CA1176159A - Pharmaceutical formulations comprising human insulin, human c-peptide, and human proinsulin - Google Patents
Pharmaceutical formulations comprising human insulin, human c-peptide, and human proinsulinInfo
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- CA1176159A CA1176159A CA000409911A CA409911A CA1176159A CA 1176159 A CA1176159 A CA 1176159A CA 000409911 A CA000409911 A CA 000409911A CA 409911 A CA409911 A CA 409911A CA 1176159 A CA1176159 A CA 1176159A
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- insulin
- proinsulin
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- 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
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- Diabetes (AREA)
- Endocrinology (AREA)
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Abstract
ABSTRACT OF THE DISCLOSURE
A pharmaceutical composition is described which comprises, in association with a pharmaceutically acceptable carrier, human insulin, human C-peptide, and human proinsulin, said human C-peptide being present in a molar ratio, human insulin to human C-peptide, of from about 1:4 to about 4:1, and said human proinsulin being present in a weight ratio, human insulin to human proinsulin, of from about 1:100 to about 100:1, and which is useful in treating diabetics and in promoting attainment of natural hormonal homeostasis, thereby preventing or substantially diminishing or retarding diabetic complications.
A pharmaceutical composition is described which comprises, in association with a pharmaceutically acceptable carrier, human insulin, human C-peptide, and human proinsulin, said human C-peptide being present in a molar ratio, human insulin to human C-peptide, of from about 1:4 to about 4:1, and said human proinsulin being present in a weight ratio, human insulin to human proinsulin, of from about 1:100 to about 100:1, and which is useful in treating diabetics and in promoting attainment of natural hormonal homeostasis, thereby preventing or substantially diminishing or retarding diabetic complications.
Description
~ ~76~
PHARMACEUTICAL FORMULATIONS COMPRISING
HUMAN INSULIN, HUMAN C-PEPTIDE, AND HUMAN PROINSULIN
Diabetes mellitus is a metabolic disorder characterized by the failure of body tissues to oxidize carbohydrates at the normal rate. Its most important factor is a deficiency of insulin. During the last 60 years people suffering from diabetes have been greatly aided by receiving controlled amounts of insulin. To the present time, the insulin used by diabetics has 10 been isolated from animal pancreases, generally bovine and porcine. Both bovine and porcine insulin differ structurally frcm insulin generated by the human pancreas. Recently, it has become possible, by re-combinant DNA methodology, to produce insulin identical 15 to that produced by the human pancreas. The use of 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 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 30 diabetes". They consist generally of microangiopathic 3~
l ~ ~615~
changes resulting in lesions in the retina and the 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 com-plications are (1) diseases of the eye, includingretinopathy, cataract formation, glaucoma, and extra-ocular muscle palsies; (2) diseases of the mouth, including gingivitis, increased incidence of dental caries, periodontal disease, and greater resorption of 10 the alveolar bone; (3) tor, sensory, and autoncmic neuropathy; (4) large-vessel disease; (5) microangio-pathy, (6) diseases of the skin, including xantho~a diabeticorum, necrobiosis lipoidica diabeticorum, furunculosis, mycosis, and pruritis; (7) diseases of 15 the kidneys, including diabetic glomerulosclerosis, arteriolar nephrosclerosis, and pyelonephritis, and (8) problems during pregnancy, including increased incidence of large babies, ~tillbirths, miscarriages, neonatal deaths, and congenital defects.
Many, and perhaps all, of the diabetic com-plications are the result of the failure of insulin alone to restore the body to its natural hormonal balance.
This invention concerns pharmaceutical 25 compositions that more nearly achieve and maintain natural hormonal homeosta~is in a diabetic state than can be achieved by administration of insulin alone.
Thus, this invention concerns a pharmaceu-tical composition which compri~es, in association with 30 a pharmaceutically acceptable carrier, human insulin, human C-peptide, and human proinsulin, said human C-~ ~761~
peptide being present in a ratio on a molar basis, human insulin to human C-peptide, of from about 1:4 to about 4:1, and said human proinsulin being present in a ratio on a weight basis, human insulin to human pro-insulin, of from about 1:100 to about 100:1.
The three essential constituents of the pharmaceutical cpositions of this invention are human insulin, human C-peptide, and human proinsulin.
The administration of a combination of human insulin, human C-peptide, and human proinsulin using a 10 composition in accordance with this invention will produce a more natural utilization of glucose and better glucose control than is achieved by insulin alone, thereby diminishing hereinbefore described adverse diabetic complications.
lS Human proinsulin is available via a variety of routes, including organic synthesis, isolation from human pancreas by conventional methodology, and, more recently, recombinant DNA methodology.
