WO1991012014A1 - A growth factor in connection with artificial transplants - Google Patents

A growth factor in connection with artificial transplants Download PDF

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Publication number
WO1991012014A1
WO1991012014A1 PCT/SE1991/000079 SE9100079W WO9112014A1 WO 1991012014 A1 WO1991012014 A1 WO 1991012014A1 SE 9100079 W SE9100079 W SE 9100079W WO 9112014 A1 WO9112014 A1 WO 9112014A1
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Prior art keywords
acid
lysine
transplants
peptide
ghk
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PCT/SE1991/000079
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French (fr)
Inventor
Lars Strid
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Individual
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Priority to DE69125854T priority Critical patent/DE69125854T2/en
Priority to EP91904533A priority patent/EP0594592B1/en
Publication of WO1991012014A1 publication Critical patent/WO1991012014A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors

Definitions

  • a growth factor in connection with artificial trans ⁇ plants is a growth factor in connection with artificial trans ⁇ plants.
  • This invention utilizes the biological activity of the copper complex of the tripeptide glycyl-L-histidyl- -L-lysine.
  • This peptide is covalently bound to artifi ⁇ cial transplants where it has a chemoattractive effect and also acts when it is released by hydrolysis of the transplants.
  • the peptide increases fibroblastic colla ⁇ gen synthesis thereby enabling a more rapid replace ⁇ ment of the transplants with human tissue.
  • the evolution of ulticellular organisms is de ⁇ pendent upon the ability of cells to communicate with each other and with their environment.
  • One method the cells use for this communication is to release pep- tides that induce a specific activity in the receiving cell.
  • Such a peptide with biological activity is the human plasma growth factor copper-binding tripeptide glycyl-L-histidyl-L-lysine (GH -Cu 2+) .
  • the peptide has also a chemoattractive effect oil cells necessary for wound- healing such as macrophages, onocytes, mast cells and capillary endothelial cells.
  • Collagen is a fibrous protein that constitutes a quarter of the total amount of protein in the human body. It is the major fibrous element of skin, bone, tendons,cartilage, ligaments and blood vessels. Colla ⁇ gen is synthesized by fibroblasts, a type of cell lo ⁇ calized in the area surrounding other cells and tissues.
  • F-X Maguart et al present data showing that GHK-Cu 2+ stimulates collagen synthesis m cultures of fibroblasts. This stimulation is observed at a peptide concentration as low as 10 -12M and reaches a maximum at 10 -9M where the increase in collagen synthesis is about 80 %.
  • GHK-Cu with a modified C-terminal carboxyl group is used as an ointment -for faster healing of wounds.
  • GHK-Cu 2+ possesses a significant superoxide dis u- tase-like activity with a rate constant of about 25 % of the activity of enzymatic Cu,Zn-superoxide dismuta- se on a molar basis.
  • a rate constant of about 25 % of the activity of enzymatic Cu,Zn-superoxide dismuta- se on a molar basis.
  • GHK-Cu 2+ inhibits this aggregation and it also inhibits the hormone thromboxane which causes thrombosis.
  • the structure of the -tripeptide GHK-Cu 2+ i.s shown in Fig 1.
  • the affinity of the peptide for copper is very high with a pK for the dissociation constant of about 16.
  • the ⁇ -amino group on the side-chain of the lysine must be free.
  • Lactic acid is metabolized to carbondioxide and water in the citric acid cycle while glycolic acid is excre ⁇ ted with the urine or is oxidized to pyruvate and is also metabolized in the citric acid cycle resulting in the same products as for lactic acid. These harmless products are very advantageous when compared with the hydrolysis products of many other polymers.
  • Polymers of lactic and glycolic acid have been used for long time as resorbable suture material.
  • this material is used for artificial ligaments the main problem is that they hydrolyse so rapidly that the body is not allowed enough time to replace them with its own tissue where collagen constitutes the main part.
  • the rapid hydroli ⁇ is could be compen ⁇ sated for if one could increase the rate of collagen synthesis.
