WO2002083100A1 - Liposomes consisting mainly of cholesterol - Google Patents
Liposomes consisting mainly of cholesterol Download PDFInfo
- Publication number
- WO2002083100A1 WO2002083100A1 PCT/HU2002/000029 HU0200029W WO02083100A1 WO 2002083100 A1 WO2002083100 A1 WO 2002083100A1 HU 0200029 W HU0200029 W HU 0200029W WO 02083100 A1 WO02083100 A1 WO 02083100A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- particles
- cholesterol
- process according
- antibody
- production
- Prior art date
Links
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims abstract description 62
- 235000012000 cholesterol Nutrition 0.000 title claims abstract description 31
- 239000002502 liposome Substances 0.000 title abstract description 12
- 239000002245 particle Substances 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 28
- 230000008569 process Effects 0.000 claims abstract description 28
- 230000003627 anti-cholesterol Effects 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 241000192041 Micrococcus Species 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 238000002649 immunization Methods 0.000 claims abstract description 6
- 238000010253 intravenous injection Methods 0.000 claims abstract description 6
- 230000003053 immunization Effects 0.000 claims abstract description 5
- 230000000638 stimulation Effects 0.000 claims abstract description 5
- 230000007423 decrease Effects 0.000 claims abstract description 4
- 230000007812 deficiency Effects 0.000 claims abstract description 4
- 230000002265 prevention Effects 0.000 claims abstract description 4
- 239000012528 membrane Substances 0.000 claims description 11
- 239000008151 electrolyte solution Substances 0.000 claims description 5
- 239000011368 organic material Substances 0.000 claims description 4
- 239000000427 antigen Substances 0.000 claims description 3
- 102000036639 antigens Human genes 0.000 claims description 3
- 108091007433 antigens Proteins 0.000 claims description 3
- 230000001900 immune effect Effects 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 229940088597 hormone Drugs 0.000 claims description 2
- 239000005556 hormone Substances 0.000 claims description 2
- 229910010272 inorganic material Inorganic materials 0.000 claims description 2
- 239000011147 inorganic material Substances 0.000 claims description 2
- 230000000717 retained effect Effects 0.000 claims description 2
- 230000004936 stimulating effect Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 239000000654 additive Substances 0.000 abstract description 4
- 239000000725 suspension Substances 0.000 abstract description 3
- 230000000087 stabilizing effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 11
- 201000001320 Atherosclerosis Diseases 0.000 description 7
- 239000013078 crystal Substances 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000005670 electromagnetic radiation Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 208000006379 syphilis Diseases 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000006395 Globulins Human genes 0.000 description 1
- 108010044091 Globulins Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 230000002546 agglutinic effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001841 cholesterols Chemical class 0.000 description 1
- 230000024203 complement activation Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- YWXYYJSYQOXTPL-SLPGGIOYSA-N isosorbide mononitrate Chemical compound [O-][N+](=O)O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 YWXYYJSYQOXTPL-SLPGGIOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
-
- 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
- A61K39/0005—Vertebrate antigens
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- 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
- A61K2039/55511—Organic adjuvants
- A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
Definitions
- the subject of the invention is a process for producing particles of bacterium-size, said particles can be obtained from cholesterol, suitable for stimulation of production of anti-cholesterol antibody, with the help of said process liposome particles of Micrococcus size (100-500 nm) from cholesterol of high purity degree can be produced.
- the membranes of said particles are of Micrococcus size and said membranes comprise of cholesterol of high purity, the set aim can be achieved.
- the invention relates to a process for producing particles of bacterium-size, said particles can be obtained from cholesterol, said particles are suitable for stimulation of production of anti-cholesterol antibody characterized by that, membranes of said particles are of Micrococcus size and said membranes comprise of cholesterol of high purity.
- the structure of the membranes of the particles is retained stable in an electrolytic solution or in a lyophilized form.
- the particles preferably include different organic materials of great molecules and inorganic materials jointly or separately as well.
- the particles preferably in themselves, with electrolytic solutions or filled with organic materials of great molecules are active from an immunological point of view and are suitable for immune-stimulation or immunization.
- the particles produced during the process according to the invention are preferably suitable for intravenous injection into any animal (human being) whose blood contains cholesterol among natural circumstances.
- a preferable application of the particles produced during the process according to the invention 'vacant' particles induce production of anticholesterol antibody.
- antibodies forming under influences of 'vacant' particles are suitable for prevention and treatment of diseases contracted due to deficiency of anticholesterol antibody or due to decline of antibody titre.