In broad outline, the production of pro-20 insulin using recombinant DNA methodology involvesobtaining, 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
PHARMACEUTICAL FORMULATIONS COMPRISING
HUMAN INSULIN, HUMAN C-PEPTIDE, AND HUMAN PROINSULIN
Diabetes mellitus is a metabolic disorder characterized by the failure of body tissues to oxidize carbohydrates at the normal rate. Its most important factor is a deficiency of insulin. During the last 60 years people suffering from diabetes have been greatly aided by receiving controlled amounts of insulin. To the present time, the insulin used by diabetics has 10 been isolated from animal pancreases, generally bovine and porcine. Both bovine and porcine insulin differ structurally frcm insulin generated by the human pancreas. Recently, it has become possible, by re-combinant DNA methodology, to produce insulin identical 15 to that produced by the human pancreas. The use of 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 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 30 diabetes". They consist generally of microangiopathic 3~
l ~ ~615~
changes resulting in lesions in the retina and the 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 com-plications are (1) diseases of the eye, includingretinopathy, cataract formation, glaucoma, and extra-ocular muscle palsies; (2) diseases of the mouth, including gingivitis, increased incidence of dental caries, periodontal disease, and greater resorption of 10 the alveolar bone; (3) tor, sensory, and autoncmic neuropathy; (4) large-vessel disease; (5) microangio-pathy, (6) diseases of the skin, including xantho~a diabeticorum, necrobiosis lipoidica diabeticorum, furunculosis, mycosis, and pruritis; (7) diseases of 15 the kidneys, including diabetic glomerulosclerosis, arteriolar nephrosclerosis, and pyelonephritis, and (8) problems during pregnancy, including increased incidence of large babies, ~tillbirths, miscarriages, neonatal deaths, and congenital defects.
Many, and perhaps all, of the diabetic com-plications are the result of the failure of insulin alone to restore the body to its natural hormonal balance.
This invention concerns pharmaceutical 25 compositions that more nearly achieve and maintain natural hormonal homeosta~is in a diabetic state than can be achieved by administration of insulin alone.
Thus, this invention concerns a pharmaceu-tical composition which compri~es, in association with 30 a pharmaceutically acceptable carrier, human insulin, human C-peptide, and human proinsulin, said human C-~ ~761~
peptide being present in a ratio on a molar basis, human insulin to human C-peptide, of from about 1:4 to about 4:1, and said human proinsulin being present in a ratio on a weight basis, human insulin to human pro-insulin, of from about 1:100 to about 100:1.
The three essential constituents of the pharmaceutical cpositions of this invention are human insulin, human C-peptide, and human proinsulin.
The administration of a combination of human insulin, human C-peptide, and human proinsulin using a 10 composition in accordance with this invention will produce a more natural utilization of glucose and better glucose control than is achieved by insulin alone, thereby diminishing hereinbefore described adverse diabetic complications.
lS Human proinsulin is available via a variety of routes, including organic synthesis, isolation from human pancreas by conventional methodology, and, more recently, recombinant DNA methodology.
In broad outline, the production of pro-20 insulin using recombinant DNA methodology involvesobtaining, 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
2~ suitable cloning and expression vehicle. The vehicle is used to transform a suitable microorganism after which the transformed microorganism is subjected to fermentation conditions leading to (a) the production of additional copies of the proinsulin gene-containing 30 vector and (b) the expression of proinsulin or a proinsulin precursor product.
! 0~15~
X-5855A ~4~
In the event the expression product is a proinsulin precursor, it generally will comprise the human proinsulin amino acid sequence joined at its amino tenminal 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 ~equence 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 con-version to their corresponding S-sulfonates.
The resulting proinsulin S-sulfonate is puriied, and the purified proinsulin S-sulfonate then is converted to proinsulin by formation of the three properly located disulfide bonds. The resulting pro-insulin product i5 purified.
A second active constituent of the composi-tions of this invention, human insulin, also is avail-able via a variety of routes, including organic syn-thesis, isolation from human pancreas by conventional techniques, conversion of isolated animal insulin, 25 conversion of human proinsulin, and recombinant DNA
methodology.
Human proin~ulin, however produced, can be enzymatically cleaved, for example, using trypsin and carboxypeptida~e B, to produce human insulin.
Using recombinant DNA methodology in a manner analogous to that hereinbefore described for the pro-I ~ 7615~
duction of human proinsulin, human insulin can be prepared by the separate expression and isolation of human insulin A-chain and human insulin B-chain fol-lowed by their proper disulfide bond formation.
Human insulin can also be prepared from porcine insulin. Human insulin differs from porcine insulin by a ~ingle 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.
lO Patent No. 3,276,961.
A third active constituent of the composition of this invention, human C-peptide, is a portion of a peptide pre~ent in human proinsulin and to which the insulin A- and B-chains are joined. The latter p~ptide, 15 termed a "connecting peptide", is removed during produc-tion 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-20 Ala-Leu-Glu-Gly-Ser-Leu-Gln-Lys-Arg.
The human C-peptide present in the composi-tion of this invention differ~ from the connecting peptide by elimination of four amino acids, two at each end. Thus, the human C-peptide has the structure 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.
The human C-peptide constituent of the com-30 position of this invention can be produced by chemicalsynthesis, see, e.g., N. Yanaihara, C. Yanaihara, M.
I ~7~5'~
~-5855A -6-Sakagami, N. Sakura, T. Hashimoto, and T. ~ishida, Diabetes 27 (suppl. 1), 149-160 (1978), or from human _ proinsulin as a result of its cleavage to produce human insulin.
Human C-peptide also is available in conjunc-tion with human insulin via the aforedescribed enzymaticcleavage of human proinsulin.