  • the free car ⁇ boxyl group of the peptide is coupled to a polymer containing free primary amino groups or to a polymer which can be modified to contain free amino groups.
  • the peptide Since the peptide has maximal activity at a concentra- t on as low as 10 -9M where it almost doubles the fibroblasts synthesis of collagen, it is fully suffi ⁇ cient that one peptide molecule is coupled to a poly ⁇ mer molecul having a molecul weight of 500 000.
  • the carbodiimide will be dicyclohexylcarbodiimid if the reaction is carried out in organic solution, or l-ethyl-3-(3-dimethylaminopropyl-)carbodiimide if the reaction is performed in a water solution.
  • the tripeptide NH 2 -glycyl-L-histidyl-L-lysine-C00H is blocked on the amino group of glycine, the imidazole group of histidine and the ⁇ -amino group of lysine with 9-fluorenylmethyl chloroformate (FM0C-C1) .
  • the free carboxyl group of lysine is activated with car- boldiimide as described above and allowed to react with the free amino group of the derivative of poly- -L-lactic acid [poly-L-lactic acid-C-NH(CH 2 ) -NH .
  • FMOC has been used as the blocking group.
  • Another blocking agent is the tert-butoxycarbonyl group (t-BOC-) . Deblocking after the synthesis is in this case performed with dilute acid (25% trifluoro- acetic acid) .
  • the peptide glycyl-L-histidyl-L-lysine is commer ⁇ cially available.
  • Another way for synthesis is by usual peptide synthesis coupling the amino blocked L-lysine, L-histi- dine and glycine one after the other to the amino de ⁇ rivative of the polymer.
  • Lactic acid and gly ⁇ olic acid are ⁇ -hydroxy- carboxylic acids.
  • a number of other ⁇ -hydroxycarboxylic acids are useful for homo- or co-polymerization. Examples are ⁇ -hydroxybutyric -acid, ⁇ -hydroxysiobutyric acid, ⁇ -hydroxyvaleric acid, cc*-hydroxyisovaleric acid.
  • ⁇ -hydroxybutyric -acid ⁇ -hydroxysiobutyric acid
  • ⁇ -hydroxyvaleric acid ⁇ -hydroxyvaleric acid
  • cc*-hydroxyisovaleric acid cc*-hydroxyisovaleric acid.
  • D- ⁇ -hydroxybutyric acid has been used as a polymer for transplants (Bri ⁇ tish Patent 1034123) .
  • R and R' represent hydrogen, methyl- or ethyl- group and n the degree of polymerization.
  • Synthetic biodegradable polyester amides have been described by T H Barrows et al at 3M Center, St Paul, Minnesota, USA.
  • Another method is to covalently couple GHK-Cu 2+ to other biocompatible materials, which may or may not be resorbed, that contain an amino group or a site where an amino group can be introduced.
  • biocompatible materials which may or may not be resorbed
  • glass or silicic acid can be silylated with 3-amino- propyl-triethoxysilone.
  • GHK-Cu 2+ could be bound to the glass.
  • the surface can first be covered with a protein, for instance serumalbumin, and the amino groups bridge-bound with glutardialdehyde. After introduction of new amino groups, the GHK-CU 2+ can be bound to the protein.
  • a protein for instance serumalbumin
  • Fig 1 shows the three-dimensional structure of GHK-Cu 2+.
  • the side-chains of lysine and histidine and the amino terminal of glycin are necessary for the copper-binding and for the biological activity.
  • One of the hydrogens of the " -carbon in the glycin can be ex ⁇ changed with another radical without disturbing the conformation of the copper-complex.
  • Proposals for new tripepticles can, for example, be Ala-His-Lys, Val- His-Lys or Leu-His-Lys.
  • One advantage of this is that we can use the D-form of the amino-terminal amino acid which renders the peptide more resistant to proteoly- tic hydrolysis.
  • reinforcing material can of course be used.
  • This material can be degredable or not degradable.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Transplantation (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Materials For Medical Uses (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

This invention utilizes the biological activity of the copper complex of the tripeptide glycyl-L-histidyl-L-lysine. This peptide is covalently bound to artificial transplants where it has a chemoattractive effect and also acts when it is released by hydrolysis of the transplants. The peptide increases fibroblastic collagen synthesis thereby enabling a more rapid replacement of the transplants with human tissue.

