Microneedle array containing active ingredients in salt form

Abstract

The present invention relates to a microneedle array, in particular an applicator system, for the intradermal delivery of an active ingredient in salt form, in particular a pharmaceutical agent in salt form, and its use, wherein the microneedle array is suitable for penetration into human or animal skin, and the microneedles are made of a formulation comprising at least one active ingredient in salt form and at least one biodegradable polymer.

Description

Technical Field

[0001] The present invention relates to a microneedle array, particularly an applicator system, for intradermal delivery of an active ingredient in salt form, particularly a medicament in salt form, and its use. The microneedle array is suitable for penetration into human or animal skin, and the microneedles are made of a formulation containing at least one active ingredient in salt form and at least one biodegradable polymer.

Background Art

[0002] Microneedle systems and devices in which microneedle arrays are used for painless intradermal (or transdermal) administration of active ingredients, particularly medicaments, are known from the prior art. Transdermal delivery of active ingredients in salt form is disclosed in Patent Document 1 by the applicant for patches or transdermal therapeutic systems (TTS).

[0003] The skin consists of several layers. The outermost layer of the skin, the stratum corneum, has known barrier properties to prevent foreign substances from penetrating into the body and the body's own substances from exiting the body. The stratum corneum, a complex structure composed of densely packed keratinocyte sheets with a thickness of about 10 micrometers to 30 micrometers, forms a watertight membrane for this purpose of protecting the body. Due to this natural impermeability of the stratum corneum, the administration of most pharmaceuticals and other substances through the skin as part of intradermal delivery is hindered.

[0004] As a result, various substances are administered, for example, by creating micropores or incisions in the stratum corneum and supplying or delivering the medicament into or under the stratum corneum. By doing so, a number of medicaments can also be administered, for example, subcutaneously, intradermally, or intracutaneously.

[0005] In conventional technology, a problem remains that active ingredients are usually delivered in the form of their base, but this form is less stable than their salt form, leading to losses. Therefore, there is a great need to provide active ingredients that should be delivered in salt form in an appropriate dosage form of salt. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] German patent no. 102007041557 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Therefore, the object of the present invention is to provide a suitable dosage form for intradermal delivery of active ingredients in salt form. [Means for solving the problem]

[0008] The above problems are solved by the technical teachings set forth in the claims.

[0009] Accordingly, the present invention relates to such teaching having the features of claim 1, which relates to a microneedle array for use in intradermal delivery of an active ingredient in salt form, comprising a plurality of microneedles on a carrier, wherein the microneedles are composed of a formulation containing at least one active ingredient in salt form and at least one biodegradable polymer.

[0010] A particular advantage is that the inserted microneedles dissolve in situ and are directly absorbed into the skin. This means that the active ingredient in salt form is introduced into the skin by being embedded within the formulation, eliminating the need for the microneedles to be hollow or to have channels. The salt-form formulation dissolves in the body, releasing the active ingredient in salt form. Furthermore, hollow microneedles have the disadvantage that the cavity may become clogged with coagulated blood during the period of wear.

[0011] According to the present invention, all suitable salt forms of active ingredients suitable for intradermal delivery are included.

[0012] The active ingredients in salt form are preferably active ingredients from the group of analgesics, such as anesthetics. Preferred substances include morphine derivatives, heroin, and buprenorphine, or fentanyl and its derivatives, sufentanil and alfentanil, all of which are in salt form. Without limiting the present invention, fentanyl citrate or buprenorphine hydrochloride are understood to be salts according to the present invention. The present invention also similarly encompasses other known opioid salts, such as oxycodone hydrochloride or morphine hydrochloride. The salts are preferably soluble in a pharmaceutically acceptable solvent such as ethanol. The term "soluble" means that 1 part of the salt dissolves in 10 to 30 parts of the solvent.

[0013] A person skilled in the art can produce a salt corresponding to the active ingredient.

