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WO1997013531A1 - Vaccins viraux solides, pouvant s'administrer par voie orale et procedes de preparation - Google Patents

Vaccins viraux solides, pouvant s'administrer par voie orale et procedes de preparation Download PDF

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Publication number
WO1997013531A1
WO1997013531A1 PCT/US1996/016278 US9616278W WO9713531A1 WO 1997013531 A1 WO1997013531 A1 WO 1997013531A1 US 9616278 W US9616278 W US 9616278W WO 9713531 A1 WO9713531 A1 WO 9713531A1
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Prior art keywords
rotavirus
infectivity
virus
vaccine
weight
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PCT/US1996/016278
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English (en)
Inventor
Jacqueline Duncan
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Zynaxis, Inc.
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Publication date
Application filed by Zynaxis, Inc. filed Critical Zynaxis, Inc.
Priority to AU76828/96A priority Critical patent/AU7682896A/en
Publication of WO1997013531A1 publication Critical patent/WO1997013531A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/15—Reoviridae, e.g. calf diarrhea virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/215—Coronaviridae, e.g. avian infectious bronchitis virus
    • A61K39/225—Porcine transmissible gastroenteritis virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5254—Virus avirulent or attenuated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2720/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsRNA viruses
    • C12N2720/00011—Details
    • C12N2720/12011—Reoviridae
    • C12N2720/12311—Rotavirus, e.g. rotavirus A
    • C12N2720/12334—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/20011—Coronaviridae
    • C12N2770/20034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • This invention relates to vaccine formulations to prevent against viral infections. More specifically, the invention provides methodology for the formulation of a solid, oral delivery system for live rotavirus vaccines. The methodology disclosed herein may be applied to both living and attenuated viruses other than rotavirus.
  • Gastric acid can be neutralized by the administration of buffers before or concurrently with vaccine administration (Halsey, N.A. , et al. , J. Infec. Dis. 158 :1261-1267, 1988), but this procedure is time consuming, expensive, and poorly tolerated by infants (Edelman, R., Pediat. Infec. Dis. J. 6_:704-710, 1987) .
  • a limitation on the effective use of the above- described vaccines is loss of infectivity of the virus during lyophilization and the measures required to protect the acid-sensitive vaccines from degradation in the stomach.
  • one log loss of infectivity is said to be tolerated by manufacturers at the preliminary lyophilization step.
  • Current vaccines are prepared with bicarbonate or citrate and resuspended in water before oral administration. Identification of an oral delivery system that performs better than, or at least equivalent to, the current norm with its concomitant loss of infectivity would be highly beneficial.
  • the object of this invention is to provide such a vaccine for oral delivery that is superior to that which is currently available.
  • the present invention provides a viral vaccine formulation suitable for processing into a variety of final dosage systems for oral administration to humans and animals, either adult or infant, including a therapeutic form of the vaccine and a carrier comprising cellulose and modified cellulose selected from the group consisting of cellulose esters, microcrystalline cellulose, carboxymethyl cellulose and mixtures thereof; a sugar selected from the group consisting of sucrose, fructose, glucose, mannose or any sugar suitable for use in pharmaceutical compositions; starch; and optionally gelatin.
  • a carrier comprising cellulose and modified cellulose selected from the group consisting of cellulose esters, microcrystalline cellulose, carboxymethyl cellulose and mixtures thereof; a sugar selected from the group consisting of sucrose, fructose, glucose, mannose or any sugar suitable for use in pharmaceutical compositions; starch; and optionally gelatin.
  • Vaccine formulations retaining high levels of infectivity have been prepared using a carrier comprising 10-50 wt % of a cellulose component, 30-70 wt % of the sugar component, 10-50 wt % of starch and 10-30 wt % of gelatin based on the total weight of the carrier material.
  • a live rotavirus vaccine including as the carrier substantially equal parts of cellulose acetate, starch, sucrose.
  • Gelatin may beneficially be included in the carrier formulation for certain applications.
  • Figure 1 is a graphical representation of the relative effect on rotavirus infectivity retention produced by incorporation into various delivery systems.
  • PLG Microspheres (2) Buchi spray drying; (3) Alginate microcapsules; (4) Cellulose granules.
  • Figure 2 is a graphical representation of the effect of various carriers on relative rotavirus infectivity retention post-drying.
  • Figure 3 is a set (A-F) of micrographs of the outer surface of granules (rotavirus dried with the carrier blend) either uncoated or coated with a polymer film coating.
  • HPMC hydroxymethylpropylcellulose
  • Figure 4 is a micrograph of a cross section of the outer surface of a tablet formulated in accordance with this invention and uniformly coated with a polymer film.
