Freeze-dried solids in vertical walled vials

Abstract

The present invention provides a system including vials and a method for using the same to provide lyophilized solids that can be removed from the vials without cracking or destroying. [Solution] A vertical wall vial system 10 is provided, comprising a vertical wall vial 14 and a solid lyophilized vaccine composition in the vertical wall vial, wherein the composition comprises an antigen and a stabilizer.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 937,061, filed on November 18, 2019, the entire content of which is incorporated herein by reference.

[0002] (Field of the Disclosure) The present disclosure generally relates to systems including vertical - wall vials and their use for providing removable lyophilized solids.

Background Art

[0003] (Background of the Disclosure) The development of stable, safe and effective biopharmaceuticals depends heavily on the use of appropriate container systems. These systems are necessary to protect and store otherwise fragile biopharmaceutical compositions from factors that promote degradation and destabilization. Lyophilization is a commonly employed freeze - drying process that results in a stable dried or powdered product, often a lyophilized solid, within a lyophilization vial. However, existing vials for lyophilization contain a neck portion, making it impossible to remove the resulting solid in an intact form.

[0004] Removable lyophilized solids would be a therapeutically useful oral or injectable option for the presentation of biopharmaceuticals such as vaccines.

Summary of the Invention

[0005] In one aspect of the present disclosure, a system is provided for providing a lyophilized solid that can be removed from a vial without cracking or breaking. In an embodiment according to the first aspect, a vertical - wall vial system includes a vertical - wall vial; and a solid lyophilized vaccine composition within the vertical - wall vial, the composition including an antigen and a stabilizer.

[0006] In some modifications of this embodiment, the source of the antigen is an animal, human, fish, bird, microorganism, parasite, protozoan, spirochete, bacterium, virus, vector, recombinant, or a combination thereof; the antigen is a nucleic acid, protein, peptide, or a combination thereof.

[0007] A second aspect of the present disclosure provides a method for providing a lyophilized solid that can be removed from a vial without cracking or destruction. In an embodiment according to the second aspect, a method for preparing a solid lyophilized vaccine composition includes: mixing an antigen and a stabilizer to obtain a formulation; filling a vertical wall vial with the formulation; lyophilizing the formulation in the vertical wall vial to form a solid lyophilized vaccine composition; and removing the solid lyophilized vaccine composition from the vertical wall vial.

[0008] In some modifications of this embodiment, the method of the present invention further comprises adding mannitol to the antigen and stabilizer formulation, and further comprising annealing the formulation at -25°C before removing the solid lyophilized vaccine composition. [Brief explanation of the drawing]

[0009] [Figure 1] Figure 1 is a perspective view of an embodiment of a vertical wall vial system including vertical wall vials.

[0010] [Figure 2] Figure 2 is a perspective view of an embodiment of solid material removed intact from the vertical wall vial shown in Figure 1.

[0011] [Figure 3] Figure 3 is a side view of an embodiment of the vertical wall vial shown in Figure 1.

[0012] [Figure 4] Figure 4 is a cross-sectional view of the vertical wall vial embodiment shown in Figure 3.

[0013] [Figure 5] Figure 5 is a perspective view of the components of the embodiment of the vertical wall vial system shown in Figure 1.

[0014] [Figure 6] Figure 6 is a perspective view of an embodiment of the vertical wall vial system of Figure 1, showing solid material at the bottom of the vertical wall vial.

[0015] [Figure 7] Figure 7 is a perspective view of an embodiment of the vertical wall vial system of Figure 1, showing solid material at the top of the vertical wall vial.

[0016] [Figure 8] Figure 8 is a schematic flowchart illustrating an embodiment of how to use the vertical wall vial system.

[0017] In the drawings, corresponding reference letters indicate corresponding parts, functions, and features through several figures. While the drawings represent embodiments of various features and components according to the present invention, they are not necessarily scaled, and certain features may be exaggerated to better illustrate and explain the invention. However, the present invention is not limited to the exact arrangement and means of the embodiments shown in the drawings.

