NZ201682A - Pharmaceutical compositions comprising human insulin and human c-peptide - Google Patents
Pharmaceutical compositions comprising human insulin and human c-peptideInfo
- Publication number
- NZ201682A NZ201682A NZ201682A NZ20168282A NZ201682A NZ 201682 A NZ201682 A NZ 201682A NZ 201682 A NZ201682 A NZ 201682A NZ 20168282 A NZ20168282 A NZ 20168282A NZ 201682 A NZ201682 A NZ 201682A
- Authority
- NZ
- New Zealand
- Prior art keywords
- human
- insulin
- peptide
- composition
- human insulin
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
Description
New Zealand Paient Spedficaiion for Paient Number £01 68£
201682
Priority Dfirfs'sj:
Complete Specification Fifed
Class: -
,*2i*-0-821
Publication Date: ..... 116. ADJa 1985 • P.O. Journal, No: ...... 1^.7^
NO DRAWINGS
No.: Date:
NEW ZEALAND
PATENTS ACT, 1953
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T-tji rv'.'. *****
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COMPLETE SPECIFICATION PHARMACEUTICAL FORMULATIONS COMPRISING HUMAN INSULIN AND HUMAN C-PEPTIDE
&? We, ELI LILLY AND COMPANY, a corporation of the State of Indiana, U.S.A., having a principal place of business at 307 East McCarty Street, City of Indianapolis, State of Indiana, United States of America hereby declare the invention for which H/ we pray that a patent may be granted to pXe/us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
- 1 - (followed by page la)
201682
PHARMACEUTICAL FORMULATIONS COMPRISING
HUMAN INGULIN AND HUMAN C PEPTIDE'
Diabetes mellitus is a metabolic disorder characterized by the failure of body tissues to oxidize carbohydrates at the normal rate. Its most important 5 factor is a deficiency of insulin. During the last 60 years people suffering frctn diabetes have been greatly aided by receiving controlled amounts of insulin. To the present time, the insulin used by diabetics has been isolated from animal pancreases, generally bovine 10 and porcine. Both bovine and porcine insulin differ structurally from insulin generated by the human pancreas. Recently, it has become possible, by recombinant DNA methodology, to produce insulin identical to that produced by the human pancreas. The use of 15 such insulin will enable the diabetic to more closely mimic the natural system than heretofore has been possible.
Nevertheless, it long has been recognized that administration of insulin to the diabetic is alone 20 insufficient to restore and/or maintain the normal metabolic state. Although insulin has its manifested effect on carbohydrate metabolism, diabetes mellitus carries additional disorders, most if not all of which are related to the structure and function of blood 25 vessels. The deficiencies leading to these disorders rarely are completely corrected by conventional insulin therapy.
Those vascular abnormalities associated with diabetes often are referred to as "complications of 2q diabetes". They consist generally of microangiopathic changes resulting in lesions in the retina and the
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kidney. Neuropathy represents an additional diabetic complication which may or may not be related directly or indirectly to the noted microangiopathic changes. Examples of specific manifestations of diabetes complications are (1) diseases of the eye, -including 5 retinopathy, cataract formation, glaucoma, and extraocular muscle palsies; (2) diseases of the mouth, including gingivitis, increased incidence of dental caries, periodontal disease, and greater resorption of the alveolar bone; (3) motor, sensory, and autonomic 10 neuropathy; (4) large-vessel disease; (5) microangiopathy; (6) diseases of the skin, including xanthoma diabeticorum, necrobiosis lipoidica diabeticorum, furunculosis, mycosis, and pruritis; (7) diseases of the kidneys, including diabetic glomerulosclerosis, 15 arteriolar nephrosclerosis, and pyelonephritis; and (8) problems during pregnancy, including increased incidence of large babies, stillbirths, miscarriages, neonatal deaths, and congenital defects.
Many, and perhaps all, of the diabetic'com-20 plications are the result of the failure of insulin alone to restore the body to its natural hormonal balance.
- This invention is directed to pharmaceutical compositions that more nearly achieve and maintain 25 natural hormonal homeostasis in a diabetic state than can be achieved by administration of insulin alone.
