IE42395B1 - Production of long acting insulin preparations - Google Patents
Production of long acting insulin preparationsInfo
- Publication number
- IE42395B1 IE42395B1 IE62/76A IE6276A IE42395B1 IE 42395 B1 IE42395 B1 IE 42395B1 IE 62/76 A IE62/76 A IE 62/76A IE 6276 A IE6276 A IE 6276A IE 42395 B1 IE42395 B1 IE 42395B1
- Authority
- IE
- Ireland
- Prior art keywords
- insulin
- process according
- stabiliser
- preparation
- production
- Prior art date
Links
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
- A61K9/0012—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
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
- C07K14/625—Extraction from natural sources
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biophysics (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Diabetes (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
A stable insulin preparation having a lasting action and having low antigenicity is prepared by reaction of acidic groups of the insulin with basic groups of organic compounds. The reaction is carried out in an aqueous buffer solution which contains a protein-dissociating or protein-depolymerising agent. Basic polypeptides, e.g. protamines, or cleavage products of basic polypeptides are preferred as organic compounds containing a basic group. The protein-dissociating or protein-depolymerising agent is preferably urea.
Description
This invention relates to a therapeutic insulin preparation and a process for producing a stable insulin preparation with protracted effect and low antigenicity by reacting insulin with an organic compound comprising basic groups.
Xn the treatment of diabetes mellitus, insulin preparations derived from swine or ox pancreas are generally used. Thus approximately 30% of the world consumption of insulin is based on swine insulin and approximately 70% on ox insulin. Insulin from other animals has been suggested, for instance sheep insulin, but so far it has not attained any major commercial significance.
Insulin therapy has previously involved many disadvantages, including the manifestation of allergy reactions and lipodystrophy.
It has long been known that conventional insulin treatment, in most patients, results in the formation of insulin antibodies, which may lead to increased insulin requirements, in that unknown amounts of insulin may be bonded to the antibodies and will, while bonded, be ineffective in regulating blood sugar levels.
The primary cause of the antibody formation and the consequent high insulin consumption has been attributed to the presence of various impurities in normal commercial insulin.
Such impurities include, for example,insulin dimer, proinsulin, intermediary insulin (the stage between proinsulin and insulin), arginine insulin, ethylester insulin, mono-desamido insulin and
- 2 4339S didesamido insulin. The first three of these compounds are known to be highly antigenic. It is also known that the fourth or the fifth, or both, are highly antigenic, while the sixth and seventh, and the insulin molecule itself, are non-antigenic or only slightly antigenic, cf. Schlichtcrull,
Monocomponent Insulin and its Clinical Implications,
16th March, 1973.
It is known to remove the impurities by gel filtration and/or ion exchange, so that it is possible to obtain highly purified insulin containing substantially only a single component. In recent years insulin preparations which have been freed of at least some of the impurities have been marketed, and in many cases they have resulted in reduced antibody formation in diabetics.
It has been found that quick-acting preparations of both swine and ox insulin can be produced so pure that they will not, or at any rate only to a very small degree, cause insulin antibody formation, cf. Schlichtcrull, Monocomponent Insulin and its Clinical Implications, 16th March 1973. Further, it has proved to be possible to produce preparations with protracted action and having substantially reduced antigenicity if the production is based on highly purified swine insulin, ef. T. Deetert et al. Diabetologia, vol 10,pp. 703-8, 1974. However, it has been found that even if ox insulin is produced in a purity that with the present analytical methods,must be regarded as just as high as the highly purified swine insulin that can be made today and so pure that, as stated above, it will not, or at any rate
42305 only to a very low degree, cause antibody formation when used in quick-acting preparations, protracted action low-antigenic preparations based on highly purified ox insulin have not yet been marketed. This is a serious drawback because protracted action preparations based on ox insulin are preferred internationally.