The compositions of this invention contain human insulin, human C-peptide, and human proinsulin.
Human proinsulin i8 present in a weight ratio, human 10 insulin to human proinsulin, of from about 1:100 to about 100:1. Preferably, the weight ratio of human insulin to human proinsulin is from about 1:2 to about 100:1, more preferably, from about 1:1 to about 2Q:l, and, most preferably, from about 4:1 to about 20:1.
15 Additional preferred weight ratio ranges, human insulin to human proinsulin, are from about 1:30 to about 100:1;
from about 1:15 to about 100:1, from about 1:10 to about 100:1, from about 1:30 to about 20:1; from about 1:15 to about 20:1; and from about 1:10 to about 20:1.
Human C-peptide is present in the composi-tions of this invention in a molar ratio, human insulin to human C-peptide, of from about 1:4 to about 4:1.
Preferably, the molar ratio of human insulin to human C-peptide i8 from about 1:2 to about 2:1, and, most 25 preferably, from about 1:1 to about 2:1.
As noted, the cpositions of this invention are useful in promoting the attainment of natural hormonal homeostasis and thereby preventing or sub-stantially diminishing or retarding those recognized 30 diabetic complications. It is recognized that certain 1 ~615C
diabetics are unable to effectively receive insulin by subcutaneous injection due to the presence of proteases at the injection site that rapidly destroy the insulin before it has an opportunity to be absorbed into the bloodstream and transported to the receptor sites.
These diabetics, if they are to receive insulin at all, must receive it by intravenous injection. The neces-sary repeated intravenous injections are undesirable due to their deleterious effect on the veins of the recipient and infections associated therewith. It has lO been discovered that human proinsulin is not degraded by these insulin-degrading proteases and, thus, it can be administered by subcutaneous injection. Its sta-bility and thus availability promote attainment of natural honmonal homeosta~is Moreover, since insulin 15 and proinsulin together form camplexes, it can be expected that proinsulin will afford protection for the otherwise degradable insulin.
It also has been noted from recent studies [Podlecki et al., Diabetes, 31, Suppl. 2, 126A (1982)]
20 that human proinsulin is internalized into target tissues, e.g. fat cells. Although its particular intracellular action on a molecular scale i9 as yet undetermined, these findings further support the disclosure herein that human proinsulin plays an active 2S role in and is necessary for the attainment of natural hormonal homeostasis.
In addition to promoting the attainment of natural hormonal homeostasis, those compositoins of this invention in which the weight ratio, human 30 insulin to human proinsulin, is equal to or less than ! ~7615C
about 1:1, afford the added benefit of an extra long hypoglycemic effect. Preferred compo~itions which carry this added benefit have a weight ratio, human insulin to human proinsulin, of from about 1:100 to about 1:1. Other preferred weight ratios, human insulin to human proinsulin, are from about 1:30 to about 1:1, and, more particularly, from about 1:30 to about l:l0, or from about 1:10 to about 1:1. Such compositions will minimize the need for customary insulin formulation additives such as protamine which is present in ~PH
10 insulin or excess zinc which is present in lente insulin.
Both such additives are artificial and unphysiologic.
Schluter et al., Diabetes 31, Suppl. 2, 135A
(1982), de~cribe studies that demonstrate that human insulin receptor binding is enhanced by the presence of 15 human proinsulin. These results again further support the disclosure herein that the availability and presence of human proinsulin results in the pro~otion or restora-tion of natural hormonal homeostasis. The amount of the compositions of this invention necessary to main-20 tain natural hormonal homeostasis or to achieve a statethat more nearly approaches natural hormonal hcmeo-stasis in the diabetic, of course, will depend upon the severity of the diabetic condition. Moreover, the amount will vary depending upon the route of admin-25 istration. Ultimately, the amount of compositionadministered and the frequency of such administration will be at the discretion of the particular physician.
In general, however, the dosage will be in the range affording from about 0.02 to about 5 units of human 30 insulin activity per kilogram body weight per day, and, preferably, from about 0.1 to about l unit of human insulin activity per kilogram body weight per day.
I ~7~15~
The composition i8 administered parenterally, including subcutaneous, intramuscular, and intravenous.
The compositions of this invention ccmprise the active ingredients, human insulin, human C-peptide, and human proinsulin, together with a pharmaceutically acceptable carrier 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 10 other components of the ccmposition and is not dele-terious to the recipient thereof.
Compositions of this invention suitable for parenteral administration conveniently comprise sterile aqueous solutions and/or suspensions of the pharma-15 ceutically active ingredients, which solutions orsuspensions preferably are made isotonic with the blood of the recipient, generally u~ing sodium chloride, glycerin, glucose, mannitol, sorbitol, and similar known agents. In addition, the compositions may 20 contain any of a number of adjuvants, such as buffers, preservatives, dispersing agents, agents that prc~ote rapid onset of action, agents that promote prolonged duration of action, and other known agents. Typical preservatives are, for example, phenol, _-cresol, 25 methyl ~-hydroxybenzoate, and others. Typical buffers are, for example, sodium phosphate, sodium acetate, sodium citrate, and others.
