Lyophilized solids in vertical wall vials

Abstract

A system including a vial and a method of use thereof to provide a lyophilized solid that can be removed from the vial without cracking or breaking.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 937,061, filed November 18, 2019, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THE DISCLOSURE The present disclosure relates generally to a system including a vertical-walled vial and its use to provide a removable lyophilized solid product. [Background technology]

[0003] Background of the Disclosure The development of stable, safe, and effective biopharmaceuticals is highly dependent 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 dry or powdered product, often a lyophilized solid, within a lyophilization vial. However, existing lyophilization vials contain necks that prevent the resulting solid from being removed in an intact form.

[0004] The releasable lyophilized cake 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 is removable from a vial without cracking or breaking. In an embodiment according to the first aspect, the vertical-walled vial system includes a vertical-walled vial; and a solid lyophilized vaccine composition within the vertical-walled vial, the composition including an antigen and a stabilizer.

[0006] In some variations of this embodiment, the source of the antigen is 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] In a second aspect of the present disclosure, a method is provided for providing a lyophilized solid that can be removed from a vial without cracking or breaking. In an embodiment according to the second aspect, the method for preparing a solid lyophilized vaccine composition includes mixing an antigen and a stabilizer to obtain a formulation; filling the formulation into a straight-walled vial; lyophilizing the formulation in the straight-walled vial to form a solid lyophilized vaccine composition; and removing the solid lyophilized vaccine composition from the straight-walled vial.

[0008] In some variations of this embodiment, the method further comprises adding mannitol to the antigen and stabilizer formulation, and further comprises annealing the formulation at −25° C. prior to removing the solid lyophilized vaccine composition. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 is a perspective view of an embodiment of a vertical-walled vial system including a vertical-walled vial.

[0010] [Figure 2] FIG. 2 is a perspective view of an embodiment of a solid body removed in intact form from the vertical-walled vial of FIG.

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

[0012] [Figure 4] FIG. 4 is a cross-sectional view of the embodiment of the straight-walled vial of FIG.

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

[0014] [Figure 6] FIG. 6 is a perspective view of the embodiment of the vertical-walled vial system of FIG. 1 showing a solid material at the bottom of the vertical-walled vial.

[0015] [Figure 7] FIG. 7 is a perspective view of the embodiment of the vertical-walled vial system of FIG. 1 showing a solid material at the top of the vertical-walled vial.

[0016] [Figure 8] FIG. 8 is a schematic flow diagram illustrating an embodiment of a method of using the vertical wall vial system.

[0017] In the drawings, corresponding reference characters indicate corresponding parts, functions, and features throughout the several views. While the drawings represent embodiments of various features and components according to the present invention, the drawings are not necessarily to scale, and certain features may be exaggerated to better illustrate and explain the present invention. However, the present invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0018] DETAILED DESCRIPTION OF THE DISCLOSED EMBODIMENTS For the purposes of promoting an understanding of the principles of the disclosed embodiments, reference will now be made to the embodiments illustrated in the drawings described below. The embodiments disclosed below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can utilize its teachings. It will be understood that no limitation of the scope of the invention is thereby intended. The invention includes any alterations and further modifications in the illustrated apparatus and described methods, and further applications of the principles of the invention as defined in the appended claims.

[0019] 1 is a perspective view of an embodiment of a vertical-walled vial system 10 in an assembled state, including a vertical-walled vial 14, a stopper 12, a closure member 16, and a solid body 20. The closure member 16 may be aluminum and is crimped onto the stopper 12 by any known method. Alternatively, the closure member 16 may be plastic. In an alternative, the stopper 12 and the closure member 16 may be constructed as a single unit, which may be configured to allow a portion of the unit to be removed, such as by using a tab. In such an example, the tab may be removed to allow insertion of a syringe or needle.

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

[0021] 3 is a side view of the embodiment of the vertical-walled vial 14 shown in FIG. The vertical-walled vial 14 includes a side wall 141, an inner surface 142, a bottom wall 143, and a collar 145 that surrounds the top end of the vertical-walled 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 midway through the width of the radial collar 145 that extends outward from the inner surface 142. The groove may allow for easy removal of the stopper 12, for example, when the vertical-walled vial 14 is sealed using a vacuum or the like. The side wall 141 and the bottom wall 143 define an interior volume 144 of the vertical-walled vial 14. As used herein, "vertical-walled" means that the side walls of the vial are not constricted, and the term is not limited to vials having side walls that are exactly perpendicular to the bottom wall. For example, the cross section of the vial along its length may gradually increase from the bottom wall to the collar, and such a frusto-conical vial may allow for the removal of intact solid material. Because the solid material may shrink during its manufacture, the cross section may also decrease gradually, as long as it is never smaller than the cross section of the solid material.

