% polysorbate.

7. A preparation is characterized in that it contains 70 to 90% by weight of polyvinylpyrrolidone. A microneedle array or product for use in controlled release in intradermal applications according to any one of claims 1 to 6.

8. A microneedle array or product for use in controlled release in intradermal application according to any one of claims 1 to 7, characterized in that a maximum dose of 50 μg / MNA of glucagon-like peptide analogue is applied.

9. A microneedle array or product for use in controlled release in intradermal application according to any one of claims 1 to 8, comprising an applicator system.

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