CA1176160A - Human proinsulin pharmaceutical formulations - Google Patents
Human proinsulin pharmaceutical formulationsInfo
- Publication number
- CA1176160A CA1176160A CA000409922A CA409922A CA1176160A CA 1176160 A CA1176160 A CA 1176160A CA 000409922 A CA000409922 A CA 000409922A CA 409922 A CA409922 A CA 409922A CA 1176160 A CA1176160 A CA 1176160A
- Authority
- CA
- Canada
- Prior art keywords
- human proinsulin
- proinsulin
- insulin
- human
- composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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
Abstract
x-5818A
ABSTRACT OF THE DISCLOSURE
A pharmaceutical composition which comprises human proinsulin in association with a pharmaceutically acceptable carrier is described which is useful in controlling a diabetic condition and in promoting attainment of natural hormonal homeostasis, thereby preventing or substantially diminishing or retarding diabetic complications.
ABSTRACT OF THE DISCLOSURE
A pharmaceutical composition which comprises human proinsulin in association with a pharmaceutically acceptable carrier is described which is useful in controlling a diabetic condition and in promoting attainment of natural hormonal homeostasis, thereby preventing or substantially diminishing or retarding diabetic complications.
Description
' ~76l6n, HUMAN PROI~SULIN PHARMACEUTICAL FORMULATIONS
Diabetes mellitus is a metabolic disorder characterized by the failure of 'oody 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 sreatly aided by receiving controlled amounts of insulin. To the present time, the insulin used by diabetics has been isolated from animal pancreases, generally bovine and porcine. Both bovine and porcine insulin differ structurally from insulin generated by the human pancreas. Recently, it has become possible, by re-combinant DNA methodology, to produce insulin identical to that produced by the human pancreas. The use of such insulin will enable the diabetic to more closely 15 mimic the natural system than heretofore has been possible.
~ evertheless, it long has been recognized that administration of insulin to the diabetic is alone insufficient to restore and/or maintain the normal 20 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 vessels. The deficiencies leading to these disorders 25 rarely are co~pletely corrected by conventional insulin therapy.
Those vascular abnormalities associated with diabetes often are referred to as "complications of diabetes". They consist generally of microangiopathic 30 changes resulting in lesions in the retina and the ~ 176160 X-5818A ~2-~idney. ~europathy 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 ccm-plications are (1) diseases of the eye, including retinopathy, 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 the alveolar bone, (3) motor, sensory, and autonomic 10 neuropathy; (4) large-vessel disease, (5) microangio-pathy, (6) diseases of the skin, including xant'noma diabeticorum, necrobiosis li~oidica 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 insulinalone 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.
Thus, this invention concerns a pharmaceutical composition which comprises human proinsulin in as-sociation with a pharmaceutically acceptable carrier.
The essential constituent of the pharma-ceutical compositions of this invention is human pro-insulin.
1 17616() X-58L8A ~3~
The administration of human proinsulin using a composition in accordance with this invention will produce a more natural utilization of glucose and better blood glucose control, thereby diminishing here-inbefore described adverse diabetic complications.
Human proinsulin is available via a variety of routes, including organic synthesis, isolation fro~
human pancreas by conventional methodology, and, more recently, recombinant DNA methodology.
In broad outline, the production of pro-~0 insulin using recombinant 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 D~A then is inserted in reading phase into a 15 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 20 vector and (b) the expression of proinsulin or a pro-insulin precursor product.
In the event the expression product i~ a proinsulin precursor, it generally will comprise the human proinsulin amino acid sequence joined at its 25 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.
30 This product is customarily referred to as a fused gene product.
! 17616() The proinsulin amino acid sequence is cleaved from t'ne 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 purified, 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 is purified.
As noted, the ccmpositions of this invention are useful in promoting the attainment of natural hormonal homeostasis and thereby preventing or sub-stantially diminishing or retarding those recognized diabetic complications. It is recognized that certain 15 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.
20 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 25 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 hormonal homeostasis.
It also has been noted from recent studies [Podlecki et al., Diabetes, 31, Suppl. 2, 126A (1982)]
! 1761~) that human proinsulin is internalized into target tissues, e.g. fat cells. Although its particular - intracellular action on a molecular scale is as yet undetermined, these findings further support the disclosùre herein that human proinsulin plays an active S role in and is necessary for the attainment of natural hormonal homostasis.
