OA20144A - Vaccine formulations comprising preservative system. - Google Patents
Vaccine formulations comprising preservative system. Download PDFInfo
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- OA20144A OA20144A OA1202100018 OA20144A OA 20144 A OA20144 A OA 20144A OA 1202100018 OA1202100018 OA 1202100018 OA 20144 A OA20144 A OA 20144A
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- Prior art keywords
- vaccine
- preservative
- formulation
- group
- vaccine formulation
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- 229960005486 vaccines Drugs 0.000 title claims abstract description 162
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- QCDWFXQBSFUVSP-UHFFFAOYSA-N Phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 claims abstract description 105
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- RLSSMJSEOOYNOY-UHFFFAOYSA-N M-Cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 claims abstract description 40
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- 238000009472 formulation Methods 0.000 claims description 103
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Abstract
The present invention relates to vaccine formulations comprising preservative systems. More particularly, the present invention relates to preservative systems for vaccine formulations which is free of thiomersal, and comprising 2phenoxyethanol and at least one other preservative selected from m-cresol, benzyl alcohol, phenol and benzoic acid.
Description
VACCINE FORMULATIONS COMPRISING PRESERVATIVE SYSTEM
FIELD OF INVENTION
The présent invention relates to preservative system and use thereof in vaccine formulations. More particularly, the présent invention relates to mono or multivalent vaccine formulations comprising preservative system and which is free of thiomersal.
BACKGROUND OF INVENTION
Vaccine is a biological préparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from attenuated or kiîled forms of the microbe, its toxins, or at least one of its surface proteins or at least one of its capsular polysaccharides. The agent stimulâtes the body's immune system to recognize the agent as a threat, destroy it, recognize and destroy any of these microorganisms that it later encounters. Besides from having a certain level of immunogenicity, potency, stability, a vaccine formulation needs to be free from microbial contamination.
Preservatives are required for multidose vaccine formulations to prevent contamination and to stabilize the composition of subséquent doses after the first dose is used. The preservative must enable the vaccine formulation to pass efficacy tests or antimicrobial challenge tests.
U.S. Patent No. 6,790,445 B1 discloses combinations of preservatives that pass antimicrobial testing requirements for United States Pharmacopeia (USP), British Pharmacopeia (BP), and Européen Pharmacopeia (EP) selected from the group consisting of (1) 1.5% benzyi alcohol; (2) 0.225% methyl paraben sodium, 0.025% propyl paraben sodium; and 0.9% benzyi alcohol, and (3) 0.225% methyl paraben sodium, 0.025% propyl paraben sodium, and 0.375% 2-phenoxyethanoi.
U.S. Patent No. 9,095,567 B2 describes a multivalent immunogenic composition comprising a polysaccharide-protein conjugates consisting of pneumococcal capsular polysaccharides from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F, individuaiiy conjugated to CRM197, and further comprising not less than 7 mg/mL of 2-phenoxyethanol (2-PE). This patent disclosed that the preservative effectiveness test (PET) results showed that al! of the tested preservatives met the USP requirements but not the EP criteria. 2-PE was the only candidate preservative which was found to be safe at higher dosages.
U.S. Patent Publication No. 2004/0258700 A1 discloses a vaccine formulation comprising an immunogen, a preservative characterized in that the preservative is a combination of at least two paraben esters and 2-phenoxyethanoi.
U.S. Patent Publication No. 2013/0273098 A1 described that the addition of the surfactant 0.1% Poloxamer 188 (Pluronic® F-68) resulted in no observed particulates with any of the preservatives tested such as phénol, 2-phenoxyethanol, m- cresol, benzyl alcohol, or chlorobutanol.
WO Publication No. 2018/169303 A1 discloses a vaccine composition comprising: (i) a capsular polysaccharide-protein conjugale; (ii) 2-phenoxyethanol (2-PE); and (iii) formaldéhyde (HCHO), and a method for preparing the same.
Hilliard et.al (1964, Journal of Pharmaceutical Sciences 53(8), 899-901) discloses the addition of 0.375 per cent v/v of 2-phenoxyethanol to poliomyelitis vaccine fumished a stabië mixture of preservatives (streptomycin, neomycin, and 2-phenoxyethanoi) which was inhibitory to both bacteria and fungi.
Stephen et.al., (1985, International Journal of Pharmaceutics, 25, 245-253) discloses antimicrobial preservatives that belong to the same Chemical groups are believed to produce mereïy additive effects when used in combination.
Preservatives generally offer limited protection against viral contamination. Bactéricides and fungicides may évincé their effects on a variety of rnicrobial cellular targets, for example; the cell wall, the cytoplasmic membrane or the cytoplasm. It is often difficult to assign a précisé target for a spécifie class of preservative; the target can and does change with preservative concentration. As a conséquence, preservatives often interfère with several different rnicrobial cellular mechanisms. Such cytotoxicity may also affect mammalian cells. Hence inclusion levels should be minimal, consistent with adéquate préservation. There is a reguiatory expectation to provîde the reason for preservative inclusion, proof of efficacy, safety information, control methods and details of labeling in the finished product.
In concept, the preservative System protects the product against rnicrobial prolifération but does not compromise product performance. In practice, this means that it must:
• exert a wide spectrum of antimicrobial activity at low inclusion ievels.
• maintain activity throughout product manufacture, shelf life and usage.
• not compromise the quality or performance of product, pack or delivery system.
• not adversely affect patient safety or tolérance of the product.
Pharmacopoeial antimicrobial effectiveness tests (AET) or preservative efficacy tests (PET) involve challenging a product with a defined number of colony forming units (cfu) of a variety of test microorganisms (bacteria, yeasts and fungi), énumération at time zéro and then monitoring kill / survival rate at defined time intervais. In addition to antimicrobial effectiveness testing (AET), it is a regulatory requirement to monitor the Chemical stability of the drug product (in its final container) throughout the product’s proposed shelf-life.
Thimerosal (also known as Thiomersal; Merthiolate) is an ethyl mercurycontaining preservative which has, since the early 1930s, been added to many multi-dose injectable formulations. Thiomersal, which contains mercury, is claimed to cause autism in chiidren and is also toxic to the environment. It would be advantageous to look for preservatives which are safe for vaccines to replace thimerosal. Thus, there <s a need for a vaccine formulation comprising preservatives that are safe as well as effective.
Although the safety profile of 2-phenoxyethanol (2-PE) is better than that of mercurial preservatives (e.g. thiomersal), but it is the weaker antimicrobial of the two and required to be include at higher concentration Ievels in the vaccine formulations.
Thus, in order to improve the preservative efficacy of 2-PE at low concentration Ievels in vaccine formulations, inventors of the présent invention through their continuous efforts hâve developed a low concentration of preservative system comprising 2-PE in combination with other preservatives. The inventors hâve found that the preservative Systems are safe and effective for use in vaccine formulations for prévention of microbial/viral growth.
OBJECTIVE OF THE INVENTION
It is an objective of the présent invention to provide a preservative composition comprising low concentration Ievels of 2-phenoxyethanol for use in vaccine formulations for prévention of microbial/viral growth.
It is another objective of the invention to provide stable multi-dose vaccine formulation that comprises low concentration Ievels of 2-phenoxyethanol.
SUMMARY OF INVENTION
Accordingly, the présent invention provides a vaccine formulation comprising a preservative System comprising 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6% and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid.
The invention also provides a vaccine formulation comprising an immunogen, a preservative System comprising 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6% and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid and one more suitable pharmaceutically acceptable excipients.
The invention also provides a process for manufacturing vaccine formulation comprising a preservative System containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6 % and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid.
The invention also provides a process for manufacturing vaccine formulation comprising preservative system containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.5 % and at least one other preservative selected from the group consisting of at least 0.005% m-cresol, benzyl alcohol, phénol and benzoic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts plot layout of sérum antibody titers in rabbit.
Figure 2A&B depicts sérum antibody titers in rabbit immunized with formulation without preservative (Example 2).
Figure 3A&B depicts sérum antibody titers in rabbit immunized with formulation containing preservative system (Example 3).