  • Effective delivery of rotavirus vaccine depends on the protection of the live rotavirus from degradation in the stomach while allowing release in the small intestine.
  • the inventor based the choice of ingredients in the present formulation in part, on known uses of cellulose acetate as a filler, sucrose as a binder, and starch as a disintegrant, and, also prior indications that certain carriers may stabilize viral preparations.
  • gelatin which is also a binder was added.
  • a carrier blend of cellulose acetate, starch, sucrose, and gelatin (30:30:30:10) stabilized the live porcine rotavirus and produced outstanding results with only minimal loss of infectivity.
  • the same carrier blend stabilized human rotavirus, but a modified carrier blend containing cellulose, starch, and sucrose (33:33:33) without gelatin performed even better.
  • Porcine rotavirus was found to be relatively stable in some commonly used organic solvents, including ether, diethylcarbonate and methylene chloride (1 log reduction in infectivity as determined by plaque assay) , but was not stable in others, such as ethyl acetate or acetone.
  • no infectivity was retained by rotavirus preparations that were microencapsulated in PLG microcapsules prepared by evaporation of the co-mixed virus and the copolymer from methyl chloride.
  • no infectivity was retained by rotavirus incorporated directly in the enteric polymers cellulose acetate phthalate, or Eudragit
  • tableting with cellulose as the carrier was found to preserve the infectivity of the rotavirus with only one log loss in infectivity after the entire process of tableting, coating with HPMC and subsequent coating with Eudragit.
  • the tableted rotavirus vaccine was found to be stable for up to sixty days at 4oc, and for four weeks at room temperature and thus would be suitable for clinical use.
  • particulate tablet vaccines suitable for administration to infants can be generated.
  • the tablet size should be less than 0.5 mm, with tablet size in the range of 0.10 to 0.25 mm being preferred.
  • compositions of the invention may be prepared in various forms for administration, including tablets or granules. Granules may be suspended in a suitable carrier medium.
  • pharmaceutically acceptable carrier medium includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • solvents diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like.
  • any conventional carrier medium is incompatible with the anti-viral compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component (s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.
  • the compounds of the present invention may be used to vaccinate patients against certain viruses.
  • the expression "immunologically effective amount” as used herein refers to a nontoxic but sufficient amount of the compositions of the invention to elicit an immune response thereby protecting the patient against subsequent viral infections. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the particular viral vaccine and the like.
  • the term patient may refer to an animal or a human being.
  • Gottfried Strain GP46 was a gift from Dr. L.J. Saif (Ohio State University, Wooster, OH) .
  • Pancreatin was purchased from Gibco BRL, Grand Island, NY.
  • Lactose, sucrose, starch, microcrystalline cellulose (Avicel) and gelatin were purchased from Foremost Ingredients, Barboo, WI; Sigma Chemical Co., St. Louis, MO Colorcon, West Point, PA; FMC Corporation, Philadelphia, PA and Geo A. Hormel and Co., Austin, MN; respectively.
  • Tableting carriers, acdisol, stearic acid and talc were purchased from FMC, Mallinckrodt Specialty Chemical Co., St. Louis, MO and Luzenac America Inc., Englewood CO.
  • Eudragit L30D is an aqueous dispersion of an anionic copolymer based on methacrylic acid and acrylic acid ethyl ester.
  • Opadry is a water-soluble hydroxylpropylmethylcellulose based polymer.
  • Sodium alginate (Keltone HV) was obtained from the Kelco Division of Merck & Co., Inc., San Diego, CA and non ⁇ pareil seeds from Paulur Corporation, Robbinsville, NJ.
  • the Coomassie Blue Binding Assay kit was purchased from Pierce, Rockford, IL.
  • Rotavirus, strain GP46 was grown on MA 104 fetal rhesus monkey kidney cells. Prior to inoculation, the cells were maintained in Dulbecco's modified medium (DMEM) supplemented with 10% bovine calf serum and antibiotics. Confluent monolayers of these cells in roller bottles were infected at a multiplicity of infection (M.O.I.) of 0.01 - 0.02. After absorption of the virus to the cells for 1 hour at 37oC, DMEM supplemented with antibiotics and containing 30 ⁇ g/ml of pancreatin was added.
  • DMEM Dulbecco's modified medium
  • M.O.I. multiplicity of infection
  • the culture supernatant containing cell debris and virus was harvested 2-3 days post- infection and clarified by centrifugation at 3,700 x g av for twenty minutes at 4oC.
  • the virus was pelleted from the clarified solution by centrifugation at 130,000 x g av for 1.5 hour at 4 ⁇ c.
