Nasal Administration System for Hepatitis B Vaccine

Abstract

The present invention relates to a nasal administration system that combines a hepatitis B vaccine composition for nasal mucosal spray administration with a medical nozzle device for administering the composition to the nasal mucosa for use in the prevention and treatment of hepatitis B.

Description

Technical Field

[0001] The present invention relates to a nasal administration system that combines a hepatitis B vaccine composition for intranasal spray administration, which is used for the prevention and treatment of hepatitis B, with a medical nozzle device for administering the composition to the nasal mucosa.

Background Art

[0002] Hepatitis B is hepatitis that develops by being infected with the hepatitis B virus (HBV), and HBV is transmitted through blood and body fluids. Persistent infection of hepatocytes with HBV causes chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma.

[0003] Currently, interferon preparations (IFN) and nucleic acid analog preparations (NA) are mainly used as the first choice for the treatment of chronic hepatitis B (CHB). Although there are effective examples where IFN enhances immunity and effectively sustains virus growth suppression, generally the HBV elimination rate is low, and its strong side effects are also a major problem. On the other hand, NA shows a high HBV elimination rate of about 95%, but the treatment effect is temporary and does not achieve a cure, so lifelong administration is required, leaving major problems in compliance and medical economics. There are also reports of the problem of the emergence of drug-resistant viruses with long-term use. Therefore, a new treatment method for CHB has been demanded.

[0004] In Japan, only hepatitis B vaccines that inoculate the HBs antigen (hepatitis B surface antigen) of the hepatitis B virus subcutaneously or intramuscularly are approved, and certain results have been achieved in significantly reducing HBV carriers. On the other hand, as a treatment for CHB, trials of immunotherapy with HBV vaccines have been conducted, but a sufficient treatment effect has not been obtained yet. To address such problems, numerous attempts have been made from various aspects to date. As a new method of administering the hepatitis B vaccine, intranasal vaccines have drawn attention. However, when currently widely used subcutaneous and intramuscular vaccines are directly administered intranasally, it has been reported in experimental animals and humans that a good immune response against the hepatitis B virus cannot be induced and the therapeutic effect is insufficient.

[0005] Under such circumstances, the Center for Genetic Engineering and Biotechnology (CIGB) in Cuba developed a therapeutic intranasal vaccine containing two types of antigens, HBs antigen and HBc antigen, and conducted a clinical trial in Bangladesh, successfully commercializing it as HeberNasvac (registered trademark, Non-Patent Document 1). However, since the immune response is insufficient with intranasal administration alone, a two-cycle vaccination that also combines subcutaneous administration is required, and it is not a complete mucosal vaccine for intranasal use.

[0006] As described above, although the development and practical application of intranasal vaccines as next-generation hepatitis B vaccines are expected to progress from conventional hepatitis B vaccines administered subcutaneously, intramuscularly, etc., sufficient effects have not been achieved, and there have been various issues in moving towards practical application.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0008] An object of the present invention is to develop an effective administration system for a hepatitis B vaccine including an administration device, and another object is that its effect can be expected to achieve a radical cure of hepatitis B.

Means for Solving the Problems

[0009] In view of the above problems, the inventors have conducted intensive studies and, as a result, by combining a nasal mucosa spray administration gel base composed of a carboxyvinyl polymer treated with an external shearing force to add spraying performance with HBs antigen and HBc antigen, it has been found that an adjuvant is not particularly required and the immunogenicity to humans can be enhanced. By using an administration method incorporated into a quantitative syringe type ejector having an optimized nasal spray nozzle, it has been found that an excellent antibody titer against hepatitis B virus can be obtained and an excellent therapeutic effect of hepatitis B can be obtained, and the present invention has been completed. That is, the present invention is as follows.

[0010] [1] (i) Both or either one of hepatitis B surface antigen (HBs antigen) and hepatitis B nucleocapsid antigen (HBc antigen), and (ii) A gel base containing a carboxyvinyl polymer treated with an external shearing force to add spraying performance A hepatitis B vaccine nasal administration system in which a hepatitis B vaccine composition for nasal mucosa spray administration containing the same is filled into a syringe type ejector having a nasal spray nozzle.