- Another preferable application of the particles produced during the process according to the invention is that antigen stimulating production of cholesterol effects hormones system substituted from cholesterol, and influences therapy.
- Crystals are collected under sterile conditions, dissolved in an organic solvent at 56-90 °C, and are stored as a supersaturated solution at 5 °C.
- Characteristics of particles produced during the process according to the invention are as follows: iff
- Particles can be dried by lyophilization
- the sheet receiving the solution is exposed to physical impact with the help of an adjustable oscillator and the surface is treated with an electromagnetic radiation of 270-1080 nm wavelength from an adjustable monochromatic power-source during flowing of the fluid.
- the monomolecular bits of membrane arranged by the oscillator and torn to films in the ultra micro grooves are entwined to globular formulas consistent with the 100- 500 nm diameter of the half of the wavelength by electromagnetic radiation.
- the bacterium-like particles produced by the above process are collected in a physiological solution under sterile conditions and are stored in the form of an 1 mg/ml suspension calculated on the dry-material content of the cholesterol at 5°C in one ml doses or in bigger volume, which can be dozed before use as required.
- the advantage of the process according to the invention is that an effective medication for preventing and healing of atherosclerosis can be produced.
- the particles produced during the process according to the invention are suitable for the production of anticholesterol antibody by active immunization.
- the particles are suitable for prevention and treatment of diseases contracted due to deficiency of anticholesterol antibody or due to decline of antibody titre.
- the stabilizing role is ensured by well-known additives and additives ensuring isotonic conditions.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Dispersion Chemistry (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The subject of the invention is a process for producing particles of bacterium-size, said particles can be obtained from cholesterol, suitable for stimulation of production of anti-cholesterol antibody, with the help of said process liposome particles of Micrococcus size (100-500 nm) from cholesterol of high purity degree can be produced. The invention relates to a process for producing liposome particles of Micrococcus size from cholesterol of high purity degree, with induce production of anticholesterol antibody in the form in intravenous injection by active immunization and are suitable for prevention and treatment of diseases contracted due to deficiency of anticholesterol antibody or due to decline of antibody titre. In case of intravenous injection of the liposome particle suspension the stabilizing role is ensured by well-known additives and additives ensuring isotonic conditions.
Description
LIPOSOMES CONSISTING MAINLY OF CHOLESTEROL
The subject of the invention is a process for producing particles of bacterium-size, said particles can be obtained from cholesterol, suitable for stimulation of production of anti-cholesterol antibody, with the help of said process liposome particles of Micrococcus size (100-500 nm) from cholesterol of high purity degree can be produced.
In the state of the art there is no effective process for preventing atherosclerosis and there is no really effective medication for curing this disease either. Consequently atherosclerosis seems to belong to the group of incurable diseases.
During our research we observed an antibody in the human body, that reacted with cholesterol. (Horvath, I. Puskas, E. Horvath, Anna Balazs, E. Horvath, A.: Autoantibody or immunological defense against cholesterol, Orvosi Hetilap Medical Weekly 1994. 135.18.965-968) Searching the biological function of antibody we succeeded in producing a composition elaborated on experimental animals to induce production of antibody.
During our examinations for the verification of lues we could detect an antibody, an anticholesterol, reacting with cholesterol in seroconvert serums of non-lues origin, which observation led to the production of the composition in question. When seeking the biological function of the antibody we produced liposome antigens suitable for immunization and we realized, that production of anticholesterol antibody can be induced by them. (Horvath, Anna Narga, L. Horvath, I. Kόkai, M. Karadi, I. Romics, L. Fust, G.: Complement activation in human sera by liposomes made from cholesterol, Mol.Immunology, 1998, 35(6-7):102 (IF: 1,824) Anticholesterol antibody produced this way protected the experimental animals from atherosclerosis. (Horvath, I. Szende, B. Horvath, Anna Kocsis, I. Horvath, A.: Influence of cholesterol liposome immunisation and immunstimulation on rabbits atherosclerosis induced by a high cholesterol diet Med. Sci.Monit. 1998. 4(3):403-
407). During human tests a higher titre of anticholesterol antibody was observed in a sound constitution compared with organism of patients of atherosclerosis of the same age and gender. (Horvath, Anna Prohaszka, Z. Duba, J. Harczos, P. Horvath, I. Nallus, G. Romics, L. Fust, Gy. Karadi, I.: Comperative examination of anticholesterol antibody titre in patiens of atherosclerosis Magyar Belorvosi Archivum Archives of Hungarian Internists 1998/3:239)
According to data of textbooks it is not possible to produce liposome from pure cholesterol, because the crystal form of pure cholesterol prevents the formation of a lipoid membrane.