[0014] A microneedle array may comprise a plurality of microneedles that can release an active ingredient in salt form through or into the patient's skin, and the microneedle array is applied to the patient's skin. Each microneedle in the microneedle array preferably has an elongated shaft having two ends, one end of which forms the base of the microneedle, thereby attaching the microneedle to a flat carrier, or thereby integrating the microneedle to a flat carrier. The end of the shaft opposite the base preferably has a tapered shape so that the microneedle can penetrate the skin as easily as possible.

[0015] The microneedle array according to the present invention is suitable for use in intradermal delivery of active ingredients in salt form, and comprises a plurality of microneedles in salt form on a carrier, wherein the microneedles contain or are composed of a formulation containing at least one active ingredient in salt form and at least one biodegradable polymer.

[0016] Particularly preferred, the biodegradable polymer may be a water-soluble polymer, preferably selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, cellulose, dextran, alpha hydroxy acids such as lactic acid and / or glycolic acid, polylactide, polyglycolide, polylactide-co-glycolide, copolymers thereof with polyethylene glycol, polyacid anhydride, poly(ortho)ester, polyurethane, polybutyric acid, polyvaleric acid, and polylactide-co-caprolactone.

[0017] Within the scope of the present invention, polymers that dissolve in water or ethanol or an alcohol / water mixture at room temperature to a maximum of 50%, or at boiling heat, i.e., at a maximum of 80%, are also considered water-soluble.

[0018] Microneedles may have an axis having a circular cross-section or a non-circular cross-section having, for example, a triangular, square, or polygonal cross-section. The axis may have one or more passages extending from the base of the needle to the tip of the needle, or nearly to the tip of the needle. Microneedles may be designed as (reverse) hooks, where one or more of these microneedles have one or more such hooks. Furthermore, microneedles may be configured in a helical shape and rotatably positioned so that when rotational motion is applied, penetration into the skin is facilitated, and intradermal anchoring can be achieved in particular at a desired penetration depth within the epidermis (German Patent Application Publication No. 10353629).

[0019] The diameter of the microneedle is typically in the range of 1 μm to 1000 μm, preferably between 10 μm and 100 μm. The diameter of the passage is typically in the range of 3 μm to 80 μm, preferably suitable for passing liquid substances, solutions, and material preparations. The length of the microneedle is typically in the range of 5 μm to 6000 μm, particularly between 100 μm and 700 μm.

[0020] The microneedles are attached to or integrated into a flat carrier at their base. Preferably, the microneedles are positioned substantially perpendicular to the surface area of ​​the carrier. The microneedles can be arranged regularly or irregularly. Arrangements of multiple microneedles may comprise microneedles having different cross-sectional shapes, different diameters, and / or different lengths. Similarly, the arrangement may comprise solid microneedles and semi-solid composites.

[0021] The density of microneedles on the carrier is 5 needles / cm³. 2 ~5000 pieces / cm 2 , especially 5 pieces / cm 2 ~1000 pieces / cm 2 But that's fine.

[0022] The microneedle array can comprise a flat carrier, where the carrier has an essentially disk-shaped, plate-shaped or film-shaped basic shape. The carrier can have a base surface area that is circular, elliptical, triangular, quadrilateral or polygonal. The carrier can be manufactured from various materials such as metals, ceramic materials, semiconductors, organic materials, polymers or composites. Materials suitable for manufacturing the carrier are preferably film or web-like materials, for example, preferably microporous membranes made of polyethylene (PE) or polypropylene (PP), or preferably diffusion membranes made of ethylene-vinyl acetate copolymer (EVA) or polyurethane (PUR). Suitable materials for manufacturing the carrier can be selected from the group consisting of polyesters such as polyethylene terephthalate (PET), polycarbonate (PC), polyether ketone (PAEK), 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), polymethyl methacrylate (PMMA), and cellulose-based plastic materials such as hydrated cellulose or cellulose acetate. Suitable materials for manufacturing the carrier can be selected from the group consisting of aluminum, iron, copper, gold, silver, platinum, metals including alloys of the above-mentioned metals, and other pharmaceutically acceptable metal foils or metallized films.