[0011] [2] The syringe type ejector has A hollow nozzle main body portion having a tip portion formed with a nozzle ejection hole, A solid filling rod disposed in the nozzle main body portion, And a nozzle chamber formed between the filling rod and the nozzle main body portion and in fluid communication between the tip opening and the nozzle ejection hole, The hepatitis B vaccine nasal administration system according to [1], which is a medical syringe having a tip opening in fluid communication with a syringe barrel and provided with a nasal spray nozzle characterized in that the nozzle ejection hole has a diameter of 0.25 mm to 0.30 mm.

[0012] [3] The hepatitis B vaccine nasal administration system according to [1] or [2], wherein the hepatitis B vaccine of (i) is 0.01 to 10 mg / mL per antigen.

[0013] The hepatitis B vaccine nasal administration system according to any one of [1] to [3], containing 0.1 w / v% to 1.0 w / v% of carboxyvinyl polymer in the composition.

[0014] The hepatitis B vaccine nasal administration system according to any one of [1] to [4], using a gel base containing a carboxyvinyl polymer treated with an external shearing force to add (1) a preparation particle size distribution range, (2) spray density uniformity, and / or (3) injection angle control as spray performance.

[0015] The hepatitis B vaccine nasal administration treatment system according to any one of [1] to [3], using a gel base containing 0.5 w / v% to 2.0 w / v% of carboxyvinyl polymer in the gel base, treating with an external shearing force to add (1) a preparation particle size distribution range, (2) spray density uniformity, and / or (3) injection angle control as spray performance, and then uniformly mixing the obtained gel base with a virus stock solution containing hepatitis B surface antigen (HBs antigen) and hepatitis B nucleocapsid antigen (HBc antigen) in a short time without applying stress.

[0016] The hepatitis B vaccine nasal administration system according to any one of [1] to [6], manufactured using a gel base added with spray performance controlled such that (1) the average particle size of the preparation is in the range of 30 μm to 80 μm and the particle size distribution is 80% or more in the range of 10 μm to 100 μm in the preparation particle size distribution, (2) the spray density becomes an even full cone without bias, and (3) the injection angle is controlled in the range of 30° to 70°, by applying an external shearing force to a base containing a carboxyvinyl polymer.

[0017] [8] Shear force is externally applied to a base containing carboxyvinyl polymer to produce a gel base added with spraying performance controlled such that (1) in the formulation particle size distribution, the average particle size of the formulation is in the range of 40 μm to 70 μm, and 90% or more of the particle size distribution is in the range of 10 μm to 100 μm, (2) the spray density is an even full cone without bias, and (3) the spray angle is controlled in the range of 40° to 60°. The nasal administration system for hepatitis B vaccine according to any one of [1] to [6].

[0018] [9] The nasal administration system for hepatitis B vaccine according to any one of [2] to [8], characterized in that the nozzle ejection hole has substantially no curved portion.

[0019]

[10] The nasal administration system for hepatitis B vaccine according to any one of [2] to [9], characterized in that at the tip where the nozzle ejection hole is formed, the thickness in the ejection direction of the formulation is 0.20 mm to 0.30 mm.

[0020]

[11] At least a part of the inner wall of the nozzle body is formed in a cylindrical shape, and at least a part of the outer wall of the filling rod is formed in a cylindrical shape including a plurality of groove portions provided in the circumferential direction. The nozzle chamber is formed between at least a part of the inner wall of the nozzle body and the groove portion of at least a part of the outer wall of the filling rod. The nasal administration system for hepatitis B vaccine according to any one of [2] to

[10] , characterized in that the filling rod has a vortex forming portion facing the tip of the nozzle body.

[0021]

[12] The nasal administration system for hepatitis B vaccine according to

[11] , characterized in that in the vortex forming portion, the direction in which the formulation flows in from the groove portion of the filling rod is displaced from the central axis to form a vortex of the formulation.

[0022]

[13] The nasal administration system for hepatitis B vaccine according to

[11] or

[12] , characterized in that at least a part of the inner wall of the nozzle body is formed such that the cross-section in a plane substantially perpendicular to the ejection direction becomes continuously or stepwise smaller toward the ejection direction.

[0023]

[14] The hepatitis B vaccine nasal administration system according to any one of [1] to

[13] for preventing and / or treating hepatitis B.

[0024]

[15] A method for preventing and / or treating hepatitis B, characterized by administering a hepatitis B vaccine composition to a patient in need of prevention and / or treatment with the hepatitis B vaccine nasal administration system according to any one of [1] to

[13] .