[0018] (Detailed description of the disclosed embodiments) For the purpose of facilitating an understanding of the principles of the disclosed embodiments, embodiments shown in the drawings described below are referenced here. The embodiments disclosed below are not intended to be exhaustive or to limit the invention to the exact forms disclosed in the following detailed description. Rather, the embodiments are selected and described so that those skilled in the art can utilize the teachings. It will be understood that there is no intention to limit the scope of the invention. The invention includes any changes and further modifications in the illustrated apparatus and described methods, as well as further applications of the principles of the invention as set forth in the claims.

[0019] Figure 1 is a perspective view of an assembled vertical wall vial system 10 including a vertical wall vial 14, a stopper 12, a sealing member 16, and a solid 20. The sealing member 16 may be aluminum and is crimped onto the stopper 12 in any known manner. The sealing member 16 may alternatively be plastic. In a variant, the stopper 12 and the sealing member 16 may be configured as a single unit, and this unit may be configured such that a part of the unit can be removed, such as by using tabs. In such an example, the tab can be removed to insert a syringe or a needle.

[0020] Figure 2 is a plan view of the solid 20 removed from the vertical wall vial system 10. In some embodiments, the solid 20 is a lyophilized drug or biopharmaceutical product. The dimensions of the solid 20 can be customized by changing the height and cross-section of the vertical wall vial 14, thereby making the resulting solid 20 larger or smaller, in part corresponding to the final animal or human subject of administration. In some embodiments, the solid 20 is designed to be administered in solid form. Alternatively, the solid 20 can be dissolved prior to administration.

[0021] Figure 3 is a side view of an embodiment of the vertical wall vial 14 shown in Figure 1. The vertical wall vial 14 includes a side wall 141, an inner surface 142, a bottom wall 143, and a collar 145 that surrounds the upper end of the vertical wall vial 14 (opposite the bottom wall 143). The side wall 141 extends vertically from the bottom wall 143 to the collar 145 and may include a circumferential inner groove 146 in the middle of the width of the radial collar 145 that extends outward from the inner surface 142. The groove may, for example, enable the easy removal of the stopper 12 when the vertical wall vial 14 is sealed using a vacuum or the like. The side wall 141 and the bottom wall 143 define the inner volume 144 of the vertical wall vial 14. As used herein, "vertical wall" means that the side wall of the vial is not constricted, and this term is not limited to vials having side walls that are exactly perpendicular to the bottom wall. For example, the cross-section in the longitudinal direction of the vial may gradually increase from the bottom wall towards the collar, and in the case of such a frustum-shaped vial, it is also possible to take out intact solids. Since solids may shrink during their manufacturing process, the cross-section may also gradually decrease as long as it is never smaller than the cross-section of the solid.

[0022] In some embodiments, the vertical wall vial 14 comprises or is manufactured from a polymeric material. In other embodiments, the vertical wall vial 14 comprises or is manufactured from glass. In other embodiments, the vertical wall vial 14 comprises or is manufactured from other materials that can withstand everyday lyophilization temperatures and pressures.

[0023] In some embodiments, the vertical wall vial 14 is a 15x35 mm vial.

[0024] In some embodiments, the vertical wall vial 14 has an outer diameter of 15 ± 0.25 mm.

[0025] In some embodiments, the side wall 141 has a height of 35 ± 0.05 mm. In some embodiments, the side wall 141 has a thickness of 1.2 ± 0.05 mm.

[0026] In some embodiments, the side wall 141 is thinner than that of a standard freeze-drying vial to allow for optimal heat transfer during freeze-drying.

[0027] In some embodiments, the bottom wall 143 has a minimum thickness of 0.70 mm.

[0028] In some embodiments, the bottom radius of the vertical wall vial 14 is 1.47 mm to 2.49 mm.

[0029] In some embodiments, the bottom wall 143 has a bottom upturn of 0.2 mm to 0.8 mm and a bottom slope of up to 0.3 mm.

[0030] In some embodiments, the internal volume 144 is 0.3 mL, 0.5 mL, 1 mL, 1.5 mL, 2 mL, 3 mL, 5 mL, 10 mL, or 20 mL.