Description

Title: 1
A growth factor in connection with artificial trans¬ plants.
Technical field:
This invention utilizes the biological activity of the copper complex of the tripeptide glycyl-L-histidyl- -L-lysine. This peptide is covalently bound to artifi¬ cial transplants where it has a chemoattractive effect and also acts when it is released by hydrolysis of the transplants. The peptide increases fibroblastic colla¬ gen synthesis thereby enabling a more rapid replace¬ ment of the transplants with human tissue.
Background:
The evolution of ulticellular organisms is de¬ pendent upon the ability of cells to communicate with each other and with their environment. One method the cells use for this communication is to release pep- tides that induce a specific activity in the receiving cell.
Such a peptide with biological activity is the human plasma growth factor copper-binding tripeptide glycyl-L-histidyl-L-lysine (GH -Cu 2+) .
L Pickart and S Lovejoy describe the properties of the peptide GHK-Cu 2+ .in Methods in Enzymology, Vol 147
(1987) pp 314-328, Academic Press. It plays a physio¬ logical role in the healing of wounds by stimulation the complex course of events necessary for the forma¬ tion of new tissues such as angiogenesis and axon and dendrite growth in neurons. The peptide has also a chemoattractive effect oil cells necessary for wound- healing such as macrophages, onocytes, mast cells and capillary endothelial cells.
Collagen is a fibrous protein that constitutes a quarter of the total amount of protein in the human body. It is the major fibrous element of skin, bone, tendons,cartilage, ligaments and blood vessels. Colla¬ gen is synthesized by fibroblasts, a type of cell lo¬ calized in the area surrounding other cells and tissues.
In a publication in FEBS Letters 238 (1988) 343-
-346, F-X Maguart et al present data showing that GHK-Cu 2+ stimulates collagen synthesis m cultures of fibroblasts. This stimulation is observed at a peptide concentration as low as 10 -12M and reaches a maximum at 10 -9M where the increase in collagen synthesis is about 80 %.
2+ In European Patent Appliction 0190736, GHK-Cu with a modified C-terminal carboxyl group is used as an ointment -for faster healing of wounds. GHK-Cu 2+ possesses a significant superoxide dis u- tase-like activity with a rate constant of about 25 % of the activity of enzymatic Cu,Zn-superoxide dismuta- se on a molar basis. When wounds and damaged tissue are present, cells from the immune system invade the injured area and large quantities of toxic oxygen radicals are released to kill invading bacteria. These radicals also destroy intact tissue which starts a vicious circle where more radicals are released, thus delaymg healing. GHK-Cu 2+ -superoxide dismutase activ¬ ity detoxifies the tissuedestroying superoxide anions.
Aggregation of blood platelets is the first stage of thrombosis. GHK-Cu 2+ inhibits this aggregation and it also inhibits the hormone thromboxane which causes thrombosis. The structure of the -tripeptide GHK-Cu 2+ i.s shown in Fig 1. The affinity of the peptide for copper is very high with a pK for the dissociation constant of about 16. For biological activity the ε-amino group on the side-chain of the lysine must be free.
The technical problem:
The use of artificial materials in surgery is gradually increasing. In orthopedic surgery, trans¬ plants are used for soft parts such as muscles, tendons and ligaments. In the case of ligaments, the preferred material used has been poly propylen bands which are unfortunately not degradable, and results have been unfavorable in the long run. When degradable material is used to replace ligaments, it is of utmost impor¬ tance that this material is biocompatible. Polymers of lactic acid and glycolic acid are degraded to non- toxic products that living tissues tolerate. In the human body they are hydrolysed to their monomers. Lactic acid is metabolized to carbondioxide and water in the citric acid cycle while glycolic acid is excre¬ ted with the urine or is oxidized to pyruvate and is also metabolized in the citric acid cycle resulting in the same products as for lactic acid. These harmless products are very advantageous when compared with the hydrolysis products of many other polymers.
Polymers of lactic and glycolic acid have been used for long time as resorbable suture material. When this material is used for artificial ligaments the main problem is that they hydrolyse so rapidly that the body is not allowed enough time to replace them with its own tissue where collagen constitutes the main part. The rapid hydroliεis could be compen¬ sated for if one could increase the rate of collagen synthesis.
The solution:
The invention presented here is that material used for transplants incorporates the copper-complex of the
2+ tripeptide glycyl-L-histidyl-L-lysme GHK-Cu . As may be seen in Fig 1, the C-terminal carboxyl group is not involved in the copper binding and for that reason is suitable for the covalent binding of the peptide to transplants.
With well-known peptide synthesis, the free car¬ boxyl group of the peptide is coupled to a polymer containing free primary amino groups or to a polymer which can be modified to contain free amino groups.
Since the peptide has maximal activity at a concentra- t on as low as 10 -9M where it almost doubles the fibroblasts synthesis of collagen, it is fully suffi¬ cient that one peptide molecule is coupled to a poly¬ mer molecul having a molecul weight of 500 000.