[0025]

[16] The hepatitis B vaccine nasal administration system according to any one of [1] to

[13] for use in preventing and / or treating hepatitis B. [Effect of the Invention]

[0026] According to the present invention, a hepatitis B nasal vaccine composition having hepatitis B surface antigen (HBs antigen) and hepatitis B nucleocapsid antigen (HBc antigen) as active ingredients, inducing an effective immune response with a smaller amount of antigen without particularly requiring an adjuvant, and having few side effects because there is no need to use an adjuvant can be provided. By using an administration method using a metering syringe type ejector having an optimized nasal spray nozzle, it is possible to accurately address the purposes of treating and preventing hepatitis B. The hepatitis B vaccine composition for transnasal mucosal spray administration of the present invention contains a gel base composed of a carboxyvinyl polymer treated with an external shearing force to add spray performance, and thus can induce an effective immune response with a smaller amount of antigen by spreading and staying widely and for a long time on the nasal mucosa. By using the system of the present invention in which the hepatitis B vaccine composition for transnasal mucosal spray administration is filled in a metering syringe type ejector having an optimized nasal spray nozzle, not only can hepatitis B be prevented, but also its effect can be expected in treatment. [Brief Description of the Drawings]

[0027]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Mode for Carrying Out the Invention

[0028] The present invention provides a hepatitis B vaccine nasal administration system filled in a medical syringe-type ejector having a tip opening in fluid communication with a syringe barrel, the system comprising a hepatitis B vaccine composition for nasal administration, which contains a gel base made of a carboxyvinyl polymer treated with an externally applied shearing force to impart spraying performance, hepatitis B surface antigen (HBs antigen), and hepatitis B nucleocapsid antigen (HBc antigen), and does not particularly require an adjuvant, and a nasal spray nozzle having a hollow nozzle body portion with a tip portion formed with a nozzle ejection hole, a solid filling rod disposed within the nozzle body portion, and a nozzle chamber formed between the filling rod and the nozzle body portion and in fluid communication between a tip opening and the nozzle ejection hole, the nozzle ejection hole having a diameter of 0.25 mm to 0.30 mm. In the present invention, the hepatitis B vaccine nasal administration system refers to an integrated product of the vaccine composition and its dispenser, in which the hepatitis B vaccine composition of the present invention is filled in the syringe-type ejector of the present invention.

[0029] The "gel base containing a carboxyvinyl polymer treated with an externally applied shearing force to impart spraying performance" used in the present invention means, for example, the "gel base containing a skin / mucous membrane adherent" disclosed in WO2007 / 123193, which contains a carboxyvinyl polymer, optionally contains gellan gum, and is a base whose viscosity is adjusted by applying an externally applied shearing force. The specific externally applied shearing force described in WO2007 / 123193 is not merely stirring or shaking, but is performed using a device that applies a shearing force known to those skilled in the art. Specifically, a high-speed rotary emulsifying device, a colloid mill type emulsifying device, a high-pressure emulsifying device, a roll mill type emulsifying device, an ultrasonic emulsifying device, and a membrane emulsifying device can be used. Particularly preferred are high-speed rotary emulsifying devices of the homomixer type, comb tooth type, and intermittent jet flow generation type. Such a base can be adjusted to various viscosities by applying an externally applied shearing force, and is characterized in that it can be controlled to be suitable for the injection angle and injection density from a spray container or the like. Further, by using a metering syringe type ejector having a nasal spray nozzle in an optimized form of the present invention, the same spray compatibility (such as spray dispersibility and uniformity of the formulation particle size) as that of a pump type sprayer such as an airless sprayer disclosed in WO2007 / 123193 can be achieved, and the adhesion of hepatitis B antigen particles to the nasal mucosa is improved over a wide range for a long time, thereby enhancing the immunogenicity of the vaccine.

[0030] The carboxyvinyl polymer used as a raw material for the gel base of the present invention is a hydrophilic polymer obtained by polymerizing acrylic acid as a main component, and pharmaceutical additives usually used for preparing an aqueous gel agent can be used without limitation. The content of the gel base containing a carboxyvinyl polymer treated with an externally applied shearing force to impart spraying performance, in terms of the content of the carboxyvinyl polymer, is 0.1 to 1.0 w / v%, preferably 0.3 to 0.7 w / v%.

[0031] The vaccine of the present invention is characterized by containing hepatitis B surface antigen (HBs antigen) and hepatitis B nucleocapsid antigen (HBc antigen) as antigens. The hepatitis B virus antigens used in the present invention refer to hepatitis B surface antigen and hepatitis B nucleocapsid antigen produced by yeast by applying recombinant DNA technology.