[0022] In some embodiments, the vertical-walled vial 14 comprises or is made of a polymeric material. In other embodiments, the vertical-walled vial 14 comprises or is made of glass. In other embodiments, the vertical-walled vial 14 comprises or is made of other materials that can withstand routine lyophilization temperatures and pressures.

[0023] In some embodiments, the straight-walled vial 14 is a 15x35 mm vial.

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

[0025] In some embodiments, sidewall 141 is 35±0.05 mm high. In some embodiments, sidewall 141 is 1.2±0.05 mm thick.

[0026] In some embodiments, sidewall 141 is thinner than a standard lyophilization vial to allow for optimal heat transfer during lyophilization.

[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 straight-walled vial 14 is between 1.47 mm and 2.49 mm.

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

[0030] In some embodiments, the interior 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 straight-walled vial 14 is cylindrical with an outer diameter of about 15±0.25 mm and a length of about 35±0.05 mm. The side wall 141 can be 1.2±0.05 mm thick. The bottom wall 143 can have a minimum thickness of 0.70 mm.

[0032] 4 is a side view of an embodiment of a straight-walled vial 14, including a sidewall 141, an inner surface 142, an inner volume 144, a collar 145, and a groove 146. In some embodiments, the collar 145 configures the straight-walled vial with the stopper 12 and closure member 16 so that the closure member 16 can be crimped onto the collar 145. The inner groove 146 can mate with a corresponding outer ridge on 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 blowback.

[0033] 5 is a perspective view of a straight-walled vial 14 having a stopper 12 inserted therein. Stopper 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. Groove 123 can function as a vent for water vapor transfer during lyophilization.

[0034] In some embodiments, plug 12 is a standard 20 mm serum plug or a lyophilization plug.

[0035] In some embodiments, plug 12 comprises or is made from rubber.

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

[0037] 7 is an inverted perspective view of the vertical-walled vial system 10 showing that the solids 20 have separated from the bottom wall 143 and the interior surface 142 and are free to move within the interior volume 144, where the solids 20 are deposited on the stopper 12. Upon removal of the closure 16 and stopper 12, the solids 20 can be removed substantially intact from the vertical-walled vial 14.

[0038] FIG. 8 is an exemplary flow diagram illustrating an embodiment of a method of using the vertical-walled vial system 10, the method including providing a vertical-walled vial (202); combining an antigen with a stabilizer (204); filling the vial with the combination (206); lyophilizing the combination (208); and removing the solid material in a substantially intact form.

[0039] In some embodiments of the methods of use of the present disclosure, the antigen is any pharmaceutical, compound, or drug used in the prevention or treatment of a disease or condition. Alternatively, the composition is an antigenic composition. Alternatively, the antigenic composition can elicit an immune response or be involved in biological activity. In some embodiments, the antigen can be derived from an animal. For example, the antigen can be derived from a mammal, such as a human. In some instances, the antigen can be derived from a non-mammalian, such as a fish or bird. In other instances, the antigen can be derived from a microorganism or a parasite. For example, the antigen can be derived from a bacterium, a virus, or a fungus. In some instances, a bacterial antigen can be derived from a spirochete. In other instances, the antigen can be derived from a bacterial vector or a viral vector, or a recombinant source thereof. In some embodiments, the antigen can be a nucleic acid, a protein, a peptide, or a combination thereof. In some embodiments, the antigen can be a live microorganism, a live modified microorganism, or an inactivated microorganism.For example, the antigen may be derived from, and used in the prevention or treatment of, one or more pathogenic 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 herpes virus (FHV), feline panleukopenia virus (FPL), feline leukemia virus (FPL), and feline leukemia virus (FPL). FeLV, Borrelia, Ehrlichia, and Giardia. In some embodiments, the antigen may be formulated with a pharmaceutical carrier or the like.

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

[0041] In some embodiments of the disclosed methods of use, the antigen may be formulated with an adjuvant, immunoadjuvant, or immunomodulator, or a combination thereof. In a variation, the antigen includes some compound that enhances the immunogenicity or physiological effectiveness of the composition when administered as a formulation.

