EP0465513A1 - Formulierungen zur stabilisierung von igm-antikörpern - Google Patents
Formulierungen zur stabilisierung von igm-antikörpernInfo
- Publication number
- EP0465513A1 EP0465513A1 EP19900905158 EP90905158A EP0465513A1 EP 0465513 A1 EP0465513 A1 EP 0465513A1 EP 19900905158 EP19900905158 EP 19900905158 EP 90905158 A EP90905158 A EP 90905158A EP 0465513 A1 EP0465513 A1 EP 0465513A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- igm
- sodium
- lyophilized
- antibodies
- 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- Withdrawn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
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- Immunoglobulins in particular, are recognized as possessing characteristics that tend to form particulates in solution, requiring filtration of these formulations prior to using them for intravenous injection.
- the formation of protein aggregates and particulates has long been a problem in the development of parenteral immunoglobulin products.
- the administration of immunoglobulin G (IgG) was limited to the intramuscular route because of endogenous anticomplementary activity due to aggregated immunoglobulin until the recent development of chemically and enzymatically treated immunoglobulin G. J. E.
- the immunoglobulin (IgM) isotype is the largest of the immunoglobulins, having a molecular weight of approximately 900,000 daltons. IgM molecules tend to be inherently unstable and precipitate readily upon being subjected to various forms of physical and chemical stress. This characteristic makes the formulation of a stable composition containing IgM intended for
- the invention comprises stabilizing compositions for IgM antibodies.
- the present compositions contain a buffer, human serum albumin, sodium chloride, and IgM antibodies or antibody fragments.
- the compositions enhance the stability of IgM antibodies in solution intended for intravenous administration.
- compositions can be lyophilized to form a dry powder. Lyophilization preserves the biological activity of the IgM antibody, and minimizes formation of particulates, which can occur in a liquid formulation under physical or chemical stress.
- the lyophilized product can be readily reconstituted to a particle-free solution which shows no loss of biological activity, and which can be administered without prior filtration.
- the present liquid and lyophilized formulations both exhibit superior stabilizing characteristics in terms of minimal protein particle formation, and preservation of immunoreactivity over time, and under stress conditions such as elevated temperatures, vial filling and shipping.
- the present liquid and lyophilized compositions have both been successful in stabilizing IgM antibodies.
- the compositions maintain a particle-free, stable solution for injectable monoclonal antibodies and do not have to be filtered prior to administration.
- the lyophilized product in particular, can be shipped and stored without loss of immunoreactivity. Neither formulation requires refrigeration or other special handling.
- Figure 1 shows gel filtration HPLC results
- Figure 2 is a diagram of the results of an immunoreactivity assay comparing the ability of
- compositions of this invention minimize the formation of protein aggregates and particulates in reagents containing immunoglobulin M (IgM) antibodies and insure that the antibody in solution maintains its immunoreactivity over time.
- the preparation comprises a sterile, pharmaceutically acceptable solution containing tromethamine or phosphate buffer, having a neutral or basic pH (e.g., 6.8 or above), sodium chloride, IgM antibodies and human serum albumin.
- Buffers have long been used to stabilize the pH of antibody products for parenteral injection. Protein solubility in the buffer solution depends upon a number of factors, such as ionic strength and pH of the
- Buffers which can be used for this formulation include tromethamine and phosphate buffers having a neutral or basic pH. Lower pH formulations showed less stability, i.e., a higher tendency to form aggregates. Tromethamine is described in the Merck Index, 10th edition, Merck and Co., Inc., Rahway, N.J. The concentration of tromethamine can be from about 5 to about 100 mM, having a pH from about 8 to about 10.
- a phosphate buffer such as sodium phosphate, can also be used.
- a concentration of from about 8 to about 20 mM phosphate can be used in the present composition, having a pH of from about 6.8 to about 7.4.
- a stabilizing protein is added to the formulation.
- Stabilizing proteins are proteins which increase the solubility and/or stability of immunoglobulins in aqueous solutions. For example, when added to an aqueous solution of immunoglobulins, these proteins prevent the immunoglobulins from precipitating out of the solution, thereby permitting higher concentrations of immunoglobulins to be solubilized.