Thought of chemoattraction and when the peptide GHK-Cu 2+ is released by hydrolysis of the transplant in the tissues, very specific biological processes are started involving many closely coordinated reactions that must be in balance in order to allow healing to occur. This includes an increase in collagen synthesis, an increase of tissue-protective superoxide dismutase activity, and a chemoattractive effect on among others mast cells and capillary endothelial cells which accu¬ mulate at the transplant -site, there stimulating new formation of blood vessels and the flow nourishment to the area.
Best mode of carrying out the invention: Example 1.
The free carboxyl group of poly-L-lactic acid are activated with carbodiimide and then allowed to react with an excess of a diamine, NH2(CH2) NH2 where n = = 2-6 depending upon the length of the desired spacer- arm. The carbodiimide will be dicyclohexylcarbodiimid if the reaction is carried out in organic solution, or l-ethyl-3-(3-dimethylaminopropyl-)carbodiimide if the reaction is performed in a water solution.
The tripeptide NH2-glycyl-L-histidyl-L-lysine-C00H is blocked on the amino group of glycine, the imidazole group of histidine and the ε-amino group of lysine with 9-fluorenylmethyl chloroformate (FM0C-C1) . The free carboxyl group of lysine is activated with car- boldiimide as described above and allowed to react with the free amino group of the derivative of poly- -L-lactic acid [poly-L-lactic acid-C-NH(CH2) -NH .
After removal of the protective FMOC-groups with piperidine and the addition of copper (II) acetate the desired product is obtained, the structure of which is shown in Fig 2. In this figure the diamine NH„ (CH2) 2 NH 2 has been used. The same methods of synthesis are also valid for poly-DL-lactic acid, poly-D-lactic acid, polyglycolic acid and their co-polymers.
Above, FMOC has been used as the blocking group. Another blocking agent is the tert-butoxycarbonyl group (t-BOC-) . Deblocking after the synthesis is in this case performed with dilute acid (25% trifluoro- acetic acid) .
The peptide glycyl-L-histidyl-L-lysine is commer¬ cially available.
Other examples
Another way for synthesis is by usual peptide synthesis coupling the amino blocked L-lysine, L-histi- dine and glycine one after the other to the amino de¬ rivative of the polymer.
Lactic acid and glyσolic acid are α-hydroxy- carboxylic acids. A number of other α-hydroxycarboxylic acids are useful for homo- or co-polymerization. Examples are α-hydroxybutyric -acid, α-hydroxysiobutyric acid, α-hydroxyvaleric acid, cc*-hydroxyisovaleric acid. To increase the amount of peptider per polymer mole¬ cule, one can treat the poly-α-hydroxycarboxylic acid with mild hydrolysis to increase the available number of carboxyl groups.
Among β-hydroxycarboxylic acid D- β -hydroxybutyric acid has been used as a polymer for transplants (Bri¬ tish Patent 1034123) .
Polymer based on p-dioxanon has also been used as transplants. This has the formula
Figure imgf000008_0001
where R and R' represent hydrogen, methyl- or ethyl- group and n the degree of polymerization.
Synthetic biodegradable polyester amides have been described by T H Barrows et al at 3M Center, St Paul, Minnesota, USA.
These polymers consist of units with the formula
-0-CH„-C-NH-(CH„) -NH-C-CH -0-C-(CH ) -C
2 ii 2 ~ n II z i IiI y
0 0 0 n
All of these polymers can be coupled covalently to GHK-Cu2+ with the samemethods described above.
Another method is to covalently couple GHK-Cu 2+ to other biocompatible materials, which may or may not be resorbed, that contain an amino group or a site where an amino group can be introduced. For example glass or silicic acid can be silylated with 3-amino- propyl-triethoxysilone. In this case a great number of GHK-Cu 2+ could be bound to the glass.
Figure imgf000008_0002
When metal transplants are to be made the surface can first be covered with a protein, for instance serumalbumin, and the amino groups bridge-bound with glutardialdehyde. After introduction of new amino groups, the GHK-CU 2+ can be bound to the protein.
Fig 1 shows the three-dimensional structure of GHK-Cu 2+. The side-chains of lysine and histidine and the amino terminal of glycin are necessary for the copper-binding and for the biological activity. One of the hydrogens of the "-carbon in the glycin can be ex¬ changed with another radical without disturbing the conformation of the copper-complex. Proposals for new tripepticles can, for example, be Ala-His-Lys, Val- His-Lys or Leu-His-Lys. One advantage of this is that we can use the D-form of the amino-terminal amino acid which renders the peptide more resistant to proteoly- tic hydrolysis.
In the practical use of the invention reinforcing material can of course be used. This material can be degredable or not degradable.
Although the invention has been described here with reference to certain examples, it should be obser¬ ved the invention is by no means restricted to such specific characteristics since closely related varia¬ tions and modifications are obvious for the specialist in the field.
Claims:
1. A method of increasing natural collagen synthesis at the site of an artifical transplant by immobilizing a biologically active agent on the transplant, c h a¬ r a c t e r i z e d b y the fact that this agent is a growth factor for collagen and that it is the copper- complex of the tripeptide glycyl-L-histidyl-L-lysine which is immobilized because the carboxyl-terminal