Antibody formation in live organisms against chemical compounds such as insulin may be due to a number of factors e.g. that there are chemical differences In the primary structure, or that the chemical compound has total dimensions (aggregation) suoh that it is incompatible with and repelled by the organism (Arquilla E.R. et al., Immuno-chemistry of Insulin, Handbook of Physiology. Ch. 9, p. 160, 1972), or that the chemical compound has a steric structure which is incompatible with and repelled by the organism (Arquilla, E.R. et al: Immunology
Conformation and Biological Activity in Insulin, Diabetes, vol. 18, p 194, 1969).
It Is also possible to cause antibody formation by administering together with the chemical compound,a component capable of activating the immunity mechanism.
Tests tend to indicate that the physical state.of insulin plays an essential part in antibody formation. (Kumar et al: Horm. Metab. Res. 6, (1974) pp. 175-177? and Piers et al: Neth J. Med. 17 (1974) pp. 234-238).
The reason why quick-acting highly purified insulin preparations do not, or only to a limited degree, cause antibody formation is probably that in those cases the insulin, besides
- 4 43395 being highly purified, is present in monomer or only loosely aggregated form, whereas in previously produced and marketed protracted-action highly purified insulin preparations the Insulin appeared in an aggregated form and with properties that resulted in antibody formation.
This problem is very pronounced with ox insulin, which is probably due to the fact that ox insulin is more inclined to form aggregates than swine insulin.
Ox insulin without additives is known to have a wider isoelectric precipitation zone or interval than swine insulin.
It is also known that this wide isoelectric precipitation zone may be restricted to the same width as known for swine insulin by the addition of certain substances such as phenol or m-cresol, as in British Patent Specification No. 1,222,100. The wider isoelectric precipitation zone of ox insulin is assumed to be due to the fact that ox insulin aggregates at pH values close to neutral.
We have now found a process by which it is possible to stabilize purified insulin, i.e. insulin which is substantially free of antigenic impurities, so that it will not form aggregates that might cause antibody formation during production, or in protracted-action preparations during storage or in use.
According to the present invention, the process comprises reacting purified insulin (as hereinbefore defined), in the presence of a stabiliser which maintains the insulin in stabilised monomer or loosely aggregated (as hereinafter defined) form, with an organic compound comprising amino and/or
423S5 substituted amino groups, so that the amino groups react with the carboxyl groups of the insulin. The insulin which is used in the process of the invention must be maintained in stabilised monomer form, by which we mean that the insulin is monomeric and is stabilised against the natural tendency of insulin to aggregate, or in loosely aggregated form, by which we mean that any Insulin aggregate is such that it can break down into insulin monomers. Accordingly, the purified insulin which is used in the invention must not be in irreversibly aggregated form, i.e. a form whioh is known to be antigenic and which cannot split up into monomeric insulin in the reaction.
Preferred organic compounds comprising amino and/or substituted amino groups for use in the invention are polypeptides such as polyarginine, somatostatin, protamine or globin.
Another suitable compound is 1,3-bis (4-amino-2- methyl-equinolyl) urea.
The reaction is advantageously carried out in the presence of glucose or a phenol such as m-cresol.
The invention may ba used with insulin derived from 20 many different animal species, such as swine, oxen and sheep, but it iB particularly significant in connection with ox insulin.
In a preferred embodiment of the invention, a solution of insulin and a stabiliser as defined above is subjected to ion exchange by elution with an eluent containing a stabiliser as defined above. A solution containing a polypeptide is mixed with an eluted fraction containing insulin thus freed of impurities; and the insulin complex which is
423SS precipitated is isolated. This procedure provides effective security against aggregation, in that the purified insulin is not first isolated. Further, the process is very simple in that the protracted-action insulin preparation is directly precipitated in a stable form.
The preferred stabiliser for use in the invention is urea.
Therapeutic compositions according to the invention comprise an insulin preparation produced according to the invention in association with a pharmaceutically acceptable carrier.
The following Examples illustrate the invention.