[0042] In some embodiments of the methods of use of the present disclosure, the antigen may be combined with a bulking agent. In alternative embodiments, the bulking agent may be used to strengthen and / or make the resulting solid more intact. For example, the bulking agent may be mannitol, starch, gelatin, or a combination thereof.

[0043] In some embodiments of the disclosed methods of use, the antigen may be formulated with a mucoadhesive agent. In some variations, the mucoadhesive agent can increase the effectiveness of the compound's interaction with the mucosa. In some embodiments, the antigen may be formulated with an agent that enhances mucosal permeability.

[0044] In some embodiments of the methods of use of the present disclosure, when the antigen is formulated with a stabilizer, the antigen comprises up to 50% of the total formulation. In some embodiments, the antigen comprises up to 75% of the total formulation. The determination of the percentage of antigen to be used in the total formulation can be based on dosage, stability data, and loss on drying.

[0045] In some embodiments of the methods of use of the present disclosure, when the antigen is combined with a stabilizer, the stabilizer may be, but is not limited to, the SGGK3 stabilizer 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 the present disclosure, when the antigen is formulated with a stabilizer, the stabilizer comprises 50% of the total formulation. In some embodiments, the stabilizer comprises 25% of the total formulation. In some embodiments, the stabilizer comprises 20% to 30% of the total formulation. [Table 1]

[0047] In some embodiments of the methods of use of the present disclosure, when the antigen is formulated with a stabilizer, the formulation diluent comprises up to 25% of the total formulation. In some embodiments, the formulation diluent is added to the formulation up to QS (quantity sufficient) to bring it to its final volume, which may vary depending on the addition of antigen. The compositions of embodiments of the formulation diluent are provided in Table 2 below. [Table 2]

[0048] In general, lyophilizing (also known as freeze drying) is a process in which a formulation containing substances dissolved in a suitable solvent is frozen and then a vacuum is applied so that the ice sublimes rather than passing through a liquid phase of thawing. Standard freeze-drying techniques for producing freeze-dried vaccines are well known.

[0049] In a variation of this embodiment, if the antigen and stabilizer composition contains crystalline components, the lyophilization formulation step (208) may include an additional annealing step. In a variation, this annealing step may be performed at -25°C to allow the crystals in the formulation to reform into a stronger structure. For example, this step may be used if the formulation contains mannitol.

[0050] In some embodiments of the methods of use of the present disclosure, the solid matter is contracted relative to the interior surface of the vertical-walled vial 14 and is able to move within the interior volume 144 .

[0051] In some embodiments of the methods of use of the present disclosure, to remove the solid material, the vertical-walled vial 14 can be inverted and the solid material 20 can fall by gravity onto the stopper 12, as shown in FIG. 7, or the solid material 20 can be completely removed from the vertical-walled vial 14 when the stopper 12 is removed from the vertical-walled vial 14. In some embodiments, removal of the solid material results in minimal loss of viability of the solid material and / or minimal residue left on the interior surface 142 of the vertical-walled vial 14. Minimal loss can be a reduction of 5% or less. In some embodiments, the solid material can be removed from the vertical-walled vial 14 without physically cracking or destroying it. [Example]

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

[0053] According to an embodiment of the disclosed method, a glass straight-walled vial system can be used to produce a releasable solid form of the lyophilized formulation.

[0054] In one experimental study, 50% Bordetella bronchiseptica antigen was formulated with 50% stabilizer (n=5 each): SGGK3 stabilizer, SGGK3 with mannitol and xanthan gum (bulking agent and mucoadhesive), Cuxhaven stabilizer B (current poultry stabilizer), or Cuxhaven with mannitol and xanthan gum (bulking agent and mucoadhesive). The formulations were used for viable cell count sampling (see Table 3 below) and added in 1.2 mL or 0.5 mL volumes to straight-walled glass vials. The straight-walled vials were lyophilized at -50°C to 28°C over a 60- to 360-minute cycle at 60 mTorr, with an additional -25°C annealing step to allow for proper crystal formation (due to the addition of mannitol).

[0055] Each straight-walled vial was evaluated for viable plate count both within the vial and after removal before and after lyophilization.

[0056] For the in-vial evaluation after lyophilization, 1.2 mL vials were each reconstituted with 1.2 mL of PBS and pooled to assess viable counts as shown in Table 3 below. The lyophilized solids were removed from the vials, placed in 50 mL C-tubes, pooled (solids from 5 vials per condition), and reconstituted with 6 mL of PBS to assess viable counts. See Table 3.

