EP3706792A1

EP3706792A1 - Microneedle system for applying a hepatitis vaccine

Info

Publication number: EP3706792A1
Application number: EP18811721.2A
Authority: EP
Inventors: Andreas Henning; Heiko Spilgies
Original assignee: LTS Lohmann Therapie Systeme AG
Current assignee: LTS Lohmann Therapie Systeme AG
Priority date: 2017-11-10
Filing date: 2018-11-12
Publication date: 2020-09-16
Also published as: JP2023169415A; RU2020116222A; AU2018365396A1; BR112020007980A2; MX2020004868A; CN111315410A; RU2020116222A3; KR20200087187A; DE102017126501A1; JP2021502353A; US20210369839A1; WO2019092257A1; CA3082197A1

Abstract

The invention relates to a microneedle system (MNS) for intradermal application of a hepatitis vaccine, namely the HBsAg antigen.

Description

Micro needle system for the application of a hepatitis vaccine

description

The present invention relates to a microneedle system (short: MNS) for

Intradermal application of a hepatitis vaccine and the antigen HBsAg.

Hepatitis vaccines or synonymous hepatitis vaccines may contain HBsAg. HBsAg is a surface protein in the viral envelope of the hepatitis B virus (HBV, 226 AA, 25.4 kDa, see database UniProt: Q773S4). HBsAg is also the most effective ingredient in the approved hepatitis B vaccines (e.g., Engerix-B, Fendrix, HBVAXPRO, and the like). HBsAg is a transmembrane protein with five

Membrane passages and three disulfide bridges on the outside of the membrane.

At the same time it is an antigen against which neutralizing antibodies are formed during hepatitis infection or after hepatitis vaccination. HBsAg are also used in the form of virus-like particle (VLP) and have no nucleic acids (EV Grgacic and DA Anderson: Virus-like particles: passport to immune recognition.) In Methods., Sep; 40 (1): 60 -5).

The skin consists of several layers. The outermost skin layer, the stratum corneum, has known barrier properties to prevent intrusion

Foreign substances in the body and to prevent leakage of own substances from the body. The stratum corneum, which is a complex structure of compacted keratotic cell debris with a thickness of about 10-30

Microns, forms a waterproof membrane to protect the body. The natural impermeability of the stratum corneum prevents that

Administering most pharmaceuticals and other substances through the skin as part of an intradermal application. Langerhans cells are consistently found in the basal granule layer of the epithelium, which play an important role in the initial defense of the immune system against invading organisms. This layer of skin is an appropriate target zone for certain types of vaccines, such as the hepatitis antigen HBsAg. Micro Needle Systems (MNS), which consist of a microneedle array (MNA) and optionally other components, can press the microneedles (also: skin penetrating elements) of the array (MNA) against the application site on the skin by means of a pressure force to penetrate the stratum corneum and on in this way to produce a fluid channel, so that a hepatitis vaccine can be administered intradermally. Such microneedle arrays (MNA) in

Microneedle systems (MNS) as well as their manufacture are described in the prior art and are also described as micro (needle) array patches (MAP, "Micro Array Patch").

It is also known that hepatitis vaccines can be administered via microneedles (e.g., DE60131688T2, WO200189622A1, WO200219985A2).

Therefore, it is an object of the present invention, an intradermal application for vaccination by means of a MNS containing an MNA based on a suitable

To allow formulation.

Surprisingly, polyvinylpyrrolidone (PVP for short) is particularly suitable for preparing a formulation for a MNA for hepatitis vaccination.

This object is achieved by a microneedle array (MNA) according to claim 1, comprising a formulation of polyvinylpyrrolidone and HBsAg for use in the intradermal administration for hepatitis vaccination.

The invention therefore also relates to a microneedle system comprising an MNA for use in the intradermal administration for hepatitis vaccination, comprising a formulation of polyvinylpyrrolidone and HBsAg.

Therefore, the invention comprises a means comprising a microneedle array comprising or consisting of a formulation of substantially polyvinylpyrrolidone and HBsAg.

Such agent is, for example, a drug, especially a vaccine, comprising a protruding microneedle array (MNA) for use in intradermal administration for hepatitis vaccination. The fundamental requirement for a successful immunization against hepatitis B is the generation of a sufficiently high antibody concentration (titer) in the body or blood (plasma) of the vaccinated persons. As a serological target value, the WHO recognizes an anti-HBsAg titer of> 10 [mLU / mL] as clinically protective, see Figure 1.