DEFINITIONS
Embodiments described herein can be understood more readily by reference to the following detailed description, examples, and drawings. Eléments, apparatus and methods described herein are merely illustrative of the principles of the présent invention and are not limited to the spécifie embodiments presented in the detailed description, examples, and drawings. Numerous modifications and adaptations will be readily apparent to those of skill in the art without departing from the spirit and scope of the invention.
Unless defined otherwise, ail technical and scientific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which the methods belong. Although any combinations, compositions or methods similar or équivalent to those described herein can also be used in the practice or testing of the embodiments of the présent invention, représentative illustrative methods and compositions are now described.
It is appreciated that certain features of the methods, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the methods and compositions, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. It is noted that, as used herein and in the appended daims, the singular forms a, an, and the include plural referents unless the context clearly dictâtes otherwise, It is further noted that the daims may be drafted to exclude any optional element. As such, this statement is intended to serve as antécédent basis for use of such exclusive terminology as solely, only and the like in connection with the récitation of daim éléments or use of a négative limitation. The term “at least one” means one and more than one.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrète components and features which may be readiiy separated from or combined with the features of any of the other embodiments without departing from the scope or spirit of the présent methods. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.
As used herein, the terms “preservative System” or “preservative composition” are interchangeable and refers to a mixture or composition that is added to a vaccine composition or formulation to prevent décomposition due to Chemical change or microbial/viral contamination. In the context of the invention preservative System refers to a composition comprising 2-phenoxyethanol and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid.
The term “immunogen or an antigen” refers to a substance which stimulâtes the production of an antibody or elicits a humoral and/or cellular immune response resulting in immunity of the host towards the pathogen.
As used herein, the term “monovalent vaccine” refers to a vaccine having one principal antigenic component.
As used herein, the term “multivalent vaccine” refers to a vaccine comprising more than one antigenic component. The term includes combination vaccine, bivalent vaccines, trivalent vaccines, tetravalent vaccines, pentavalent vaccines, hexavalent vaccines and the like.
As used herein, the term “Vi:O2” refers to a bivalent vaccine formulation against typhoid and paratyphoid comprising antigens from Salmonella typhi and Salmonella paratyphi.
As used herein, the term “MR” refers to a bivalent vaccine formulation against measles and rubella.
As used herein the term “Td” refers to Diphtheria and Tetanus Vaccine [Adsorbed, Reduced Antigen(s) content].
As used herein, the term “DTwP” refers to a trivalent vaccine formulation against diphtheria, tetanus and whole-cell pertussis.
As used herein, the term “Vi:O2-HepA” refers to a trivalent vaccine formulation against typhoid, paratyphoid and Hepatitis A.
As used herein, the term “MMR” refers to a trivalent vaccine formulation against measles, mumps and rubella.
As used herein, the term “DTwP -Hib” refers to a tetravalent vaccine formulation against diphtheria, tetanus, whole-cell pertussis and haemophilus influenzae type b.
As used herein, the term “DTaP -Hib” refers to a tetravalent vaccine formulation against diphtheria, tetanus, acelîular pertussis and haemophilus influenzae type b.
As used herein, the term “DTwP-IPV” refers to a tetravalent vaccine formulation against diphtheria, tetanus, whole-cell pertussis and inactivated polio virus.
As used herein, the term “DTwP -HepB” refers to a tetravalent vaccine formulation against diphtheria, tetanus, whole-cell pertussis and hepatitis B.
As used herein, the term “ACW-135XY” refers to a pentavalent conjugate vaccine formulation against meningococcai group A, C, W-135, X and Y.
As used herein, the term “DtwPHib-HepB” refers to a pentavalent vaccine formulation against diphtheria, tetanus, whole-cell pertussis, haemophilus influenzae type b and hepatitis B.
As used herein, the term “DtaPHib-HepB” refers to a pentavalent vaccine formulation against diphtheria, tetanus, acelluiar pertussis, haemophilus influenzae type b and hepatitis B.
As used herein, the term “DtwPHib-HepB-IPV” refers to a hexavalent vaccine formulation against diphtheria, tetanus, whole-cell pertussis, haemophilus influenzae type b, hepatitis B and inactivated polio virus.
As used herein, the term “DtaPHib-HepB-IPV” refers to a hexavalent vaccine formulation against diphtheria, tetanus, acelluiar pertussis, haemophilus influenzae type b, hepatitis B and inactivated polio virus.
As used herein, the term “pharmaceutically acceptable carrier(s)” refers to one or more optional components which may be added to the vaccine formulation for administration of the antigens and/'or viruses which does not itseif induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity. The term includes one or more excipient, adjuvants, diluents, buffers or surfactants, or a combination thereof. By pharmaceutically acceptable or pharmacologically acceptable is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual in a formulation or composition without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
As used herein, the phrase “microbial or viral contamination” refers to undesired growth of microbes or viruses in vaccine formulation.
DETAILED DESCRIPTION OF THE INVENTION
As used herein the vaccine or immunogen of the présent invention includes pneumococcal conjugale, meningococcal conjugale, typhoid conjugale, paratyphoid conjugale, Hib conjugale and multivalent vaccine comprising one or more antigens selected from Measles (M), Mumps (M), Rubella (R), Hepatilis A Virus (HAV), Hepatitis C Virus (HCV), Diphtheria (D), Tetanus (T), whole cell (wP) oraceilular Pertussis (aP), Hib Polysaccharide, Hepatitis B (HepB) and Inactivated Poliomyelitis Virus (IPV).
Monovalent vaccines includes antigens selected or isolated from Streptococcus pneumonia (Pneumococcal capsular polysaccharide), Neisseria meningitides (Men A, C, W-135 or Y), Salmonella typhi (Vi), Salmonella paratyphi (0:2), Haemophilus influenza (Hib-PRP), Corynebacterium Diptheriae (Diptheriae Toxoid-DT), Bordetella pertussis (wP/ aP), Clostridium tetani (Tetanus Toxoid), Hepatitis A Virus (HAV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), Inactivated Japanese Encephaiitis Virus, Rabies Virus and Inactivated Poliomyelitis Virus.
Multivalent vaccine includes bivalent, trivalent, tetravalent, Pentavaient and Hexavalent such as DT (Diptheriae Toxoid) , MR (Measles and Rubella Vaccine), Vi:O2 (Salmonella typhi and Salmonella paratyphi) conjugale, Vi:O2-HepA (Salmonella typhi, Salmonella paratyphi and Hepatitis A vaccine), MMR (Measles, Mumps, and Rubella vaccine), DTwP vaccine (vaccine against diphtheria, tetanus and whole-cell pertussis), ACW-135XY (Conjugale vaccine against meningococcal group A, C, W-135, X and Y), DTwP-Hib (Vaccine against diphtheria, tetanus. whole-cell pertussis and haemophilus influenzae type b), DTaP-Hib (Diphtheria, Tetanus, Acellular Pertussis and haemophilus influenzae type b), DTwP-HepB (Vaccine against diphtheria, tetanus, whole-cell pertussis and hepatitis B), DTwPHib-HepB (Vaccine against diphtheria, tetanus, whole-cell pertussis, haemophilus influenzae type b and hepatitis B), DTaPHib-HepB (Diphtheria, Tetanus, Acellular Pertussis, haemophilus influenzae type b and hepatitis B), DTwP-IPV (Vaccine against diphtheria, tetanus, whole-cell pertussis and inactivated polio virus), DTwPHib-HepB-IPV (Vaccine against diphtheria, tetanus, whole-cell pertussis, haemophilus influenzae type b, hepatitis B and inactivated polio virus), DTaPHib-HepB-IPV (Vaccine against diphtheria, tetanus, acellular pertussis, haemophilus influenzae type b, hepatitis B and inactivated polio virus).
The percentage of concentration (%) as used herein is weight by volume (w/v) or weight by weight (w/w).
The présent invention provides mono and multivalent combination vaccine formulation comprising preservative system containing 2-phenoxyethanol at a concentration in the range of 0.1% io 0.6 % and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid.