Thus, this invention concerns a pharmaceutical composition being in a form suitable for use as an antidiabetic agent which comprises, in association with a pharma-jq ceutically acceptable carrier, the two components human insulin and huiran C-peptide (as herein defined) in a ratio on a molar »
201682
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basis, human insulin to human C-peptide, of from 1:4 to 4:1.
The two essential constituents of the pharmaceutical compositions of this invention are human insulin and human C-peptide.
Human insulin is available via a variety of routes, including organic synthesis, isolation from human pancreas, conversion of human proinsulin, conversion of isolated animal insulin, and, more recently, recombinant DMA methodology.
Using recombinant DNA methodology, human insulin can be prepared by the separate expression and isolation of human insulin A-chain and human insulin B-chain followed by their proper disulfide bond formation. Alternatively, the recombinant DNA expression 15 product can be human proinsulin itself or a human proinsulin precursor which is converted to human proinsulin. The proinsulin then is enzymatically cleaved, for example, using trypsin and carboxypeptidase B, to produce human insulin.
2q Human insulin can also be prepared from porcine insulin. Human insulin differs from porcine insulin by a single amino acid, i.e., the B-chain carboxyl terminal amino acid. Alanine, the B-30 amino acid of porcine insulin, is cleaved and replaced by threonine. In this regard, see, for example, U.S. Patent No. 3,276,961.
The other active constituent of the can-position of this invention, human C-peptide, is a portion of a peptide present in human proinsulin and to which the insulin A- and B-chains are joined. This peptide, termed a "connecting peptide", is removed
2016
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during production of human insulin from proinsulin. The connecting peptide present in human proinsulin has the formula
Arg-Arg-Glu-Ala-Glu-Asp-Leu-Gln-Val-Gly-Gln-Val-Glu-Leu-Gly-Gly-Gly-Pro-Gly-Ala-Gly-Ser-Leu-Gln-Pro-Leu-Ala-Leu-Glu-Gly-Ser-Leu-Gln-Lys-Arg.
The human C-peptide present in the composition of this invention differs from the connecting peptide by elimination of four amino acids, two at each end. Thus, the human C-peptide has the structure
G1u-Ala-Glu-Asp-Leu-Gln-Val-Gly-Gln-Val-Glu-Leu-Gly-
Gly-Gly-Pro-Gly-Ala-Gly-Ser-Leu-Gln-Pro-Leu-Ala-
Leu-Glu-Gly-Ser-Leu-Gln.
The human C-peptide constituent of the ccm-^5 position of this invention can be produced by chemical synthesis, see, e.g., N. Yanaihara, C. Yanaihara, M. Sakagami, N. Sakura, T. Hashimoto, and T. Nishida, Diabetes 27 (suppl. 1), 149-160 (1978), or front human proinsulin as a result of its cleavage to produce human 20 insulin.
As noted, therefore, the active constituents of the composition of this invention are available via a variety of routes including human proinsulin. In broad outline, the production of insulin using re-25 ccmbinant DNA methodology involves obtaining, whether by isolation, construction, or a combination of both, a sequence of DNA coding for the amino acid sequence of human proinsulin. The human proinsulin DNA then is inserted in reading phase into a suitable cloning and 30 expression vehicle. The vehicle is used to transform a suitable microorganism after which the transformed
2016
microorganism is subjected to fermentation conditions leading to (a) the production of additional copies of the proinsulin gene-containing vector and (b) the expression of proinsulin or a proinsulin precursor product.
In the event the expression product is a proinsulin precursor, it generally will comprise the human proinsulin amino acid sequence joined at its amino terminal end to a fragment of a protein normally expressed in the gene sequence into which the pro-
insulin gene has been inserted. The proinsulin amino acid sequence is joined to the protein fragment through a specifically cleavable site, typically methionine. This product is customarily referred to as a fused gene product.
The proinsulin amino acid sequence is cleaved from the fused gene product using cyanogen bromide after which the cysteine sulfhydryl moieties of the proinsulin amino acid sequence are stabilized by conversion to their corresponding S-sulfonates.
The resulting proinsulin S-sulfonate is purified, and the purified proinsulin S-sulfonate then is converted to proinsulin by formation of the three properly located disulfide bonds.
Upon purification of the proinsulin, it is
2g enzymatically cleaved, typically using trypsin and carboxypeptidase B, resulting in formation of human insulin and human C-peptide.