[0031] In some embodiments, the vertical wall vial 14 is cylindrical in shape, having an outer diameter of approximately 15 ± 0.25 mm and a length of approximately 35 ± 0.05 mm. The side walls 141 may have a thickness of 1.2 ± 0.05 mm. The bottom wall 143 may have a minimum thickness of 0.70 mm.

[0032] Figure 4 is a side view of an embodiment of a vertical wall vial 14, including a side wall 141, an inner surface 142, an inner volume 144, a collar 145, and a groove 146. In some embodiments, the collar 145 is configured such that the vertical wall vial is combined with a stopper 12 and a sealing member 16, and as a result, the sealing member 16 can be pressed onto the collar 145. The inner groove 146 can be fitted with a corresponding outer ridge of the stopper 12. In some embodiments, the inner radius from one inner surface 142 to another is 12.6 ± 0.2 mm. In some embodiments, the collar 145 has a height of 3.4 mm to 3.78 mm. In some embodiments, the groove 146 is configured to have a blowback.

[0033] Figure 5 is a perspective view of a vertical wall vial 14 having a plug 12 inserted inside. The plug 12 includes a head 121, a neck 122 extending from the head and having a smaller cross-section than the head, and a groove 123 dividing at least a portion of the neck. The groove 123 can function as a vent for water vapor transfer during freeze-drying.

[0034] In some embodiments, the stopper 12 is a standard 20 mm serum stopper or a freeze-dried stopper.

[0035] In some embodiments, the stopper 12 is made of or manufactured from rubber.

[0036] Figure 6 is a perspective view of an embodiment of the vertical wall vial system 10 shown in Figure 1, showing that the solid material 20 is deposited on the bottom wall 143 of the vertical wall vial 14. In some embodiments, the solid material 20 can separate from the inner surface 142 and rise slightly above the bottom wall 143.

[0037] Figure 7 is an inverted perspective view of the vertical wall vial system 10, showing that the solid material 20 has separated from the bottom wall 143 and inner surface 142 and is freely moving within the inner volume 144, with the solid material 20 accumulating on the stopper 12 in this figure. When the sealing member 16 and stopper 12 are removed, the solid material 20 can be removed from the vertical wall vial 14 substantially intact.

[0038] Figure 8 is a typical flowchart showing an embodiment of how to use the vertical wall vial system 10, which includes providing a vertical wall vial (202); compounding an antigen with a stabilizer (204); filling the vial with the compound (206); lyophilizing the compound (208); and removing the solid in a substantially intact form.

[0039] In some embodiments of the methods of use of this disclosure, the antigen is any pharmaceutical, compound, or drug used for the prevention or treatment of a disease or condition. In variations, the composition is an antigenic composition. In variations, the antigenic composition can evoke an immune response or be involved in biological activity. In some embodiments, the antigen may be of animal origin. For example, the antigen may be of mammalian origin, e.g., human origin. In some examples, the antigen may be of non-mammalian origin, e.g., fish or bird origin. In other examples, the antigen may be of microbial or parasitic origin. For example, the antigen may be of bacterial, viral, or fungal origin. In some examples, a bacterial antigen may be of spirochete origin. In other examples, the antigen may be of bacterial vector origin or viral vector origin, or source of recombinants thereof. In some embodiments, the antigen may be a nucleic acid, protein, peptide, or a combination thereof. In some embodiments, the antigen may be a living microorganism, a living modified microorganism, or an inactivated microorganism.For example, the antigen may be derived from one or more pathogenic infections, or may be used for the prevention or treatment of such infections, including Bordetella bronchiseptica (Bb), rabies virus, canine influenza virus (CIV), canine adenovirus-2 (CAV2), canine adenovirus-1 (CAV1), canine distemper virus (CDV), canine parainfluenza virus (CPiV), canine parvovirus (CPV), feline calicivirus (FCV), feline herpesvirus (FHV), feline panleukopenia virus (FPL), feline leukemia virus, This includes, but is not limited to, FeLV, Borrelia, Ehrlichia, and Giardia. In some embodiments, the antigen may be formulated together with a pharmaceutical carrier or the like.