[0032] For the above-mentioned hepatitis B virus antigen, a virus stock solution purified or concentrated for mixing with a transnasal spray administration gel base is used. In the vaccine of the present invention, the concentration of the hepatitis B virus antigen is preferably 0.01 - 10 mg / mL per one vaccine antigen, and more preferably 0.05 - 5 mg / mL.

[0033] Hepatitis B surface antigen (HBs antigen) takes a particle form (diameter about 50 - 60 nm) presenting many antigen proteins on the lipid membrane. The antigen protein presented is originally a protein composed of three domains (S, Pre-S1, Pre-S2). The antigen possessing all three domains is the L-type antigen (HBsAg L-protein), the one lacking Pre-S1 is the M-type antigen, and the one lacking both Pre-S1 and Pre-S2 is distinguished as the S-type antigen (HBsAg S-protein). In any case, the antigen is produced using recombinant yeast.

[0034] An adjuvant is a general term for substances having regulatory activities such as enhancing or suppressing the immune response. It is an immunopotentiator added to a vaccine to enhance the immunogenicity of an antigen, and many substances have been studied so far. On the other hand, while the use of an adjuvant can improve the immune effect of a vaccine, there are also drawbacks such as the possibility of side effects such as inflammation. Naturally, several candidates can be mentioned as adjuvants for transnasal administration vaccines, but since there is no adjuvant widely recognized as safe, transnasal administration vaccines containing adjuvants with established efficacy and safety have not yet been approved.

[0035] The inventor used the above-described transnasal spray administration gel base having excellent spraying performance and high nasal mucosa spreading rate for the hepatitis B sub-vaccine, so that it is not necessary to use other administration routes such as subcutaneous administration in combination, and without using an adjuvant, a vaccine that is effective with a smaller amount of antigen and has fewer side effects can be obtained. By combining it with a device that enables spraying even with a highly viscous gel base, the average particle diameter of the sprayed preparation is in an appropriate range of 50 μm to 120 μm (preferably in the range of 70 μm to 100 μm), and the preparation particle size distribution is 50% or more (preferably 60% or more) in the range of 10 μm to 100 μm. The injection angle from the device is set in the range of 30° to 70° (preferably in the range of 40° to 60°) so that it can be administered to the necessary site in the nasal cavity, and the injection density enables uniform nasal spray administration in a full cone. Thus, the present inventors have found a hepatitis B vaccine composition for transnasal spray administration for transnasal spray administration, and have reached the present invention by discovering its production method, as well as a preventive method and a treatment method using the same.

[0036] In the present invention, "full cone", which represents a uniform spray density without bias in spray density, is one of the spray pattern shapes and means the entire homogeneous circular area, and the opposite term is the "hollow cone", which is a donut type localized only around the circumference.

[0037] In addition to the hepatitis B virus antigen and the transnasal spray administration gel base, the vaccine of the present invention may further contain a carrier acceptable as a pharmaceutical. As the carrier, carriers usually used in the production of vaccines and intranasal administration type preparations can be used, and specifically, saline, buffered saline, dextrose, water, glycerin, isotonic aqueous buffers, and combinations thereof can be mentioned. In addition, preservatives (e.g., thimerosal), tonicity agents, pH adjusters, surfactants, stabilizers (e.g., sodium edetate hydrate), and inactivators (e.g., formalin) are appropriately formulated therein.

[0038] The vaccine of the present invention is for nasal spray administration. The vaccine of the present invention can be used to prevent or treat hepatitis B.

[0039] As a method of administering the vaccine, the optimized nasal spray nozzle of the present invention can be used for one or both nostrils and can be used as a disposable device.

[0040] The dosage is determined in consideration of the age, sex, weight, etc. of the subject, but the concentration of the hepatitis B virus antigen is preferably 0.01 to 10 mg / mL per vaccine antigen, and more preferably 0.05 to 5 mg / mL. The amount of antigen administered is preferably 0.1 to 5 mg per vaccine antigen, and more preferably 0.5 to 2 mg.

[0041] Hereinafter, embodiments of the nasal spray nozzle used in the metered syringe type ejector having the nasal spray nozzle of the present invention will be described with reference to the accompanying drawings. In the following description of the embodiments, terms indicating directions (for example, "front", "rear", "proximal", and "distal", etc.) are used as appropriate for easy understanding, but these are for the purpose of explanation and these terms do not limit the present invention. Also, in each of the accompanying drawings, similar components are illustrated using similar reference numerals.