Claims

carboxyl group of lysine is covalently bound to the transplant.
2. A method according to claim 1 c h a r a c t e¬ r i z e d b the fact that the transplant consists of poly-L-lactic acid, polyglycolic acid or copolymer of this, where the carboxyl group of the polymer has first been bound by a peptidebond to a diamine, pref¬ erably 1,6,-hexandiamine, and where the free amino group of the product is bound by a peptide bond to the carboxyl group of the lysine in the copper complex of
2+ the tripeptide glycyl-L-histidy-L-lysine (GHK-Cu ) .
3. A method accordning to claim 2 c h a r a c t e¬ r i z e d b y the fact that the transplants are homo- or copolymers of the L-hydroxy-derivatives of glycolic acid, lactic acid, butyric acid, isobutyric acid, valeric acid or isovaleric acid.
4. A method according to claim 2 c h a r a c t e¬ r i z e d b y the fact that the transplant is a polymer based on p-dioxanone consisting of units with the formula
R R'
I I
-0-CH-C-O-CH-C- I u R R O n
where R and R' indicate hydrogen, methyl or ethyl group and n the degree of polymerization.
PCT/SE1991/000079 1990-02-06 1991-02-04 A growth factor in connection with artificial transplants Ceased WO1991012014A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE69125854T DE69125854T2 (en) 1990-02-06 1991-02-04 GROWTH FACTOR IN CONNECTION WITH ARTIFICIAL TRANSPLANTS
EP91904533A EP0594592B1 (en) 1990-02-06 1991-02-04 A growth factor in connection with artificial transplants

