EP0914141A1 - Stabilized antihepatitis-b vaccine tablets - Google Patents
Stabilized antihepatitis-b vaccine tabletsInfo
- Publication number
- EP0914141A1 EP0914141A1 EP97916601A EP97916601A EP0914141A1 EP 0914141 A1 EP0914141 A1 EP 0914141A1 EP 97916601 A EP97916601 A EP 97916601A EP 97916601 A EP97916601 A EP 97916601A EP 0914141 A1 EP0914141 A1 EP 0914141A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hepatitis
- surface protein
- approximately
- antigenic
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Virology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Inorganic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
A stabilized antihepatitis-B vaccine tablet and method of making the same wherein said tablet contains a stabilized antigenic hepatitis-B virus surface protein which, upon administration to a mammal, renders the mammal immune to hepatitis-B infection. The key to this stabilization is C5H10O5, or arabic gum.
Description
STABILIZED ANTIHEPATITIS-B VACCINE TABLETS Summary of the Invention
The invention consists in a method of stabilization of a surface antigen which can be subsequently administered to combat hepatitis-B. Specifically, 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.
Usually, hepatitis-B disease is combated using intravenous or subcutaneous injections of a vaccine. However, 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.
Thus, individuals who normally would not have access to hepatitis-B vaccines via injections due to the lack of proper refrigeration would have access to the antihepatitis-B vaccine tablets. This is particularly true regarding individuals living in third world countries.
In addition, 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
H1N.
The rationale of this invention is founded on the fact that 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. Thus, this method of attaining results that are identical to those obtained through subcutaneous injections. Specifically, 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) will not penetrate the vena porta which enters the liver, but will eventually wind up in the thoracic duct. From the thoracic duct, the substance (e.g. antigenic surface protein) 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.
The advantages of this invention are numerous including elimination of the need of refrigeration, which renders the product particularly appropriate for shipping into tropical and third-world environments.
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.
Lastly, there is an approximate 60% of production cost reduction utilizing the method of this invention.
Detailed Description of the Preferred Embodiment Example 1
This invention involves a series of mixing steps. 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 H2O; 500 grams of pharmaceutical grade lactose; and 4 grams of lyophilized highly purified ("HP") albumin. 125 grams of Na2HPO4 and 110 grams of NaH2PO4 are then mixed into the solution in addition to 40 grams of thimerosal.
This mixture is then combined with a Stock Solution. The Stock Solution must be free of alcohol. The Stock Solution is created by dilution x 20 of distilled H2O; 1250 grams pharmaceutical grade C5H10O5; 7,800 grams pharmaceutical grade NaCl; and 8,800 grams pharmaceutical grade AI2HO3. 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 C5H10O5 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. When shaken, an opaque gray suspension takes place, lasting for several minute, which is the material used for stabilization. Fermentation and purification processes have been optimized, scaled up and standardized to maintain consistency and reproducibility from batch to batch.
To test the efficacy of these tablets 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.
Claims
1. A method of stabilization of an antigenic surface protein which can subsequently be administered to a mammal to combat hepatitis-B infection comprising: mixing antigenic hepatitis-B surface protein with a stabilizing agent wherein said agent is C5H10O5.
2. The method of claim 1 wherein said antigenic hepatits-B surface protein is present with said CsHioOsin a range of approximately 75% to 85% by weight antigenic hepatitis-B protein to approximately 15% to 25% by weight CsH10O5.
3. The method of claim 2 wherein said antigenic hepatitis-B surface protein is present with said C5H10O5 in a ratio of approximately 80% by weight antigenic hepatitis-B surface protein to approximately 20% by weight C5H10O5.
4. The method of claim 3 wherein said mammal is a human.
5. The method of claim 4 wherein after said mixing said antigenic hepatitis-B surface protein and C5H10O5 are subsequently formed into sublingual tablets.
6. The method of claim 5 wherein said C5H10O5 is present in a stock solution prior to mixing with said antigenic hepatitis-B surface protein.
7. The method of claim 6 wherein 20 grams of said antigenic hepatitis-B surface protein is mixed with said stock solution wherein said stock solution contains 1,250 grams of pharmaceutical grade C5H10O5.
8. The method of claim 7 wherein said 20 grams of antigenic hepatitis-B surface protein is lyophilized and mixed with water, lactose and albumin to create a primary mixture prior to mixing with said stock solution.
9. The method of claim 8 wherein Na2HPO4, NaHPO4 and thimerosal is added to said primary mixture prior to mixing with said stock solution.