- HSA human serum albumin
- HSA is present in the formulation in an amount of about 2.5 to about 10% by weight per volume. Levels of HSA of from about 2.5% (w/v), to about 5% (w/v), are particularly effective in maintaining a stable solution of IgM.
- stabilizing reagents for HSA e.g., sodium caprylate and N-acetyl tryptophanate
- HSA is less stable in solution (i.e., more likely to aggregate) in the absence of these compounds.
- a 25% solution (w/v) of HSA contains 20 mM sodium caprylate and 20 mM N-acetyl tryptophanate., therefore, 2.5% (w/v) HSA added to a formulation includes 2 mM sodium capylate and 2 mM N-acetyl tryptophanate.
- Other stabilizing reagents can be used other than N-acetyl tryptophanate. and sodium caprylate, which are mentioned above for illustrative purposes.
- Sodium chloride is added to the present composition to increase the ionic strength which is required for the solubility of the IgM proteins.
- IgM proteins are more soluble in an aqueous salt solution than in water alone.
- the amount of sodium chloride added is from about 200 to about 350 mM .
- About 270-300 mM sodium chloride is particularly effective for this purpose.
- the present liquid and lyophilized compositions can be used to stabilize all subclasses of IgM antibodies, as well as IgM.
- the present compositions are
- One embodiment of this invention comprises a composition containing from about 5mM to about 100mM tromethamine (pH 8-10), from about 200 mM to about 300mM sodium chloride, from about 2.5 to about 5% (w/v) HSA and from about 2.5 to about 10.0mg/ml IgM antibody.
- Sodium caprylate in an amount of from about 2 mM to about 4 mM and N-acetyl tryptophanate in an amount of from about 2 mM to about 4 mM can, optionally, be included to stabilize the HSA.
- a preferred embodiment of the invention comprises about 4.5 mM tromethamine (pH 8.5) about 270 mM sodium chloride, about 2.5% (w/v) HSA, about 5 mg/ml IgM antibodies or antibody fragments, and about 2 mM each of N-acetyl tryptophanate and sodium caprylate.
- This formulation enhances the stability of immunological activity of the monoclonal antibody, and prevents the immunoglobulins in solution intended for intravenous administration to human subjects from precipitating and forming particulates in the final product vial.
- Another embodiment of the present invention comprises a composition containing from about 8 mM to about 20 mM of sterile, pyrogen-free sodium phosphate (pH 6.8-7.4), from about 250 mM to about 350 mM sodium chloride, from about 2.5 to about 5% (w/v) HSA and from about 2.5 to about 10.0 mg/ml IgM antibody or antibody fragments.
- Sodium caprylate and N-acetyl tryptophanate may be included in the formulation in the amount of about 2 mM to about 4 mM of each.
- this formulation comprises about 8 mM sodium phosphate (pH 7.2), about 270 mM sodium chloride, about 5.0% (w/v) human serum albumin, about 5 mg/ml IgM antibodies or antibody fragments, and about 2 mM each of sodium caprylate and N-acetyl tryptophanate.
- the above formulations can be lyophilized to form a dry, storable powder, which can be easily reconstituted to a particle free solution suitable for intravenous
- Lyophilization is a freeze drying process which is often used in the preparation of pharmaceutical products to preserve their biological activity.
- the liquid composition is prepared, then lyophilized to form a dry cake-like product.
- the process generally involves drying a previously frozen sample in a vacuum to remove the ice, leaving the non-water components intact, in the form of a powdery or cake-like substance.
- lyophilized product can be stored for prolonged periods of time, and at elevated temperatures, without loss of biological activity, and can be readily reconstituted into a particle-free solution by the addition of an appropriate diluent.
- An appropriate diluent can be any liquid which is biologically acceptable and in which the lyophilized powder is completely soluble. Water, particularly sterile, pyrogen-free water, is the
- lyophilization is that the water content is reduced to levels which greatly reduce the various molecular events which lead to instability of the product.
- the lyophilized product is also better able to withstand the physical stresses of shipping.
- the reconstituted product is particle free, so it can be administered intravenously without prior filtration.