[0042] [Medical syringe] FIG. 1 is a partially cut-away side view showing a schematic configuration of an entire medical syringe 1 equipped with a nasal spray nozzle 10 according to an embodiment of the present invention. As shown in FIG. 1, the medical syringe 1 generally includes a syringe body 4 made of synthetic resin or glass having a syringe barrel 3 capable of being filled with a preparation 2, a plunger rod 5 inserted into the syringe barrel 3 of the syringe body 4, and a piston 7 attached via a fixing portion 5a provided at the distal end of the plunger rod 5 and slidable within the syringe barrel 3 to send the preparation within the syringe barrel 3 out from the distal end opening 6 of the syringe body 4, a finger hook portion 8 disposed around the proximal end of the syringe body 4, and a plunger operation portion 9 for transmitting the force applied from the finger of an operator such as a doctor to the plunger rod 5. The medical syringe 1 shown in FIG. 1 is the same as the metering syringe type ejector described in WO2013 / 145789.

[0043] Note that the nasal spray nozzle 10 according to the present invention is applicable to a medical syringe 1 having an arbitrary form in which the preparation accommodated in the syringe barrel 3 is extruded by the plunger rod 5 (and the piston 7), and does not limit the scope of the claims according to the present invention. Therefore, in this specification, the description of the detailed configuration of the medical syringe (nasal metering syringe type ejector) 1 will be omitted, and the configuration and operation of the nasal spray nozzle 10 used therein will be described in more detail. Note that the entire content of WO2013 / 145789 is incorporated herein by reference in its entirety.

[0044] [Nasal Spray Nozzle] In addition, as shown in FIG. 1, the medical syringe 1 further includes a nasal spray nozzle 10 disposed opposite to the tip opening 6 of the syringe body 4, and a protective cap 50 for protecting the sterilized tip portion 22 from contaminants and mechanical impacts. FIGS. 2(a) and (b) are partial cutaway exploded perspective views showing the schematic configuration of the nasal spray nozzle 10 according to an embodiment of the present invention. As shown in the drawings, the nasal spray nozzle 10 generally has a hollow nozzle body portion 20 having a tip portion 22 in which a nozzle ejection hole 21 is formed, and a solid filling rod (filling bar) 30 disposed within the nozzle body portion 20. FIGS. 2(a) and (b) show the states before and after the filling rod 30 is disposed or inserted into the nozzle body portion 20. The tip portion 22 of the nozzle body portion 20 has a substantially circular shape, and the nozzle ejection hole 21 is formed at the center of the tip portion 22.

[0045] FIG. 3(a) is a vertical cross-sectional view of the nasal spray nozzle 10 shown in FIG. 2(b) as seen in a vertical plane passing through the nozzle ejection hole 21. FIGS. 3(b) to (d) are horizontal cross-sectional views as seen from lines B-B, C-C, and D-D of FIG. 3(a), respectively. The hollow nozzle body portion 20 has an inner wall 23 that forms a substantially cylindrical internal space 24. As shown in FIGS. 3(c) and 3(d), the internal space 24 includes a nozzle small-diameter portion 25 closer to the nozzle ejection hole 21 of the hollow nozzle body portion 20, a nozzle large-diameter portion 26 into which the tip opening 6 of the syringe body 4 is inserted, and a nozzle shoulder portion 27 formed such that the diameter of the internal space 24 continuously or stepwise decreases from the nozzle large-diameter portion 26 toward the nozzle small-diameter portion 25.

[0046] On the other hand, the solid filling rod 30 inserted into the nozzle body portion 20 has an outer wall 33 having an outer shape that is substantially complementary to the inner wall 23 (internal space 24) of the nozzle body portion 20. As shown in FIGS. 2(a), 3(c), and (d), the diameters of the rod large-diameter portion 36 and the rod small-diameter portion 35 are formed such that they continuously or stepwise decrease from the rod large-diameter portion 36 toward the rod small-diameter portion 35, and it has a rod shoulder portion 37.

[0047] As shown in Fig. 3(a), a protrusion 23a is provided on the inner wall 23 of the nozzle body 20, and a recess 33a for receiving the protrusion 23a is provided on the outer wall 33 of the filling rod 30. When the filling rod 30 is inserted into the internal space 24 of the nozzle body 20, it is preferable that the protrusion 23a and the recess 33a are fitted together so that they can be securely fixed.