Moreover, an acid, such as hydrochloric acid, or a base, such as sodium hydroxide, can be used ~or pH
! 0~15~
X-5855A ~4~
In the event the expression product is a proinsulin precursor, it generally will comprise the human proinsulin amino acid sequence joined at its amino tenminal 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 ~equence 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 con-version to their corresponding S-sulfonates.
The resulting proinsulin S-sulfonate is puriied, and the purified proinsulin S-sulfonate then is converted to proinsulin by formation of the three properly located disulfide bonds. The resulting pro-insulin product i5 purified.
A second active constituent of the composi-tions of this invention, human insulin, also is avail-able via a variety of routes, including organic syn-thesis, isolation from human pancreas by conventional techniques, conversion of isolated animal insulin, 25 conversion of human proinsulin, and recombinant DNA
methodology.
Human proin~ulin, however produced, can be enzymatically cleaved, for example, using trypsin and carboxypeptida~e B, to produce human insulin.
Using recombinant DNA methodology in a manner analogous to that hereinbefore described for the pro-I ~ 7615~
duction of human proinsulin, human insulin can be prepared by the separate expression and isolation of human insulin A-chain and human insulin B-chain fol-lowed by their proper disulfide bond formation.
Human insulin can also be prepared from porcine insulin. Human insulin differs from porcine insulin by a ~ingle 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.
lO Patent No. 3,276,961.
A third active constituent of the composition of this invention, human C-peptide, is a portion of a peptide pre~ent in human proinsulin and to which the insulin A- and B-chains are joined. The latter p~ptide, 15 termed a "connecting peptide", is removed during produc-tion 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-20 Ala-Leu-Glu-Gly-Ser-Leu-Gln-Lys-Arg.
The human C-peptide present in the composi-tion of this invention differ~ from the connecting peptide by elimination of four amino acids, two at each end. Thus, the human C-peptide has the structure 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.
The human C-peptide constituent of the com-30 position of this invention can be produced by chemicalsynthesis, see, e.g., N. Yanaihara, C. Yanaihara, M.
I ~7~5'~
~-5855A -6-Sakagami, N. Sakura, T. Hashimoto, and T. ~ishida, Diabetes 27 (suppl. 1), 149-160 (1978), or from human _ proinsulin as a result of its cleavage to produce human insulin.
Human C-peptide also is available in conjunc-tion with human insulin via the aforedescribed enzymaticcleavage of human proinsulin.
The compositions of this invention contain human insulin, human C-peptide, and human proinsulin.
Human proinsulin i8 present in a weight ratio, human 10 insulin to human proinsulin, of from about 1:100 to about 100:1. Preferably, the weight ratio of human insulin to human proinsulin is from about 1:2 to about 100:1, more preferably, from about 1:1 to about 2Q:l, and, most preferably, from about 4:1 to about 20:1.
15 Additional preferred weight ratio ranges, human insulin to human proinsulin, are from about 1:30 to about 100:1;
from about 1:15 to about 100:1, from about 1:10 to about 100:1, from about 1:30 to about 20:1; from about 1:15 to about 20:1; and from about 1:10 to about 20:1.
Human C-peptide is present in the composi-tions of this invention in a molar ratio, human insulin to human C-peptide, of from about 1:4 to about 4:1.
Preferably, the molar ratio of human insulin to human C-peptide i8 from about 1:2 to about 2:1, and, most 25 preferably, from about 1:1 to about 2:1.
As noted, the cpositions of this invention are useful in promoting the attainment of natural hormonal homeostasis and thereby preventing or sub-stantially diminishing or retarding those recognized 30 diabetic complications. It is recognized that certain 1 ~615C
diabetics are unable to effectively receive insulin by subcutaneous injection due to the presence of proteases at the injection site that rapidly destroy the insulin before it has an opportunity to be absorbed into the bloodstream and transported to the receptor sites.
These diabetics, if they are to receive insulin at all, must receive it by intravenous injection. The neces-sary repeated intravenous injections are undesirable due to their deleterious effect on the veins of the recipient and infections associated therewith. It has lO been discovered that human proinsulin is not degraded by these insulin-degrading proteases and, thus, it can be administered by subcutaneous injection. Its sta-bility and thus availability promote attainment of natural honmonal homeosta~is Moreover, since insulin 15 and proinsulin together form camplexes, it can be expected that proinsulin will afford protection for the otherwise degradable insulin.
It also has been noted from recent studies [Podlecki et al., Diabetes, 31, Suppl. 2, 126A (1982)]
20 that human proinsulin is internalized into target tissues, e.g. fat cells. Although its particular intracellular action on a molecular scale i9 as yet undetermined, these findings further support the disclosure herein that human proinsulin plays an active 2S role in and is necessary for the attainment of natural hormonal homeostasis.
In addition to promoting the attainment of natural hormonal homeostasis, those compositoins of this invention in which the weight ratio, human 30 insulin to human proinsulin, is equal to or less than ! ~7615C
about 1:1, afford the added benefit of an extra long hypoglycemic effect. Preferred compo~itions which carry this added benefit have a weight ratio, human insulin to human proinsulin, of from about 1:100 to about 1:1. Other preferred weight ratios, human insulin to human proinsulin, are from about 1:30 to about 1:1, and, more particularly, from about 1:30 to about l:l0, or from about 1:10 to about 1:1. Such compositions will minimize the need for customary insulin formulation additives such as protamine which is present in ~PH
10 insulin or excess zinc which is present in lente insulin.
