Classifications

• • 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
  • A61K39/29—Hepatitis virus
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • 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
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • 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
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • 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
• • 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
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
  • A61K2039/541—Mucosal route
  • A61K2039/542—Mucosal route oral/gastrointestinal
• • 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
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55505—Inorganic adjuvants
• • 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
  • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
• • 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
  • C12N2730/00—Reverse transcribing DNA viruses
  • C12N2730/00011—Details
  • C12N2730/10011—Hepadnaviridae
  • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
  • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

• the invention consists in a method of stabilization of a surface antigen which can be subsequently administered to combat hepatitis-B.
• the antigen is in tablet form and does not require refrigeration and its sublingual absorption eliminates the need for antihepatitis-B injections. This is achieved via a stabilizing agent.
• Hepatitis-B is an inflammation of the liver, usually from a viral infection, but sometimes from toxic agents. Specifically, hepatitis-B is a viral disease with a long incubation period, usually 50- 160 days, caused by the hepatitis-B virus and is usually transmitted by injection of infected blood, blood derivatives or by use of contaminated needles, lancets or other instruments. Hepatitis-B is clinically and pathologically similar to viral hepatitis type A, but there is no cross-protective immunity.
• hepatitis-B disease is combated using intravenous or subcutaneous injections of a vaccine.
• the vaccine must be refrigerated in order to retain its activity.
• the present invention consists of antihepatitis-B tablets which are stabilized and therefore do not require refrigeration. These novel tablets consist of stabilized hepatitis-B surface antigen.
• these tablets eliminate the need for painful injections and reduce the risk of possible infection due to contaminated needles of various diseases including hepatitis and
• the sublingual lymphatic plexi absorbs the antigenic surface protein, thus effectively bypassing the entire digestive tract and the liver.
• the lymphatic plexi will eventually decant the surface protein, concurrently with the mechanisms of homeostasis, into the capillaries and then into the vena cava superior, where it will attain systemic distribution.
• this method of attaining results that are identical to those obtained through subcutaneous injections.
• any substance that is acceptable for the sublingual lymphatic plexi i.e. none of its components has diameters larger than the diameter of the lymphatic capillaries
• the substance e.g. antigenic surface protein
• the substance will penetrate the blood stream through the vena cava superior (having bypassed the liver) and pass directly into the right cardiac atrium, where it will attain systemic circulation.
• This invention also eliminates the need of injections, thereby reducing the possibility of transferring diseases such as AIDS. Also, the pain and discomfort of an injection is avoided.
• the hepatitis-B vaccine is in the form of stabilized sublingual tablets and begins with mixing 20 grams of lyophilized antigenic, hepatitis-B surface protein (greater than 97% pure) with 2500 milliliters of bi-distilled H 2 O; 500 grams of pharmaceutical grade lactose; and 4 grams of lyophilized highly purified ("HP") albumin. 125 grams of Na 2 HPO 4 and 110 grams of NaH 2 PO 4 are then mixed into the solution in addition to 40 grams of thimerosal.
• the Stock Solution must be free of alcohol.
• the Stock Solution is created by dilution x 20 of distilled H 2 O; 1250 grams pharmaceutical grade C 5 H 10 O 5 ; 7,800 grams pharmaceutical grade NaCl; and 8,800 grams pharmaceutical grade AI 2 HO 3 . This mixing is done at approximately 40° F temperature and approximately 60% of relative humidity. The mixings are carried out in a surgically sterile environment and can be done with automated equipment.
• the importance of the Stock Solution is mainly the stabilizing agent C 5 H 10 O 5 commonly known as arabic gum.
• This mixture is then fine sprayed onto 88.35 kilograms granulates of excipient made of 50% lactose plus 50% rice starch, both pharmaceutical grade.
• the dilution contains 11.65 kilograms of dissolved solids. This totals, after drying, 100 kilograms which is enough for compressing 1 ,000,000 sublingual tablets of 100 mg each.
• the spraying of the granules to be compressed must be carried out over a period of not less than 100 minutes for the above described quantity. During this process the entire mass of granules should be thoroughly and constantly agitated.
• the tablets must be compressed to high density, yet it should take not less than 10 minutes to break up under the tongue.
• the entire process must be carried out in an environment which is in exact conformity to the norms of Good Manufacturing Practice (GMP).
• the tablets are then vacuum dried at temperatures between 6-10°C.
• the finished product must be stored in blister-packaged strips. After blister-packaging, the finished product does not require refrigeration and can safely be stored at room temperatures up to 28°C. However, for extended periods, from 6 months to five years, it is recommended to store under moderate refrigeration (from 6°C to 12°C). The vaccines should never be kept frozen.
• the surface antigen for the antihepatitis-B vaccine tablets is obtained from a yeast culture that has been transformed by inserting into its genome, the gene coding for the surface of the hepatitis-B virus, using recombinant DNA procedures and standard molecular biology techniques.
• the purified surface antigen is obtained as an aggregate, forming particles of approximately 22 nm, and is ultimately absorbed in an aluminum hydroxide gel (0.5 mg A/3 +/dose of 20 g) to which thimerosal is added as preservative (0.5 mg/dose of 20 g).
• the final product has the appearance of a white/gray substance which sediments on the bottom of the container, defining two phases: a clear supernatant, essentially protein-free, composed of phosphate buffered saline (PBS) with the preservative substance dissolved, and secondly a precipitated aluminum hydroxide gel with more than 98% of the antigen absorbed.
• PBS phosphate buffered saline
• an opaque gray suspension takes place, lasting for several minute, which is the material used for stabilization.
• Fermentation and purification processes have been o p timized, scaled up and standardized to maintain consistency and reproducibility from batch to batch.
• Twenty-four hamsters were certified hepatitis antigen-B-free utilizing a standard ELISA test.
• the sublingual environment of twelve hamsters was painted with solutions of the tableted vaccine, with tablet masses corresponding to the hamster's weight, twice each vaccination day on the first day, the seventh day and the thirtieth day.
• the control group was left untreated. Seven days after the last dose, hepatitis-B antibodies were detected in hepatitis-B treated hamster's blood serum utilizing a standard ELISA test. The control group of twelve remained negative. Subsequently, all twenty-four hamsters were contaminated with hepatitis-B virus. None of the animals treated with the tableted vaccine contracted the disease, while the entire control group became hepatits-B infected.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Immunology (AREA)
• Virology (AREA)
• Mycology (AREA)
• Microbiology (AREA)
• Communicable Diseases (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Inorganic Chemistry (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Medicinal Preparation (AREA)

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• 1997
  • 1997-03-31 AU AU25203/97A patent/AU2520397A/en not_active Abandoned
  • 1997-03-31 EP EP97916601A patent/EP0914141A1/de not_active Withdrawn
  • 1997-03-31 KR KR1019980708467A patent/KR20000010591A/ko not_active Application Discontinuation
  • 1997-03-31 CN CN97194006A patent/CN1216471A/zh active Pending
  • 1997-03-31 JP JP9537890A patent/JP2000509036A/ja active Pending
  • 1997-03-31 WO PCT/IB1997/000448 patent/WO1997039762A1/en not_active Application Discontinuation
  • 1997-03-31 HU HU9902293A patent/HUP9902293A3/hu unknown
  • 1997-03-31 CA CA002285184A patent/CA2285184A1/en not_active Abandoned

Non-Patent Citations (1)

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