  • the virus was then pelleted by resuspending the virus pellet in media and centrifugation on a 30% glycerol - phosphate buffered saline (PBS) cushion at 200,000 x g av for 4.5 hours at 97/13531 PCMJ 96/1627
  • a formulation of cellulose acetate, sucrose, starch and gelatine in a ratio of 30:30:30:10 was selected for trial and its ability to stabilize the live, rotavirus vaccine was tested.
  • the carriers were ground in a Waring blender.
  • the solution of live rotavirus was then added and the ingredients mixed well until a wet mass formed. This was dried in a desiccator at 4°C under vacuum.
  • the dried carrier blend was ground with a small mill to form a dry powder.
  • the formulations included lactose alone, sucrose alone, gelatin alone, or the carrier blend of cellulose, starch, sucrose, and gelatin at a ratio of 30:30:30:10.
  • the ingredients were suspended in distilled H 2 0, and mixed with rotavirus strain Gottfried GP46 (1.9 x IO 7 pfu) until a wet mass was formed.
  • the wet mass was dried in a desiccator at 4oc under vacuum until a level of 5% water weight was reached, then ground with a small mill to form a fine, dry powder.
  • the viral activity retained after processing was determined by plaque assay.
  • the rotavirus was applied to the surface of non-pareil sugar seeds.
  • the dried live rotavirus strain Gottfried GP46 at a concentration 10 7 - IO 9 pfu was suspended in 100 ml of an aqueous HPMC film-forming polymer that contained 1 - 2% sucrose. This was applied to the surface of 200 g non- pareil seeds by the Wurster spray coating method administered in a STREA-1 laboratory unit as previously described.
  • Microspheres/granules were mounted on a specimen disc and coated with a 20 angstrom layer of palladium gold. The coating was carried out using the electron microscope-500 sputter coater. After coating, the samples were examined and photographed using an ISI-SX40 SEM.
  • Rotavirus-containing microspheres were prepared by Southern Research Institute, Birmingham, Alabama. Three milligrams of purified rotavirus strain SB-IA containing approximately IO 12 pfu of infectious particles was microencapsulated in biodegradable and biocompatible polymers of PLG by a modification of an emulsion- based methylene chloride solvent evaporation procedure as described by Cowsar, D.R., et al . , Meth. Enz . 112 :101- 116, 1985. The surface morphology was evaluated by electron microscopy and a smooth surface of continuous polymeric coating was confirmed.
  • the vaccine content was estimated by dissolving a sample of the microspheres in methylene chloride, extracting the rotavirus, determining the amount of protein and calculating the percent antigen by weight. The core loading of 0.55% was satisfactory. The size of the microspheres was determined using a Malvern light scattering device and was found to range from 1 to 10 ⁇ m.
  • a sample of the microspheres was dissolved in methylene chloride, the virus extracted twice with PBS, and the infectivity measured by plaque assay.
  • CAP has been used widely as an enteric coating polymer for pharmaceutical tablets or granules. CAP dissolves at approximately pH 5.5, and thus it withstands prolonged contact with acid contents of the stomach, but dissolves and releases drugs readily in the small intestine.
  • the rotavirus strain SB-IA preparation containing approximately IO 8 pfu of infectious particles were resuspended in 100 ⁇ l of 1.5 M sucrose containing 10 mM poly-L-lysine and mixed with 40 ml of an aqueous solution of CAP (25 mg/ml, pH 6.5) .
  • Microcapsules were produced by atomization of the CAP and vaccine emulsion through a Buchi 190 mini-spray dryer (Brinkmann, Westbury, NY) .
  • the infectivity of the microencapsulated rotavirus was determined by in vi tro analysis. Aliquots containing fifty mg of microcapsules were made and placed into 2 tubes. One sample was treated with 0.1 N HCl and 37oc for 30 minutes. The microcapsules did not dissolve in the acidic solution and appeared to be intact. The microcapsules were then pelleted by low speed centrifugation and dissolved in 0.5 ml of simulated intestinal fluid, pH 6.8 - 7.5 (USP XXI) . The other 50 mg of microcapsules were dissolved in 0.5 ml of simulated intestinal fluid without pretreatment with acid. Both samples were then examined for virus infectivity by plaque assay.
  • the alginate microcapsules containing live rotavirus strain SB-IA vaccine formed by chelation of the sodium alginate with calcium ions.
  • Rotavirus at a concentration of 1 x 10 a pfu was mixed with 3 ml of sodium alginate solution (1.2% w/v in normal saline) .
  • This suspension was then dripped slowly through a 19 gauge needle into a solution of calcium chloride (1.5% w/v in distilled water) while stirring at 500 rpm.
  • the microcapsules containing rotavirus were collected by sieving, rinsed three times with a normal saline solution, and then dried at 4oc under vacuum.