[0023] The carrier is preferably made of a flexible material, for example, a plastic material. A carrier made of a flexible material can better conform to the surface of the skin and its curvatures than a carrier made of a non-flexible material. Thus, better contact between the microneedle array and the skin is achieved, thereby improving the reliability of the microneedle array.

[0024] In a preferred embodiment, the microneedle array is a flat or planar microneedle array.

[0025] In another embodiment of the present invention, an applicator system can be used to place the microneedle array on the skin under pressure and apply a sudden load to the skin. In another preferred embodiment, a microneedle system comprising a microneedle array is configured with an applicator. Such an applicator can advantageously activate a pressure mechanism so that the microneedle array penetrates the skin or the stratum corneum (see, for example, WO 2008 / 091602 pamphlet, WO 2016 / 162449 pamphlet).

[0026] In a further embodiment, an applicator system comprising a microneedle array enables easy handling for not only fixing to the skin but also applying pressure to the skin, and is particularly composed of a general functional object that may include at least one fixing means.

[0027] Within the scope of the present invention, an applicator system is a system comprising a device that provides a microneedle array on the skin for administering an active ingredient in salt form and delivers the active ingredient in salt form intradermally.

[0028] In a preferred embodiment, the applicator system may comprise an electrically or mechanically controlled trigger device. For example, the applicator system may comprise a plunger that places or applies the microneedle array on the skin so that the microneedles penetrate the skin.

[0029] The trigger device may comprise, for example, a pump, a syringe or a spring that can push the plunger with sufficient energy. The plunger may have any shape and nature, and first, it should be realized that the microneedle array is provided from a first position to a second position for administering the active ingredient on the skin.

[0030] The applicator system may further comprise a push button or a thread. In further embodiments, the microneedle array may include a fixation means which is preferably attached to the skin of a patient or subject by a fragment or patch of contact adhesive, also known as a needle patch. Suitable contact adhesives include high-viscosity substances that adhere to the skin after light pressure is applied, known as pressure-sensitive adhesives (PSAs). These have high cohesive and adhesive strength. For example, poly(meth)acrylate-based, polyisobutylene-based, or silicone-based contact adhesives can be used. In further embodiments, the fixation means may be made of a band, elastic band, rubber, or strap. Such a fixation means can provide secure attachment to the body.

[0031] Accordingly, the present invention also relates to an applicator system according to the present invention comprising a microneedle array, or a microneedle array for intradermal delivery comprising a means for fixation to the skin.

[0032] According to the present invention, the term “intradermal delivery” (synonym: “intracutaneous delivery”) describes the administration of any active ingredient into the skin via a microneedle array, which requires microneedles to perforate or penetrate the skin.

[0033] Accordingly, the present invention also relates to a method for intradermal delivery comprising applying a microneedle array, comprising a plurality of microneedles on a carrier, particularly by an applicator system, wherein the microneedles are made of a formulation containing at least one active ingredient in salt form and at least one biodegradable polymer.

[0034] The present invention relates to the use of a microneedle array comprising a plurality of microneedles on a carrier, and more particularly to the use of a corresponding applicator system, wherein the microneedles are made of a formulation containing at least one active ingredient in salt form and at least one biodegradable polymer.

[0035] The following examples are used to further illustrate the present invention, but the present invention is not limited to these examples. [Example 1]