Example 1
250 mg of recrystallized ox insulin was dissolved in 5.2 ml of stabilized buffer solution consisting of 7 M deionized urea and 0.02 M of tris buffer having a pH of 8.1. The solution was mixed with 5.2 ml of 7 M urea. The pH of the mixture was adjusted to 8.1. A column, 5 cm in diameter, was packed with a layer 2.1 cm high of DEAE cellulose (Whatman DE 52Whatman is a Trade Mark) and equilibrated with a buffer solution of the above composition. The insulin solution was introduced in the column and elution performed at a rate of 75 ml per hour according to the following schedule.
2.5 hours with a buffer of the composition defined above;
hours with a buffer of the composition defined above to which had been added 0.0045 mole of sodium
- 7 42395 chloride per litre; and hours with a buffer of the composition defined above to which had been added 0.011 mole of sodium chloride per litre.
The eluate was divided into fractions. The highly purified fractions were collected and the content of insulin determined. In a 7 M urea solution of the same volume as the mixture of the'highly purified fractions, protamine was dissolved in the amount necessary for obtaining the isophanic ratio of highly purified insulin to protamine, i.e. the ratio at which the maximum haze of the suspension formed by the reaction is achieved.
The insulin solution was added slowly and dropwise to the protamine solution while stirring and diluted to a urea concentration of 1 M. A protamine-insulin complex in amorphous state is precipitated.
The precipitate was isolated by centrifugation.When 300 pg of the precipitate was subjected to isoelectric focusing in polyacrylamide gel and using 2% w/v of ampholine (pH 3—10) in 6 M Of deionized urea, essentially only one band was visible. ;
Example 2
The procedure of Example 1 was repeated, except that 0.5% w/w.Zn ions, based on the amount of insulin (as ZnC^) and 0.3% w/v m-cresol, based on the volume of the mixture, was added to the protamine solution. The protamine insulin complex was then precipitated in crystalline form.
423Sg
The precipitate was isolated by centrifugation.
When 300 pg of the precipitate was subjected to isoelectric focusing in polyacrylamide gel using 2% w/v of ampholine (pH 3—10) in 6 M deionized urea, essentially only one band was visible.
Example 3.
The procedure of Example 1 was repeated, but recrystallised ox insulin purified by gel filtration of Sephadex G-50 was used as starting material. (Sephadex is a Trade Mark).
The prepared product was of the same purity as the product described in Example 1.
Example 4
The procedures of Examples 1 and 2 were repeated, but as starting material swine insulin was used, prepared by saltingout an aqueous crude extract formed in the production of insulin by addition of salt to obtain 3.5 M at pH 8.5. The obtained salt cake was desalted in conventional manner prior to the ion exchange.
The prepared product was of the same purity as the product described in Example 1.
Example 5
The procedure of Example 4 was repeated and the obtained salt cake Was subjected to gel filtration of Sephadex G-50.
The product was of the same purity as the product described in Example 1.
Example 6
The procedures of Examples 1—3 were repeated, but swine insulin was used instead of ox insulin.
- 9 43395
The formed protamine-swine insulin complex was as pure as the complex prepared in Example 1.
Example 7
The procedure of Example 1 was repeated but, instead of protamine, poly-L-arginine vzith a degree of polymerization 295 was used. The precipitate was isolated in the manner described in Example 1.
• Example 8
The procedure of Example 1 was repeated, but to the pooled highly purified insulin fractions, 0.2% w/v aqueous solution of bis-(4-amino-2-methyl-6-quinolyl)-urea hydrochloride was added in an amount equivalent to 10% by weight of the insulin amount present in the fractions. By diluting the product to a urea concentration of 1 M with 0.025 M sodium phosphate buffer (pH 7.3), an insulin complex was precipitated, which was maintained for some time and then isolated by centrifuging.
The prepared product was of the same purity as the product described in Example 1.