  • Granules were prepared by forming a carrier blend of cellulose, starch, sucrose and gelatin at a ratio of 30:30:30:10: in a Waring blender.
  • One batch of granules was prepared by adding a solution of rotavirus strain SB- IA at a concentration of 4.51 x IO 7 pfu per 300 mg of carrier blend, and a second batch prepared by adding a solution of SB-IA at a concentration of 3.91 x IO 4 pfu per 20 mg of carrier blend.
  • the wet mass was dried under vacuum at 4°C and then ground with a small mill to form granules.
  • a second batch of granules containing 3.91 x IO 4 pfu rotavirus strain SB-1A/20 mg carrier blend was enterically coated with Eudragit L30D as described above except that granules received a protective coating of
  • Opadry prior to the application of the Eudragit. It has previously been determined that enteric polymers can inactivate certain ingredients such as viruses, proteins, and peptides.
  • the protective coating, Opadry is a water-soluble hydroxypropylmethlycellulose-based polymer. The Opadry was applied to the granules by the Wurster spray coating method in a fluid bed laboratory unit, STREA-1, with a weight increase of the granules of approximately 8-10%. A further weight gain of 25% occurred on coating with Eudragit.
  • Disintegration analysis was used to determine the effectiveness of the film coatings in protecting the live rotavirus vaccine from exposure to gastric fluid.
  • the granules were weighed prior to and after exposure to simulated gastric fluid (USP XXI; pH 1.2) at 37oC for 1 hour, and the percent gastric uptake determined.
  • the granules then were exposed to simulated intestinal fluid (USP; pH 6.8 - 7.5) at 37°C, and the time required for complete disintegration determined.
  • Rotavirus Gottfried strain GP46 was prepared for tableting using a drying procedure as described for the preparation of the granules except that 1) the rotavirus was dried with the carrier blend of cellulose, starch, sucrose and gelatin at a concentration of 9.7 x 10 s pfu/lOOmg of carrier blend, or 2) the rotavirus was dried with lactose at a concentration of 6.7 x 10 4 pfu/ 20 mg lactose.
  • Tablets formed from preparation 1 were composed of the following ingredients (% dry weight) : lactose filler (74.70 %) , acdisol disintegrant (3 %) , stearic acid lubricant (1.5 %) , talc as a processing aid (1.0 %) , and the dried rotavirus preparation with carriers (19.70 %) .
  • Tablets formed from preparation 2 were composed as follows: lactose (54.10 %) , acdisol (3 %) , stearic acid (1.50 %) , talc (1.0%) , and the dried rotavirus preparation with carriers (40.40 %) .
  • the dry ingredients from each preparation were mixed well to form a dry blend, incorporated into a 3 mm dye and pressed at 550 lb pressure to produce 50 mg, 3 mm tablets.
  • the tablets were enterically coated with Opadry and Eudragit L30D as described for the coating of the granules.
  • the subcoating of Opadry was applied until the weight of the tablets increased by 6-8%.
  • an enteric coating of Eudragit L30D was applied until the weight of the tablets was further increased by 20-25%.
  • Tablets from the three processing steps including uncoated tablets, tablets coated with Opadry, and tablets coated with both Opadry and Eudragit L30D, were stored at 4oc under vacuum with desiccant.
  • the tablets were evaluated for in vi tro stability by plaque assay and disintegration testing as described for the granules. 97/13531 PC17US96/16278
  • the chosen carrier blend of cellulose acetate, starch, sucrose and gelatine (bloom 175) at a ratio of 30:30:30:10 (w/w) resulted in essentially complete retention of the rotavirus vaccine infectivity after drying compared to a control solution of the virus as determined by plaque assay.
  • This preparation was readily soluble in PBS and this carrier blend would facilitate subsequent granulation and tableting procedures.
  • the rotavirus vaccine was mixed with individual carriers. These carriers included cellulose acetate, starch, sucrose or gelatin bloom 175 or compounds with similar properties including microcrystalline cellulose, fructose, glucose, mannose, or gelatin blooms 150, 175, 200 or 300.
  • the live, rotavirus vaccine was prepared, blended with the respective carrier, and the blend was then dried and assayed for infectivity as described in the above materials and methods. In this experiment, some of the formulations were not readily soluble in PBS and required incubation at 37oC for 10 minutes to dissolve. The formulations blended with gelatin blooms 200 and 300 were relatively insoluble and required incubation at 37o for 20 and 30 minutes respectively.
  • Example III As individual carriers were not able to stabilize the live, rotavirus vaccine during drying, an experiment was conducted to determine if any two carriers in combination could stabilize this vaccine.