[0048] Also, as is clear from Figs. 2(a), (b) and 3(a)-(d), the filling rod 30 has a plurality of groove portions 38, 39 arranged at intervals in the circumferential direction at the rod small diameter portion 35 and the rod large diameter portion 36. Further, the filling rod 30 is inserted into the nozzle body 20 so that a gap 40 (Fig. 3(a)) is formed between the nozzle shoulder portion 27 and the rod shoulder portion 37. Therefore, the nasal spray nozzle 10 assembled as shown in Fig. 2(b) forms a nozzle chamber 42 that can be in fluid communication through the groove portions 38, 39 and the gap 40, and the preparation 2 sent out from the tip opening 6 of the syringe body 4 can be guided to the tip portion 22 of the nasal spray nozzle 10 through the nozzle chamber 42.

[0049] Furthermore, as shown in Fig. 3(b), the filling rod 30 has a vortex forming portion 44 facing the tip portion 22 of the nasal spray nozzle 10. The vortex forming portion 44 is configured to form a vortex before the preparation 2 flowing in from each groove portion 38 of the rod small diameter portion 35 is ejected from the nozzle ejection hole 21 of the nozzle body 20. Specifically, the end portion of the rod small diameter portion 35 constituting the vortex forming portion 44 is formed to extend in a direction displaced from the vertical central axis of the nozzle ejection hole 21. By forming a vortex in this way before the preparation 2 is ejected from the nozzle ejection hole 21, the ejection angle of the preparation can be enlarged and the preparation can be sprayed more uniformly.

[0050] As is apparent from FIGS. 3(c) and 3(d), it is preferable to design the groove portion 38 of the rod small diameter portion 35 to be smaller than the groove portion 39 of the rod large diameter portion 36 to increase the pressure of the preparation in the vortex forming portion 44 before being injected from the nozzle ejection hole 21. Further, since the diameters of the rod large diameter portion 36 and the rod small diameter portion 35 are designed to continuously or stepwise decrease from the rod large diameter portion 36 toward the rod small diameter portion 35, it is easy to deeply insert into the nasal cavity of a patient or the like, and it is possible to facilitate the spraying of the preparation onto the vicinity of the inferior turbinate and the deep part thereof of the patient or the like. That is, the diameter of the rod small diameter portion 35 is preferably sufficiently smaller than the nostrils of the patient or the like without giving a sense of fear to the patient or the like.

Example

[0051] Hereinafter, the present invention will be described in detail by way of examples, but the present invention is not limited to these examples at all. By the method shown below, a gel base for spray administration and a hepatitis B virus stock solution were each prepared, and the two were mixed as follows to prepare a hepatitis B vaccine composition for transnasal mucosal spray administration.

[0052] 〔Production of gel base〕 Gel base for spray administration Example 1 TIFF0007685834000001.tif66155

[0053] Gel base for spray administration Example 2 TIFF0007685834000002.tif66155

[0054] 〔Virus stock solution containing hepatitis B virus antigen〕 Virus stock solution Example 1 TIFF0007685834000003.tif57153

[0055] Virus stock solution Example 2 TIFF0007685834000004.tif57153

[0056] Mixing of Gel Base and Virus Stock Solution The above gel base Example 1 and virus stock solution Example 1 were mixed and stirred at a ratio of (1:1) to obtain a homogeneous hepatitis B vaccine composition for intranasal spray administration (Example 1). Similarly, the above gel base Example 2 and virus stock solution Example 2 were mixed and stirred at a ratio of (2:8) to obtain a homogeneous hepatitis B vaccine composition for intranasal spray administration (Example 2). This mixing and stirring can be achieved in a short time with gentle mixing and stirring without applying stress such as heat and pressure to the hepatitis B vaccine antigen. The component quantities, physical property values of the obtained hepatitis B vaccine composition for intranasal spray administration, and the added spray performance when sprayed using an appropriate device are shown.