10. The method of claim 9 wherein said stock solution also contains bi-distilled water, NaCl and AI2HO3,
1 1. The method of claim 10 wherein mixing said primary mixture with said stock solution is done at at approximately 4°F and approximately 60% relative humidity.
12. The method of claim 1 1 wherein the combination of said primary mixture and said stock solution is fine sprayed onto an excipient of approximately 50% lactose and approximately 50% rice starch to create a final mixture.
13. The method of claim 12 wherein said final mixture is compressed into sublingual tablets and said tablets are vacuum dried at temperatures between 6 and 10°C.
14. A stabilized antihepatitis-B vaccine tablet which is capable, upon administration to an uninfected mammal, of combating hepatitis-B should said mammal become subsequently exposed to hepatitis-B virus wherein said tablet contains antigenic hepatitis-B surface protein and a stabilizing agent C5H10O5.
15. The tablet of claim 14 wherein said antigenic hepatitis-B surface protein is present approximately 75%-85% by weight antigenic hepatitis-B surface protein to approximately 15%-25% by weight C5H10O5.
16. The tablet of claim 15 wherein said antigenic hepatitis-B surface protein is present approximately 80% by weight antigenic hepatitis-B surface protein to 20% by weight C5H10O5.
17. The tablet of claim 16 wherein said uninfected mammal is a human.
18. The tablet of claim 16 wherein said tablet is a sublingual tablet.
19. The tablet of claim 18 wherein said tablet takes at most approximately 10 minutes to dissolve under said mammal's tongue.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US63551496A | 1996-04-22 | 1996-04-22 | |
US635514 | 1996-04-22 | ||
PCT/IB1997/000448 WO1997039762A1 (en) | 1996-04-22 | 1997-03-31 | Stabilized antihepatitis-b vaccine tablets |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0914141A1 true EP0914141A1 (en) | 1999-05-12 |
Family
ID=24548102
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97916601A Withdrawn EP0914141A1 (en) | 1996-04-22 | 1997-03-31 | Stabilized antihepatitis-b vaccine tablets |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0914141A1 (en) |
JP (1) | JP2000509036A (en) |
KR (1) | KR20000010591A (en) |
CN (1) | CN1216471A (en) |
AU (1) | AU2520397A (en) |
CA (1) | CA2285184A1 (en) |
HU (1) | HUP9902293A3 (en) |
WO (1) | WO1997039762A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6592869B2 (en) * | 1999-08-24 | 2003-07-15 | Teva Pharmaceutical Industries, Ltd. | Vaccine composition and method of using the same |
TR200200477T2 (en) * | 1999-08-24 | 2002-06-21 | Teva Pharmaceutical Industries Limited | A vaccine composition and method of use. |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57136528A (en) * | 1981-02-09 | 1982-08-23 | Hayashibara Biochem Lab Inc | Preparation of viral vaccine |
ZA878295B (en) * | 1986-11-06 | 1988-05-03 | Amarillo Cell Culture Co. Inc. | Treatment of immuno-resistant disease |
ES2108258T3 (en) * | 1992-01-17 | 1997-12-16 | Alfatec Pharma Gmbh | GRANULES CONTAINING PEPTIDIC DRUG SUBSTANCES AND THEIR PREPARATION AS WELL AS THEIR USE. |
-
1997
- 1997-03-31 CN CN97194006A patent/CN1216471A/en active Pending
- 1997-03-31 EP EP97916601A patent/EP0914141A1/en not_active Withdrawn
- 1997-03-31 KR KR1019980708467A patent/KR20000010591A/en not_active Application Discontinuation
- 1997-03-31 CA CA002285184A patent/CA2285184A1/en not_active Abandoned
- 1997-03-31 WO PCT/IB1997/000448 patent/WO1997039762A1/en not_active Application Discontinuation
- 1997-03-31 AU AU25203/97A patent/AU2520397A/en not_active Abandoned
- 1997-03-31 HU HU9902293A patent/HUP9902293A3/en unknown
- 1997-03-31 JP JP9537890A patent/JP2000509036A/en active Pending
Non-Patent Citations (1)
Title |
---|
See references of WO9739762A1 * |
Also Published As
Publication number | Publication date |
---|---|
HUP9902293A2 (en) | 1999-11-29 |
AU2520397A (en) | 1997-11-12 |
HUP9902293A3 (en) | 2000-04-28 |
CN1216471A (en) | 1999-05-12 |
WO1997039762A1 (en) | 1997-10-30 |
CA2285184A1 (en) | 1997-10-30 |
JP2000509036A (en) | 2000-07-18 |
KR20000010591A (en) | 2000-02-15 |
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