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9000409-4 1990-02-06
SE9000409A SE465154B (en) 1990-02-06 1990-02-06 GROWTH FACTOR IN CONNECTION WITH ARTIFICIAL TRANSPLANTS

Publications (1)

Publication Number Publication Date
WO1991012014A1 true WO1991012014A1 (en) 1991-08-22

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EP (1) EP0594592B1 (en)
AT (1) ATE151988T1 (en)
AU (1) AU7323591A (en)
DE (1) DE69125854T2 (en)
DK (1) DK0594592T3 (en)
ES (1) ES2103802T3 (en)
SE (1) SE465154B (en)
SG (1) SG47783A1 (en)
WO (1) WO1991012014A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2707653A1 (en) * 1993-07-16 1995-01-20 Vetoquinol Sa Conjugate between a biocompatible and biodegradable polymer and a molecule in particular a biologically active molecule, with mobile hydrogen, its preparation process and pharmaceutical composition comprising this conjugate.
WO2014161863A1 (en) 2013-04-03 2014-10-09 Irbm Science Park S.P.A. Dermatological and/or cosmetic peptides for use in skin treatment

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190736A2 (en) * 1985-02-08 1986-08-13 Procyte Corporation Chemical derivatives of GHL-Cu
WO1988003417A1 (en) * 1986-11-03 1988-05-19 Material Consultants Oy Surgical biocomposite material and a method for producing the material
WO1988008714A1 (en) * 1987-05-11 1988-11-17 Procyte Corporation Methods and compositions for preventing ulcers
WO1989012441A1 (en) * 1988-06-16 1989-12-28 Procyte Corporation Cosmetic and skin treatment compositions
EP0358819A1 (en) * 1987-06-26 1990-03-21 Dow Corning Kabushiki Kaisha Artificial skin

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190736A2 (en) * 1985-02-08 1986-08-13 Procyte Corporation Chemical derivatives of GHL-Cu
WO1988003417A1 (en) * 1986-11-03 1988-05-19 Material Consultants Oy Surgical biocomposite material and a method for producing the material
WO1988008714A1 (en) * 1987-05-11 1988-11-17 Procyte Corporation Methods and compositions for preventing ulcers
EP0358819A1 (en) * 1987-06-26 1990-03-21 Dow Corning Kabushiki Kaisha Artificial skin
WO1989012441A1 (en) * 1988-06-16 1989-12-28 Procyte Corporation Cosmetic and skin treatment compositions

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2707653A1 (en) * 1993-07-16 1995-01-20 Vetoquinol Sa Conjugate between a biocompatible and biodegradable polymer and a molecule in particular a biologically active molecule, with mobile hydrogen, its preparation process and pharmaceutical composition comprising this conjugate.
WO2014161863A1 (en) 2013-04-03 2014-10-09 Irbm Science Park S.P.A. Dermatological and/or cosmetic peptides for use in skin treatment

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SE9000409D0 (en) 1990-02-06
SE465154B (en) 1991-08-05
ATE151988T1 (en) 1997-05-15
DE69125854T2 (en) 1997-10-23
AU7323591A (en) 1991-09-03
SG47783A1 (en) 1998-04-17
EP0594592B1 (en) 1997-04-23
DK0594592T3 (en) 1997-10-27
EP0594592A1 (en) 1994-05-04
ES2103802T3 (en) 1997-10-01
DE69125854D1 (en) 1997-05-28

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