[0057] Example 1 TIFF0007685834000005.tif84155

[0058] Example 2 TIFF0007685834000006.tif84155

[0059] Therefore, when the hepatitis B vaccine intranasal inoculation preparation of Example 2 produced using a gel base prepared by applying an external shear force was filled into a medical syringe having a tip opening in fluid communication with a syringe barrel, and used with a nasal spray nozzle comprising a hollow nozzle body portion having a tip portion in which a nozzle ejection hole is formed, a solid filling rod disposed within the nozzle body portion, and a nozzle chamber formed between the filling rod and the nozzle body portion and in fluid communication between the tip opening and the nozzle ejection hole, and the nozzle ejection hole having a diameter in the range of 0.25 mm to 0.30 mm, it was confirmed that: (1) in the formulation particle size distribution, the average particle size of the formulation was in the range of 30 μm to 80 μm [59.7 μm], and the particle size distribution was 80% or more in the range of 10 μm to 100 μm [88.8%]; (2) the spray density was an even full cone without bias; and (3) the injection angle was controlled in the range of 30° to 70° [55°], resulting in a hepatitis B vaccine intranasal inoculation system.

[0060] Prevention and treatment effects by human clinical trials (Subject) To verify the preventive effect, an immune response test of the subjects was conducted in advance with subcutaneous and intramuscularly inoculated vaccines, and they were classified into (1) vaccine non-responders in whom antibody induction was not observed, (2) vaccine responders in whom antibody induction was observed, and (3) unvaccinated subjects, and these were used as the subjects. To verify the therapeutic effect, (4) asymptomatic carriers with HBV viremia but without hepatitis onset and (5) CHB patients undergoing NA treatment were used as the subjects.

[0061] [Verification of Preventive Effect] For each case, the hepatitis B vaccine composition for intranasal spray administration prepared in Example 2 was intranasally spray-administered in a total volume of 1.0 mL, 0.5 mL per nostril, using a syringe-type ejector having a nasal spray nozzle. (1) Vaccine non-responders, (2) vaccine responders, and (3) unvaccinated subjects were intranasally administered three times at two-week intervals.

[0062] [Effect on Subcutaneous and Intramuscularly Inoculated Vaccine Non-Responders] Thirteen vaccine non-responders who showed no immune response to subcutaneous and intramuscularly inoculated vaccines were given three intranasal administrations of the vaccine, and the HBs antibody titer and HBc antibody titer were measured one month after the final administration. In all 13 cases, the HBs antibody and HBc antibody seroconverted (Table 1). TIFF0007685834000007.tif99156

[0063] [Effect on Subcutaneous and Intramuscularly Inoculated Vaccine Responders] Nineteen vaccine responders were given three intranasal administrations of the vaccine, and the HBs antibody titer and HBc antibody titer were measured one month after the final administration. In all 19 cases, the HBs antibody was above the upper limit of the measurement limit, and the HBc antibody seroconverted (Table 2). TIFF0007685834000008.tif132156

[0064] [Effect on Unvaccinated Subjects] Seven unvaccinated individuals were administered the vaccine intranasally three times, and the HBs antibody titer and HBc antibody titer were measured one month after the final administration. Except for one case, HBs antibody and HBc antibody seroconversion occurred in six cases (Table 3). TIFF0007685834000009.tif62156

[0065] [Verification of Therapeutic Effect] For each case, the hepatitis B vaccine composition for intranasal spray administration prepared in Example 2 was administered by nasal spray at a rate of 0.5 mL per nostril for a total of 1.0 mL using a syringe-type ejector equipped with a nasal spray nozzle. (4) Asymptomatic carriers and (5) CHB patients undergoing NA treatment were administered intranasally a total of 10 times at two-week intervals.

[0066] (Effect on Asymptomatic Carriers) Forty-one asymptomatic carriers were administered the vaccine intranasally 10 times. The changes in HBV-DNA level, HBs antigen level, and HBs antibody positivity rate were evaluated before administration and six months after the final administration. Although no clear change was observed in the HBV-DNA level six months after the end of administration, the HBs antigen level decreased to 78.6% when the pre-treatment level was set at 100. Since 20 out of 41 cases showed seroconversion of HBs antibody, the seroconversion rate was 48.8% (Table 4). TIFF0007685834000010.tif35155

[0067] (CHB Patients Undergoing NA Treatment) Twenty-nine CHB patients undergoing NA treatment were administered the vaccine intranasally 10 times. The changes in HBV-DNA level, HBs antigen level, and HBs antibody positivity rate were evaluated six months after the final administration. Due to NA treatment, HBV-DNA was below the detection sensitivity in all cases before treatment, and remained below the detection sensitivity six months after treatment. The HBs antigen level was 79.3% when the pre-treatment level was set at 100, and since 11 out of 29 cases showed seroconversion of HBs antibody, the seroconversion rate was 37.9% (Table 5). TIFF0007685834000011.tif35155 [Explanation of Symbols]