[0040] In some embodiments of the uses of the present disclosure, the solid freeze-dried composition is a vaccine for use in animal subjects. For example, the animal subject may be a mammal, such as a human, cattle, pig, cat, dog, horse, rabbit, or wild animal. In other examples, the subject may be a non-mammal, such as a fish or bird.

[0041] In some embodiments of the methods of use of this disclosure, the antigen may be formulated with an adjuvant, an immunoadjuvant, or an immunomodulator, or a combination thereof. In variations, the antigen may include several compounds that enhance the immunogenicity or physiological efficacy of the composition when administered as a formulation.

[0042] In some embodiments of the methods of use of this disclosure, the antigen may be compounded with a filler. In variations, the filler may be used to solidify the resulting solid and / or to make the resulting solid more intact. For example, the filler may be mannitol, starch, gelatin, or a combination thereof.

[0043] In some embodiments of the methods of use of this disclosure, the antigen may be combined with a mucoadhesive agent. In variations, the mucoadhesive agent can increase the effectiveness of the interaction between the compound and the mucosa. In some embodiments, the antigen may be combined with an agent that enhances mucosal permeability.

[0044] In some embodiments of the methods of use of this disclosure, when the antigen is combined with a stabilizer, the antigen constitutes up to 50% of the total formulation. In some embodiments, the antigen constitutes up to 75% of the total formulation. The percentage of antigen used in the total formulation can be determined based on the dose, stability data, and loss upon drying.

[0045] In some embodiments of the methods of use of this disclosure, when an antigen is combined with a stabilizer, the stabilizer may, but is not limited to, the SGGK3 stabilizers disclosed herein. In some embodiments, the SGGK3 stabilizer consists of two solutions, SGGK3 Sol. 1 and SGGK3 Sol. 2. In some embodiments, SGGK3 Sol. 1 constitutes 60% of the SGGK3 stabilizer, and SGGK3 Sol. 2 constitutes 40% of the total stabilizer. The compositions of SGGK3 Sol. 1 and SGGK3 Sol. 2 are provided in Table 1 below.

[0046] In some embodiments of the methods of use of this disclosure, when the antigen is combined with a stabilizer, the stabilizer constitutes 50% of the total composition. In some embodiments, the stabilizer constitutes 25% of the total composition. In some embodiments, the stabilizer constitutes 20% to 30% of the total composition. [Table 1]

[0047] In some embodiments of the methods of use of this disclosure, when an antigen is combined with a stabilizer, the diluent constitutes up to 25% of the total composition. In some embodiments, the diluent is added to the composition up to a QS (sufficient amount) until its final volume is reached, and this amount may vary depending on the addition of the antigen. The compositions of embodiments of the diluent are provided in Table 2 below. [Table 2]

[0048] Generally, lyophilizing (also known as freeze-drying) is a process in which a formulation containing a substance dissolved in a suitable solvent is frozen, and then the mixture is placed under vacuum, causing the ice to sublimate rather than thaw through a liquid phase. Standard lyophilizing techniques for producing freeze-dried vaccines are well known.

[0049] In a modified version of this embodiment, if the antigen and stabilizer compositions contain crystalline components, the lyophilization compounding step (208) may include an additional annealing step. In this modified version, the annealing step may be carried out at -25°C, which can allow the crystals in the formulation to be reformed into a stronger structure. For example, this step can be used if the formulation contains mannitol.

[0050] In some embodiments of the methods of use of this disclosure, the solid material has contracted relative to the inner surface of the vertical wall vial 14 and can move within the inner volume 144.

[0051] In some embodiments of the methods of use of this disclosure, when removing solid material, the vertical wall vial 14 can be inverted and the solid material 20 can be allowed to fall by gravity onto the stopper 12, as shown in Figure 7, or the stopper 12 can be removed from the vertical wall vial 14, thereby completely removing the solid material 20 from the vertical wall vial 14. In some embodiments, the removal of solid material results in minimal loss of the viability of the solid material and / or minimal residue left on the inner surface 142 of the vertical wall vial 14. Minimal loss may be a reduction of 5% or less. In some embodiments, the solid material can be removed from the vertical wall vial 14 without physically cracking or destroying it. [Examples]

[0052] Example 1: Glass vertical wall vial formulation with stabilizer

[0053] According to embodiments of the method of the present disclosure, a glass straight-walled vial system can be used to produce a removable solid of a lyophilized formulation.