[0036] 100 mg of fentanyl citrate, 6.9 g of Resomer R 202 H (polylactide, PDLLA), and approximately 3 g of ethanol were dissolved by boiling. While still hot, this solution was poured to a thickness of 15 μm and 2.5 cm. 2 Needles with a height of approximately 0.4 mm to 0.8 mm after cooling were printed using a 3D printer onto circular polyethylene terephthalate film pieces having a surface area of ​​. These needles consisted of 1.43% fentanyl citrate and 98.57% Resomer R 202 H, and still contained trace amounts of ethanol. After evaporation of the solvent, the printer was set to yield approximately 20.7 mg containing 0.3 mg of fentanyl acetate. 0.3 mg of fentanyl citrate corresponds to the initial daily dose for percutaneous pain management. The PET film was positioned with its surface bent away from the needles, on a mesh coated with contact adhesive, so that the adhesive mesh extended beyond the needle patch. For storage, the polymer needles were protected by covering the needle patch and contact adhesive mesh with a thermoformed sheet of 175 μm silicone-treated HDPE film. For delivery, the thermoformed film was peeled off. The needle patch is applied to the patient in pain and secured by an adhesive layer that extends beyond the needle area in all directions. During this process, the needles, made of fentanyl citrate and Resomer R 202, perforate the stratum corneum. Resomer R 202 disintegrates, releasing fentanyl citrate into the subcutaneous tissue, from where it reaches the blood circulation system with some delay. [Example 2]

[0037] 5 g of fentanyl citrate was extruded in 95 g of polyvinyl alcohol by melt extrusion at a temperature above the glass transition temperature of the two-component mixture into a homogeneous strand, a so-called "extruded filament," suitable for a specific 3D printer, and then wound into a roll. This active ingredient polymer strand was melted using a 3D printer and shaped into needles. This resulted in needles with a height of 0.5 mm to 1.0 mm. To ensure that the curing process was carried out as quickly as possible and to prevent the hygroscopic polymer from absorbing water, the room temperature and humidity were kept as low as possible. The film was positioned with its surface bent away from the needles, on a film coated with contact adhesive, so that the adhesive film extended beyond the needle patch in the form of an "over-patch." For storage, the polymer needles were protected by covering the needle patch and contact adhesive mesh with a thermoformed sheet of 175 μm silicone-treated HDPE film. For delivery, the thermoformed film was peeled off. The needle patch is applied to the patient in pain and secured by an adhesive layer that extends beyond the needle area in all directions. During this process, the needles, made of fentanyl citrate and polyvinyl alcohol, perforate the stratum corneum. The polyvinyl alcohol dissolves, releasing the fentanyl citrate beneath the stratum corneum, from where it reaches the blood circulation system. [Example 3]

[0038] 5 g of fentanyl citrate was heated in 95 g of polyvinyl alcohol to a temperature exceeding the melting point of the mixture, and the molten mixture was formed into needles by injection molding. This yielded needles with a height of 0.5 mm to 1.0 mm. To ensure that the curing process was carried out as quickly as possible and to prevent the hygroscopic polymer from absorbing water, the room temperature and humidity were kept as low as possible. The film was positioned with its surface bent away from the needles, on a film coated with contact adhesive, so that the adhesive film extended beyond the needle patch in the form of an "overpatch". For storage, the polymer needles were protected by covering the needle patch and contact adhesive mesh with a thermoformed sheet of 175 μm silicone-treated HDPE film. For delivery, the thermoformed film was peeled off. The needle patch was applied to the patient with pain and secured by the adhesive layer that extended beyond the needle area in all directions. In the process, the needles made of fentanyl citrate and polyvinyl alcohol perforated the stratum corneum. Polyvinyl alcohol dissolves, releasing fentanyl citrate beneath the stratum corneum, which then reaches the blood circulation system. [Example 4]

[0039] 7.5 g of buprenorphine HCl was heated in 92.5 g of polyvinyl alcohol to a temperature exceeding the melting point of the mixture and extruded using a twin-screw extruder. The resulting strand was printed in the form of needles on a film that does not allow the active ingredient to pass through, using a 3D printing method, to obtain needles with a height of 0.5 mm to 1.0 mm. To ensure that the curing process was carried out as quickly as possible and to prevent the hygroscopic polymer from absorbing water, the room temperature and humidity were kept as low as possible. The film was positioned with its surface bent away from the needles, on a film coated with contact adhesive, so that the adhesive film extended beyond the needle patch in the form of an "overpatch". For storage, the polymer needles were protected by covering the needle patch and contact adhesive mesh with a thermoformed sheet of 175 μm silicone-treated HDPE film. For delivery, the thermoformed film was peeled off. The needle patch was applied to the patient experiencing pain and secured by the adhesive layer that extended beyond the needle area in all directions. During this process, needles made of buprenorphine HCl and polyvinyl alcohol perforate the stratum corneum. The polyvinyl alcohol dissolves, releasing buprenorphine HCl beneath the stratum corneum, which then reaches the blood circulation system. [Example 5]