Both such additives are artificial and unphysiologic.
Schluter et al., Diabetes 31, Suppl. 2, 135A
(1982), de~cribe studies that demonstrate that human insulin receptor binding is enhanced by the presence of 15 human proinsulin. These results again further support the disclosure herein that the availability and presence of human proinsulin results in the pro~otion or restora-tion of natural hormonal homeostasis. The amount of the compositions of this invention necessary to main-20 tain natural hormonal homeostasis or to achieve a statethat more nearly approaches natural hormonal hcmeo-stasis in the diabetic, of course, will depend upon the severity of the diabetic condition. Moreover, the amount will vary depending upon the route of admin-25 istration. Ultimately, the amount of compositionadministered and the frequency of such administration will be at the discretion of the particular physician.
In general, however, the dosage will be in the range affording from about 0.02 to about 5 units of human 30 insulin activity per kilogram body weight per day, and, preferably, from about 0.1 to about l unit of human insulin activity per kilogram body weight per day.
I ~7~15~
The composition i8 administered parenterally, including subcutaneous, intramuscular, and intravenous.
The compositions of this invention ccmprise the active ingredients, human insulin, human C-peptide, and human proinsulin, together with a pharmaceutically acceptable carrier 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 10 other components of the ccmposition and is not dele-terious to the recipient thereof.
Compositions of this invention suitable for parenteral administration conveniently comprise sterile aqueous solutions and/or suspensions of the pharma-15 ceutically active ingredients, which solutions orsuspensions preferably are made isotonic with the blood of the recipient, generally u~ing sodium chloride, glycerin, glucose, mannitol, sorbitol, and similar known agents. In addition, the compositions may 20 contain any of a number of adjuvants, such as buffers, preservatives, dispersing agents, agents that prc~ote rapid onset of action, agents that promote prolonged duration of action, and other known agents. Typical preservatives are, for example, phenol, _-cresol, 25 methyl ~-hydroxybenzoate, and others. Typical buffers are, for example, sodium phosphate, sodium acetate, sodium citrate, and others.
Moreover, an acid, such as hydrochloric acid, or a base, such as sodium hydroxide, can be used ~or pH
3~ adjustment. In g~neral, the pH of the aqueous composi-tion ranges frcm about 2 to about 8, and, preferably, from about 6.8 to about 8Ø
, .~'.~ 7615C`
X-58S5~ --10-Other suitable additives are, for example, divalent zinc ion, which, if present at all, is gener-ally present in an amount from about 0.01 mg. to about 0.5 mg. per 100 units of human insulin, and 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 3 mg. per 100 units of human insulin activity.
Examples of particular pharmaceutical com-positions of this invention are provided in the exam-10 pLes appearing hereinbelow.
ExamPle 1 -- ~eutral Regular Human Insulin:Human C-Peptide:Human Proinsulin Formulation [1:4 human insulin:human C-peptide on molar ba~is and 100:1 human insulin:
human proinsulin on weight basis at 40 Units (U) insulin per cubic centi-- meter (cc.)]
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 U/mg.)400 U
Human C-Peptide 30 mg.
Human Proinsulin 0.14 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.
I .~ 7615g Example 2 -- Neutral Regular Human Insulin:Human C-Peptide:Human Proinsulin Formulation [1:1 human insulin:human C-peptide on molar basi-~ and 20:1 human insulin:human proinsulin on weight 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.
10 Human Proinsulin L.8 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:Human Proinsulin Formulation [1:1 human insulin:human C-peptide on molar basis and 20:1 human insulin:human proinsulin on weight basis at 40 U
insulin per cc.]
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 U/mg.) 400 U
25 Human C-Peptide 8 mg.
Human Proinsulin O.7 mg.
Phenol, distilled 25 mg.
Zinc Oxide 0.78 mg.
Glycerin 160 mg.
30 Protamine Sulfate 4.0 - 6.0 mg.
Sodium Phosphate, crystals38 mg.
Water and either 10~ hydrochloric acid or 10~
sodium hydroxide sufficient to make a camposition volume of 10 cc. and a final pH of 7.1-7.4.
~ ~76159 Example 4 -- Protamine, Zinc Human Insulin:Human C-Peptide:Human Proinsulin Fonnulation [2:1 human insulin:human C-peptide on molar basis and 1:1 human insulin:human proinsulin on weight basis at lO0 U
insulin per cc.]
To prepare 10 cc. of the ccmposition, mix Human Zinc Insulin (28 U/mg.) 1000 IJ
Human C-Peptide 9 mg.
Human Proinsulin 36 mg.
Phenol, distilled 25 mg.
Zinc oxide 2.0 mg.
Glycerin 160 mg.
Protamine Sulfate 10 - 15 mg.
Sodium Phosphate, crystals38 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 5 -- Isophane Protamine, Zinc Human Insulin:
Human C-Peptide:Human Proinsulin Formu-lation ~l:l human insulin:human C-peptide on molar basis and 4:1 human insulin:
human proinsulin on weight basis at 40 U
insulin per cc.]