When working out the invention we set the aim to find a solution for producing particles suitable for stimulation of production of anti-cholesterol antibody.
When realizing the solution according to the invention we recognized, that the membranes of said particles are of Micrococcus size and said membranes comprise of cholesterol of high purity, the set aim can be achieved.
The invention relates to a process for producing particles of bacterium-size, said particles can be obtained from cholesterol, said particles are suitable for stimulation of production of anti-cholesterol antibody characterized by that, membranes of said particles are of Micrococcus size and said membranes comprise of cholesterol of high purity.
In a preferred application of the process according to the invention the structure of the membranes of the particles is retained stable in an electrolytic solution or in a lyophilized form. The particles preferably include different organic materials of great molecules and inorganic materials jointly or separately as well.
The particles preferably in themselves, with electrolytic solutions or filled with organic materials of great molecules are active from an immunological point of view and are suitable for immune-stimulation or immunization.
The particles produced during the process according to the invention are preferably suitable for intravenous injection into any animal (human being) whose blood contains cholesterol among natural circumstances. A preferable application of the particles produced during the process according to the invention 'vacant' particles induce production of anticholesterol antibody.
Another preferable application of the particles produced during the process according to the invention antibodies forming under influences of 'vacant' particles are suitable for prevention and treatment of diseases contracted due to deficiency of anticholesterol antibody or due to decline of antibody titre. Another preferable application of the particles produced during the process according to the invention is that antigen stimulating production of cholesterol effects hormones system substituted from cholesterol, and influences therapy.
The process according to the invention is set forth by the following:
Production of basic materials of the process according to the invention is as follows:
Purification of cholesterol:
Ordinary cholesterol is specially purified for the process:
1. We produce a saturated solution in an organic solvent at 56-90 °C, then it is crystallized by changing the temperature.
2. Crystals are collected on a sterile sieve, dried, then another saturated solution is prepared in another organic solvent at 56-90 °C.
3. It is crystallized by changing the temperature, then collected on an other sterile sieve the crystals are dissolved in a third organic solvent at 56-90 °C, and are crystallized again by changing the temperature.
4. Crystals are collected under sterile conditions, dissolved in an organic solvent at 56-90 °C, and are stored as a supersaturated solution at 5 °C.
Production of liposome:
Supersaturated solution is heated to the level of saturation, then an unsaturated solution is made.
1. We create conditions for producing liquid membranes arranged as crystals by changing the cholesterol in the unsaturated cholesterol solution with continuous, equal changing of the combination of polar and non-polar solutions. Transmitting physical energy of determined amplitude and energy it is transformed to particles having a characteristic structure that can be observed by a microscope.
2. In order to establish stabile particles it is treated for 1 to 10 minutes changing the rate of different solutions equally and continuously, increasing frequency of physical impact many times, then it is dosed to the required volumes after control by a microscope of dark visual field.
Characteristics of particles produced during the process according to the invention are as follows: iff
1. Their outer appearance on an ultramicroscope is similar to Micrococcus.
2. They settle relatively quickly when suspended in electrolytic solutions, and they retain their characteristics for years even at room temperature.
3. Particles can be dried by lyophilization,
4. They tend to agglutination.
5. Agglutinative features are decreased or eliminated in solutions of albumin and globulin.
The process according to the invention will be shown with the following example:
Example 1
20 grams of cholesterol is solved in 1000 ml ethanol and under pressure it is spread with a speed of lOOOul/sec on the 15 ° angle surface dented trough-like of metal sheet of determined silicium content or an acid-proof metal sheet or on the surface of a sheet formed as a pipe, which has equal ultramicro grooves parallel with the axis of the pipe. The three-dimensional sizes of the grooves of the surface parallel with the axis of the trough are controlled by a MULTISCOPE. The grooves can be 100-1000 nm deep and wide.
The sheet receiving the solution is exposed to physical impact with the help of an adjustable oscillator and the surface is treated with an electromagnetic radiation of 270-1080 nm wavelength from an adjustable monochromatic power-source during flowing of the fluid.
The monomolecular bits of membrane arranged by the oscillator and torn to films in the ultra micro grooves are entwined to globular formulas consistent with the 100- 500 nm diameter of the half of the wavelength by electromagnetic radiation. The bacterium-like particles produced by the above process are collected in a physiological solution under sterile conditions and are stored in the form of an 1 mg/ml suspension calculated on the dry-material content of the cholesterol at 5°C in one ml doses or in bigger volume, which can be dozed before use as required.