Schluter _ al., Diabetes 31, Suppl. 2, 135A_ (1982), describe studies that demonostrate that human insulin receptor binding is enhanced by the presence of 10 human proinsulin. These results again further support the disclosure herein that the availability and pres-ence of human proinsulin results in the promotion or restoration of natural hormonal homeostasis.
The amount of the compositions of this 15 i.nvention necessary to maintain natural hormonal homeostasis or to achieve a state that more nearly approaches natural hormonal hcmeostasis in the dia-betic, of course, will depend upon the severity of the diabetic condition. Moreover, the amount will vary 20 depending upon the route of administration. Ultimately, the amount of composition administered and the fre-quency of such administration will be at the discretion of the particular physician. In general, however, on the basis that 1 mg. of human proinsulin affords 2S approximately 3.5 Units of human insulin activity, the dosage of human proinsulin will be in the range af-fording from about 0.02 to about 5 units of human insulin activity per kilogram body weight per day, and, preferably, from about 0.1 to about l unit of human 30 insulin activity per kilogram body weight per day.
-! 17~16n The cG~position is administered parenterally, including subcutaneous, intramuscular, and intravenous.
The compositions of this invention ccmprise the active ingredient, human proinsulin, together with a phanma-ceutically acceptable carrier therefor and, optionally, other therapeutic ingredients. The amount of active ingredient 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 of the co~position and is not dele-10 terious to the recipient thereof.
Compositions of this invention suitable forparenteral administration conveniently comprise sterile aqueous solutions and/or suspensions of the pharma-ceutically active ingredients, which solutions or 15 suspensions preferably are made isotonic with th~ 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, 20 preservatives, dispersing agents, agents that promote rapid onset of action, agents that promote prolonged duration of action, and other such agents. Typical preservatives are, for example, phenol, m-^resol, methyl p-hydroxybenzoate, and others. Typical buffers 25 are, for example, sodium phosphate, sodium acetate, sodium citrate, and other known buffers.
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 compo-sition ranges frcm about 2 to about 8, and, preferably,from about 6.8 to about 8Ø
! 1 7616() Other suitable additives are, for example, divalent zinc ion, which, if present at all, is gener-ally present in an amount from about 0.1 mg. to about 3 mg. per 100 units of human proinsulin, and protamine salt (for example, in the form of its sulfate), which, if present at all, is generally present in an amount from about 0.5 mg. to about 20 mg. per 100 units of human proinsulin.
Examples of particular pharmaceutical compo-sitions of this invention are provided in the examples 10 appearing hereinbelow.
Example 1 -- ~eutral Regular Human Proinsulin Formu-lation [40 Units (U) human proinsulin per cubic centimeter (cc.)~
To prepare 10 cc. of the composition, mix Human Proinsulin (3.5 U/mg.) 114 mg. (400 U) 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 2 -- Protamine, Zinc Human Proinsulin Formu-lation [40 U human proinsulin per cc.]
To prepare 10 cc. of the ccmposition, mix Human Proinsulin (3.5 U/mg.) 114 mg. (400 U) Phenol, distilled25 mg.
Zinc Oxide0.95 - 3.8 mg.
Glycerin 160 mg.
30 Protamine Sulfate32 - 64 mg.
Sodium Phosphate, crystals 38 mg.
! li 76l6n 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 3 -- Isophane Protamine, Human Proinsulin Formulation [40 U human proinsulin per cc.]
To prepare 10 cc. of the composition, mix Human Proinsulin (3.5 U/mg.) 114 mg. (400 U) m-Cresol, distilled16 mg.
Phenol, distilled6.5 mg.
Glycerin 160 mg.
Protamine Sulfate9.6 - 19.2 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 -- Zinc Human Proinsulin Formulation [40 U
human proinsulin per cc.]
To prepare 10 cc. of the composition, mix Human Proinsulin (3.5 U/mg.) 114 mg. (400 U) Sodium Acetate, Anhydrous 16 mg.
Sodium Chloride, Granular 70 mg.
Methyl p-Hydroxybenzoate 10 mg.
Zinc Oxide 1 - 8 mg.
Water and either 10~ hydrochloric acid or 10%
sodium hydroxide sufficient to make a cGmposition volume of 10 cc. and a final pH of 7.2-7.5.