~ ~7615~
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 U/mg.) 400 U
Human C-Peptide 8 mg.
Human Proinsulin 3.6 mg.
_-Cre~ol, distilled 16 mg.
Phenol, distilled 6.5 mg.
Glycerin 160 mg.
Protamine Sulfate 1.2 - 2.4 mg.
Sodium Phosphate, crystals38 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 6 -- Isophane Protamine, Zinc Human Insulin:
Human C-Peptide:Human Proinsulin Formu-lation [4:1 human insulin:human C-peptide on molar basis and 1:2 human in~ulin:
human proinsulin on weight 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 5 mg.
Human Proinsulin 71 mg.
m-Cresol, distilled 16 mg.
Phenol, distilled Z.5 mg.
Glycerin 160 mg.
Protamine Sulfate 3.0 - 6.0 mg.
Sodium Phosphate, Crystals38 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.
~ 1 76~5 Example 7 -- Zinc Human Insulin Suspension:Human C-Peptide:Human Proinsulin Formulation [1:2 human insulin:human C-peptide on molar basis and 1:10 human insulin:human proinsulin on weight basis at 40 U
insulin per cc.]
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 U/mg.) 400 U
Human C-Peptide 15 mg.
10 Human Proinsulin 143 mg.
Sodium Acetate, Anhydrous16 mg.
Sodium Chloride, Granular70 mg.
Methyl _-Hydroxybenzoate10 mg.
Zinc Oxide 0.63 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 7.2-7.5.
Example 8 -- Zinc Human Insulin Suspension:Human C-Peptide:Human Proinsulin Formulation tl:l human insulin:human C-peptide on molar basis and 20:1 human insulin:human proinsulin on weight basis at 100 U
insulin per cc.
~ 1! 7~5~
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 Utmg.) 1000 U
Human C-Peptide 19 mg.
Human Proinsulin 1.8 mg.
Sodium Acetate, Anhydrous16 mg.
Sodium Chloride, Granular70 mg.
Methyl ~-Hydroxybenzoate10 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.
Example 9 -- Neutral Regular Human Insulin:Human C-Peptide:Human Proinsulin Formulation [1:4 human insulin:human C-peptide on molar basis and 100:1 human insulin:
human proinsulin on weight basis at 40 U insulin per cc.]
To prepare 10 cc. of the composition, mix Human Sodium Insulin (28 U/mg.) 400 U
Human C-Peptide 30 mg.
Human Proinsulin 0.14 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.
~ l7~159 Example 10 -- ~eutral Regular Human Insulin:Human C-Peptide:Human Proinsulin Formulation [1:1 human insulin:human C-peptide on molar basis and 20:1 human insulin:human proinsulin on weight basis at 100 U
insulin per cc.]
To prepare 10 cc. of the composition, mix Human Sodium Insulin (28 U/mg.) 1000 U
Human C-Peptide 19 mg.
Human Proinsulin 1.8 mg.
Phenol, distilled 20 mg.
Glycerin 160 mg.
Water and either 10% hydrochloric acid or 10%
sodium hydroxide sufficient to make a composition lS volume of lO cc. and a final pH of 7.0-7.8.
, .~'.~ 7615C`
X-58S5~ --10-Other suitable additives are, for example, divalent zinc ion, which, if present at all, is gener-ally present in an amount from about 0.01 mg. to about 0.5 mg. per 100 units of human insulin, and 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 3 mg. per 100 units of human insulin activity.
Examples of particular pharmaceutical com-positions of this invention are provided in the exam-10 pLes appearing hereinbelow.
ExamPle 1 -- ~eutral Regular Human Insulin:Human C-Peptide:Human Proinsulin Formulation [1:4 human insulin:human C-peptide on molar ba~is and 100:1 human insulin:
human proinsulin on weight basis at 40 Units (U) insulin per cubic centi-- meter (cc.)]
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 U/mg.)400 U
Human C-Peptide 30 mg.
Human Proinsulin 0.14 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.
I .~ 7615g Example 2 -- Neutral Regular Human Insulin:Human C-Peptide:Human Proinsulin Formulation [1:1 human insulin:human C-peptide on molar basi-~ and 20:1 human insulin:human proinsulin on weight 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.
10 Human Proinsulin L.8 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:Human Proinsulin Formulation [1:1 human insulin:human C-peptide on molar basis and 20:1 human insulin:human proinsulin on weight basis at 40 U
insulin per cc.]
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 U/mg.) 400 U
25 Human C-Peptide 8 mg.
Human Proinsulin O.7 mg.
Phenol, distilled 25 mg.
Zinc Oxide 0.78 mg.
Glycerin 160 mg.
30 Protamine Sulfate 4.0 - 6.0 mg.
Sodium Phosphate, crystals38 mg.
Water and either 10~ hydrochloric acid or 10~
sodium hydroxide sufficient to make a camposition volume of 10 cc. and a final pH of 7.1-7.4.
~ ~76159 Example 4 -- Protamine, Zinc Human Insulin:Human C-Peptide:Human Proinsulin Fonnulation [2:1 human insulin:human C-peptide on molar basis and 1:1 human insulin:human proinsulin on weight basis at lO0 U
insulin per cc.]