The compositions of this invention contain human insulin and human C-peptide in a ratio, on a molar basis, of from about 1:4 to about 4:1. Preferably, the ratio of human insulin to human C-peptide
20168
is from about 1:2 to about 2:1, and, most preferably, from about 1:1 to about 2:1.
As noted, the compositions of this invention are useful in promoting the attainment of natural hormonal hcmeostasis and thereby preventing or sub-5 stantially diminishing or retarding those recognized diabetic complications. The amount of the compositions of this invention necessary to maintain natural hormonal hcmeostasis or to achieve a state that more nearly approaches natural hormonal hcmeostasis in the diabetic, 10 of course, will depend upon the severity of the diabetic condition. Moreover, the amount will vary depending upon the route of administration. Ultimately, the amount of composition administered and the frequency of such administration will be at the discretion of the 15 particular physician. In general, however, the dosage will be in the range affording from about 0.02 to about 5 units of human insulin per kilogram body weight per day, and, preferably, from about 0.1 to about 1 unit of human insulin per kilogram body weight per day. 20 The composition is administered parenterally,
including subcutaneous, intramuscular, and intravenous. The compositions of this invention comprise the active ingredients, human insulin and human C-peptide, together with a pharmaceutically acceptable carrier 25 therefor and, optionally, other therapeutic ingredients. The total amount of active ingredients present in the composition ranges from about 99.99 to about 0.01 percent by weight. The carrier must be acceptable in the sense that it is compatible with other components 20 of the composition and is not deleterious to the recipient thereof.
2016
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Compositions of this invention suitable for parenteral administration conveniently ccmprise sterile aqueous solutions and/or suspensions of the pharma-ceutically active ingredients, which solutions or suspensions preferably are made isotonic with the blood ® of the recipient, generally using sodium chloride, glycerin, glucose, mannitol, sorbitol, and similar known agents. In addition, the compositions may contain any of a number of adjuvants, such as buffers, preservatives, dispersing agents, agents that promote 10 rapid onset of action, agents that promote prolonged duration of action, and other known agents. Typical preservatives are, for example, phenol, m-cresol,
methyl £-hydroxybenzoate, and others. Typical buffers are, for example, sodium phosphate, sodium acetate, 15 sodium citrate, and others.
Moreover, an acid, such as hydrochloric acid, or a base, such as sodium hydroxide, can be used for pH adjustment. In general, the pH of the aqueous composition ranges frcm about 2 to about 8, and, pref-20 erably, frcm about 6.8 to about 8.0.
Other suitable additives are, for example, divalent zinc ion which, if present at all, is generally present in an amount from about 0.01 mg. to about 0.5 mg. per 100 units of human insulin, and 25 protamine salt (for example, in the form of its sulfate), which, if present at all, is generally present in an amount frcm about 0.1 mg. to about 2 mg. per 100 units of human insulin.
Examples of particular pharmaceutical com-20 positions of this invention are provided in the examples appearing herein below.
201682
-X=S^2- -8-
Example 1 — Neutral Regular Human InsulinrHuman
C-Peptide Formulation [1:4 human in-sulin:human C-peptide on molar basis at 40 Units (U) insulin per cubic centimeter (cc.)]
To prepare 10 cc. of the composition, mix
Human Zinc Insulin (28 u/mg.) 400 U
Human C-Peptide 30 mg.
Phenol, distilled 20 mg.
Glycerin 160 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a ccmposition volume of 10 cc. and a final pH of 7.0-7.8.
Example 2 — Neutral Regular Human Insulin:Human 15 C-Peptide Formulation [1:1 human in-
sulin:human C-peptide on molar basis at 100 U insulin per cc.]
To prepare 10 cc. of the composition, mix
Human Zinc Insulin (28 u/mg.) 1000 U
Human C-Peptide 19 mg.
Phenol, distilled 20 mg.
Glycerin 160 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a composition volume of 10 cc. and a final pH of 7.0-7.8.
Example 3 — Protamine, Zinc Human Insulin:Human
C-Peptide Formulation [1:1 human insulin :human C-peptide on molar basis at 40 U insulin per cc.]