In an embodiment, the présent invention provides pneumococcal capsular polysaccharide protein conjugale vaccine formulation comprising one or more pneumococcal polysaccharide protein conjugates and a preservative system containing 2-phenoxyethanol at a concentration in the range of 0.1 % to 0.6 % and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid and one or more pharmaceutically acceptable carriers or excipients.
In yet another embodiment, the présent invention provides meningococcal conjugale vaccine formulation comprising N. meningitidis serogroup A, C, W-135, X and Y capsular polysaccharide antigens individualïy conjugated to carrier protein and a preservative system containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6 % and at least one other preser/ative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid and one or more pharmaceutically acceptable carriers or excipients.
In yet another embodiment, the présent invention provides typhoid conjugale vaccine formulation comprising VI polysaccharide conjugated to carrier protein and a preservative system containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6% and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid and one or more pharmaceutically acceptable carriers or excipients.
In yet another embodiment, the présent invention provides paratyphoid conjugale vaccine formulation comprising 0:2 polysaccharide conjugated to carrier protein and a preservative system containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6% and al least one other preservative selected from the group consisting of m-cresoi, benzyl alcohol, phénol and benzoic acid and one or more pharmaceutically acceptable carriers or excipients.
In yet another embodiment, îhe présent invention provides Hib conjugale vaccine formulation comprising polyribosylribitol phosphate (PRP) capsular polysaccharide conjugated to carrier protein and a preservative system containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6 % and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid and one or more pharmaceuticaïly acceptable carriers or excipients.
In an embodiment, the présent invention provides a pneumococcal capsular polysaccharide protein conjugate vaccine formulation comprising one or more pneumococcal polysaccharide protein conjugales and a preservative system containing 2phenoxyethanol at a concentration of 0.1% to 0.6% and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid at a concentration of 0.005% to 0.3% and one or more pharmaceuticaïly acceptable carriers.
The carrier protein according to the présent invention is selected from the group consisting of CRM197, PspA, PsaA, Protein D, diphtheria toxoid (DT), tetanus toxoid (TT) and the like or combination thereof.
Pneumococcal conjugate vaccine according to the présent invention includes one or more capsular polysaccharides from Streptococcus pneumonia serotype selected from Streptococcus pneumonia serotypes 1, 2, 3, 4, 5, 6A, 6B, 6C, 6D, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15A, 15B, 15C, 16F, 17F, 18C, 19F, 19A, 20A, 20B, 22F, 23A, 23B, 23F, 24B, 24F, 31, 33F, 34, 35B, 35F, 38, 39 and 45 wherein each polysaccharide is conjugated to a carrier protein preferably selected from PsaA, CRM197, inactivated bacterial toxins such as diphtheria toxoid (DT), tetanus toxoid (TT), pertussis toxoid. choiera toxoid, or Haemophilus influenzae protein D or combination thereof and a preservative System containing 2phenoxyethanol at a concentration in the range of 0.1% to 0.6% and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol, benzoic acid and one or more pharmaceuticaïly acceptable carriers.
In an embodiment, the présent invention provides a pneumococcal conjugate vaccine formulation comprising pneumococcal capsular polysaccharides wherein each polysaccharide is selected from Streptococcus pneumonia serotypes 1, 2, 3, 4, 5, 6A, 6B, 6C, 6D, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15A, 15B, 15C, 16F, 17F, 18C, 19F, 19A, 20A, 20B, 22F, 23A, 23B, 23F, 24B, 24F, 31, 33F, 34, 35B, 35F, 38, 39, and 45 conjugated to a carrier protein and a preservative System containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6% and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid.
In an embodiment, the présent invention provides a pneumococcal conjugale vaccine formulation comprising pneumococcal capsular polysaccharides wherein each polysaccharide is selected from Streptococcus pneumonia serotypes 1, 2, 3, 4, 5, 6A, 6B, 60, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15A, 15B, 15C, 16F, 17F, 180, 19F, 19A, 20A, 20B, 22F, 23A, 23B, 23F, 24B, 24F, 31,33F, 34, 35B, 35F, 38, 39 and 45 conjugated to a carrier protein and a preservative System containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0,6 % and at least one other preservative selected from the group consisting of 0.005% to 0.3% of m-cresol, 0.01% to 1% of benzyl alcohol, 0.01% to 1% of benzoic acid by weight of the vaccine formulation.
Pneumococcal capsular polysaccharide protein conjugale vaccine according to the présent invention is a multivalent immunogenic composition such as 10 valent, 13 valent, 14 valent, 15 valent, 16 valent, 17 valent, 18 valent, 19 valent, 20 valent, 22 valent, 23 valent, 24 valent, 25 valent or 26 valent pneumococcal vaccine composition.
In an embodiment, Pneumococcal capsular polysaccharide protein conjugale vaccine according to the présent invention is a 14 valent immunogenic composition comprising capsular polysaccharides frorn Streptococcus pneumoniae serotypes 1,3,4, 5,6B, 7F, 9V, 14, 180, 19A, 19F, 22F, 23F and 33F.
In yet another embodiment, Pneumococcal capsular polysaccharide protein conjugale vaccine according to the présent invention is a 20 valent immunogenic composition comprising capsular polysaccharides from Streptococcus pneumoniae serotypes 1,3,4,5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 180, 19A, 19F, 22F, 23A, 23F and 35B.
In yel another embodiment, Pneumococcal capsular polysaccharide protein conjugale vaccine according to the présent invention is 20 valent immunogenic composition comprising capsular polysaccharides from Streptococcus pneumoniae serotypes 1,3,4,5, 6A, 6B, 6C/6D, 7F, 9V, 14, 15A, 15C, 180, 19A, 19F, 23A, 23B, 23F, 24F and 35B.
In yet another embodiment, Pneumococcal capsular polysaccharide protein conjugale vaccine according to the présent invention is a 24 valent immunogenic composition cornprising capsular polysaccharides from Streptococcuspneumoniae serotypes 1, 3,4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 180, 19A, 19F, 22F. 23A, 23B, 23F, 24F, 33F and 35B.
In an embodiment, the présent invention provides a pneumococcai conjugale vaccine formulation comprising pneumococcai capsular polysaccharides wherein each polysaccharide is selected from Streptococcus pneumonia serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F conjugated to a carrier protein and a preservative system containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6 % and at least one other preservative selected from the group consisting of 0.005% to 0.3% of mcresol, 0.01 % to 1 % of benzyl alcohol, 0.01% to 1 % of benzoic acid by weight of the vaccine formulation.
In yet another embodiment, the présent invention provides a pneumococcai conjugale vaccine formulation comprising pneumococcai capsular polysaccharides wherein each polysaccharide is selected from Streptococcus pneumonia serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F conjugated to a carrier protein and a preservative system containing 2-phenoxyelhanol at a concentration in the range of 0.1% to 0.5 % and at least one other preservative selected from the group consisting of 0.005% to 0.3% of mcresol, 0.01 % to 1 % of benzyl alcohol, 0.01 % to 1 % of benzoic acid by weight of the vaccine formulation.
The carrier protein according to the présent invention is preferably protein that is non-toxic and non-reactogenic and obtainable in sufficient amount and is selected from PsaA, CRM197, inaclivated bacterial loxins such as diphlheria loxoid (DT), letanus toxoid (TT;, pertussis toxoid, choiera toxoid, exotoxin A from Pseudomonas aeruginosa, bacterial outer membrane proteins such as ouler membrane complex C (OMPC), porins, transferrin binding proteins, pneumolysin, PspA, C5a peptidase from Group A or Group B streptococcus, or Haemophilus influenzae protein D, ovalbumin, keyhole limpet hemocyanin (KLH), bovine sérum albumin (BSA) and purified protein dérivative of tuberculin (PPD) and combination thereof. For examples, some polysaccharides are conjugated to CRM197 as carrier protein and some polysaccharides are conjugated to PsaA or DT or TT and the like.
In yet another embodiment, the présent invention provides a multidose polysaccharide protein conjugale vaccine formulation comprising a preservative system containing 2phenoxyethanoï at a concentration in the range of 0.1% to 0.5% and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid and a pharmaceutically acceptable vehîcle and one or more pharmaceuîically acceptable excipients / adjuvants.
