Microneedle system for hepatitis vaccine application

Abstract

The present invention relates to a microneedle system (abbreviated as MNS) for the intradermal application of a hepatitis vaccine, namely the antigen HBsAg. [Selected Figure] Figure 1

Description

Technical Field

[0001] The present invention relates to a hepatitis vaccine, namely a microneedle system (abbreviated as MNS) for intradermal application of the antigen HBsAg.

Background Art

[0002] Hepatitis vaccines may contain HBsAg. HBsAg is the surface protein of the viral envelope of hepatitis B virus (HBV, 226AA, 25.4 kDa, see database UniProt: Q773S4). In addition, HBsAg is the most effective component in approved hepatitis B vaccines (such as Engerix-B, Fendrix, HBVAXPRO and many others). HBsAG is a transmembrane protein with five transmembrane passages and three disulfide bridges on the outside of the membrane. At the same time, HBsAG is an antigen against which neutralizing antibodies are formed during hepatitis infection or after hepatitis vaccination. HBsAG is also used in the form of virus-like particles (VLPs) and does not contain nucleic acids (Non-Patent Document 1).

[0003] The skin consists of several layers. The outermost skin layer, the stratum corneum, has known barrier properties, preventing foreign substances from entering the body and preventing native substances from leaving the body. The stratum corneum is a complex structure of densely packed keratinocyte residues with a thickness of approximately 10 to 30 micrometers, forming a water-resistant membrane for protecting the body. The natural impermeability of the stratum corneum hinders the application of most pharmaceuticals and other substances through the skin by intradermal application. Langerhans cells are found throughout the basal granular layer of the epithelium and play an important role in the initial defense of the immune system against invading organisms. This layer of the skin becomes a suitable target zone for certain vaccines such as the hepatitis antigen HBsAg.

[0004] A microneedle system (MNS) consists of a microneedle array (MNA) and optionally further components, which use compressive force to press the microneedles (also called skin penetration elements) of the array (MNA) against the application site of the skin, causing them to penetrate the stratum corneum, thus creating a fluid channel, thereby allowing intradermal application of hepatitis vaccines. Such microneedle arrays (MNA) in a microneedle system (MNS) and their manufacture are described in the prior art and are also called micro(needle) array patches (MAP, or "Micro Array Patch").

[0005] It is also known that hepatitis vaccines can be administered using microneedles (for example, Patent Documents 1, 2, and 3). [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] DE60131688T2 [Patent Document 2] WO200189622A1 [Patent Document 3] WO200219985A2 [Non-patent literature]

[0007] [Non-Patent Document 1] EVGrgacic and DA Anderson: Virus-like particles: passport to immune recognition. In Methods. September 2006; 40(1): 60-5 [Overview of the project] [Problems that the invention aims to solve]

[0008] Therefore, an object of the present invention is to enable intradermal application of vaccines using MNS containing MNA, which is primarily composed of a suitable formulation.

[0009] Surprisingly, polyvinylpyrrolidone (PVP) is particularly suitable for the manufacture of MNA formulations for hepatitis vaccination. [Means for solving the problem]

[0010] This objective is achieved by a microneedle array (MNA) according to claim 1, comprising a formulation of polyvinylpyrrolidone and HBsAg for use in intradermal application of hepatitis vaccine, according to the present invention.

[0011] Therefore, the present invention also relates to a microneedle system comprising an MNA containing a formulation of polyvinylpyrrolidone and HBsAg for use in the intradermal application of hepatitis vaccine.

[0012] Therefore, the present invention includes a product comprising a formulation substantially of polyvinylpyrrolidone and HBsAg, or a product having a microneedle array comprising said formulation.

[0013] Such products include, for example, pharmaceutical products containing protruding microneedle arrays (MNAs) for use in the intradermal application of hepatitis vaccines, particularly vaccines.

[0014] A fundamental requirement for successful immunization against hepatitis B is to achieve sufficiently high antibody concentrations (titers) in the body or blood (plasma) of vaccinated individuals. The WHO recognizes a serological target of anti-HBsAg titer >10 [mLU / mL] as a clinically protective level (see Figure 1).