[0040] 5 g of buprenorphine HCl was dissolved in a 30% ethanol solution of 25 g of polyvinylpyrrolidone K30 and weighed into a matrix having negative depressions for a needle array of 64 needles, for example, with a length of approximately 0.8 mm and a width of approximately 0.2 mm, and a needle spacing of approximately 0.3 mm. On top of that, a height of approximately 0.2 mm and 1 cm 2A recess was present for the array plate with a surface area. After removing the solvent by drying, a base plate without active ingredients, prepared with a 30% methanol solution of PVP VA64, was weighed onto the needles to create a flexible plate, which was then bonded to the needles to form a unit. The film was positioned with its surface bent away from the needles, on a film coated with contact adhesive, so that the adhesive film extended beyond the needle patch in the form of an "overpatch". For storage, the polymer needles were protected by covering the needle patch and contact adhesive mesh with a thermoformed sheet of 175 μm silicone-treated HDPE film. For delivery, the thermoformed film was peeled off. The needle patch was applied to the patient in pain and secured by the adhesive layer extending beyond the needle area in all directions. During this process, the needles, made of buprenorphine HCl and polyvinylpyrrolidone, perforated the stratum corneum. PVP K30 dissolved, thereby releasing buprenorphine HCl below the stratum corneum, from where it reached the blood circulation system.

Claims

1. A microneedle array for use in intradermal delivery of buprenorphine hydrochloride, an analgesic in salt form, comprising a plurality of microneedles on a carrier, wherein the microneedles are applied by an applicator system, the applicator system comprising a trigger device, and the microneedles are composed of a formulation containing at least one water-soluble polymer in which at least one analgesic in salt form, buprenorphine hydrochloride, is melted and embedded, and the microneedles dissolve in situ as the analgesic in salt form and are absorbed directly into the skin.

2. The applicator system comprises a trigger device having a plunger, a push button, or a screw, comprising a microneedle array for use in intradermal delivery of an analgesic in salt form according to claim 1.

3. The water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, cellulose, dextran, polymers derived from alpha hydroxy acids such as lactic acid and / or glycolic acid, polylactide, polyglycolide, polylactide-co-glycolide, copolymers thereof with polyethylene glycol, polyacid anhydride, poly(ortho)ester, polyurethane, and polylactide-co-caprolactone, characterized in that the microneedle array for use in intradermal delivery according to claim 1 or 2.

4. A microneedle array for use in intradermal delivery according to any one of claims 1 to 3, characterized in that the microneedle array is planar.

5. The density of microneedles on the carrier is 5 needles / cm³. 2 ~5000 pieces / cm 2 A microneedle array for use in intradermal delivery according to any one of claims 1 to 4, characterized in that it is the same as described in any one of claims 1 to 4.

6. Microneedle arrays are particularly useful for adhesive strips, patches, bands, elastic bands, and rubber bands. A microneedle array for use according to any one of claims 1 to 5, characterized by comprising a fixing means selected from the group consisting of or a strap.

7. An applicator system comprising a microneedle array for use in intradermal delivery according to any one of claims 1 to 6, wherein the applicator system comprises a trigger device.

8. An applicator system comprising a microneedle array for use in intradermal delivery according to claim 7, characterized in that the trigger device comprises a plunger, a push button, or a screw.

9. An applicator system comprising a microneedle array for use in intradermal delivery according to claim 7, characterized in that the trigger device is electrically or mechanically controlled.