In yet another embodiment, the présent invention provides conjugale vaccine formulation comprising a preservative System containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6% and at least one other preservative selected from the group consisting of 0.005% to 0.3% of m-cresol, 0.01% to 1% of benzyl alcohol, 0.01 % to 1% of benzoic acid by weight of the vaccine formulation and a pharmaceutically acceptable vehicle and one or more pharmaceutically acceptable excipients/adjuvants.
A composition according to the présent invention may be manufactured conventionally. In particular, it may be formulated with a pharmaceutically acceptable carrier, diluent or excipient, e.g. water, buffered saline, gfycerol, propyiene glycol and dextrose solution. In addition, the composition may contain buffer such as sodium phosphate, potassium phosphate, sodium sucdnate, histidine and the like; or a stabifeer, polysorbate, MPLA (monophosphoryl lipid A), and the fike; an adjuvant such as an aluminum compound, e.g. an aluminium hydroxide, an aluminium phosphate or an aluminium hydroxyphosphate, and, a lyophilization excipient In general these ingredients/carriers may be selected as a function of the mode and route of administration and based on standard pharmaceutical practices.
The composition of the présent invention is formulated as multiple dose vial.
In yet another embodiment, the présent invention provides a method of preserving vaccine formulation, which method comprises, mixing vaccine solution and one or more excipients such as an adjuvants, diluents, buffers or surfactants with a a preservative System conta in in g 2-phenoxyethanol at a concentration in the range of 0.1% to 0.5% and at least one other preservative selected from the group consisting of m-cresol, benzyl alcohol, phénol and benzoic acid to form a mixture of vaccine solution and preservative.
In a preferred embodiment, the présent invention provides a vaccine formulation comprising a preservative System containing 2-phenoxyethanol at a concentration in the range of 0.1% to 0.5% and at least one other preservative selected from the group consisting of 0.005% to 0.3% of m-cresol, 0.01% to 1% of benzyl alcohol, 0.01% to 1% of benzoic acid and a pharmaceutically acceptable vehicle and one or more pharmaceutically acceptable excipients / adjuvants. The pharmaceutically acceptable excipients or adjuvants may be selected from group of adjuvants such as aluminum hydroxide, aluminum phosphate, surfactants such as polysorbate 20, polysorbate 80, poloxamers, vehicles, solvents or co-solvents such as soyabean oîis, PEG, stabifizers such as EDTA and may include antioxidants such as polyphenols, Tocopheryi Polyethylene Glycol Succinate (TPGS). The pH of the vaccine formulation according to the présent invention is adjusted to maintain between 4.0 to 8.0.
In another preferred embodiment, the présent invention provides a vaccine formulation comprising 0.3% to 0.4% of 2-PE and 0.1% to 0.3% of m-cresol as preservative and one or more pharmaceuticaliy acceptable carrier or excipient.
In another preferred embodiment, the présent invention provides a vaccine formulation comprising 0.1% to 0.4% of 2-PE and 0.01% to 0.05% m-cresol as preservative and one or more pharmaceutically acceptable carrier or excipient.
In another preferred embodiment, the présent invention provides a 14 valent pneumococcal conjugate vaccine formulation comprising:
a) capsular polysaccharide selected from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F individually conjugated to carrier protein selected from CRM197, pneumococcal surface protein A (PspA), pneumococcal adhesin protein (PsaA) or combination thereof,
b) a preservative System containing 0.1% to 0.4 % of 2-PE and 0.005% to 0.3% of mcresol and
c) one or more pharmaceutically acceptable carrier or excipient.
In preferred embodiment, the présent invention provides a 20 valent pneumococcal conjugate vaccine formulation comprising:
a) capsular polysaccharide selected from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11 A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B individually conjugated to carrier protein selected from CRM197, pneumococcal surface protein A (PspA), pneumococcal adhesin protein (PsaA) or combination thereof,
b) a preservative System containing 0.1% to 0.4 % of 2-PE and 0.005% to 0.1% of mcresoï and
c) one or more pharmaceutically acceptable carrier or excipient.
In preferred embodiment, the présent invention provides a 24 valent pneumococcal conjugate vaccine formulation comprising:
a) capsular polysaccharide selected from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F. 23A, 23B, 23F, 24F,
33F and 35B individually conjugated to carrier protein selected from CRM197, pneumococcal surface protein A (PspA), pneumococcal adhesin protein (PsaA) or combination thereof,
b) a preservative System containing 0.1% to 0.4 % of 2-PE and 0.005% to 0.1% of mcresoi and
c) one or more pharmaceutically acceptable carrier or excipient.
The amount of pneumococcal conjugale in each vaccine dose is selected as an amount that induces an immunoprotective response without significant, adverse effects. Such an amount may vary depending upon the pneumococcal serotype. Each 0.5 mL dose is formulated to contain: 2 to 4pg of each polysaccharide; about 30 -70pg CRM197 carrier protein.
In another preferred embodiment the présent invention provides a conjugale vaccine formulation comprising polysaccharide protein conjugale vaccine selected from the group consisting of pneumococcal conjugale, meningococcal conjugale, typhoid conjugale, paratyphoid or Hib conjugale and a preservative System containing 0.1 % to 0.4 % 2-PE and 0.01 % to 0.3% m-cresol and one or more pharmaceutically acceptable carrier or excipient.
In yet another embodiment, the présent invention provides a pneumococcal conjugale vaccine formulation comprising pneumococcal capsular polysaccharides wherein each polysaccharide is selected from Streptococcus pneumonia serotypes 1, 2, 3, 4, 5, 6A, 6B, 6C, 7F, 8, 9N, 9V, 10A, 11 A, 12F, 14, 15A, 15B, 15C, 16F, 17F, 18C, 19F, 19A, 20A, 20B, 22F, 23A, 23B, 23F, 24B, 24F, 31,33F, 34, 35B, 35F, 38, 39, and 45 conjugated to a carrier protein and a preservative System containing 0.1 lo 0.5% of 2-phenoxyelhanol at a concentration in the range of and 0.01% to 0.3% of m-cresol by weight of the vaccine formulation.
Compositions of the présent invention may be administered to a subject in need thereof by conventional rouies used in the field of vaccines. For example, compositions of the présent invention may be administered systemically, such as parenterally (e.g. subcutaneously, intramuscularly, intradermally and/or intravenously) or mucosally (e.g., orally and/or nasally).
In some embodiments, the présent invention also provides methods of inducing an immune response in a subject in need thereof. The methods for inducing the immune response comprise administering an immunologically effective amount of the vaccine composition described herein to the subject in need thereof.
According to the methods of the présent invention, the subject to whom the compositions described herein to be administered is a human, such as an infant (less than about 1 year of âge), a toddler (about 12 months to about 24 months of âge), a young cniïd (about 2 years to about 5 years of âge), an older child (about 5 years to about 13 years of âge), an adolescent (about 13 years to about 18 years of âge), an aduit (about 18 years to about 65 years of âge), or an elder (more than about 65 years of âge).
In another preferred embodiment, the présent invention provides an immunogenic composition of pneumococcal conjugate vaccine comprising 0.1% to 0.4% of 2-PE and 0.01% to 0.3% of m-cresoï and one or more pharmaceuticalÎy acceptable vehicie and one or more pharmaceutically acceptable excipients/adjuvants.
In another preferred embodiment, the présent invention provides an immunogenic composition of meningococcal conjugate vaccine comprising 0.3% to 0.4% of 2-PE and 0.1% to 0.3% of m-cresoi and one or more pharmaceuticahy acceptable vehicie and one or more pharmaceutically acceptable excipients/adjuvants.
In another preferred embodiment, the présent invention provides an immunogenic composition of typhoid conjugate vaccine comprising 0.3% to 0.4% of 2-PE and 0.1% to 0.3% of m-cresoi and one or more pharmaceutically acceptable vehicie and one or more pharmaceutically acceptable excipients/adjuvants.