[0054] In one embodiment, the test groups were prepared by combining 50% Bordetella bronchiseptica antigen with 50% stabilizer (n=5 each): SGGK3 stabilizer, SGGK3 with mannitol and xanthan gum (filler and mucosal adhesion), Cuxhaven stabilizer B (current poultry stabilizer), or Cuxhaven with mannitol and xanthan gum (filler and mucosal adhesion). The preparations were used to sample the number of viable cells (see Table 3 below) and added to vertical-walled glass vials in 1.2 mL or 0.5 mL increments. The vertical-walled vials were freeze-dried at -50°C to 28°C with 60 mTorr for 60 to 360 minutes, followed by an additional -25°C annealing step to enable proper crystal formation (due to mannitol addition).

[0055] Each vertical walled vial was evaluated for viable plate count both before and after lyophilization, both inside the vial and after removal.

[0056] For evaluation within vials after lyophilization, each 1.2 mL vial was reconstituted with 1.2 mL of PBS, pooled as shown in Table 3 below, and the viable count was evaluated. The lyophilized solid was removed from the vial, placed in a 50 mL C tube, pooled (solid from five vials for each condition), reconstituted with 6 mL of PBS, and the viable count was evaluated. See Table 3.

[0057] Formulations containing the SGGK3 stabilizer yielded an acceptable lyophilized appearance in vertical-walled vials, while Cuxhaven B formulations had a poor appearance in vertical-walled vials, and some formulations containing Cuxhaven B appeared not to be completely dried.

[0058] Solids obtained from formulations containing the SGGK3 stabilizer could be easily removed from vertical-walled vials by simply tapping the vial, leaving virtually no residue. Formulations containing Cuxhaven B were not removed from vertical-walled vials. All formulations in vertical-walled vials showed minimal loss upon drying (as shown in Table 3).

[0059] As shown in Table 3, the solid obtained from the formulation containing the SGGK3 stabilizer showed no loss of viable cells when removed from the vial as a solid. [Table 3]

[0060] The solids obtained from formulations containing the SGGK3 stabilizer are functional; see Table 4 below. [Table 4]

[0061] Example 2: Glass and plastic vial formulations containing stabilizers

[0062] According to embodiments of the method of the present disclosure, a plastic vial system can be used to produce a removable solid of a lyophilized formulation comparable to a removable solid produced using a glass vertical-walled vial.

[0063] In one embodiment, the test group contained 50% live Bordetella bronchiseptica antigen mixed with a stabilizer (25% SGGK3 with a 25% diluent). The mixture was sampled for viable cell count (see Table 5 below) and added to glass vertical-walled vials at a dose of 1.2 mL or 0.3 mL (n=20 each), or to 3 mL plastic vertical-walled vials at a dose of 1.2 mL or 0.5 mL (n=20 each). The vertical-walled vials were lyophilized as detailed in Example 1 above.

[0064] Once drying was complete, five 1.2 mL vials were reconstituted with 1.2 mL of PBS and pooled for evaluation of the viable cell count after freeze-drying, as shown in Table 5 below.

[0065] The solid obtained from the formulation containing the SGGK3 stabilizer was easily removed from the glass vertical-walled vial. [Table 5]

[0066] Terms such as "comprises," "comprising," "contains," and "possess" generally mean "includes" or "including," and are interpreted as open conjunctions unless otherwise explicitly stated. Descriptions of specific components, structures, steps, etc., following open-ended transitional terms do not limit the claim in any way to those specifically listed components, structures, steps, etc. The terms "consisting of" or "consists of" are closed conjunctions.

[0067] Unless otherwise explicitly stated, if a method is described herein as comprising a series of steps, the order of steps presented herein is not necessarily the only order in which such steps may be performed, some of the steps described may be omitted, and / or other steps not described herein may be added to the method.

[0068] Unless otherwise explicitly stated, terms are used in their singular form for clarity, and are intended to include their plural form.

[0069] In this specification, the phrases "in one embodiment" or "in one aspect" do not necessarily all mean the same embodiment or aspect.