To prepare 10 cc. of the ccmposition, mix Human Zinc Insulin (28 U/mg.) 1000 IJ
Human C-Peptide 9 mg.
Human Proinsulin 36 mg.
Phenol, distilled 25 mg.
Zinc oxide 2.0 mg.
Glycerin 160 mg.
Protamine Sulfate 10 - 15 mg.
Sodium Phosphate, crystals38 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 5 -- Isophane Protamine, Zinc Human Insulin:
Human C-Peptide:Human Proinsulin Formu-lation ~l:l human insulin:human C-peptide on molar basis and 4:1 human insulin:
human proinsulin on weight basis at 40 U
insulin per cc.]
~ ~7615~
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 U/mg.) 400 U
Human C-Peptide 8 mg.
Human Proinsulin 3.6 mg.
_-Cre~ol, distilled 16 mg.
Phenol, distilled 6.5 mg.
Glycerin 160 mg.
Protamine Sulfate 1.2 - 2.4 mg.
Sodium Phosphate, crystals38 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 6 -- Isophane Protamine, Zinc Human Insulin:
Human C-Peptide:Human Proinsulin Formu-lation [4:1 human insulin:human C-peptide on molar basis and 1:2 human in~ulin:
human proinsulin on weight 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 5 mg.
Human Proinsulin 71 mg.
m-Cresol, distilled 16 mg.
Phenol, distilled Z.5 mg.
Glycerin 160 mg.
Protamine Sulfate 3.0 - 6.0 mg.
Sodium Phosphate, Crystals38 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.
~ 1 76~5 Example 7 -- Zinc Human Insulin Suspension:Human C-Peptide:Human Proinsulin Formulation [1:2 human insulin:human C-peptide on molar basis and 1:10 human insulin:human proinsulin on weight basis at 40 U
insulin per cc.]
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 U/mg.) 400 U
Human C-Peptide 15 mg.
10 Human Proinsulin 143 mg.
Sodium Acetate, Anhydrous16 mg.
Sodium Chloride, Granular70 mg.
Methyl _-Hydroxybenzoate10 mg.
Zinc Oxide 0.63 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 7.2-7.5.
Example 8 -- Zinc Human Insulin Suspension:Human C-Peptide:Human Proinsulin Formulation tl:l human insulin:human C-peptide on molar basis and 20:1 human insulin:human proinsulin on weight basis at 100 U
insulin per cc.
~ 1! 7~5~
To prepare 10 cc. of the composition, mix Human Zinc Insulin (28 Utmg.) 1000 U
Human C-Peptide 19 mg.
Human Proinsulin 1.8 mg.
Sodium Acetate, Anhydrous16 mg.
Sodium Chloride, Granular70 mg.
Methyl ~-Hydroxybenzoate10 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.
Example 9 -- Neutral Regular Human Insulin:Human C-Peptide:Human Proinsulin Formulation [1:4 human insulin:human C-peptide on molar basis and 100:1 human insulin:
human proinsulin on weight basis at 40 U insulin per cc.]
To prepare 10 cc. of the composition, mix Human Sodium Insulin (28 U/mg.) 400 U
Human C-Peptide 30 mg.
Human Proinsulin 0.14 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.
~ l7~159 Example 10 -- ~eutral Regular Human Insulin:Human C-Peptide:Human Proinsulin Formulation [1:1 human insulin:human C-peptide on molar basis and 20:1 human insulin:human proinsulin on weight basis at 100 U
insulin per cc.]
To prepare 10 cc. of the composition, mix Human Sodium Insulin (28 U/mg.) 1000 U
Human C-Peptide 19 mg.
Human Proinsulin 1.8 mg.
Phenol, distilled 20 mg.
Glycerin 160 mg.
Water and either 10% hydrochloric acid or 10%
sodium hydroxide sufficient to make a composition lS volume of lO cc. and a final pH of 7.0-7.8.
Claims (18)
1. A pharmaceutical composition which comprises, in association with a pharmaceutically acceptable carrier, human insulin, human C-peptide, and human proinsulin, said human C-peptide being present in a ratio on a molar basis, human insulin to human C-peptide, of from about 1:4 to about 4:1, and said human proinsulin being present in a ratio on a weight basis, human insulin to human proinsulin, of from about l:l00 to about l00:1.
2. Composition of claim 1, in which the molar ratio of human insulin to human C-peptide is from about 1:2 to about 2:1.
3. Composition of claim l, in which the molar ratio of human insulin to human C-peptide is from about 1:1 to about 2:1.
4. Composition of claim l, in which the weight ratio of human insulin to human proinsulin is from about l:l0 to about 100:1.
5. Composition of claim 4, in which the weight ratio of human insulin to human proinsulin is from about 1:2 to about l00:1.
6. Composition of claim 1 or 4, in which the weight ratio of human insulin to human proinsulin is from about l:1 to about 20:1.
7. Composition of claim l or 4, in which the weight ratio of human insulin to human proinsulin is from about 4:1 to about 20:1.