Particularly preferred is a microneedle array according to the invention which has an HBsAg content of 0.1 g to 100 g per microneedle array.

The term "intradermal administration (synonym:" intracutaneous administration ") describes according to the invention the administration of vaccines, here: HBsAg from the MNA into the skin and requires a piercing of the microneedles into the skin.

The invention likewise relates to a method for carrying out an intradermal application for use in the intradermal administration for hepatitis vaccination comprising a) fixing a microneedle system according to the invention to the skin, b) penetrating a microneedle array comprising a formulation of PVP and HBsAg into the skin.

In the context of this invention, a microneedle system is one such system that includes a device that causes the microneedle array to be delivered to the skin for administration of the vaccines and administered intradermally.

The microneedle system may, in a preferred embodiment, comprise an applicator, such as a triggering device, which is controlled electrically or mechanically. The applicator can, for example, have a piston which seals the

Micro-needle array touches or applies to the skin so that the microneedles penetrate into the skin.

The triggering device may comprise, for example, a pump, a syringe or a spring, so that a piston stroke can take place with sufficient energy. The piston can be of any shape and nature and should primarily

accomplish that the microneedle array from a first position to a second Position for administering the vaccines is provided on the skin. The applicator may further comprise a push button or thread.

The microneedle array may have a plurality of microneedles for delivery of a vaccine through the skin or into the skin of a patient, with the microneedle array applied to the skin of the patient. Each of the

Microneedles of the microneedle array preferably have an elongated shaft with two ends, one end of the shaft being the base of the microneedle with which the microneedle is attached to the planar support or with which the microneedle is integrated into the planar support. The base of the opposite end of the shaft is preferably designed tapered to allow the easiest possible penetration of the microneedle into the skin. Each hollow microneedle has at least one passage or channel or at least one bore extending from the base of the microneedle to the tip of the microneedle or approximately to the tip of the microneedle. The passages preferably have a round diameter.

The microneedles may have a shaft with a round cross-section or a non-round cross-section, for example with a triangular, quadrangular or a polygonal cross-section. The shaft may have one or more passages that extend from the needle base to the needle tip or approximately to the needle tip. The microneedles can as

(Wider-) hooks may be formed, wherein one or more of these microneedles has one or more such hooks. Furthermore, the microneedles

be designed helically and rotatably mounted and thereby the

Applying a rotating movement to facilitate penetration into the skin and cause anchoring in the skin (DE 103 53 629 A1), in particular at the desired depth of penetration in the epidermis.

The diameter of a microneedle is usually between 1 μιτι and 1000 μιτι, preferably between 10 μιτι and 100 μιτι. The diameter of a

Passage is usually between 3 μιτι and 80 μιτι and is for the

Passage of preferably liquid substances, solutions and preparations of substances suitable. The length of a microneedle is usually between 5 μηη and 6,000 μητι, in particular between 100 μηη and 700 μηη.

The microneedles are attached with their base to a flat carrier or integrated into a flat carrier. The microneedles are preferably in

Substantially arranged perpendicular to the surface of the carrier standing. The

Microneedles can be arranged regularly or irregularly. A

An array of multiple microneedles may comprise microneedles having different cross-sectional shapes, different sized diameters and / or different lengths. For example, the array of multiple microneedles may comprise only hollow microneedles.

The microneedle array may comprise a planar carrier, wherein the carrier has a substantially disc-shaped, plate-shaped or foil-like basic shape. The carrier may have a round, oval, triangular, square or polygonal base. The carrier may be made of different materials, for example of a metal, a ceramic material, a

Semiconductor, an organic material, a polymer or a composite.

In another preferred embodiment, the following are preferred in a formulation for making the microneedles besides PVP consisting of or comprising: disaccharide, preferably trehalose, nonionic surfactants, preferably polysorbate (ethoxylated sorbitan fatty acid esters such as Tween), polyalcohol, especially glycerol (glycerol ).