  • the live, rotavirus vaccine was prepared, blended with the carriers, and then dried as described above in materials and methods. These processing steps were accomplished in approximately 1 hour 40 minutes and, except for the drying step, were performed at room temperature. In this experiment, some of the formulations were not readily soluble in PBS and required incubation at 40oC for 10 minutes. The blends were then assayed for infectivity as described in materials and methods.
  • sucrose and starch and sucrose and gelatin resulted in improved retention of rotavirus infectivity, but all of these resulted in a greater than 1 log loss (Table II) .
  • routine use of such high levels of gelatin presents difficulties in solubilizing the formulation and in fabrication of final dosage units.
  • the formulation of sucrose and gelatine would present difficulties in subsequent granulation and tableting procedures, and a combination of sucrose and starch is probably not suitable for subsequent granulation.
  • the carriers were blended and mixed with free rotavirus as described above in materials and methods. These processing steps were accomplished in approximately 1 hour 50 minutes and, except for the drying process, were performed at room temperature. In this experiment some of the formulations were not readily soluble in PBS and required incubation at 40°C for 10 minutes. The blends were then assayed for infectivity as described above in materials and methods .
  • Example VI Preparation of Dried Human Rotavirus Vaccine with Carriers ⁇ An experiment was conducted using human rotavirus to determine if the carrier formulation preserved the activity of human rotavirus and to determine if it was possible to further improve the results from the combination of any three carriers used previously in Example IV. Fewer ingredients would be advantageous in subsequent process development of the formulation into a product.
  • a formulation of cellulose acetate, sucrose, and starch in a ratio of 33:33:33 was chosen because it is readily soluble, and would facilitate subsequent tableting or granulation.
  • the formulation of cellulose acetate, sucrose, starch, and gelatin in a ratio of 30:30:30:10 was used as a basis of comparison because it showed good retention of infectivity in Experiments I and V. Also, two other formulations were tried, which are identical to the previous ones used in this experiment, except for the carrier cellulose acetate, which was replaced with microcrystalline cellulose, because this preparation of cellulose has demonstrated improved granulation and tableting over other celluloses.
  • Human rotavirus (HRV strain D x BRV strain UK, Reassortant clone 41-1-1 FRHL-2) was supplied to us by Dr. Kapikian (NIH) .
  • This virus was grown on MA 104 fetal rhesus monkey kidney cells. Prior to inoculation, these cells were maintained in Dulbecco's Modified Eagle medium (DMEM) supplemented with 10% bovine calf serum and antibiotics. Confluent monolayers of these cells in roller bottles were infected at a multiplicity of infection (M.O.I.) of 0.01. After absorption of the virus to the cells for 1 hour at 37oC, DMEM supplemented with antibiotics and containing 0.5 ⁇ g/ml trypsin was added.
  • DMEM multiplicity of infection
  • the culture supernatant containing cell debris and virus was harvested 48 hours post-infection and fresh medium without trypsin was added for another 24 hours.
  • the harvested media were pooled and clarified by centrifugation at 3,700 x g tor 20 minutes at 4 ⁇ c.
  • the virus was then purified by resuspending the virus pellet in medium and centrifugation on a 30% glycerol-phosphate buffered saline (PBS) cushion at 200,000 x g av for 4.5 hours at 4oc.
  • PBS glycerol-phosphate buffered saline
  • These pellets were resuspended in PBS supplemented with 1% bovine serum albumin (BSA) , divalent cations, Ca ++ and Mg ++ and stored at -80°c.
  • BSA bovine serum albumin
  • the live rotavirus vaccine was prepared, blended with the carriers and the blend dried as described in materials and methods. These processing steps were accomplished in approximately 1 hour
  • microcrystalline cellulose for cellulose acetate resulted in greater loss of infectivity.
  • the chosen carrier blend of cellulose acetate, starch and sucrose at a ratio of 33:33:33 was the best formulation with the most retention of human rotavirus infectivity. This formulation is also readily soluble and would facilitate subsequent tableting or granulation.
  • Microencapsulation of live rotavirus indicated that incorporation of live rotavirus into PLG microspheres with solvent removal by either extraction or evaporation, completely destroyed all viral infectivity (Fig. 1) . Furthermore, microencapsulation of rotavirus in CAP polymer particles by the process of atomization in a Brinkmann Buchi 190 mini-spray dryer, completely destroyed rotavirus infectivity. Incorporation of live rotavirus into alginate microcapsules resulted in significant loss of infectivity of approximately 2 log after exposure of microcapsules to gastric fluid, but reduced infectivity by only 0.73 log when exposed to PBS alone.