201682
, X-.53&Z~r -9-
To prepare 10 cc. of the composition, mix
Human Zinc Insulin (28 U/mg.) 400 U
Human C-Peptide 8 mg.
Phenol, distilled 25 mg.
Zinc Oxide 0.78 mg.
Glycerin 160 mg.
Protamine Sulfate 4.0-6.0 mg.
Sodium Phosphate, crystals 38 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a composition volume of 10 cc. and a final pH of 7.1-7.4.
Example 4 -- Protamine, Zinc Human Insulin:Human
C-Peptide Formulation [2:1 human insulin:human C-peptide on molar basis at 100 U insulin per cc.]
To prepare 10 cc. of the composition, mix
Human Zinc Insulin (28 u/mg.) 1000 U
Human C-Peptide 9 mg.
Phenol, distilled 25 mg.
Zinc oxide 2.0 mg.
Glycerin 160 mg.
Protamine Sulfate 10-15 mg.
Sodium Phosphate, crystals 38 mg.
Water and either 10% hydrochloric acid or 25 10% sodium hydroxide sufficient to make a ccmposition volume of 10 cc. and a final pH of 7.1-7.4.
Example 5 — Isophane Protamine, Zinc Human Insulin:
Human C-Peptide Formulation [1:1 human insulin:human C-peptide on molar basis at 40 U insulin per cc.]
201
2
x^5&a2- -10-
To prepare 10 cc. of the composition, mix
Human Zinc Insulin (28 u/mg.) 400 U
Human C-Peptide 8 mg.
m-Cresol, distilled 16 mg.
Phenol, distilled 6.5 mg.
Glycerin 160 mg.
Protamine Sulfate 1.2-2.4 mg.
Sodium Phosphate, crystals 38 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a ccmposition volume of 10 cc.
and a final pH of 7.1-7.4.
Example 6 — Isophane Protamine, Zinc Human Insulin:
Human C-Peptide Formulation [4:1 human insulinrhuman C-peptide on molar basis at 100 U insulin per cc.]
To prepare 10 cc. of the ccmposition, mix
Human Zinc Insulin (28 u/mg.) 1000 U
Human C-Peptide 5 mg.
m-Cresol, distilled 16 mg.
Phenol, distilled 6.5 mg.
Glycerin 160 mg.
Protamine Sulfate 3.0-6.0 mg.
Sodium Phosphate, Crystals 38 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a ccmposition volume of 10 cc.
and a final pH of 7.1-7.4.
v_Jt=S&9-2—
Example 7 — Zinc Human Insulin Suspension:Human
C-Peptide Formulation [1:2 human insulin human C-peptide on molar basis at 40 U insulin per cc.]
g To prepare 10 cc. of the composition, mix
Human Zinc Insulin (28 u/mg.) 400 U
Human C-Peptide 15 mg.
Sodium Acetate, Anhydrous 16 mg.
Sodium Chloride, Granular 70 mg.
Methyl jg-Hydroxybenzoate 10 mg.
Zinc Oxide 0.63 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a ccmposition volume of 10 cc.
and a final pH of 7.2-7.5.
Example 8 — Zinc Human Insulin Suspension:Human
C-Peptide Formulation [1:1 human insulin human C-peptide on molar basis at 100 U insulin per cc.]
To prepare 10 cc. of the ccmposition, mix
Human Zinc Insulin (28 U/mg.) 1000 U
Human C-Peptide 19 mg.
Sodium Acetate, Anhydrous 16 mg.
Sodium Chloride, Granular 70 mg.
Methyl jD-Hydroxybenzoate 10 mg.
Zinc Oxide 1.6 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a ccmposition volume of 10 cc.
and a final pH of 7.2-7.5.
2016
Example 9 -- Neutral Regular Human InsulinrHuman
C-Peptide Formulation [1:4 human in-sulin:human C-peptide on molar basis at 40 U insulin per cc.]
To prepare 10 cc. of the ccmposition, mix
Human Sodium Insulin (28 u/mg.) 400 U
Human C-Peptide 30 mg.
Phenol, distilled 20 mg.
Glycerin 160 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a ccmposition volume of 10 cc.
and a final pH of 7.0-7.8.
Example 10 — Neutral Regular Human Insulin:Human 15 C-Peptide Formulation [1:1 human insulin:human C-peptide on molar basis at 100 U insulin per cc.]