Diabetes mellitus is a metabolic disorder characterized by the failure of 'oody 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 sreatly aided by receiving controlled amounts of insulin. To the present time, the insulin used by diabetics has been isolated from animal pancreases, generally bovine and porcine. Both bovine and porcine insulin differ structurally from insulin generated by the human pancreas. Recently, it has become possible, by re-combinant DNA methodology, to produce insulin identical to that produced by the human pancreas. The use of such insulin will enable the diabetic to more closely 15 mimic the natural system than heretofore has been possible.
~ evertheless, it long has been recognized that administration of insulin to the diabetic is alone insufficient to restore and/or maintain the normal 20 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 vessels. The deficiencies leading to these disorders 25 rarely are co~pletely corrected by conventional insulin therapy.
Those vascular abnormalities associated with diabetes often are referred to as "complications of diabetes". They consist generally of microangiopathic 30 changes resulting in lesions in the retina and the ~ 176160 X-5818A ~2-~idney. ~europathy 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 ccm-plications are (1) diseases of the eye, including retinopathy, 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 the alveolar bone, (3) motor, sensory, and autonomic 10 neuropathy; (4) large-vessel disease, (5) microangio-pathy, (6) diseases of the skin, including xant'noma diabeticorum, necrobiosis li~oidica 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 insulinalone 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.
Thus, this invention concerns a pharmaceutical composition which comprises human proinsulin in as-sociation with a pharmaceutically acceptable carrier.
The essential constituent of the pharma-ceutical compositions of this invention is human pro-insulin.
1 17616() X-58L8A ~3~
The administration of human proinsulin using a composition in accordance with this invention will produce a more natural utilization of glucose and better blood glucose control, thereby diminishing here-inbefore described adverse diabetic complications.
Human proinsulin is available via a variety of routes, including organic synthesis, isolation fro~
human pancreas by conventional methodology, and, more recently, recombinant DNA methodology.
In broad outline, the production of pro-~0 insulin using recombinant 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 D~A then is inserted in reading phase into a 15 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 20 vector and (b) the expression of proinsulin or a pro-insulin precursor product.
In the event the expression product i~ a proinsulin precursor, it generally will comprise the human proinsulin amino acid sequence joined at its 25 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.
30 This product is customarily referred to as a fused gene product.
! 17616() The proinsulin amino acid sequence is cleaved from t'ne 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 purified, 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 is purified.
As noted, the ccmpositions of this invention are useful in promoting the attainment of natural hormonal homeostasis and thereby preventing or sub-stantially diminishing or retarding those recognized diabetic complications. It is recognized that certain 15 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.
20 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 25 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 hormonal homeostasis.
It also has been noted from recent studies [Podlecki et al., Diabetes, 31, Suppl. 2, 126A (1982)]
! 1761~) that human proinsulin is internalized into target tissues, e.g. fat cells. Although its particular - intracellular action on a molecular scale is as yet undetermined, these findings further support the disclosùre herein that human proinsulin plays an active S role in and is necessary for the attainment of natural hormonal homostasis.
Schluter _ al., Diabetes 31, Suppl. 2, 135A_ (1982), describe studies that demonostrate that human insulin receptor binding is enhanced by the presence of 10 human proinsulin. These results again further support the disclosure herein that the availability and pres-ence of human proinsulin results in the promotion or restoration of natural hormonal homeostasis.
The amount of the compositions of this 15 i.nvention necessary to maintain natural hormonal homeostasis or to achieve a state that more nearly approaches natural hormonal hcmeostasis in the dia-betic, of course, will depend upon the severity of the diabetic condition. Moreover, the amount will vary 20 depending upon the route of administration. Ultimately, the amount of composition administered and the fre-quency of such administration will be at the discretion of the particular physician. In general, however, on the basis that 1 mg. of human proinsulin affords 2S approximately 3.5 Units of human insulin activity, the dosage of human proinsulin will be in the range af-fording from about 0.02 to about 5 units of human insulin activity per kilogram body weight per day, and, preferably, from about 0.1 to about l unit of human 30 insulin activity per kilogram body weight per day.
-! 17~16n The cG~position is administered parenterally, including subcutaneous, intramuscular, and intravenous.
The compositions of this invention ccmprise the active ingredient, human proinsulin, together with a phanma-ceutically acceptable carrier therefor and, optionally, other therapeutic ingredients. The amount of active ingredient 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 of the co~position and is not dele-10 terious to the recipient thereof.