[0070] The following is a list of reference figures used throughout this specification. [Explanation of Symbols]

[0071] TIFF2026062967000007.tif73141

[0072] While the present invention has been described as having designs as shown by embodiments and examples, the present invention can be further modified within the spirit and scope of this disclosure. Therefore, this application is intended to cover any variations, uses, or adaptations of the present invention using its general principles. Furthermore, this application is intended to cover any departures from this disclosure that fall within the scope of known or customary practices in the art to which the present invention relates.

Claims

1. Vertical wall vial (14); and A vertical wall vial system (10) comprising a solid lyophilized vaccine composition in a vertical wall vial (14), wherein the composition comprises an antigen and a stabilizer.

2. A vertical walled vial system (10) according to claim 1, wherein the vertical walled vial (14) includes a bottom wall (143), a side wall (141) connected to and extending from the bottom wall (143), and a radial collar (145) on the opposite side of the bottom wall, extending outward from the side wall at the open end of the side wall.

3. A vertical wall vial system (10) according to claim 1, further comprising a plug (12) that can be inserted into the open end.

4. The vertical wall vial system (10) according to claim 3, further comprising a sealing member (16) made of plastic or aluminum.

5. The source of the antigen is an animal, human, fish, bird, microorganism, parasite, protozoan, spirochete, bacterium, virus, vector, recombinant, or a combination thereof; and A vertical wall vial system (10) according to claim 1, wherein the antigen is a nucleic acid, a protein, a peptide, or a combination thereof.

6. A vertical wall vial system (10) according to claim 1, wherein the source of the antigen is Bordetella bronchiseptica.

7. The antigen sources are Bordetella bronchiseptica (Bb), rabies virus, canine influenza virus (CIV), canine adenovirus-2 (CAV2), canine adenovirus-1 (CAV1), canine distemper virus (CDV), canine parainfluenza virus (CPiV), canine parvovirus (CPV), feline calicivirus (FCV), feline herpesvirus (FHV), feline panleukopenia virus (FPL), and feline leukemia virus. A vertical wall vial system (10) according to claim 1, selected from the group consisting of FeLV, Borrelia, Ehrlichia, and Giardia.

8. The vertical wall vial system (10) according to claim 1, wherein the composition further comprises an adjuvant, an immunoadjuvant, an immunomodulator, or a combination thereof.

9. Stabilizers, Bacto peptone; sucrose; Dipotassium hydrogen phosphate; Potassium dihydrogen phosphate; Potassium hydroxide; and A vertical wall vial system (10) according to claim 1, comprising gelatin.

10. The vertical wall vial system (10) according to claim 9, wherein the stabilizer further comprises mannitol, xanthan gum, a filler, a mucoadhesive agent, an agent that enhances mucosal permeability, or a combination thereof.

11. The vertical wall vial system (10) according to claim 1, wherein the solid freeze-dried vaccine composition further comprises a diluent consisting of MEM powder, sodium bicarbonate, HEPES acid, and purified water.

12. A method for producing a solid freeze-dried vaccine composition, A compound is obtained by mixing an antigen and a stabilizer; Fill the vertical walled vial (14) with the mixture; Freeze-drying the formulation in a vertical walled vial (14) to form a solid freeze-dried vaccine composition; and A method comprising removing the solid lyophilized vaccine composition from a vertical wall vial (14).

13. The method according to claim 12, wherein the solid freeze-dried vaccine composition is for use in humans, fish, birds, cattle, pigs, cats, dogs, horses, rabbits, or wild animals.

14. The method according to claim 12, wherein the antigen is Bordetella bronchiseptica, and the solid lyophilized vaccine composition is for use in dogs, cats, or rabbits.

15. The method according to claim 12, further comprising adding mannitol to the antigen and stabilizer formulation, and further comprising annealing the formulation at -25°C before removing the solid lyophilized vaccine composition.

16. The method according to claim 12, wherein the solid freeze-dried vaccine composition has a diameter smaller than the inner surface (142) of the vertical wall vial (14).

17. The method according to claim 12, wherein a solid freeze-dried vaccine composition is removed without cracking or destruction.

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