[0015] Particularly preferred is the microneedle array according to the present invention, in which the HBsAg content is 0.1 μg to 100 μg / microneedle array.

[0016] The term "intradermal application" (synonym: "intracutaneous application") refers to the administration of a vaccine, in this specification: of HBsAg, from the MNA into the skin, and requires the insertion of the microneedles into the skin.

[0017] The present invention is similarly a method of performing intradermal application for use in the intradermal application of hepatitis vaccination, comprising: a) fixing the microneedle system according to the present invention to the skin; b) inserting a microneedle array containing a formulation of PVP and HBsAg into the skin. The present invention relates to a method comprising the above steps.

Brief Description of the Drawings

[0018] [Figure 1] It is a diagram showing that in all MNA groups and injection groups, serologically appropriate and sufficiently strong (> red line) anti-HBsAg antibody formation was achieved for the evaluation of vaccination success.

Embodiments for Carrying Out the Invention

[0019] In the context of the present invention, the microneedle system is a system comprising a device for applying a microneedle array for administering a vaccine to the skin and applying it intradermally.

[0020] The microneedle system may include an applicator such as a trigger device. In a preferred embodiment, the applicator is electrically or mechanically controlled. For example, the applicator may have a piston for placing or applying the microneedle array on / to the skin, as a result of which the microneedles penetrate the skin.

[0021] The trigger device may include, for example, a pump, a syringe or a spring, such that an impact of the plunger with sufficient energy is carried out. The plunger may be of any shape and nature and is mainly aimed at bringing a microneedle array from a first position to a second position for the administration of a vaccine on the skin. The applicator may also include a push button or a thread.

[0022] The microneedle array may have a plurality of microneedles for delivering a vaccine through or into the skin of a patient, and the microneedle array is applied to the skin of the patient. Each of the microneedles of the microneedle array preferably has an elongated shaft with two ends, one end of the shaft being the base of the microneedle, whereby the microneedle is attached to a flat carrier or whereby the microneedle is incorporated into a flat carrier. The end of the shaft opposite the base is preferably tapered so that the microneedle can penetrate the skin as easily as possible. Each hollow microneedle has at least one passage or channel or at least one cavity, which extends from the base of the microneedle to the tip of the microneedle or to approximately the tip of the microneedle. The passage preferably has a circular diameter.

[0023] The microneedle may have a shaft with a circular cross-section or a non-circular cross-section, for example, a triangular, square or polygonal cross-section. The shaft may have one or more passages that run from the base of the needle to the tip of the needle or to approximately the tip of the needle. The microneedle may be designed as a barb, and one or more of these microneedles may have one or more such barbs. Furthermore, the microneedle may be arranged in a helical shape so as to be rotatable, whereby penetration into the skin is promoted when a rotational movement is applied and it is fixed in the skin, particularly at a desired penetration depth of the epidermis (DE10353629A1).

[0024] The diameter of the microneedles is typically 1 μm to 1,000 μm, preferably 10 μm to 100 μm. The diameter of the passages is typically 3 μm to 80 μm, preferably suitable for passages of liquid substances, solutions, and compound preparations. The length of the microneedles is typically 5 μm to 6,000 μm, particularly 100 μm to 700 μm.

[0025] Microneedles are attached to or incorporated into a flat carrier using their base. Preferably, the microneedles are positioned approximately perpendicular to the surface of the carrier. The microneedles can be arranged in regular or irregular patterns. Multiple microneedle arrangements can include microneedles of various cross-sectional shapes, diameters, and / or lengths. For example, a multiple microneedle arrangement may include only hollow microneedles.

[0026] A microneedle array may have a flat carrier, which has a substantially disc-like, plate-like, or film-like basic shape. The carrier may have a circular, oval, triangular, square, or polygonal base region. The carrier may be made of a variety of materials such as metals, ceramic materials, semiconductors, organic materials, polymers, or composites.