[0068] 1... Medical syringe, 2... Preparation, 3... Syringe barrel, 4... Syringe body, 5... Piston rod, 5a... Fixed part, 6... Tip opening, 7... Piston, 8... Finger hook part, 9... Piston operation part, 10... Nasal spray nozzle, 20... Nozzle body part, 21... Nozzle ejection hole, 22... Tip part, 23... Inner wall of the nozzle body part, 23a... Protrusion part, 24... Internal space, 25... Nozzle small diameter part, 26... Nozzle large diameter part, 27... Nozzle shoulder part, 30... Filling rod (filling stick), 33... Outer wall of the filling rod, 33a... Recess, 35... Rod small diameter part, 36... Rod large diameter part, 37... Rod shoulder part, 38, 39... Groove part, 40... Gap, 42... Nozzle chamber, 44... Vortex formation part, 4 6... Curved part, 50... Protective cap.

Claims

1. (i) both hepatitis B surface antigen (HBs antigen) and hepatitis B nucleocapsid antigen (Hbc antigen), and (ii) a gel base containing a carboxyvinyl polymer treated with an externally applied shearing force to impart spraying performance A hepatitis B vaccine nasal administration system for treating hepatitis B, which is filled into a syringe-type ejector having a nasal spray nozzle, and contains a hepatitis B vaccine composition for nasal mucosal spray administration containing the above.

2. The syringe-type ejector has a hollow nozzle body portion having a tip portion formed with a nozzle ejection hole, a solid filling rod disposed within the nozzle body portion, and a nozzle chamber formed between the filling rod and the nozzle body portion and in fluid communication between the tip opening and the nozzle ejection hole, The hepatitis B vaccine nasal administration system according to claim 1, which is a medical syringe having a tip opening in fluid communication with a syringe barrel, and is provided with a nasal spray nozzle characterized in that the nozzle ejection hole has a diameter of 0.25 mm to 0.30 mm.

3. The hepatitis B vaccine nasal administration system according to claim 1 or claim 2, wherein the hepatitis B vaccine of (i) is 0.01 to 10 mg / mL per antigen.

4. The hepatitis B vaccine nasal administration system according to any one of claims 1 to 3, which contains 0.1 w / v% to 1.0 w / v% of carboxyvinyl polymer in the composition.

5. The hepatitis B vaccine nasal administration system according to any one of claims 1 to 4, which uses a gel base containing a carboxyvinyl polymer treated with an externally applied shearing force to impart (1) formulation particle size distribution range, (2) spray density uniformity, and / or (3) spray angle control as spraying performance.

6. Using a gel base containing 0.5 w / v% to 2.0 w / v% of carboxyvinyl polymer in the gel base, and applying an externally applied shearing force to impart (1) formulation particle size distribution range, (2) spray density uniformity, and / or (3) spray angle control as spraying performance, and after obtaining the gel base, the hepatitis B vaccine nasal administration treatment system according to any one of claims 1 to 3, which is obtained by uniformly mixing a virus stock solution containing hepatitis B surface antigen (HBs antigen) and hepatitis B nucleocapsid antigen (Hbc antigen) without applying stress in a short time.

7. The hepatitis B vaccine nasal administration system according to any one of claims 2 to 6, wherein the nozzle ejection hole substantially has no curved portion.

8. The hepatitis B vaccine nasal administration system according to any one of claims 2 to 7, wherein, at the tip where the nozzle ejection hole is formed, the thickness in the ejection direction of the formulation is 0.20 mm to 0.30 mm.

9. At least a part of the inner wall of the nozzle main body is formed in a cylindrical shape, and at least a part of the outer wall of the filling rod is formed in a cylindrical shape including a plurality of groove portions provided in the circumferential direction. The nozzle chamber is formed between at least a part of the inner wall of the nozzle main body and the groove portion of at least a part of the outer wall of the filling rod. The hepatitis B vaccine nasal administration system according to any one of claims 2 to 8, wherein the filling rod has a vortex forming portion facing the tip of the nozzle main body.

10. The hepatitis B vaccine nasal administration system according to claim 9, wherein, in the vortex forming portion, the direction in which the formulation flows in from the groove portion of the filling rod is displaced from the central axis to form a vortex of the formulation.

11. The hepatitis B vaccine nasal administration system according to claim 9 or 10, wherein at least a part of the inner wall of the nozzle main body is formed such that the cross section in a plane substantially perpendicular to the ejection direction continuously or stepwise decreases toward the ejection direction.

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