Example 9
The procedure of Example 8 was repeated, but as starting material was used recrystallised ox insulin purified by gel fitration on Sephadex G-50. The prepared product was of the same purity as the product described in Example 1.
Example 10
The procedures of Examples 8 and 9 were repeated but swine insulin was used Instead of ox insulin.
The formed swine insulin complex was as pure as the complex prepared in Example 1.
- 10 A ·) r» Λ e? 4t Λ μ V 5
Example 11
The procedure of Example 8 was repeated, but as starting material was used swine insulin, produced by salting-out an aqueous crude extract formed in the production of insulin by addition of salt to obtain 3.5 M at pH 8.5.
The obtained salt cake was desalted in conventional manner prior to the ion exchange.
The prepared product was of the same purity as the product described in Example 1.
Example 12
The procedure of Example 11 was repeated and the obtained salt cake was subjected to gel filtration on Sephadex G-50.
The product was of the same purity as the product described in Example 1.
Claims (11)
1. A process for the production of a stable insulin preparation with protracted action and low antigenicity, which comprises reacting purified insulin (as hereinbefore defined), in the presence of a stabiliser which maintains the insulin in stabilised monomer or loosely aggregated (as hereinbefore defined) form, with an organic compound comprising amino and/or substituted amino groups, such that the amino groups react with the carboxyl groups of the insulin.
2. A process according to Claim 1 in which the purified insulin is ox insulin.
3. A process according to Claim 1 or Claim 2 in which the organic compound is a basic polypeptide.
4. A process according to Claim 3 in which the basic polypeptide is a protamine.
5. A process according to any preceding claim in which the stabiliser is urea.
6. A process for the production of a stable insulin preparation with protracted action and low antigenicity, which comprises subjecting a solution of insulin and a stabiliser which maintains the insulin in solubilised monomer or loosely aggregated {as hereinbefore defined) form to ion exchange by elution with an eluent containing a stabiliser as defined above; mixing a solution containing a basic polypeptide with an eluted fraction containing insulin thus freed of impurities; and isolating the insulin complex which is precipitated.
7. A process according to Claim 6 in which the stabiliser is urea. -1242395
8. A process according to Claim 6 or Claim 7 in which the basic polypeptide is polyarginine, somatostatin, protamine or globin.
9. A process according to Claim 1 substantially 5 as herein described with reference to any of the Examples.
10. A therapeutic insulin preparation when produced by a process according to any preceding claim.
11. A therapeutic composition comprising a preparation as claimed in Claim 10 in association with a pharmaceutically 10 acceptable carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK8375AA DK140801B (en) | 1975-01-15 | 1975-01-15 | Process for the preparation of a stable long-acting insulin preparation. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE42395L IE42395L (en) | 1976-07-15 |
| IE42395B1 true IE42395B1 (en) | 1980-07-30 |
Family
ID=8089535
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE62/76A IE42395B1 (en) | 1975-01-15 | 1976-01-13 | Production of long acting insulin preparations |