- tromethamine 50 mM , pH 8.50
- 300 mM sodium chloride NaCl
- the solution was filtered with a 0.2 ⁇ syringe filter into a 50 ml centrifuge tube.
- Sodium azide 0.22 ml of 10%
- the placebo formulation contained 45 mM Tris buffer (pH 8.35), 270 mM NaCl, 2.5% HSA, 2 mM sodium caprylate and 2 mM N-acetyl tryptophanate.
- the liquid IgM formulation was dispensed in 1 ml increments into 2 ml Type 1 Tubing vials (West Co.). A total of 20 vials were filled. The vials were placed in a lyophilizer (FTS) having a 1' x 1' shelf. In order to generate a full thermal load, the remainder of the shelf space was loaded with placebo vials.
- FTS lyophilizer
- the vials were capped with 13 mM gray butyl
- lyophilization closures #224142, Wheaton.
- the shelves of the lyophilizer were prechilled to about 5oC, ⁇ 2°C.
- the test vials and placebo vials were loaded onto a shelf in a tray, and a slight vaccuum was induced in the chamber to maintain a good door seal.
- a total of 20 vials of product and 355 vials of placebo were filled to occupy the entire shelf space.
- the shelf surface temperature was set for about -40oC.
- the vials were allowed to remain at -40oC for at least one hour.
- the condenser was chilled to about -70oC.
- the pressure in the chamber was reduced by means of a mechanical pump to less than 50 Torr.
- the shelf surface temperature was regulated such that the product temperature remained between -47oC and -42°C.
- a mass spectrum of the residual gasses in the chamber was recorded.
- the shelf surface temperature was then set for about +20°C. When the temperature reached and maintained +20oC for at least 2 hours, the partial pressures of the residual gasses in the chamber was recorded.
- the chamber was then backfilled with dry nitrogen to a pressure of about 600 Torr.
- the product was removed from the dryer and crimp seals were applied to the vials.
- the formulated protein formed a very dense cake upon freezing.
- the lyophilized cakes that were formed did not possess any crust or glaze on the surface, and were uniform throughout the vial.
- the crimp seals were removed from the vials to expose the closure, and the closure was removed from one vial containing the product and one placebo vial.
- a sterile pipette was filled with 1.0 ml of
- the vials were held directly in front of a black background for visual examination. This was accomplished by placing a light source below the vial so that the beam of light proceded upwards through the liquid. Changes in color, turbidity, flocculation, fine precipitation or any other particulate matter were examined. No discernable difference could be seen between the non- lyophilized formulation and the lyophilized reconstituted formulation.
- the lypophilized product and placebo were measured by HPLC (Waters) gel filtration. Non- lyophilized product and placebo were also run.
- HPLC Waters
- a DuPont Zorbax GF-450 gel column was equilibrated with a mixture of 0.2M sodium phosphate buffer (pH 6.8) and 0.3 M NaCl at a flow rate of 1 ml/min. Absorbance wavelength was set for 214 nm.
- pre-lyophilized product and placebo was injected onto the column through an automatic injector and run for 15 minutes.
- the immunological activity of the IgM in each formulation was determined using an enzyme-linked immunoassay to measure binding to solid-phase lipid A.
- a vial of Salmonella minnesota R595 lipid A (List Biological Laboratories, Inc., Campbell, CA ; catalog #401) was reconstituted to 1 mg/ml with 0.5% TEA
- the plates were removed from the incubator and washed three times with s/pf saline, then blocked by dispensing 200 ⁇ l/well of a buffer consisting of: 10 mM HEPES, s/pf saline and 2% heat-inactivated FBS, pH 7.2 (Buffer #2). The plates were covered and incubated for 1 hour at 37°C. After incubation, the plates were washed three times with s/pf saline.
- Buffer #2 was dispensed into the wells in rows B-H (50 ⁇ l/well).
- the IgM standard was dispensed into row A, columns 1-3 (100 ⁇ l/well).
- Test formulations were dispensed in triplicate in row A, columns 4-12 (100 ⁇ l/well).
- Serial 50 ⁇ l dilutions were then made down the rows of the plate to row H. 50 ⁇ l of the 100 ⁇ l in row H was discarded, and the negative control was added.