In another preferred embodiment, the présent invention provides an immunogenic composition of paratyphoid vaccine comprising 0.3% to 0.4% of 2-PE and 0.1% to 0.3% of m-cresoi and one or more pharrnaceuticaïly acceptable vehicie and one or more pharmaceutically acceptable excipients / adjuvants
In another preferred embodiment, the présent invention provides an immunogenic composition of Hib conjugate vaccine comprising 0.3% to 0.4% of 2-PE and 0.1% to 0.3% of m-cresol and one or more pharmaceutically acceptable vehicie and one or more pharmaceutically acceptable excipients/adjuvants.
Preservative efficacy in medicines is typically investigated using challenge tests. In such tests, the product is artificially contaminated with a high concentration of standard bacterial and fungal test strains. The rate and extent of réductions in inoculum viability over a specified period forms the basis for acceptance/rejection of preservative efficacy.
The efficacy of 2-phenoxyethanol (2-PE) and m-cresol preservative composition with least yet effective dose when tested has shown strong microbicidal activity against Grampositive bacteria, Gram-negative bacteria, yeast and fungi.
BIOBALL® (manufactured by BTF Pty Ltd.) is a small water-soluble bail containing a précisé number of microorganisms delivering unprecedented accuracy for quantitative microbiological quality control.
Compositions of the invention can be prepared using conventional techniques which involves dissolving and mixing the ingrédients as appropriate to give the desired end product.
EXAMPLES
The following examples are provided to iliustrate the disclosure and are merely for illustrative purpose only and should not be construed to limit the scope of the disclosure.
Exampie 1: Detailed study of the preservative sélection and efficacy study
The aim of the study was to establish the least concentration of preservative which is susceptible to bacteria and fungi that can be used in the formulation of vaccines, specifically Pneumococcal Conjugate Vaccine (PCV). Two types of preservatives with different concentrations were chosen for the study. The test cultures were received in the form of Bioball® (manufactured by BTF Pty Ltd.) from which the préparation of glycerol aiiquots was carried out.
In this study, the usage of minimal and effective dosage of preservative in multivalent PCV was investigated. Microbial content and preservative efficacies were studied according to United States Pharmacopeia (USP) ‘USP29, General Chapter 5T. Microorganisms count in test samples with different strengths of preservatives along with drug product (vaccine formulation) were checked from day 0 to 35th day.
The inoculum with initial count of 1x105 to 1x107 cells of micro-organisms which are the most common contaminants (Staphylococcus au reus, Pseudomonas aeruginosa, a yeast
Candida albicans, Escherichia coli and Aspergillus brasiliensis) were inoculated individually for evaluating the strength of each preservative.
In the current study, incubation of test samples with test organisms (Table 1) was carried out in LabTech™ incubator for a period of 35 days.
Table 1: Details of Test Organism
| S.No | Name of the Organism | Strain IÜ |
| Candida albicans | NCPF3139 | |
| Pseudomonas aeruginosa | NCTC12924 | |
| i. | Staphylococcus aureus | NCTC10788 |
| Escherichia coli | NCTC12923 | |
| Aspergillus brasiliensis | NCPF2275 |
Inoculum détermination
In the event of addition of known amount of population of different test organism into the test samples, Initially the test cultures were checked for the viability by serial diluting 1 mL of cryo-vial content from 10-1 to 10'8 with stérile saline solution. From the last 6 dilutions 100 pL suspension was plated (Pour plate method) on suitable media plates and were incubated at optimal conditions. Post incubation period, plates were observed, and colonies were enumerated to find CFU/mL of each test organism.
Table 2: Incubation details
| Name of the organism | Suitable media | Incubation condition | |
| Température | Time (Hrs) | ||
| Candida albicans | Sabouraud Dextrose Agar (TSA) | 22.5±2.5°C | 44-72 |
| Pseudomonas aeruginosa | SoybeanCasein | 32.5±2.5°C | 18-24 |
| Staphylococcus aureus | Digest Agar (SCDA) | 18-24 | |
| Escherichia coli | 18-24 | ||
| Aspergillus brasiliensis | Sabouraud Dextrose Agar (SDA) | 22.5±2.5°C | 36-48 |
Based on the results obtained in the inoculum détermination, the final volume of inoculum to be added to formulations was calcuîated to maintain the required final concentration as per compendial requirement.
As the product of interest for which the effective dose of antimicrobial substance to be 5 established will fall under category-1 as per USP29 General Chapter 51, the volume of the suspension inoculum used is between 0.5% and 1.0% of the volume of the product.
Table 3: Details of inoculum Volume to be added
| Name of the organism | Volume of test sample | Volume of inoculum required | Approx. final conc. of cells in each test sample |
| Pseudomonas aeruginosa | 5mL | 100pL | 1.9*10Λ6 |
| Staphylococcus aureus | 5mL | 100pL | 1.4*10Λ6 |
| Escherichia coli | 5mL | 100pL | 6*10Λ7 |
| Candida albicans | 5mL | 100pL | 2*10Λ6 |
| Aspergillus brasiliensis | 5mL | 200pL | 2*10Λ5 |
Sample préparation and inoculum addition
Initially, formulations were prepared without drug product to test the broad concentration 10 range of preservative individuaiiy and in combination. Based on the results thereof experiments at lower concentration range of preservative individuaiiy and in combination with drug product was designed.
The concentration of test microorganisms that were added to the product are such that the final concentration of the test préparation after inoculation meets ail the compendial 15 requirements. These details are tabulated in Tables 4a and Table 4b.
Table 4a: Formulation Details (Without drug product)
| S. No. | Composition | |||||
| 2-phenoxyethanol | Metacresol | ΑΓ++ Content | Saline (0.9% W/V) | |||
| (%) | mg/ml | (%) | mg/mL | mg/mL | mg/mL | |
| 1 | 0.2 | 2 | NA | 1 | q.s | |
| 2 | 0.4 | 4 | 1 | q.s | ||
| 3 | 0.6 | 6 | 1 | q.s | ||
| 4 | NA | 0.05 | 0.5 | 1 | q.s | |
| c | 0.1 | 1 | 1 | q.s | ||
| 6 | 0.2 | 2 | 1 | q.s | ||
| 7 f | 0.3 | 3 | -1 1 | q.s | ||
| 8 | 0.2 | 2 | 0.3 | 3 | 1 | q.s |
| 9 | 0.3 | 3 | 0.1 | 1 | 1 | q.s |
| 10 | 0.4 | 4 | 0.2 | 2 | 1 | q.s |
| 11 | 0.5 | 5 | 0.2 | 2 | 1 | q.s |
| 12 | 0.5 | 5 | 0.3 | 3 | 1 | q.s |
| 13 | 0.6 | 6 | 0.2 | 1 | 1 | q.s |
| 14 | 0.6 | 6 | 0.3 | 3 | 1 | q.s |
| 15 | 0.8 | 8 | 0.1 | 1 | 1 | q.s |
Table 4b: Formulations Details (With drug product)
| S. No. | Composition | |||||
| 2-phenoxyethanol | Metacresol | ΑΓ++ Content | Saline (0.9% W/V) | |||
| Percentage | mg/mL | Percentage | mg/mL | mg/mL | mg/mL | |
| 1 | 0.3 | 3 | 0.1 | 1 | 1 | q.s |
| 2 | 0.3 | 3 | 0.05 | 0.5 | 1 | q.s |
| 3 | 0.3 | 3 | 0.025 | 0.25 | 1 | q.s |
| 4 | 0.3 | 3 | 0.005 | 0.05 | 1 | q.s |
| 5 | 0.3 | 3 | NA | 1 | q.s | |
| 6 | NA | 0.05 | 0.5 | 1 | q.s | |
| 7 | 0.2 | 2 | 0.05 | 0.5 | 1 | q.s |
| 8 | 0 | 0 | 0 | 0 | 1 | q.s |
Further based on the results of the inocuium détermination process, known concentration of cells were inoculated into formulations with drug product samples. Post inoculation samples were incubated at respective températures, collected and serially diluted at appropriate intervals to détermine number of viable cells présent in each test sample.