Country Status (36)
| Country | Link |
|---|---|
| JP (1) | JPS5946939B2 (en) |
| AR (1) | AR213088A1 (en) |
| AT (1) | AT362492B (en) |
| BE (1) | BE837600A (en) |
| BR (1) | BR7600206A (en) |
| CA (1) | CA1094549A (en) |
| CH (1) | CH631625A5 (en) |
| CS (1) | CS208147B2 (en) |
| DD (1) | DD124379A5 (en) |
| DE (1) | DE2600971C2 (en) |
| DK (1) | DK140801B (en) |
| EG (1) | EG11988A (en) |
| ES (1) | ES444558A1 (en) |
| FI (1) | FI66751C (en) |
| FR (1) | FR2297634A1 (en) |
| GB (1) | GB1524431A (en) |
| GR (1) | GR58608B (en) |
| HU (1) | HU175142B (en) |
| IE (1) | IE42395B1 (en) |
| IL (1) | IL48845A (en) |
| IN (1) | IN143279B (en) |
| IT (1) | IT1054211B (en) |
| KE (1) | KE2919A (en) |
| LU (1) | LU74175A1 (en) |
| MX (1) | MX4052E (en) |
| MY (1) | MY7900169A (en) |
| NL (1) | NL166464C (en) |
| NO (1) | NO146698C (en) |
| NZ (1) | NZ179733A (en) |
| OA (1) | OA05209A (en) |
| PL (1) | PL99927B1 (en) |
| PT (1) | PT64696B (en) |
| RO (1) | RO71576A (en) |
| SE (1) | SE437219B (en) |
| YU (1) | YU8376A (en) |
| ZA (1) | ZA7658B (en) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK374579A (en) * | 1979-09-07 | 1981-03-08 | Nordisk Insulinlab | PROCEDURE FOR THE PREPARATION OF AN INJUCABLE INSULIN PREPARATION |
| US4459226A (en) * | 1982-02-26 | 1984-07-10 | Eli Lilly And Company | Process for recovering insulin |
| US4801575A (en) * | 1986-07-30 | 1989-01-31 | The Regents Of The University Of California | Chimeric peptides for neuropeptide delivery through the blood-brain barrier |
| AU609769B2 (en) * | 1987-02-10 | 1991-05-09 | Drug Delivery Systems Inc. | Electrolytic transdermal delivery of proteins |
| US4878892A (en) * | 1987-02-10 | 1989-11-07 | Drug Delivery Systems Inc. | Electrolytic transdermal delivery of polypeptides |
| US5447728A (en) | 1992-06-15 | 1995-09-05 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
| US5714167A (en) | 1992-06-15 | 1998-02-03 | Emisphere Technologies, Inc. | Active agent transport systems |
| US6221367B1 (en) | 1992-06-15 | 2001-04-24 | Emisphere Technologies, Inc. | Active agent transport systems |
| US5629020A (en) * | 1994-04-22 | 1997-05-13 | Emisphere Technologies, Inc. | Modified amino acids for drug delivery |
| US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| US5750147A (en) | 1995-06-07 | 1998-05-12 | Emisphere Technologies, Inc. | Method of solubilizing and encapsulating itraconazole |
| US6051258A (en) | 1995-06-07 | 2000-04-18 | Emisphere Technologies, Inc. | Proteinoid emulsions and methods for preparation and use thereof |
| EP2077132A1 (en) | 2008-01-02 | 2009-07-08 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dispensing device, storage device and method for dispensing a formulation |
| EP2414560B1 (en) | 2009-03-31 | 2013-10-23 | Boehringer Ingelheim International GmbH | Method for coating a surface of a component |
| WO2010133294A2 (en) | 2009-05-18 | 2010-11-25 | Boehringer Ingelheim International Gmbh | Adapter, inhalation device, and atomizer |
| JP5658268B2 (en) | 2009-11-25 | 2015-01-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Nebulizer |
| US10016568B2 (en) | 2009-11-25 | 2018-07-10 | Boehringer Ingelheim International Gmbh | Nebulizer |
| CN102686260B (en) | 2009-11-25 | 2014-10-01 | 贝林格尔.英格海姆国际有限公司 | Nebulizer |
| US9943654B2 (en) | 2010-06-24 | 2018-04-17 | Boehringer Ingelheim International Gmbh | Nebulizer |