- the plate was covered and incubated for 2 hours at 37°C, then washed three times with s/pf saline.
- Substrate solution was prepared by adding 1
- optical density of the solutions were measured at 414 nm or using a plate reader.
- the data were analyzed using a 4 parameter fit of OD versus
- Lyophilized product samples were stored at 4oC, 22oC and 40oC. The samples were evaluated periodically for activity and appearance (i.e., particulate
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32857989A | 1989-03-27 | 1989-03-27 | |
US328579 | 1989-03-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0465513A1 true EP0465513A1 (de) | 1992-01-15 |
Family
ID=23281559
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19900905158 Withdrawn EP0465513A1 (de) | 1989-03-27 | 1990-03-13 | Formulierungen zur stabilisierung von igm-antikörpern |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0465513A1 (de) |
JP (1) | JPH04504253A (de) |
CA (1) | CA2049342A1 (de) |
WO (1) | WO1990011091A1 (de) |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HUT63343A (en) * | 1990-07-03 | 1993-08-30 | Akzo Nv | Process for producing immunereactive compounds |
JPH0565233A (ja) * | 1991-03-08 | 1993-03-19 | Mitsui Toatsu Chem Inc | モノクローナル抗体含有凍結乾燥製剤 |
WO1993006862A1 (fr) * | 1991-10-11 | 1993-04-15 | Toray Industries, Inc. | Composition a base d'anticorps |
WO1993013752A1 (en) * | 1992-01-21 | 1993-07-22 | Sri International | Improved process for preparing micronized polypeptide drugs |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US6991790B1 (en) | 1997-06-13 | 2006-01-31 | Genentech, Inc. | Antibody formulation |
AU2444899A (en) * | 1998-01-22 | 1999-08-09 | Astrazeneca Ab | Pharmaceutical formulation comprising an antibody and a citrate buffer |
US8703126B2 (en) | 2000-10-12 | 2014-04-22 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
AU2002213441B2 (en) | 2000-10-12 | 2006-10-26 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
DE60229961D1 (de) * | 2001-08-29 | 2009-01-02 | Chugai Pharmaceutical Co Ltd | Antikörper enthaltende stabilisierte zubereitungen |
KR100913714B1 (ko) | 2001-11-08 | 2009-08-24 | 패시트 바이오테크 코포레이션 | Igg 항체의 안정한 액상 약학 제형물 |
US20040033228A1 (en) | 2002-08-16 | 2004-02-19 | Hans-Juergen Krause | Formulation of human antibodies for treating TNF-alpha associated disorders |
PL2335725T3 (pl) | 2003-04-04 | 2017-04-28 | Genentech, Inc. | Preparaty zawierające wysokoskoncentrowane przeciwciała i białka |
JP5322405B2 (ja) * | 2007-06-07 | 2013-10-23 | 小林製薬株式会社 | タンパク質含有組成物 |
US8883146B2 (en) | 2007-11-30 | 2014-11-11 | Abbvie Inc. | Protein formulations and methods of making same |
AU2010221156A1 (en) | 2009-03-06 | 2011-09-22 | Genentech, Inc. | Antibody formulation |
KR101903931B1 (ko) | 2010-03-01 | 2018-10-02 | 바이엘 헬스케어 엘엘씨 | 조직 인자 경로 억제제 (tfpi)에 대한 최적화된 모노클로날 항체 |
US10294296B2 (en) | 2010-08-23 | 2019-05-21 | Xbiotech, Inc. | Treatment for neoplastic diseases |
EP2707030B1 (de) | 2011-05-09 | 2020-02-19 | Mayo Foundation For Medical Education And Research | Krebsbehandlungen |
CA2838964C (en) * | 2011-07-05 | 2021-07-13 | Novozymes Biopharma Dk A/S | Albumin formulation and use |
CN108404127A (zh) | 2011-09-23 | 2018-08-17 | 埃克斯生物科技公司 | 恶病质治疗 |
US9592297B2 (en) | 2012-08-31 | 2017-03-14 | Bayer Healthcare Llc | Antibody and protein formulations |
AU2013327638B2 (en) | 2012-10-01 | 2018-06-14 | Mayo Foundation For Medical Education And Research | Cancer treatments |