Preservative efficacv tested against Staphylococcus aureus and Escherichia coli
Formulations inoculated with Staphylococcus aureus showed more than 2 iog réduction from initial cell count in ail test samples and on 35th day showed no growth for ail the compositions. Volume of sample used was 100 pL.
Table 5: Test results for Staphylococcus aureus (NCTC10788)
| Preservative | 0th day | 7111 day | 28th day | 35th day | ||||
| 105 | Viability | 105 | Viability | 105 | Viability | 105 | Viability | |
| 2-PE 3mg+ m-C 1 mg | 196 | 1.9*10Λ8 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.5 mg | 84 | 8.4*10Λ7 | 11 | 1.1*10Λ7 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.25 mg | 154 | 4 ΑΛΟ l.UH IUO | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.05 mg | TNTC | NA | n | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg | 56 | 5.6*10Λ 7 | 1 | 1*10Λ6 | 0 | 0 | 0 | 0 |
| m-C 0.5 mg | TNTC | NA | 9 | 9*10Λ6 | 0 | 0 | 0 | 0 |
| 2-PE 2mg+ m-C 0.5 mg | 112 | 1.12*10Λ8 | 0 | 0 | 0 | 0 | 0 | 0 |
| Placebo | 57 | 5.7*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
2-PE = 2-phenoxyethanol; m-C = m-cresol
Formulations inoculated with Escherichia coli showed more than 2 log réduction in samples containing 2-PE 3mg+ m-C 1 mg; 2-PE 3mg+ m-C 0.5 mg; 2-PE 3mg+ m-C 0.25 mg and 2-PE 2mg+ m-C 0.5 mg; and with 2-PE 3mg; m-C 0.5 mg and 2-PE 3mg+ m-C 0.05 mg;
preservatives showed log réduction and few counts observed on 35th day.
Table 6: Test results for Escherichia co//(NCTC12923)
| Preservative | 0th day | 7th day | 28th day | 35th day | ||||
| 105 | Viability | 105 | Viability | 105 | Viability | 105 | Viability | |
| 2-PE 3mg+ m-C 1 mg | 188 | 1.88*10Λ8 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.5 mg | 60 | 6.0*10Λ7 | 1 | 1*ΐΌΛ6 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.25 mg | 37 | 3.7*10Λ7 | 9 | 9*10Λ6 | U | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.05 mg | 39 | 3.9*10Λ7 | 28 | 2.8*10Λ7 | 5 | 5*10Λ6 | 0 | 0 |
| 2-PE 3mg | 56 | 5.6*10Λ7 | 43 | 4.3*10Λ7 | 26 | 2.6*10Λ7 | 1 | 1*10Λ5 |
| m-C 0.5 mg | 131 | 1.31*10Λ8 | 40 | 4.0*10Λ7 | 103 | 1.03*10Λ8 | 1 | 1*10Λ5 |
| 2-PE 2mg+ m-C 0.5 mg | 49 | 4.9*10Λ7 | 4 | 4*10Λ6 | 0 | 0 | 0 | 0 |
| Placebo | TNTC | TNTC | 5 | 5*10Λ6 | 122 | 1.22*10Λ8 | 15 | 1.5*10Λ7 |
2-PE = 2-phenoxyethanol; m-C = m-cresol
AH the preservative compositions for Staphylococcus aureus and Escherichia coli met the compendial requirements.
Preservative efficacy tested against Pseudomonas aeruginosa and Candida albicans
Formulations inoculated with Pseudomonas aeruginosa and Candida albicans showed more than 2 log réduction from initial cell count. Pseudomonas aeruginosa showed no growth for ail the compositions except for the formulation not containing any preservative (Placebo). From 2nd day onwards there was no growth in ail preservative compositions.
Candida albicans showed no growth for ail the compositions from 12th day. From 2nd day onwards decrease in cell count were observed.
Table 7: Test results for Pseudomonas aeruginosa (NCTC12924)
| Preservative | 0® day | 7th day | 28® day | 35® day | ||||
| 105 | Viability | 105 | Viability | 105 | Viability | 105 | Viability | |
| 2-PE 3mg+ m-C 1 mg | 12 | 1 2*10λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.5 mg | 63 | 6.3*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.25 mg | 62 | 6.3*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.05 mg | 51 | 5.1*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg | 65 | 6.5*10Λ 7 | 0 | 0 | 0 | 0 | 0 | 0 |
| m-C 0.5 mg | 242 | 2.42* 10Λ8 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 2mg+ m-C 0.5 mg | 31 | 3.1*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| Placebo | TNTC | ΝΑ | TNTC | ΝΑ | 300 | 3*10Λ8 | 300 | 3*10Λ8 |
2-PE = 2-phenoxyethanol; m-C = m-cresol
Table 8: Test results for Candida albicans (NCPF3139)
| Preservative | 0® day | 7111 day | 28® day | 35* day | ||||
| 105 | Viability | 105 | Viability | 105 | Viability | 105 | Viability | |
| 2-PE 3mg+ m-C 1 mg | 3 | 3*10Λ5 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.5 mg | 7 | 7*10Λ5 | 1 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.25 mg | 7 | 7*10Λ5 | 2 | 2*10Λ5 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.05 mg | 6 | 6*10Λ5 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg | 4 | 4*10Λ5 | 3 | 3*10Λ5 | 0 | 0 | 0 | 0 |
| m-C 0.5 mg | 4 | 4*10Λ5 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 2mg+ m-C 0.5 mg | 4 | 4*10Λ5 | 1 | 1*10Λ5 | 0 | 0 | 0 | 0 |
| Placebo | 2 | 2*10Λ5 | 1 | 1*10Λ5 | 0 | 0 | 0 | 0 |
2-PE = 2-phenoxyethanol; m-C = m-cresol
Ail the preservative compositions for Pseudomonas aeruginosa and Candida albicans met 5 the compendial requirements.
Preservative efficacy tested against Aspergillus brasiliensis
Aspergillus brasiliensis showed no growth in ail preservative compositions from 12th day onwards except the formulation which doesn’t contain any preservative (placebo). From 2nd day onwards cell count réduction was observed in ail the preservative compositions.
Table 9: Test results for Aspergillus brasiliensis (NCPF2275)
| Preservative | 0® day | 7® day | 28® day | 35® day | |||
| 105 | Viability | 105 | Viability | 105 | Viability | 105 | Viability |
| 2-PE 3mg+ m-C 1 mg | 25 | 2.5*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.5 mg | 16 | 1.6*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.25 mg | 86 | 8.6*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| 2-PE 3mg+ m-C 0.05 mg | 10 | 1.0*10Λ7 | 3 | 3*10Λ6 | 0 | 0 | 0 | 0 |
| 2-PE 3mg | 18 | 1 8*10Λ7 | 5 | 5*10Λ6 | 0 | 0 | 0 | 0 |
| m-C 0.5 mg | 11 | 1 1*10^7 | 5 | 5*10Λ6 | 0 | 0 | 0 | 0 |
| 2-PE 2mg+ m-C 0.5 mg | 38 | 3.8*10Λ7 | 0 | 0 | 0 | 0 | 0 | 0 |
| Placebo | 12 | 1.2*10Λ7 | 6 | 6*10Λ6 | 7 | 7*10Λ6 | 5 | 5*10Λ6 |
2-PE = 2-phenoxyethanol; m-C = m-cresol
AI! the preservative compositions for Aspergillus brasiliensis met the compendial requirements.
Based on the results it is évident that the formulation containing combined preservatives with 0.05% (0.05mg/ml) of meta-Cresol and 0.2% (2mg/ml) of 2-Phenoxy éthanol is efficacious in preventing microbial growth in final formulations.
