EP0969740A1 - Procede ameliore pour fabriquer du collagene - Google Patents

Procede ameliore pour fabriquer du collagene

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Publication number
EP0969740A1
EP0969740A1 EP98912152A EP98912152A EP0969740A1 EP 0969740 A1 EP0969740 A1 EP 0969740A1 EP 98912152 A EP98912152 A EP 98912152A EP 98912152 A EP98912152 A EP 98912152A EP 0969740 A1 EP0969740 A1 EP 0969740A1
Authority
EP
European Patent Office
Prior art keywords
collagen
solution
composition
injectable
range
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.)
Withdrawn
Application number
EP98912152A
Other languages
German (de)
English (en)
Inventor
Linus Vidal
Benedicto De Campos Vidal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clearcoll Pty Ltd
Original Assignee
Clearcoll Pty Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Clearcoll Pty Ltd filed Critical Clearcoll Pty Ltd
Publication of EP0969740A1 publication Critical patent/EP0969740A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L89/00—Compositions of proteins; Compositions of derivatives thereof
    • C08L89/04—Products derived from waste materials, e.g. horn, hoof or hair
    • C08L89/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin, e.g. gelatin

Definitions

  • This invention relates to collagen, particularly to an improved form of collagen and to a process for preparing improved collagen.
  • Collagen is the major protein component of bone, cartilage, ligament, tendon, skin and connective tissue in animals.
  • the word 'collagen' is often used as a generic term to cover a wide range of protein molecules which share a common triple helical structure.
  • Type I collagen is the major collagen of skin, tendon and ligament, whereas Type III collagen is important in blood vessels.
  • the collagen molecule is composed of three collagen polypeptides which form a tight triple helix. The majority of each polypeptide is characterised by repeating amino acid sequence Gly-X-Y-, where X and Y can be any amino acid but are most usually proline and hydroxyproline.
  • X and Y can be any amino acid but are most usually proline and hydroxyproline.
  • At each end of the collagen polypeptide there is a non triple helical telopeptide region. The telopeptide regions of the collagen chains are responsible for the crosslinking between the chains.
  • Collagen is synthesised within the cell as precursor collagen ( ⁇ ) chains. During further cellular processing the telopeptide regions at each end of the collagen molecule are formed. These regions play an essential role in the maturation of the collagen matrix by intramolecular crosslinking formation which is a crucial step in the formation of strong coUagenous tissues. In the extracellular matrix, the collagen is incorporated into fibrils, which then further associate in tissue to form fibre bundles.
  • collagen Because of its vital role in all connective tissues, collagen has increasingly become the basis of biomaterials, including native, unmodified tissue grafts, manufactured medical products including replacement components for the cardiovascular system, as well as injectable collagen for soft tissue augmentation. It is particularly in the form of injectable or soluble collagen where much recent research has been conducted, as such soluble collagen has many medical as well as cosmetic applications.
  • a range of commercially available coUagenous biomaterials and soluble collagen implants are available including ZYDERM and ZYPLAST (injectable collagen implants, Collagen Corporation, Palo Alto), ATELOCOLLAGEN (injectable collagen implants, Koken Company, Tokyo), GELFOAM (gelatin haemostat foams, Upjohn Co.
  • ZYDERM collagen implant (sometimes termed ZCI) is a sterile suspension of bovine collagen fibrils in 20mM sodium phosphate, 130mM NaCl and 0.3 % Lignocaine, pH7.2. It is prepared from pepsin solublised collagen which is precipitated as fibrils which are then collected and resuspended in final buffer to protein concentrations of either 35 or 65mg/ml. It is then packed into syringes for delivery. Electron microscopy reveals that ZCI comprises a polydisperse mixture of collagen fibrils.
  • ZYPLAST which is a more recent product is also an injectable sterile suspension of bovine collagen fibrils in phosphate-buffered physiological saline but has collagen fibrils stabilised by a low level of glutaraldehyde.
  • the crosslinked collagen has protein concentration of 35mg/ml, with a pH of 7-7.6.
  • Another potential source of immunogenicity was the presence of denatured collagen, as individual chains tend to be more immunogenic than intact helical collagen molecules.
  • Tests which have been performed to evaluate the general toxicity of collagen biomaterials including soluble collagen have been performed on animals including rats, guinea pigs and rabbits in order to assess short and long term acute or chronic inflammation, as well as immunological testing. Tests have also been performed on humans in respect of immunological responses to dermal ZYDERM and ZYPLAST implants from patients undergoing predominantly aesthetic cosmetic surgery for correction of scars or wrinkles. These products are perhaps the most widely characterised and used examples of purified and reconstituted collagen explant material.
  • injectability through a fine gauge needle is difficult and blobbing or lumping of the injectate occurs. This is potentially problematic particularly where injecting into fine facial lines is required. Further, often the needle causes final shearing of the product. Also, constant flow cannot be assured and often delivery of the exact amount cannot be achieved. An easily injectable soluble collagen product which still has similar collagen concentration is therefore desirable.
  • the viscosities of currently commercially available collagen products are such that when such products are taken out of the lowered temperatures at which they are stored, prior to use, they are incapable of being immediately injected.
  • the collagen products are so viscous that warming of the product (such as by immersing the syringe in warm water) is required. This warming can sometimes cause denaturing of the collagen.