To prepare 10 cc. of the ccmposition, mix
Human Sodium Insulin (28 u/mg.) 1000 U Human C-Peptide 19 mg.
Phenol, distilled 20 mg.
Glycerin 160 mg.
Water and either 10% hydrochloric acid or 10% sodium hydroxide sufficient to make a composition volume of 10 cc.
and a final pH of 7.0-7.8.
—X-*5ff9^TF) -13-
201682
Claims (6)
1. A pharmaceutical composition being in a form suitable for lose as an antidiabetic agent which oarprises, in association with a fhanna-oeutically acceptable carrier, the two components human insulin and human C-peptide (as herein defined) in a ratio on a molar basis, human insulin 5 to human C-peptide, of from 1:4 to 4:1.
2. A composition of claim I, in which the raolar ratio of human insulin to human C-peptide is from 1:2 to 2:1.
3. A composition of claim 1, in which the 10 molar ratio of human insulin to human C-peptide is from 1:1 to 2:1.
4. A composition of claim 1, which contains divalent zinc ion.
5. A composition of claim 1, which contains 15 protamine salt.
6. A pharmaceutical composition as claimed in any one of claims 1 to 5, substantially as hereinbefore described with reference to any one of the examples. $?vtfo t',m\ ka day of h<y fit i 20 x i /.nx. a mh iicwnst 25 30
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US29671581A | 1981-08-27 | 1981-08-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ201682A true NZ201682A (en) | 1985-08-16 |
Family
ID=23143238
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ201682A NZ201682A (en) | 1981-08-27 | 1982-08-24 | Pharmaceutical compositions comprising human insulin and human c-peptide |
Country Status (20)
Country | Link |
---|---|
JP (1) | JPS5846024A (en) |
AU (1) | AU551879B2 (en) |
BE (1) | BE894185A (en) |
CA (1) | CA1176158A (en) |
CH (1) | CH650679A5 (en) |
DE (1) | DE3232034A1 (en) |
DZ (1) | DZ452A1 (en) |
FR (1) | FR2513126B1 (en) |
GB (1) | GB2104382B (en) |
IE (1) | IE54119B1 (en) |
IL (1) | IL66611A0 (en) |
IT (1) | IT1153182B (en) |
LU (1) | LU84359A1 (en) |
MW (1) | MW3882A1 (en) |
NL (1) | NL192192C (en) |
NZ (1) | NZ201682A (en) |
PH (1) | PH19361A (en) |
SE (1) | SE460334B (en) |
ZA (1) | ZA826159B (en) |
ZW (1) | ZW17482A1 (en) |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3326473A1 (en) * | 1983-07-22 | 1985-01-31 | Hoechst Ag, 6230 Frankfurt | PHARMACEUTICAL AGENT FOR TREATING THE DIABETES MELLITUS |
CA1296253C (en) * | 1986-10-20 | 1992-02-25 | Praveen Tyle | Stabilized growth hormone compositions |
AU8175387A (en) * | 1986-10-20 | 1988-05-06 | Novo Industri A/S | Protamine zinc insulin preparations |
AU612141B2 (en) * | 1987-02-25 | 1991-07-04 | Novo Nordisk A/S | Novel insulin derivatives |
US5212154A (en) * | 1987-08-14 | 1993-05-18 | Akzo N.V. | Preparation for treating complications in diabetes |
ATE63821T1 (en) * | 1987-08-14 | 1991-06-15 | Akzo Nv | MEDICATION FOR PREVENTING OR COMBATING COMPLICATIONS OF DIABETES. |
SE520392C2 (en) | 1996-09-27 | 2003-07-01 | Creative Peptides Sweden Ab C | Specific peptides for the treatment of diabetes mellitus |
GB0323979D0 (en) | 2003-10-13 | 2003-11-19 | Creative Peptides Sweden Ab | Therapeutic applications for c-peptide |
US8263551B2 (en) | 2004-11-22 | 2012-09-11 | Novo Nordisk A/S | Soluble, stable insulin-containing formulations with a protamine salt |