Example 2: Formulation of a 14-Valent Pneumococcai Conjugate Vaccine (without preservative)
| Conjugate serotype | Quantity (pg) / dose (0.5 ml) |
| 1 | 2.2 |
| 3 | 2.2 |
| 4 | 2.2 |
| 5 | 2.2 |
| 6Β | 4.4 |
| 7F | 2.2 |
| 9V | 2.2 |
| 14 | 2.2 |
| 18C | 2.2 |
| 19A | 2.2 |
| 19F | 2.2 |
| 22F | 2.2 |
| 23F | 2.2 |
| 33 F | 2.2 |
| Excipients | |
| Succinic acid | 295 pg |
| Eiemental aluminium as aluminium phosphate gel | 0.5mg |
| poloxamer 188 | 1000 pg |
| 0.9 % sodium chloride solution (w/v) | ne |
Example 3: Formulation of a 14-Valent Pneumococcal Conjugale Vaccine (with preservative)
| Conjugate serotype | Quantity (pg) ! dose (0.5 ml) |
| 1 | 2.2 |
| 3 | 2.2 |
| 4 | 2.2 |
| 5 | 2.2 |
| 6B | 4.4 |
| 7F | 2.2 |
| 9V | 2.2 |
| 4 A I** | 2.2 |
| 18C | 2.2 |
| 19A | 2.2 |
| 19F | 2.2 |
| 22 F | 2.2 |
| 23F | 2.2 |
| 33F | 2.2 |
| Excipients | |
| Succinic acid | 295 pg |
| Elemental aluminium as aluminium phosphate gel | 0.5mg |
| poloxamer 188 | 1000 pg |
| 2-phenoxyethanol | 3 mg |
| m-cresol | 1 mg |
| 0.9 % sodium chloride solution (w/v) | qs |
Given below is the process steps involved in manufacturing Formulation of a 14-Valent Pneumococcal Conjugale Vaccine.
Part quantity of saline was laken followed by addition of pneumococcal monovalent conjugale bulk (PnMBC). It was mixed for few minutes to gel uniformity and then batch 5 quantity of 10% stérile Pôloxamer 188 solution was sïowîy added and again mixed for about minutes for uniformity. This was followed by addition stérile filtered succinic acid stock solution, then 2-phenoxyethanol stock solution and metacresol stock solution. Mixed for few minutes and batch quantity of aluminium phosphate gel was added to the blend under continuous stirring. After mixing for few minutes, pH of the mixture was checked and 10 adjusted to ~5.8±0.2 using 1N NaOH and volume make up was done with remaining part of saline. Blending was continued further for 2 hours at 200 ±50 RPM for adsorption to get final bulk.
Post sampling, both the vaccine bulks were aseptically and separately filled into viais inside laminarairflow unit, sampled the viais required for testing and remaining viais stored at 215 8°C chamber.
Example 4: Formulation of Hexavalent vaccine
| Each 0.5 mi dose of vaccine contains | Quantity / dose of 0.5ml |
| Diphtheria toxoid (DT) | 25 Lf |
| Tetanus toxoid (TT) | 5 Lf |
| whole-cell Bordetella pertussis (wP) | 16 or 20 IOU |
| Haemophilus influenzae type B polysaccharide (Hib-PRP) - TT conjugale | 11 micrograms |
| Hepatitis B surface antigen (HepB) | 12.5 microgram |
| Inactivated poliomyelitis virus (IPV) |
| Type 1 | 20 DU |
| Type 2 | 4 DU |
| Type 3 | 16 DU |
| Al content | 0.3 mg |
| 2-phenoxyethanol (2-PE) | 2 mg |
| m-Cresol | 1 mg |
The process steps invoived in manufacturing the hexavaient formulation described above is given below:
i. HepB antigen, diphtheria toxoid and tetanus toxoid were added to a blending vessel containing aluminium phosphate and the mixture was stirred for 12-16 hrs, ii. the pH of wP was adjusted to 6.8-7.2 and added to the DT-HepB mixture obtained in step (i), and the pH was adjusted to 6.2-6.5, iii, to the above DTwP-Hep B mixture, S19 IPV bulk antigen was added, followed by saline solution, iv. a solution of 2-PE was added and the mixture was cooled at 2-8 °C,
v. to the mixture obtained in step (iv) HibTT was added, vi. the volume was adjusted with normal saline solution and filled the solution in individual containers.
Example 5: Formulation of a 14-Valent Pneumococcal Conjugale Vaccine (with preservative)
| Conjugale serotype | Quantity (pg) / dose (0.5 ml) |
| 1 | 2.2 |
| 3 | 2.2 |
| 4 | 2.2 |
| 5 | 2.2 |
| 6B | 4.4 |
| 7F | 2.2 |
| 9V | 2.2 |
| 14 | 2,2 |
| 18C | 2.2 |
| 19A | 2 2 |
| 19F | 2.2 |
| 22 F | 2.2 |
| 23F | 2.2 |
| 33 F | 2.2 |
| Excipients | |
| Succinic acid | 295 pg |
| Elemental aluminium as aluminium phosphate gel | 0.5mg |
| Polysorbate 20 | 100 pg |
| 2-phenoxyethanol | 3 mg |
| Benzyi alcohol | 2 mg |
| 0.9 % sodium chloride solution (w/v) | qs |
Example 6: Formulation of a 14-Valent Pneumococcal Conjugate Vaccine (with preservative)
| Conjugate serotype | Quantity (pg) / dose (0.5 ml) |
| 1 | 2.2 |
| 3 | 2.2 |
| 4 | 2.2 |
| 5 | 2.2 |
| 6B | 4.4 |
| 7F | 2.2 |
| 9V | 2.2 |
| 14 | 2.2 |
| 18C | 2.2 |
| 19A | 2 2 |
| 19F | 2.2 |
| 22 F | 2.2 |
| 23F | 2.2 |
| 33F | 2.2 |
| Excipients | |
| Succinic acid | 295 pg |
| Elemental aluminium as aluminium phosphate gel | 0.5mg |
| Polysorbate 80 | 100 pg |
| 2-phenoxyethanol | 3 mg |
| Benzoic acid | 2 mg |
| 0.9 % sodium chloride solution (w/v) | qs |
Example 7: Formulation of a 14-Valent Pneumococcal Conjugate Vaccine (with preservative)
| Conjugate serotype | Quantity (pg) / dose (0.5 ml) |
| 1 | 2.2 |
| 3 | 2.2 |
| 4 | 2.2 |
| 5 | 2.2 |
| 6B | 4.4 |
| 7F | 2.2 |
| 9V | 2.2 |
| 14 | 2.2 |
| 18C | 2.2 |
| 19A | 2 2 |
| 19F | 2.2 |
| 22 F | 2.2 |
| 23F | 2.2 |
| 33 F | 2.2 |
| Excipients | |
| Succinic acid | 295 pg |
| Elemental aluminium as aluminium phosphate gel | 0.5mg |
| poloxamer 188 | 1000 pg |
| 2-phenoxyethanol | 3 mg |
| Phénol acid | 2 mg |
| 0.9 % sodium chloride solution (w/v) | qs |
Example 8: Immunization of rabbits with the preservative containing formulation of PCV
In order to ascertain whetherthe formulation containing preservative composition has any négative influence on sérum antibody titer, vaccine formulation containing two preservatives was préparée (Exampïe 2). Another formulation without any preservative but containing exactly the same excipient was prepared as ‘control’ (Example 3). These polysaccharide conjugaies were adsorbed onto aluminum phosphate gel and assessed for critical vaccine quality attributes in accordance with the pharmacopoeial guidelines.
Healthy rabbits having weight of 1.5 to 2 kg each were bred and reared in a contained facility. Rabbits were immunized with the aforementioned formulation. Each group, consisting of 7 rabbits, were immunized with either Exemple 2 or Exampïe 3 formulation on days 1, 15 and 29. Blood samples were collected on days 0 (pre-immune), 15 (test bleed) and 36 (final bleed). Rabbit sera collected on day 0 (PD1 ) and Day 40 (PD3) were analyzed for serotype spécifie immune response using ELISA. The ELISA was performed as per the WHO suggested protocol.
| Group size | Schedule | |
| Immunization | Bleeding | |
| 7 Rabbits each | Day 1, Day 15 & Day 29 | Day 0 (PI), Day 12, Day 26 & Day 40 (PD3) |
Titer estimation
Antibody titer in the immunized animais was assigned as inverse of dilution factor that showed twice as much OD^onm as the pre-immune titer (approximately 0.2 OD). Sérum antibody titer of each animal (n=7) was plotted using MedCalc on logarithmic scale (on yaxis). The error bar indicates variance at 95% Confidence Interval (Cl). The mid-point in the error bar represents the group average sérum antibody titer.