  • the live rotavirus was dried on several different substrates (Fig. 2) . Drying of the live rotavirus in solution at a dose of 1.9 x IO 7 pfu, on sucrose alone, gelatin alone, or lactose alone resulted in a loss of infectivity of between 1.39 and 2.45 logs. In contrast, drying on the carrier blend containing cellulose, sucrose, gelatin and starch resulted in preservation of infectivity with a log loss of 0.29.
  • Enteric coating of the granules with Eudragit L30D resulted in a reduction of infectivity of 1.61 log (Table X) .
  • Spray drying is commonly used to encapsulate active ingredients, but also involves temperature changes, mechanical action and drying steps. Although, no organic solvent was used in this case, this process also resulted in almost complete loss of infectivity (Fig. 1) .
  • the alginate microcapsule delivery system with a liquid core and semipermeable membrane is an acceptable environment for live cells, however, it has not been determined that alginate is an acceptable environment for a live rotavirus vaccine.
  • a satisfactory level of rotavirus infectivity was maintained in alginate microcapsules that had not been exposed to gastric acid, but after exposure to gastric acid, rotavirus infectivity was reduced by 2 log (Fig. 1) .
  • the porosity of the alginate microspheres produces a delivery system that cannot be effective for oral administration of a live rotavirus vaccine, unless these pores can be sealed completely.
  • Non-pareil seeds, or sugar beads were also included in this comparison.
  • This technology which involves the loading of an active ingredient onto the surface of a seed is commonly used to deliver drugs, especially if a sustained or controlled release of the active ingredient is desired throughout the gut. Furthermore, the active ingredient is close to the surface and thus very quickly available if a burst release of the active ingredient is desired throughout the gut . It would seem that this type of delivery system could be appropriately modified for the delivery of most vaccines, proteins or peptides. However, our results indicate that this technology is not suitable for the delivery of live rotavirus vaccines (Table VIII) .
  • the polymers used for microencapsulating the rotavirus vaccine such as PLG, CAP, and alginate do not stabilize the live rotavirus vaccine during the drying process.
  • a carrier blend of cellulose, starch, sucrose and gelatin is capable of maintaining rotavirus infectivity.
  • the carrier blend was chosen to form granules for further analysis.
  • the effect of the enteric coating processes, such as application of HPMC and Eudragit L30D, on the recovery of rotavirus infectivity after exposure to simulated gastric fluid was determined (Tables X and XI) .
  • Tableting is also a practical and economical laboratory procedure that can be used to demonstrate the feasibility of preparing an effective rotavirus vaccine delivery system based on smaller, aggregated particles. Tablets, of themselves, are not considered an appropriate delivery system for infants and children, who would be the most important target group for this vaccine. Tableting resulted in improved retention of infectivity at every step in the processing with a total cumulative loss of 1.46 log (Table IX) . Disintegration testing and SEM photography indicated complete sealing on enteric coating (Fig. 4) .
  • the actual loss of infectivity may be lower than that recorded in the analysis as the methods used to remove the Eudragit L30D to assay contents for remaining rotavirus infectivity contributed to the loss of rotavirus infectivity.
  • This concept is supported by the comparative losses assayed after the HPMC and Eudragit L30D coating.
  • HPMC coating involves longer exposure to increased temperatures and mechanical processes than Eudragit coating, it is reasonable to assume that a greater loss of rotavirus infectivity would be observed during the HPMC coating than during the Eudragit L30D coating. Consequently, a more accurate assessment of loss of infectivity may be indicated by the loss subsequent to the HPMC coating step.
  • TGEV transmissible gastroenteritis virus
  • Batch 2 was prepared from porcine coronavirus TGEV also obtained from Dr. Hesse (Schering-Plough) .
  • the virus was grown on ST cells in 850 cm 2 roller bottles. Prior to inoculation with virus, the cells were maintained in Dulbecco's modified Eagle medium supplemented with 7% fetal bovine serum and antibiotics. A confluent monolayer of cells was infected at an M.O.I, ot 0.1-0.001. After absorption ot the virus to the cells for 1 hour at 37oC, DMEM supplemented with fetal bovine serum and antibiotics was added.
  • the culture supernatant containing cell debris and virus was harvested 2-3 days post-infection from 184 roller bottles (13.8 liters) and clarified by centrifugation in a Sorvall centrifuge at 6,000 rpm for 20 min. The supernatant was harvested and the virus concentrated using an Amicon Spiral Ultracentrifuge Cartridge S1Y100 under pressure (20-30 p.s.i.) . The permeate containing the virus (750 ml) was then further concentrated by centrifugation using a Beckman TI 45 rotor at 45,000 rpm for 1 hour. The pellet was resuspended in 50 ml of PBS. At this stage of purification, the virus had been concentrated 276-fold and the infectious titer was 8.11 x 10 s TCID S0 /ml .