Table 1

Substance I Name Function Concentration / dose in

% By weight

HBsAg / vaccine antigen drug / vaccine 0.1 μg to 100 μg per

MNA Polyvinylpyrrolidone (PVP) excipient 1% to 95% (m / m)

Trehalose excipient 0.1% to 50% (m / m)

Polysorbate excipient 0.01% to 10% (m / m)

Glycerol excipient 0.1% to 10% (m / m)

Water solvent 20% to 95% (m / m)

After drying the liquid formulation, e.g. to a microneedle array (MNA) with 1-20% (m / m) residual water content, followed by a correspondingly changed by the loss of water composition of the MNA.

Therefore, the invention relates to a microneedle array or means, in particular

A pharmaceutical composition for use in the intradermal administration for hepatitis vaccination, wherein a formulation to 95 wt.% Polyvinylpyrrolidone, in particular 0.1 wt .-% to 50 wt .-% trehalose, in particular 0.01 wt .-% to 10 wt .-%

Polysorbate, in particular 0.1 wt .-% to 10 wt .-% glycerol contains.

Furthermore, it is particularly advantageous that the MNA according to the invention without

Adjuvants can get along, see Figure 1.

Examples and figures:

For the preparation of the microneedles according to the invention, the known

Methods such as McCrudden MT, Alkilani AZ, McCrudden CM, McAlister E, McCarthy HO, Woolfson AD, et al. Design and physicochemical characterization of novel dissolving polymer microneedle arrays for transdermal delivery of high dose, low molecular weight drugs. J Control Release. 2014; 180: 71-80.

The o.g. Formulation show in a preclinical in vivo study

(Guinea pig) excellent results of the resulting antibody titers in Blood of the vaccinated animals after application of the micro (needle) array patch (MAP), see Figure 1.

The study design includes a Prime / Boost / Boost (0/1/3 months) in 4 groups x 12 animals, including 3 MAP groups with (20/40 / 60Mg HBsAg / MNA) and one

Reference group with intramuscular injection, i.m. with 20 g HBsAg / i.m.). the primary endpoint is 4 months with followers at 6 and 12 months.

The results of the study show that in all MNA and injection groups a sufficient strong (> red line) formation of the anti-HBsAg antibodies serologically relevant for the evaluation of the vaccination success was achieved.

Furthermore, the test groups have no relevant differences between adjuvanted (see FIG. 1, freeze-dried) and non-adjuvanted formulations (see FIG. 1, non-freeze-dried) and intradermal administration of the antigen by means of a microarray and conventional application by means of an injection needle.

Claims

claims

1 . A microneedle array comprising a formulation of polyvinylpyrrolidone and HBsAg for use in intradermal administration for hepatitis vaccination.

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

A microneedle array comprising a formulation of polyvinylpyrrolidone and HBsAg for use according to claim 1 or 2, wherein the formulation contains disaccharide, nonionic surfactants and polyhydric alcohol.

A microneedle array comprising a formulation of polyvinylpyrrolidone and HBsAg for use according to any one of the preceding claims, wherein the formulation contains trehalose and / or polysorbate and / or glycerol.

5. agent, in particular pharmaceutical, comprising a microneedle array

comprising a formulation of polyvinylpyrrolidone and HBsAg according to any one of claims 1 -4 for use in the intradermal administration for hepatitis vaccination.

6. microneedle array or means for use in the intradermal administration for hepatitis vaccination according to any one of the preceding claims, characterized in that a formulation contains up to 95 wt.% Polyvinylpyrrolidone and other auxiliaries and additives.

7. microneedle array or agent for use in the intradermal administration for hepatitis vaccination according to any one of the preceding claims, characterized in that a formulation to 95 wt .-% polyvinylpyrrolidone and to 0.1 wt .-% to 50 wt .-% trehalose contains.

8. microneedle array or means for use in the intradermal administration for hepatitis vaccination according to any one of the preceding claims, characterized in that a formulation contains up to 95% by weight of polyvinylpyrrolidone and up to 0.01% by weight to 10% by weight of polysorbate.

9. microneedle array or agent for use in the intradermal administration for hepatitis vaccination according to any one of the preceding claims, characterized in that a formulation to 95 wt .-% polyvinylpyrrolidone and to 0.1 wt .-% to 10 wt .-% glycerol contains.

10. microneedle array or means for use in the intradermal administration for hepatitis vaccination according to any one of the preceding claims, characterized in that an applicator is used.

1 1. A method for carrying out an intradermal application for the vaccination of HBsAg antigen comprising a microneedle array comprising a formulation of polyvinylpyrrolidone and HBsAg according to one of claims 1 to 9.