The advantage of the process according to the invention is that an effective medication for preventing and healing of atherosclerosis can be produced. The particles produced during the process according to the invention are suitable for the production of anticholesterol antibody by active immunization. In the form of intravenous injection the particles are suitable for prevention and treatment of diseases contracted due to deficiency of anticholesterol antibody or due to decline of antibody titre. In case of intravenous injection of the liposome particle suspension the stabilizing role is ensured by well-known additives and additives ensuring isotonic conditions.
Claims
1. Process for producing particles of bacterium-size, said particles can be obtained from cholesterol, said particles are suitable for stimulation of production of anticholesterol antibody characterized by that, membranes of said particles are of Micrococcus size and said membranes comprise of cholesterol of high purity.
2. Process according to claim 1 characterized by that, the structure of the membrane is retained stable in an electrolytic solution or in a lyophilized form.
3. Process according to claim 1 or 2 characterized by that, the particles include different organic materials of great molecules and inorganic materials jointly or separately as well.
4. Process according to claim 1 to 3 characterized by that, the particles in themselves, with electrolytic solutions or filled with organic materials of great molecules are active from an immunological point of view and are suitable for immune-stimulation or immunization.
5. Process according to claim 1 to 4 characterized by that, they are suitable for intravenous injection into any animal (human being) whose blood contains cholesterol among natural circumstances.
6. Process according to claim 5 characterized by that, 'vacant' particles induce production of anticholesterol antibody.
7. Process according to claim 1 to 6 characterized by that, antibodies forming under influences of 'vacant' particles are suitable for prevention and treatment of diseases contracted due to deficiency of anticholesterol antibody or due to decline of antibody titre.
8. Process according to claim 1 to 7 characterized by that, antigen stimulating production of cholesterol effects hormones system substituted from cholesterol, and influences therapy.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0101480A HUP0101480A2 (en) | 2001-04-11 | 2001-04-11 | Process for producing particles with bacterium size from cholesterol |
| HUP0101480 | 2001-04-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2002083100A1 true WO2002083100A1 (en) | 2002-10-24 |
Family
ID=89979198
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2002/000029 WO2002083100A1 (en) | 2001-04-11 | 2002-04-10 | Liposomes consisting mainly of cholesterol |
Country Status (2)
| Country | Link |
|---|---|
| HU (1) | HUP0101480A2 (en) |
| WO (1) | WO2002083100A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004047806A1 (en) * | 2002-11-26 | 2004-06-10 | Horvath Istvan | Process for obtaining bacterium-size particles |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5043107A (en) * | 1986-08-21 | 1991-08-27 | Vestar Research, Inc. | Preparation small unilamellar vesicles including polyene antifungal antibiotics |
| WO1997038731A1 (en) * | 1996-04-18 | 1997-10-23 | The Regents Of The University Of California | Immunoliposomes that optimize internalization into target cells |
-
2001
- 2001-04-11 HU HU0101480A patent/HUP0101480A2/en unknown
-
2002
- 2002-04-10 WO PCT/HU2002/000029 patent/WO2002083100A1/en not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5043107A (en) * | 1986-08-21 | 1991-08-27 | Vestar Research, Inc. | Preparation small unilamellar vesicles including polyene antifungal antibiotics |
| WO1997038731A1 (en) * | 1996-04-18 | 1997-10-23 | The Regents Of The University Of California | Immunoliposomes that optimize internalization into target cells |
Non-Patent Citations (2)
| Title |
|---|
| PRODUCT INFORMATION: "Cholesterol", SIGMA-ALDRICH CATALOGUE, XP002209134, Retrieved from the Internet <URL:http://www.sigma-aldrich.com/sacatalog.nsf/ProductLookup/sigmaC3045?OpenDocument> [retrieved on 20020808] * |
| SWARTZ G M ET AL: "ANTIBODIES TO CHOLESTEROL (LIPOSOMES/LIPID A/COMPLEMENT/ATHEROSCLERROSIS", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US, vol. 85, March 1988 (1988-03-01), pages 1902 - 1906, XP000942042, ISSN: 0027-8424 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004047806A1 (en) * | 2002-11-26 | 2004-06-10 | Horvath Istvan | Process for obtaining bacterium-size particles |
Also Published As
| Publication number | Publication date |
|---|---|
| HU0101480D0 (en) | 2001-06-28 |
| HUP0101480A2 (en) | 2004-01-28 |
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