  • Two lots of dried TGEV were prepared.
  • the first lot incorporated 550 ul of Batch 1 TGEV prepared as described above.
  • a formulation of cellulose acetate, sucrose, starch, and gelatin in a ratio of 30:30:30:10 was chosen.
  • the carriers were ground and blended in a Waring blender, the TGEV solution was added to 500 mg of the carrier blend and mixed until a wet mass was formed. This was dried in a desiccator at 4° under vacuum.
  • the dried TGEV carrier blend was ground with a small mill to form a dry powder. This powder was then incorporated into tablets.
  • the second lot of dried TGEV was also formulated with cellulose acetate, sucrose, starch, and gelatin in a ratio of 30:30:30:10 as described above except that 500 ⁇ l of Batch 2 of the purified virus was used. Thus, 4.055 x IO 9 TCID 50 /500 ⁇ l of virus was incorporated into the carrier blend.
  • the two batches ot dried TGEV antigen were separately incorporated into tablets. The same procedure was used in both cases.
  • the tablets were composed of the following ingredients (% dry weight) : lactose filler (78%) , acdisol disintegrant (8%) , stearic acid lubricant (1.5%) , talc as a processing aid (1.0%) , and the dried rotavirus antigen (12.5%) .
  • the dry ingredients from each preparation were mixed well to form a dry blend, incorporated into a 3 mm dye and pressed at 550 lb pressure to produce 40 mg, 3 mm tablets.
  • Opadry which is an HPMC-based polymer. This was applied by the Wurster
  • the liquid oral polymer was prepared by mixing 3 g carboxymethylcellulose with 100 ml H 2 0, and stirring overnight. Live virus at a concentration of IO 7
  • TCID 50 /0.5 ml H 2 0 was thoroughly mixed with 5 ml of the liquid oral polymer and administered to the pigs orally, for the primary inoculation, as well as the booster immunization given at week 8.
  • FC* - Contact 0/2 0/2 1 controls
  • the following example pertains to vaccine formulations that would be suitable for administration to human infants. Minute tablets or pellets can be synthesized by the above protocols with slight modifications. The tablets would then be beneficially resuspended in a suitable fluid and the vaccine would be administered orally. The need for concomitant buffer administration would be eliminated as the tablets would be coated as described in the previous examples . Thus the following methodology provides for a commercially superior, orally administered vaccine for the immunization of infants against rotavirus infection. Human Rotavirus Vaccine Antigen
  • Human Rotavirus vaccine (1.6 x IO 10 TCID50) would be prepared exactly as in Example VI. The pellets would be resuspended in 800 ml H 2 0. This solution would be used to prepare the dried human rotavirus antigen.
  • One lot of dried rotavirus would be prepared.
  • the first lot would incorporate 800 ml of the rotavirus vaccine as prepared above.
  • a formulation of cellulose acetate, sucrose, starch, and gelatin in a ratio of 30:30:30:10 would be chosen (800g) .
  • the carrier would be ground and blended in a waring blender, the rotavirus solution would be added to 800g of the carrier blend and mixed until a wet mass forms. This would be dried in a desiccator at 4°C under vacuum.
  • the dried rotavirus carrier blend would be ground with a mill to form a dry powder. This powder would then be incorporated into tiny granules and enterically coated.
  • the granules would be formed in a Glatt GPCG-1 fluid bed coater/granulator apparatus with a rota- processing insert.
  • the 800 g of dried rotavirus blend would be placed in the rota-processing unit and rotated at a high speed. Water would be sprayed with an atomizing gun while the powder is rotating in the Glatt processing unit. As the dried powder wets, agglomerates would begin to form. These should become larger as more water is applied. When the agglomerates reach an acceptable size (100-200 ⁇ ) , the process would be stopped.
  • the agglomerated particles should be round and hard because of the centrifugal process used to form them.
  • Opadry and Eudragit L30D would be applied as described in Example VII.
  • Opadry would be applied such that a weight increase of the granules would be 4-6%.
  • Eudragit L30D would then be applied such that a weight increase would be 10-12%.
  • enteric coatings have been exemplified above, other biologically acceptable coating materials may be employed, such as time release coating compositions
  • the viral infectivity of the agglomerates would then be determined by plaque assay as described in materials and methods.

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Abstract

L'invention concerne des compositions et des excipients utiles pour des formulations de vaccins et pour leur administration. L'invention concerne également des substances et des procédés qui permettent une immunisation efficace des patients contre certains virus, en particulier des rotavirus, pour apporter une protection par immunisation contre une infection subséquente par des virus. La figure est une représentation graphique de l'effet de divers vecteurs sur la retention du caractère infectieux relatif des rotavirus après le séchage.