[0057] Formulations containing the SGGK3 stabilizer produced an acceptable lyophilized appearance in the vertical wall vials, while Cuxhaven B formulations appeared poor in the vertical wall vials, and some formulations containing Cuxhaven B did not appear completely dry.

[0058] The solids from the formulations containing the SGGK3 stabilizer were easily removed from the vertical-walled vials by simply tapping the vial, leaving little residue in the vial. The formulations containing Cuxhaven B did not remove from the vertical-walled vials. All formulations in the vertical-walled vials showed minimal loss upon drying (as shown in Table 3).

[0059] As shown in Table 3, the solids obtained from the formulations containing the SGGK3 stabilizer did not lose viable counts when removed from the vial as solids. [Table 3]

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

[0061] Example 2: Glass and Plastic Vial Formulations with Stabilizers

[0062] According to embodiments of the disclosed methods, plastic vial systems can be used to produce removable solids of lyophilized formulations that are comparable to removable solids produced using glass, straight-walled vials.

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

[0064] Once drying was complete, the 1.2 mL vials were reconstituted with 1.2 mL of PBS each and pooled (5 vials) for post-lyophilization in-vial evaluation and assessed for viable counts as shown in Table 5 below.

[0065] The solids obtained from the formulations containing the SGGK3 stabilizer were easily removed from the glass straight-walled vials. [Table 5]

[0066] The terms "comprises," "comprising," "containing," "having," and the like mean "includes," "including," etc., unless a contrary intention is expressly stated, and are generally construed as open-ended transitional phrases. The recitation of specifically recited components, structures, steps, etc. following an open-ended transitional phrase in no way limits the claim to the specifically recited components, structures, steps, etc. The terms "consisting of" or "consists of" are closed-ended transitional phrases.

[0067] Unless expressly intended to the contrary, when a method is described herein as including a series of steps, the order of the steps as presented herein is not necessarily the only order in which such steps may be performed, and some of the steps described may conceivably be omitted and / or certain other steps not described herein may be added to the method.

[0068] Unless a contrary intention is expressly stated, terms are used in their singular form for clarity and are intended to include their plural form.

[0069] The appearances of the phrases "in one embodiment" or "in one aspect" in this specification do not necessarily all refer to the same embodiment or aspect.

[0070] Below is a list of reference numbers used throughout this specification. [Explanation of symbols]

[0071] TIFF0007802664000006.tif80153

[0072] While this invention has been described as having a design illustrated by embodiments and examples, the invention can be further modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains.

Claims

1. vertical-walled vials (14); and A vertical-walled vial system (10) for extracting and administering a solid freeze-dried vaccine composition in solid form, comprising: a solid freeze-dried vaccine composition in a vertical-walled vial (14), the composition comprising an antigen and a stabilizer, the vertical-walled vial (14) allowing the solid freeze-dried vaccine composition to be extracted substantially intact and administered in solid form.

2. 2. The vertical-walled vial system of claim 1, wherein the vertical-walled vial includes a bottom wall, a side wall connected to and extending from the bottom wall, and a radial collar extending outward from the side wall at an open end of the side wall opposite the bottom wall.

3. 10. The vertical-walled vial system (10) of claim 1, further comprising a stopper (12) insertable into the open end.

4. 4. The vertical-walled vial system (10) of claim 3, further comprising a closure member (16) made of plastic or aluminum.

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

6. 2. The vertical-walled vial system (10) of 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 herpes virus (FHV), feline panleukopenia virus (FPL), and feline leukemia virus (FLV).

10. The vertical-walled vial system (10) of claim 1, wherein the bacterial strain selected from the group consisting of FeLV, Borrelia, Ehrlichia, and Giardia.

8. 10. The vertical-walled vial system (10) of claim 1, wherein the composition further comprises an adjuvant, an immunoadjuvant, an immunomodulatory agent, or a combination thereof.

9. The stabilizer, Bacto peptone; sucrose; dipotassium hydrogen phosphate; Potassium dihydrogen phosphate; potassium hydroxide; and 10. The vertical-walled vial system (10) of claim 1, comprising: gelatin.

10. 10. The vertical-walled vial system (10) of claim 9, wherein the stabilizer further comprises mannitol, xanthan gum, a bulking agent, a mucoadhesive agent, an agent that enhances mucosal permeability, or a combination thereof.

11. 10. The vertical-walled vial system (10) of claim 1, wherein the solid lyophilized vaccine composition further comprises a compounding diluent consisting of MEM powder, sodium bicarbonate, and HEPES acid.

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