GB0511269D0 (en) | 2005-06-02 | 2005-07-13 | Creative Peptides Sweden Ab | Sustained release preparation of pro-insulin C-peptide |
GB0601950D0 (en) * | 2006-01-31 | 2006-03-15 | Creative Peptides Sweden Ab | Compositions and methods of treating diabetes |
EP2350118B1 (en) | 2008-09-19 | 2016-03-30 | Nektar Therapeutics | Carbohydrate-based drug delivery polymers and conjugates thereof |
MX2012013375A (en) * | 2010-05-17 | 2013-04-11 | Cebix Inc | Pegylated c-peptide. |
WO2013075117A2 (en) | 2011-11-17 | 2013-05-23 | John Wahren | Pegylated c-peptide |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2789080A (en) * | 1952-08-14 | 1957-04-16 | Christensen Henry Marinus | Insulin-albumin compositions |
CH330318A (en) * | 1953-09-08 | 1958-05-31 | British Drug Houses Ltd | Process for the production of an insulin preparation with an extended duration of action |
-
1982
- 1982-08-23 CH CH5010/82A patent/CH650679A5/en not_active IP Right Cessation
- 1982-08-23 CA CA000409900A patent/CA1176158A/en not_active Expired
- 1982-08-23 IL IL66611A patent/IL66611A0/en unknown
- 1982-08-23 ZW ZW174/82A patent/ZW17482A1/en unknown
- 1982-08-24 PH PH27772A patent/PH19361A/en unknown
- 1982-08-24 MW MW38/82A patent/MW3882A1/en unknown
- 1982-08-24 DZ DZ826637A patent/DZ452A1/en active
- 1982-08-24 BE BE6/47701A patent/BE894185A/en not_active IP Right Cessation
- 1982-08-24 NL NL8203315A patent/NL192192C/en not_active IP Right Cessation
- 1982-08-24 ZA ZA826159A patent/ZA826159B/en unknown
- 1982-08-24 NZ NZ201682A patent/NZ201682A/en unknown
- 1982-08-25 AU AU87594/82A patent/AU551879B2/en not_active Expired
- 1982-08-25 FR FR8214595A patent/FR2513126B1/en not_active Expired
- 1982-08-25 SE SE8204873A patent/SE460334B/en not_active IP Right Cessation
- 1982-08-25 JP JP57148494A patent/JPS5846024A/en active Pending
- 1982-08-26 LU LU84359A patent/LU84359A1/en unknown
- 1982-08-26 IE IE2064/82A patent/IE54119B1/en not_active IP Right Cessation
- 1982-08-26 GB GB08224484A patent/GB2104382B/en not_active Expired
- 1982-08-27 IT IT8223017A patent/IT1153182B/en active
- 1982-08-27 DE DE19823232034 patent/DE3232034A1/en active Granted
Also Published As
Publication number | Publication date |
---|---|
JPS5846024A (en) | 1983-03-17 |
LU84359A1 (en) | 1983-02-28 |
NL192192C (en) | 1997-03-04 |
MW3882A1 (en) | 1984-07-11 |
AU8759482A (en) | 1983-03-03 |
ZA826159B (en) | 1984-04-25 |
DE3232034A1 (en) | 1983-03-10 |
PH19361A (en) | 1986-04-02 |
CH650679A5 (en) | 1985-08-15 |
AU551879B2 (en) | 1986-05-15 |
GB2104382B (en) | 1984-12-19 |
SE460334B (en) | 1989-10-02 |
DE3232034C2 (en) | 1991-04-11 |
IT8223017A0 (en) | 1982-08-27 |
NL192192B (en) | 1996-11-01 |
BE894185A (en) | 1983-02-24 |
SE8204873L (en) | 1983-02-28 |
IT1153182B (en) | 1987-01-14 |
DZ452A1 (en) | 2004-09-13 |
SE8204873D0 (en) | 1982-08-25 |
IE54119B1 (en) | 1989-06-21 |
FR2513126A1 (en) | 1983-03-25 |
IE822064L (en) | 1983-02-27 |
IL66611A0 (en) | 1982-12-31 |
GB2104382A (en) | 1983-03-09 |
NL8203315A (en) | 1983-03-16 |
FR2513126B1 (en) | 1986-04-18 |
ZW17482A1 (en) | 1982-11-17 |
CA1176158A (en) | 1984-10-16 |
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