8. Composition of claim l, which contains divalent zinc ion.
9. Composition of claim l, which contains protamine salt.
X-5855A-(F) -18-
X-5855A-(F) -18-
10. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:30 to about 100:1.
11. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:15 to about 100:1.
12. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:30 to about 20:1.
13. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:15 to about 20:1.
14. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:10 to about 20:1.
15. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:100 to about 1:1.
16. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:30 to about 1:1.
17. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:30 to about 1:10.
18. Composition of claim 1, in which the weight ratio of human insulin to human proinsulin is from about 1:10 to about 1:1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29671681A | 1981-08-27 | 1981-08-27 | |
| US296,716 | 1981-08-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1176159A true CA1176159A (en) | 1984-10-16 |
Family
ID=23143244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000409911A Expired CA1176159A (en) | 1981-08-27 | 1982-08-23 | Pharmaceutical formulations comprising human insulin, human c-peptide, and human proinsulin |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS5846026A (en) |
| AU (1) | AU551734B2 (en) |
| BE (1) | BE894187A (en) |
| CA (1) | CA1176159A (en) |
| CH (1) | CH650680A5 (en) |
| DE (1) | DE3232035A1 (en) |
| FR (1) | FR2511868B1 (en) |
| GB (1) | GB2104381B (en) |
| IL (1) | IL66612A (en) |
| IT (1) | IT1153183B (en) |
| LU (1) | LU84357A1 (en) |
| MW (1) | MW3982A1 (en) |
| NL (1) | NL8203313A (en) |
| NZ (1) | NZ201685A (en) |
| PH (1) | PH18640A (en) |
| SE (1) | SE8204872L (en) |
| ZA (1) | ZA826160B (en) |
| ZW (1) | ZW17682A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4652548A (en) * | 1981-08-27 | 1987-03-24 | Eli Lilly And Company | Pharmaceutical formulations comprising human insulin, human C-peptide, and human proinsulin |
| DE3326473A1 (en) * | 1983-07-22 | 1985-01-31 | Hoechst Ag, 6230 Frankfurt | PHARMACEUTICAL AGENT FOR TREATING THE DIABETES MELLITUS |
| JPS62222379A (en) * | 1986-03-25 | 1987-09-30 | Mutoh Ind Ltd | Method and device for processing hidden line and hidden surface in computer graphics |
| US9389582B2 (en) | 2014-06-02 | 2016-07-12 | Lexmark International, Inc. | Replaceable unit for an image forming device having magnets of varying angular offset for toner level sensing |
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 CA CA000409911A patent/CA1176159A/en not_active Expired
- 1982-08-23 IL IL66612A patent/IL66612A/en unknown
- 1982-08-23 CH CH5011/82A patent/CH650680A5/en not_active IP Right Cessation
- 1982-08-23 ZW ZW176/82A patent/ZW17682A1/en unknown
- 1982-08-24 ZA ZA826160A patent/ZA826160B/en unknown
- 1982-08-24 NL NL8203313A patent/NL8203313A/en not_active Application Discontinuation
- 1982-08-24 NZ NZ201685A patent/NZ201685A/en unknown
- 1982-08-24 MW MW39/82A patent/MW3982A1/en unknown
- 1982-08-24 PH PH27769A patent/PH18640A/en unknown
- 1982-08-24 BE BE6/47703A patent/BE894187A/en not_active IP Right Cessation
- 1982-08-25 FR FR8214596A patent/FR2511868B1/en not_active Expired
- 1982-08-25 JP JP57148496A patent/JPS5846026A/en active Pending
- 1982-08-25 SE SE8204872A patent/SE8204872L/en not_active Application Discontinuation
- 1982-08-25 AU AU87597/82A patent/AU551734B2/en not_active Ceased
- 1982-08-26 GB GB08224483A patent/GB2104381B/en not_active Expired
- 1982-08-26 LU LU84357A patent/LU84357A1/en unknown
- 1982-08-27 IT IT23018/82A patent/IT1153183B/en active
- 1982-08-27 DE DE19823232035 patent/DE3232035A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| ZW17682A1 (en) | 1982-11-24 |
| LU84357A1 (en) | 1983-02-28 |
| CH650680A5 (en) | 1985-08-15 |
| AU8759782A (en) | 1983-03-03 |
| FR2511868A1 (en) | 1983-03-04 |
| ZA826160B (en) | 1984-04-25 |
| IL66612A (en) | 1985-11-29 |
| SE8204872D0 (en) | 1982-08-25 |
| IT1153183B (en) | 1987-01-14 |
| PH18640A (en) | 1985-08-23 |
| GB2104381B (en) | 1984-12-05 |
| NL8203313A (en) | 1983-03-16 |
| GB2104381A (en) | 1983-03-09 |
| SE8204872L (en) | 1983-02-28 |
| BE894187A (en) | 1983-02-24 |
| AU551734B2 (en) | 1986-05-08 |
| JPS5846026A (en) | 1983-03-17 |
| DE3232035A1 (en) | 1983-03-10 |
| MW3982A1 (en) | 1984-06-13 |
| IT8223018A0 (en) | 1982-08-27 |
| FR2511868B1 (en) | 1986-05-09 |
| NZ201685A (en) | 1985-09-13 |
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