Compositions of this invention suitable forparenteral administration conveniently comprise sterile aqueous solutions and/or suspensions of the pharma-ceutically active ingredients, which solutions or 15 suspensions preferably are made isotonic with th~ 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, 20 preservatives, dispersing agents, agents that promote rapid onset of action, agents that promote prolonged duration of action, and other such agents. Typical preservatives are, for example, phenol, m-^resol, methyl p-hydroxybenzoate, and others. Typical buffers 25 are, for example, sodium phosphate, sodium acetate, sodium citrate, and other known buffers.
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 compo-sition ranges frcm about 2 to about 8, and, preferably,from about 6.8 to about 8Ø
! 1 7616() Other suitable additives are, for example, divalent zinc ion, which, if present at all, is gener-ally present in an amount from about 0.1 mg. to about 3 mg. per 100 units of human proinsulin, and protamine salt (for example, in the form of its sulfate), which, if present at all, is generally present in an amount from about 0.5 mg. to about 20 mg. per 100 units of human proinsulin.
Examples of particular pharmaceutical compo-sitions of this invention are provided in the examples 10 appearing hereinbelow.
Example 1 -- ~eutral Regular Human Proinsulin Formu-lation [40 Units (U) human proinsulin per cubic centimeter (cc.)~
To prepare 10 cc. of the composition, mix Human Proinsulin (3.5 U/mg.) 114 mg. (400 U) 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 2 -- Protamine, Zinc Human Proinsulin Formu-lation [40 U human proinsulin per cc.]
To prepare 10 cc. of the ccmposition, mix Human Proinsulin (3.5 U/mg.) 114 mg. (400 U) Phenol, distilled25 mg.
Zinc Oxide0.95 - 3.8 mg.
Glycerin 160 mg.
30 Protamine Sulfate32 - 64 mg.
Sodium Phosphate, crystals 38 mg.
! li 76l6n 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 3 -- Isophane Protamine, Human Proinsulin Formulation [40 U human proinsulin per cc.]
To prepare 10 cc. of the composition, mix Human Proinsulin (3.5 U/mg.) 114 mg. (400 U) m-Cresol, distilled16 mg.
Phenol, distilled6.5 mg.
Glycerin 160 mg.
Protamine Sulfate9.6 - 19.2 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 -- Zinc Human Proinsulin Formulation [40 U
human proinsulin per cc.]
To prepare 10 cc. of the composition, mix Human Proinsulin (3.5 U/mg.) 114 mg. (400 U) Sodium Acetate, Anhydrous 16 mg.
Sodium Chloride, Granular 70 mg.
Methyl p-Hydroxybenzoate 10 mg.
Zinc Oxide 1 - 8 mg.
Water and either 10~ hydrochloric acid or 10%
sodium hydroxide sufficient to make a cGmposition volume of 10 cc. and a final pH of 7.2-7.5.
Claims (3)
1. A pharmaceutical composition which comprises human proinsulin in association with a pharmaceutically acceptable carrier.