[0027] In another preferred embodiment, in addition to PVP in the formulation for the manufacture of microneedles, the following substances are present, or include the following: disaccharides, preferably trehalose; nonionic surfactants, preferably polysorbates (ethoxylated sorbitan fatty acid esters such as Tween); and polyhydric alcohols, particularly glycerol (glycerin).

[0028] [Table 1]

[0029] After drying a liquid formulation, if a microneedle array (MNA) is formed with a residual water content of, for example, 1-20% (m / m), the composition of the MNA changes accordingly due to water loss.

[0030] Accordingly, the present invention relates to a microneedle array or product, particularly a pharmaceutical product, for use in intradermal application of hepatitis vaccine, wherein the formulation comprises up to 95% by weight of polyvinylpyrrolidone, particularly 0.1% to 50% by weight of trehalose, particularly 0.01% to 10% by weight of polysorbate, and particularly 0.1% to 10% by weight of glycerol.

[0031] Furthermore, a particular advantage of the MNA according to the present invention is that it can be performed without adjuvants (see Figure 1). [Examples]

[0032] Examples and drawings: For the production of the microneedles according to the present invention, known methods such as those described in "Design and physicochemical characterization of novel dissolving polymeric microneedle arrays for transdermal delivery of high dose, low molecular weight drugs" by McCrudden MT, Alkilani AZ, McCrudden CM, McAlister E, McCarthy HO, Woolfson AD et al., J Control Release, 2014; Vol. 180: pp. 71-80 can be applied.

[0033] In preclinical in vivo studies (guinea pigs), the above formulations showed superior results in terms of antibody titers obtained in the blood of vaccinated animals after application of micro(needle) array patches (MAP); see Figure 1.

[0034] This study design included a prime / boost / boost (0 / 1 / 3 months) regimen in 4 groups of 12 animals, of which 3 groups were MAP groups (20 / 40 / 60 μg HBsAg / MNA) and 1 group was a reference group receiving intramuscular injection (im) (20 μg HBsAg / im). The primary endpoint was titer at 4 months, and at 6 and 12 months of follow-up.

[0035] The test results show that in all MNA and injection groups, the formation of serologically appropriate and sufficiently potent (>red line) anti-HBsAg antibodies was achieved for evaluating the success of the vaccination.

[0036] Furthermore, no relevant differences were observed between the adjuvant formulation (see Figure 1, shaded area) and the non-adjuvant formulation (see Figure 1, non-shaded area) in the experimental group, nor between intradermal administration of the antigen using a microarray and conventional application using an injection needle.

Claims

1. A microneedle array comprising a formulation of polyvinylpyrrolidone and HBsAg for use in intradermal application of hepatitis vaccine, The formulation comprises a disaccharide, a nonionic surfactant, and a polyhydric alcohol. Polyvinylpyrrolidone 1-95% by weight, Trehalose 0.1-50% by weight, Polysorbate 0.01 to 10% by weight, Glycerol 0.1-10% by weight, The microneedle array is characterized by containing, but not containing an adjuvant, hyaluronic acid, dextran, or water-soluble polysaccharides other than the disaccharide.

2. A microneedle array comprising a formulation of polyvinylpyrrolidone and HBsAg for use according to claim 1, wherein the HBsAg content is 0.1 μg to 100 μg / microneedle array.

3. A product, particularly a pharmaceutical product, comprising a microneedle array containing a formulation of polyvinylpyrrolidone and HBsAg according to claim 1 or 2, for use in intradermal application of hepatitis vaccine.

4. The formulation is characterized by comprising up to 95% by weight of polyvinylpyrrolidone and further excipients and additives, and is a microneedle array or product for use in the intradermal application of hepatitis vaccine according to any one of claims 1 to 3.

5. A microneedle array or product for use in intradermal application of hepatitis vaccine according to any one of claims 1 to 4, characterized in that the microneedle array includes an applicator.

6. A microneedle array or product for use in intradermal application of hepatitis vaccine according to any one of claims 1 to 5, characterized in that the microneedle array comprises an applicator together with a trigger device.

7. A microneedle array or product comprising a formulation of polyvinylpyrrolidone and HBsAg according to any one of claims 1 to 6 for use in intradermal application of HBsAg vaccination.

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