| WO2012130757A1 (en) | 2011-04-01 | 2012-10-04 | Boehringer Ingelheim International Gmbh | Medical device comprising a container |
| US9827384B2 (en) | 2011-05-23 | 2017-11-28 | Boehringer Ingelheim International Gmbh | Nebulizer |
| WO2013152894A1 (en) | 2012-04-13 | 2013-10-17 | Boehringer Ingelheim International Gmbh | Atomiser with coding means |
| US9744313B2 (en) | 2013-08-09 | 2017-08-29 | Boehringer Ingelheim International Gmbh | Nebulizer |
| ES2836977T3 (en) | 2013-08-09 | 2021-06-28 | Boehringer Ingelheim Int | Nebulizer |
| EP3139979B1 (en) | 2014-05-07 | 2023-07-05 | Boehringer Ingelheim International GmbH | Unit, nebulizer and method |
| UA121114C2 (en) | 2014-05-07 | 2020-04-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | Nebulizer, indicator device and container |
| ES2874029T3 (en) | 2014-05-07 | 2021-11-04 | Boehringer Ingelheim Int | Nebulizer |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1285023A (en) * | 1968-08-09 | 1972-08-09 | Novo Terapeutisk Labor As | Improvements in or relating to injectable insulin preparations |
| US3758683A (en) * | 1971-04-30 | 1973-09-11 | R Jackson | Insulin product |
-
1975
- 1975-01-15 DK DK8375AA patent/DK140801B/en not_active IP Right Cessation
-
1976
- 1976-01-06 ZA ZA00760058A patent/ZA7658B/en unknown
- 1976-01-07 GR GR49734A patent/GR58608B/en unknown
- 1976-01-07 IN IN41/CAL/76A patent/IN143279B/en unknown
- 1976-01-12 NZ NZ179733A patent/NZ179733A/en unknown
- 1976-01-12 FI FI760058A patent/FI66751C/en not_active IP Right Cessation
- 1976-01-12 CA CA243,587A patent/CA1094549A/en not_active Expired
- 1976-01-13 IE IE62/76A patent/IE42395B1/en unknown
- 1976-01-13 IT IT19221/76A patent/IT1054211B/en active
- 1976-01-13 SE SE7600284A patent/SE437219B/en not_active IP Right Cessation
- 1976-01-13 LU LU74175A patent/LU74175A1/xx unknown
- 1976-01-13 DE DE2600971A patent/DE2600971C2/en not_active Expired
- 1976-01-14 BR BR7600206A patent/BR7600206A/en unknown
- 1976-01-14 PL PL1976186526A patent/PL99927B1/en unknown
- 1976-01-14 AT AT21376A patent/AT362492B/en not_active IP Right Cessation
- 1976-01-14 NO NO760118A patent/NO146698C/en unknown
- 1976-01-14 OA OA55703A patent/OA05209A/en unknown
- 1976-01-14 DD DD190805A patent/DD124379A5/xx unknown
- 1976-01-14 FR FR7600854A patent/FR2297634A1/en active Granted
- 1976-01-14 GB GB1309/76A patent/GB1524431A/en not_active Expired
- 1976-01-14 RO RO7684491A patent/RO71576A/en unknown
- 1976-01-14 YU YU00083/76A patent/YU8376A/en unknown
- 1976-01-14 NL NL7600338.A patent/NL166464C/en not_active IP Right Cessation
- 1976-01-14 PT PT64696A patent/PT64696B/en unknown
- 1976-01-14 MX MX764822U patent/MX4052E/en unknown
- 1976-01-15 CS CS76270A patent/CS208147B2/en unknown
- 1976-01-15 CH CH47076A patent/CH631625A5/en not_active IP Right Cessation
- 1976-01-15 ES ES444558A patent/ES444558A1/en not_active Expired
- 1976-01-15 HU HU76NO198A patent/HU175142B/en unknown
- 1976-01-15 IL IL48845A patent/IL48845A/en unknown
- 1976-01-15 BE BE163542A patent/BE837600A/en not_active IP Right Cessation
- 1976-01-16 JP JP51003293A patent/JPS5946939B2/en not_active Expired
- 1976-01-17 EG EG16/76A patent/EG11988A/en active
-
1978
- 1978-01-14 AR AR261924A patent/AR213088A1/en active
-
1979
- 1979-02-07 KE KE2919A patent/KE2919A/en unknown
- 1979-12-30 MY MY169/79A patent/MY7900169A/en unknown
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