PCT/US1996/016278 1995-10-13 1996-10-11 Vaccins viraux solides, pouvant s'administrer par voie orale et procedes de preparation WO1997013531A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999013869A1 (fr) * 1997-09-12 1999-03-25 Gerold Lukowski Formes medicamenteuses stables en milieu humide et resistant au suc gastrique, a l'usage des animaux
WO2001037810A2 (fr) * 1999-11-24 2001-05-31 Willmar Poultry Company, Inc. Apport in ovo d'un implant contenant un agent immunogene
US20110189654A1 (en) * 2008-05-27 2011-08-04 Qiagen Gmbh Diagnostic reagent, containing bioparticles, method for production thereof and use thereof as internal standard in nucleic acid preparation and nucleic acid detection methods
US20120087944A1 (en) * 2010-10-08 2012-04-12 R.P. Scherer Technologies, Llc Oral vaccine fast-dissolving dosage form using starch
WO2020109485A1 (fr) * 2018-11-29 2020-06-04 Catalent U.K. Swindon Zydis Limited Vaccin orodispersible comprenant des virosomes
RU2808276C2 (ru) * 2018-11-29 2023-11-28 Каталент Ю.Кей. Суиндон Зайдис Лимитед Перорально диспергируемая вакцина, содержащая виросомы

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4877612A (en) * 1985-05-20 1989-10-31 Frank M. Berger Immunological adjuvant and process for preparing the same, pharmaceutical compositions, and process
US5176909A (en) * 1989-09-29 1993-01-05 The Nisshin Oil Mills, Ltd. Stable immunogen composition for oral administration

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4877612A (en) * 1985-05-20 1989-10-31 Frank M. Berger Immunological adjuvant and process for preparing the same, pharmaceutical compositions, and process
US5176909A (en) * 1989-09-29 1993-01-05 The Nisshin Oil Mills, Ltd. Stable immunogen composition for oral administration

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999013869A1 (fr) * 1997-09-12 1999-03-25 Gerold Lukowski Formes medicamenteuses stables en milieu humide et resistant au suc gastrique, a l'usage des animaux
WO2001037810A2 (fr) * 1999-11-24 2001-05-31 Willmar Poultry Company, Inc. Apport in ovo d'un implant contenant un agent immunogene
WO2001037810A3 (fr) * 1999-11-24 2001-11-22 Willmar Poultry Co Inc Apport in ovo d'un implant contenant un agent immunogene
US6682754B2 (en) 1999-11-24 2004-01-27 Willmar Poultry Company, Inc. Ovo delivery of an immunogen containing implant
US20110189654A1 (en) * 2008-05-27 2011-08-04 Qiagen Gmbh Diagnostic reagent, containing bioparticles, method for production thereof and use thereof as internal standard in nucleic acid preparation and nucleic acid detection methods
US20120087944A1 (en) * 2010-10-08 2012-04-12 R.P. Scherer Technologies, Llc Oral vaccine fast-dissolving dosage form using starch
US9956169B2 (en) * 2010-10-08 2018-05-01 R.P. Scherer Technologies, Llc Oral vaccine fast-dissolving dosage form using starch
WO2020109485A1 (fr) * 2018-11-29 2020-06-04 Catalent U.K. Swindon Zydis Limited Vaccin orodispersible comprenant des virosomes
CN113301917A (zh) * 2018-11-29 2021-08-24 康特伦英国斯温顿捷迪斯有限公司 包含病毒体的可经口分散疫苗
EP3886896A1 (fr) * 2018-11-29 2021-10-06 Catalent U.K. Swindon Zydis Limited Vaccin orodispersible comprenant des virosomes
US11224571B2 (en) 2018-11-29 2022-01-18 Catalent U.K. Swindon Zydis Limited Oral dispersible vaccine comprising virosomes
JP2022510372A (ja) * 2018-11-29 2022-01-26 キャタレント・ユーケー・スウィンドン・ザイディス・リミテッド ビロソームを含む経口分散性ワクチン
US11523988B2 (en) 2018-11-29 2022-12-13 Catalent U.K. Swindon Zydis Limited Oral dispersible vaccine comprising virosomes
RU2808276C2 (ru) * 2018-11-29 2023-11-28 Каталент Ю.Кей. Суиндон Зайдис Лимитед Перорально диспергируемая вакцина, содержащая виросомы
IL282371B1 (en) * 2018-11-29 2024-11-01 Catalent Uk Swindon Zydis Ltd Oral dispersible vaccine comprising virosomes
IL282371B2 (en) * 2018-11-29 2025-03-01 Catalent Uk Swindon Zydis Ltd Orodispersible vaccine containing virosomes

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