A guide to reading the plot is given below which describes how the plot is laid out (Figure 1). Briefly, the x-axis legend contains the Formulation ID, bleed analyzed, and the serotype tested. For exampïe, Pi_ST1 means, sérum antibody titer in rabbit immunized with formulation disclosed in Example 2 at pre-immune bleed against Serotype 1, PD3_ST1 means, sérum antibody titer in rabbit immunized with formulation disclosed in Example 2 at post dose 3 bleed against Serotype 1, PD3_ST22F means, sérum antibody titer in rabbit immunized with formulation disclosed in Example 2 at post dose 3 bleed against Serotype 22F and so on (Figure 2 A & B). It is common to expect background titers in the pre-immune rabbits. However, post third dose of immunization the sérum antibody titer increases several-fold indicating robust and spécifie immune response in the immunized animais.
Similarly, Pi_ST1 in Figure 3 A & B means, sérum antibody titer in rabbit immunized with formulation disclosed in exampie 3 at pre-immune bleed against Serotype 1, PD3_ST1 means, sérum antibody titer in rabbit immunized with formulation disclosed in exampie 3 at post dose 3 bleed against Serotype 1, PD3_ST22F means, sérum antibody titer in rabbit immunized with formulation disclosed in example 3 at post dose 3 bleed against Serotype 22F and so on. It is observed that the sérum antibody titers in rabbit immunized with formulation described in exemple 3 was similar to those observed in rabbits immunized with formulation disclosed in example 2. Hence, the data herein indicates that the presence of preservative composition has no négative effect on immunogenicity of the vaccine formulation.
The concentration of preservative chosen to test the immune response was 0.6 mg/ml of 2-PE and 0.2 mg/mL of m-cresol. As shown in the figures, there is no inhibitory effect on the immune response in rabbits at this concentration of preservatives and it is expected that the concentrations lower than this will not hâve any négative effect on the immune response too.
Claims (12)
1. A vaccine formulation comprising an antigen and a preservative System comprising 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6 % and at least one other preservative selected from the group consisting of m-cresol, benzyl aîcohoi, phénol and benzoic acid.
2. The vaccine formulation as claimed in claim 1, wherein the concentration of mcresol, benzyl alcohol, phénol and benzoic acid is in a range from 0.005% to 0.3%.
3. The vaccine formulation as claimed in claim 1, comprising one or more pharmaceutically acceptable carriers.
4. The vaccine formulation as claimed in claim 1, wherein the vaccine formulation is a monovalent vaccine or a multivalent combination vaccine.
5. A monovalent vaccine formulation as claimed in claim 4, wherein the monovalent vaccine formulation comprises antigens selected or isolated from a group consisting of Streptococcus pneumonie (Pneumococcal capsuîar polysaccharide), Neisseria meningitides (Men A, C, W-135, X or Y), Salmonella typhi (Vi), Salmonella paratyphi (0:2), Haemophilus influenza (Hib-PRP), Corynebacterium Diptheriae (Diptheriae Toxoid-DT), Bordeteila pertussis (wP/ aP), Clostridium tetani (Tetanus Toxoid), Hepatitis A Virus (HAV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), inactivated Japanese Encephalitis Virus, Rabies Virus and Inactivated Poliomyelitis Virus.
6. A multivalent vaccine formulation as claimed in claim 4, wherein the multivalent vaccine formulation is selected from a group consisting of a bivalent vaccine, trivalent vaccine, tetravalent vaccine, pentavalent vaccine, hexavalent vaccine and pneumococcal conjugale vaccine.
7. The multivalent vaccine formulation as claimed in claim 6, wherein the bivalent vaccine is selected from a group consisting of Td vaccine, Vi:O2 conjugale and MR;
and, wherein the trivalent vaccine is selected from a group consisting of DTwP, Vi:O2HepA and MMR;
and, wherein the tetravalent vaccine is selected from a group consisting of DTwP-Hib, DTaP-Hib, DTwP-IPV, DTwP-HepB, ACW-135Y;
and, wherein the pentavalent vaccine is selected from a group consisting of DTwPHibHepB and DTaPHib-HepB;
and, wherein the hexavalent vaccine is selected from a group consisting of DTwPHibHepB-IPV and DTaPHib-HepB-IPV.
8. The vaccine formulation as claimed in claim 6, wherein the pneumococcal conjugate vaccine comprises one or more pneumococcal capsular polysaccharide protein conjugates, preservative System as ciaimed in ciaim 1 and optionally, one or more pharmaceutically acceptable carriers.
9. The vaccine formulation as claimed in ciaim 8, wherein the pneumococcal capsular polysaccharide protein conjugates comprises Streptococcus pneumonie capsular polysaccharides selected from a group comprising serotype 1, 2, 3, 4, 5, 6A, 6B, 6C, 6D, 7F, 8, 9N,9V, 10A, 11A, 12F, 14, 15A, 15B, 15C, 16F, 17F, 18C, 19F, 19A, 20A, 20B, 22F, 23A, 23B, 23F, 24B, 24F, 31, 33F, 34, 35B, 35F, 38, 39 and 45;
and, wherein each polysaccharide is conjugated to a carrier protein selected from PsaA, CRM197 and inactivated bacterial toxins selected from diphtheria toxoid (DT), tetanus toxoid (TT), pertussis toxoid, choiera toxoid and Haemophilus influenzae protein D, or combination thereof.
10. The vaccine formulation as claimed in claim 3, wherein each pneumococcal capsular polysaccharide is selected from Streptococcus pneumonia serotypes 1,2, 3, 4, 5, 6A, 6B, 6C, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15A, 15B, 15C, 16F, 17F, 18C, 19F, 19A, 20A, 20B, 22F, 23A, 23B, 23F, 24B, 24F, 31, 33F, 34, 35B, 35F, 38, 39, and 45 conjugated to a carrier protein and a preservative System as ciaimed in claim 1, wherein the preservative composition comprises 2-phenoxyethanol at a concentration in the range of 0.1% to 0.6 % and at least one other preservative selected from a group comprising mcresol at a concentration in the range of 0.005% to 0.3%, benzyl alcohol at a concentration in the range of 0.01% to 1% and benzoic acid at a concentration in the range of 0.01% to 1 % and one or more pharmaceutically acceptable carriers or excipients.
11. The vaccine formulation as claimed in claim 10, wherein the vaccine formulation is selected from one of the following:
a. 14 valent pneumococcal capsular polysaccharide protein conjugale vaccine comprising capsular polysaccharides from Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F and 33F;
b. 20 valent pneumococcal capsular polysaccharide protein conjugate vaccine comprising capsular polysaccharides from Streptococcus pneumoniae serotypes 1,
3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 11A, 12F, 14, 15A, 18C, 19A, 19F, 22F, 23A, 23F and 35B;
c. 20 valent pneumococcal capsular polysaccharide protein conjugate vaccine comprising capsular polysaccharides from Streptococcus pneumoniae serotypes 1,
3, 4, 5, 6A, 6B, 6C/6D, 7F, 9V, 14, 15A, 15C, 18C, 19A, 19F, 23A, 23B, 23F, 24F and 35B;
d. 24 valent pneumococcal capsular polysaccharide protein conjugate vaccine comprising capsular polysaccharides from Streptococcus pneumoniae serotypes 1,
3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 180, 19A, 19F, 22F. 23A, 23B, 23F, 24F, 33F and 35B.
12. Use of a preservative system comprising 2-phenoxyethanoi at a concentration in the range of 0.1% to 0.6 % and at least one other preservative selected from the group consisting of m-cresol, benzyi alcohol, phénol and benzoïc acid for the prévention of microbial or viral contamination in a vaccine formulation.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201841027285 | 2018-07-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA20144A true OA20144A (en) | 2021-12-13 |
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