2. Composition of claim 1, which contains divalent zinc ion.
3. Composition of claim 1, which contains protamine salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29675281A | 1981-08-27 | 1981-08-27 | |
| US296,752 | 1981-08-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1176160A true CA1176160A (en) | 1984-10-16 |
Family
ID=23143402
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000409922A Expired CA1176160A (en) | 1981-08-27 | 1982-08-23 | Human proinsulin pharmaceutical formulations |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5846023A (en) |
| AU (1) | AU552054B2 (en) |
| BE (1) | BE894186A (en) |
| CA (1) | CA1176160A (en) |
| CH (1) | CH650677A5 (en) |
| DE (1) | DE3232036A1 (en) |
| FR (1) | FR2511866B1 (en) |
| GB (1) | GB2104380B (en) |
| HU (1) | HU193522B (en) |
| IE (1) | IE53829B1 (en) |
| IL (1) | IL66610A (en) |
| IT (1) | IT1153184B (en) |
| LU (1) | LU84358A1 (en) |
| MW (1) | MW3782A1 (en) |
| MY (1) | MY8700757A (en) |
| NL (1) | NL8203316A (en) |
| NZ (1) | NZ201683A (en) |
| PH (1) | PH18716A (en) |
| SE (1) | SE8204871L (en) |
| ZA (1) | ZA826157B (en) |
| ZW (1) | ZW17382A1 (en) |
Families Citing this family (6)
| 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 |
| DE3576120D1 (en) * | 1984-06-09 | 1990-04-05 | Hoechst Ag | INSULIN PREPARATIONS, METHOD FOR THE PRODUCTION AND USE THEREOF. |
| US5034415A (en) * | 1987-08-07 | 1991-07-23 | Century Laboratories, Inc. | Treatment of diabetes mellitus |
| US4789660A (en) * | 1987-09-10 | 1988-12-06 | American Home Products Corporation | Insulin administration using methyl and propyl paraben |
| ES2331342B1 (en) * | 2006-05-22 | 2010-10-13 | Consejo Superior Investg.Cientificas | USE OF PROINSULIN FOR THE PREPARATION OF A NEUROPROTECTING PHARMACEUTICAL COMPOSITION, THERAPEUTIC COMPOSITION CONTAINING IT AND ITS APPLICATIONS. |
| USD1010056S1 (en) * | 2020-08-25 | 2024-01-02 | Magpul Industries Corp. | Gun sight |
-
1982
- 1982-08-23 IL IL66610A patent/IL66610A/en unknown
- 1982-08-23 ZW ZW173/82A patent/ZW17382A1/en unknown
- 1982-08-23 CH CH5008/82A patent/CH650677A5/en not_active IP Right Cessation
- 1982-08-23 CA CA000409922A patent/CA1176160A/en not_active Expired
- 1982-08-24 ZA ZA826157A patent/ZA826157B/en unknown
- 1982-08-24 NL NL8203316A patent/NL8203316A/en not_active Application Discontinuation
- 1982-08-24 NZ NZ201683A patent/NZ201683A/en unknown
- 1982-08-24 BE BE6/47702A patent/BE894186A/en not_active IP Right Cessation
- 1982-08-24 MW MW37/82A patent/MW3782A1/en unknown
- 1982-08-24 PH PH27771A patent/PH18716A/en unknown
- 1982-08-25 JP JP57148493A patent/JPS5846023A/en active Pending
- 1982-08-25 AU AU87595/82A patent/AU552054B2/en not_active Ceased
- 1982-08-25 SE SE8204871A patent/SE8204871L/en unknown
- 1982-08-25 FR FR8214597A patent/FR2511866B1/en not_active Expired
- 1982-08-25 HU HU822743A patent/HU193522B/en unknown
- 1982-08-26 LU LU84358A patent/LU84358A1/en unknown
- 1982-08-26 GB GB08224482A patent/GB2104380B/en not_active Expired
- 1982-08-26 IE IE2062/82A patent/IE53829B1/en unknown
- 1982-08-27 IT IT23019/82A patent/IT1153184B/en active
- 1982-08-27 DE DE19823232036 patent/DE3232036A1/en not_active Withdrawn
-
1987
- 1987-12-30 MY MY757/87A patent/MY8700757A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE53829B1 (en) | 1989-03-15 |
| FR2511866A1 (en) | 1983-03-04 |
| MY8700757A (en) | 1987-12-31 |
| IT1153184B (en) | 1987-01-14 |
| DE3232036A1 (en) | 1983-03-10 |
| NZ201683A (en) | 1985-08-16 |
| MW3782A1 (en) | 1984-06-13 |
| IL66610A (en) | 1985-11-29 |
| AU8759582A (en) | 1983-03-03 |
| BE894186A (en) | 1983-02-24 |
| ZA826157B (en) | 1984-04-25 |
| JPS5846023A (en) | 1983-03-17 |
| GB2104380B (en) | 1984-12-05 |
| GB2104380A (en) | 1983-03-09 |
| LU84358A1 (en) | 1983-02-28 |
| FR2511866B1 (en) | 1986-08-14 |
| HU193522B (en) | 1987-10-28 |
| SE8204871L (en) | 1983-02-28 |
| IL66610A0 (en) | 1982-12-31 |
| AU552054B2 (en) | 1986-05-22 |
| NL8203316A (en) | 1983-03-16 |
| SE8204871D0 (en) | 1982-08-25 |
| CH650677A5 (en) | 1985-08-15 |
| IT8223019A0 (en) | 1982-08-27 |
| ZW17382A1 (en) | 1982-11-17 |
| IE822062L (en) | 1983-02-27 |
| PH18716A (en) | 1985-09-11 |
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