CN106604750B (zh) | 2014-06-16 | 2021-05-07 | 梅约医学教育与研究基金会 | 治疗骨髓瘤 |
HUE047393T2 (hu) * | 2014-10-06 | 2020-04-28 | Mayo Found Medical Education & Res | Szállító antitest komplexek és módszerek ezek hasznosítására |
US9446148B2 (en) | 2014-10-06 | 2016-09-20 | Mayo Foundation For Medical Education And Research | Carrier-antibody compositions and methods of making and using the same |
TW201707725A (zh) | 2015-08-18 | 2017-03-01 | 美國馬友醫藥教育研究基金會 | 載體-抗體組合物及其製造及使用方法 |
EP3337823A4 (de) * | 2015-08-18 | 2019-05-08 | Mayo Foundation for Medical Education and Research | Trägerbindemittelzusammensetzungen sowie verfahren zur herstellung und verwendung davon |
TW201713360A (en) | 2015-10-06 | 2017-04-16 | Mayo Foundation | Methods of treating cancer using compositions of antibodies and carrier proteins |
US11571469B2 (en) | 2016-01-07 | 2023-02-07 | Mayo Foundation For Medical Education And Research | Methods of treating cancer with interferon wherein the cancer cells are HLA negative or have reduced HLA expression |
EP3413874A4 (de) | 2016-02-12 | 2020-01-22 | Mayo Foundation for Medical Education and Research | Behandlungen für blutkrebs |
WO2017165439A1 (en) | 2016-03-21 | 2017-09-28 | Mayo Foundation For Medical Education And Research | Methods for improving the therapeutic index for a chemotherapeutic drug |
CA3018341A1 (en) | 2016-03-21 | 2017-09-28 | Mayo Foundation For Medical Education And Research | Methods for reducing toxicity of a chemotherapeutic drug |
US10618969B2 (en) | 2016-04-06 | 2020-04-14 | Mayo Foundation For Medical Education And Research | Carrier-binding agent compositions and methods of making and using the same |
MX2019002474A (es) | 2016-09-01 | 2019-09-18 | Mayo Found Medical Education & Res | Composiciones de agente de unión de portador-ligando-1 de muerte programada y métodos de uso de las mismas para el tratamiento de cánceres. |
CA3035377A1 (en) | 2016-09-01 | 2018-03-08 | Mayo Foundation For Medical Education And Research | Nanoparticle compositions for targeting t-cell cancers |
RU2019110071A (ru) | 2016-09-06 | 2020-10-08 | Мэйо Фаундейшн Фор Медикал Эдьюкейшн Энд Рисерч | Способы лечения злокачественных новообразований, экспрессирующих pd-l1 |
WO2018048958A1 (en) | 2016-09-06 | 2018-03-15 | Mayo Foundation For Medical Education And Research | Paclitaxel-albumin-binding agent compositions and methods for using and making the same |
EP3509635A1 (de) | 2016-09-06 | 2019-07-17 | Vavotar Life Sciences LLC | Verfahren zur behandlung von dreifach negativem brustkrebs unter verwendung von zusammensetzungen aus antikörpern und trägerproteinen |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1546177A (en) * | 1976-11-19 | 1979-05-16 | Biokema Sa | Process for the preparation of a stable injectable solution |
JPS5822085B2 (ja) * | 1977-07-19 | 1983-05-06 | 株式会社ミドリ十字 | 静注用ガンマ・グロブリン製剤 |
EP0303088B1 (de) * | 1987-08-10 | 1992-11-11 | Miles Inc. | Gereinigtes IgM |
-
1990
- 1990-03-13 JP JP50510090A patent/JPH04504253A/ja active Pending
- 1990-03-13 WO PCT/US1990/001383 patent/WO1990011091A1/en not_active Application Discontinuation
- 1990-03-13 EP EP19900905158 patent/EP0465513A1/de not_active Withdrawn
- 1990-03-13 CA CA 2049342 patent/CA2049342A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO9011091A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1990011091A1 (en) | 1990-10-04 |
JPH04504253A (ja) | 1992-07-30 |
CA2049342A1 (en) | 1990-09-28 |
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