  • a collagen product having a viscosity such that it is immediately injectable upon removal from lowered temperatures would therefore be an advantage.
  • a collagen composition which is translucent to clear in appearance, which is of high purity, which is immunologically inert, which is of such viscosity that it can be easily injected at temperatures in the range of from 8-18°C and which after injection into the skin, lasts without dissipating or disappearing for a period of 9-24 months.
  • a first aspect of this invention provides an injectable collagen composition comprising substantially 100% Type I collagen, said injectable composition having a pH in the range of from about 3 to 6 and a collagen concentration of from about 20-90 mg/ml.
  • an injectable collagen composition comprising substantially 100% Type I collagen, said injectable composition having a pH in the range of from about 3 to 6 and a collagen concentration of from about 20-90 mg/ml and a viscosity such that said composition is injectable through at least a 30 gauge needle without blobbing.
  • an injectable collagen composition comprising substantially 100% Type I collagen, said injectable composition having a pH in the range of from about 3 to 6 and a collagen concentration of from about 20-90 mg/ml, and a viscosity such that said composition is injectable through at least a 30 gauge needle without blobbing at a temperature in the range of from about 8 to 18°C.
  • an injectable collagen composition comprising substantially 100%
  • Type I collagen said injectable composition having a pH in the range of from about 3 to 6 and a collagen concentration of from about 20-90 mg/ml, and wherein said composition is substantially translucent to clear in appearance.
  • the pH of the composition is in the range of from about 3.5-5.5, more typically in the range of from about 4-5 and most typically in the range of from about 4.2-4.8.
  • the collagen concentration is in the range of from about 20-60 mg/ml, more typically in the range of from about 20-40mg/ml, most typically in the range of from about 22-38mg/ml.
  • the injectable composition is injectable using a 30-35 gauge needle, most typically a 32 or 33 gauge needle is used.
  • the viscosity of the composition is such that it is injectable through a 30-35 gauge needle when the composition is at a temperature within the range of 10-15° C, more typically a temperature in the range of from 10-13°C .
  • a process for the preparation of a collagen composition comprising the steps of:
  • the mehanical processing includes any mechanical means for breaking up or fragmenting the tendons.
  • mechanical processing can be any form of comminuting such as dicing, chopping, homogenising or other physical treatment and most typically takes the form of mincing.
  • the minced tendon fragments which result are more typically in the size range of from about 0.5-4mm, most typically 1- 3mm.
  • a process for the preparation of a collagen composition comprising the steps of: (a) mechanically processing mammalian connective tissue to form connective tissue fragments of from about 0.1 -5mm in length,
  • the mixing of the solution occurs in a range of 3500-22000rpm, such that polypeptide chains of each collagen molecule in said solution at least begin to unweave from each other.
  • the mammalian connective tissue can be obtained from porcine and bovine origin and most typically includes skin, cartilage, tendon and muscle.
  • the bovine tendons are obtained from young bovines, most typically bovines which are up to about 1 year in age and which are termed 'vealers' , the bovine tendons most preferred in this process effectively being veal tendons.
  • the connective tissue fragments have a diameter similar to their length.
  • the connective tissue fragments have both length and diameter in the range of from about 0. l-5mm.
  • bovine tendon fragments of from about 0.1-5mm in length and diameter, (b) digesting said fragments in acidic solution containing at least one proteolytic (non collagenase) enzyme,
  • the sterile conditions include treating the bovine tendons with bleach or some other sterilizing or antiseptic agent to ensure a pyrogen free environment. Such treatment may typically be the chemical sterilisation of the tendons in dilute hypochlorite solution. Alternatively, it is also typical that the bovine tendons are first physically processed to fragments which are then chemically sterilised. Most typically, immersion of the tendons in dilute (250ppm) sodium hypochlorite solution for any time from about several minutes to about two hours occurs.
  • the tendons or fragments are typically washed to remove the sterilisation agent.
  • the acidic solution in which digestion occurs is selected from any carboxylic acid solution or from any mineral acid solution or a mixture of both. More typically the acidic solution is acetic acid solution which may or may not be mixed with fuming concentrated HC1.
  • the pH of the digestion solution is in the range of from about 1 to about 6. It is also typical that the enzyme present in the acidic solution is selected from pepsin, trypsin and any other non-collagenase enzyme. Most typically, the enzyme is pepsin.
  • the digestion occurs at a temperature of between 8-20°C, more usually 8-15°C and most typically 8-12°C.
  • the time for digestion is variable, but typically occurs in the range of from about 4 to 28 hours, more typically 5-24 hours, most typically in the range of from about 5- 20 hours.
  • the digestion solution comprises for each lOOg of tendon fragments, 30 litres of 10% acetic acid, 20ml fuming HC1 and lg of pepsin.
  • the digesting occurs for up to 24 hours at 8-10°C.
  • the solution is then submitted to mixing, preferably in the form of mechanical blending, such as a laboratory blender.
  • the solution may be treated in order to inactivate the enzyme and/or to remove traces of the acid and enzyme.
  • Such treatment can occur either before or after the mixing of the digestion solution which is undertaken to unweave the collagen fragments.
  • the blended solution is chilled to a temperature of about 5-10°C for a period of up to about 24 hours before it is mechanically sheared.
  • the mechanical shearing of the solution takes the form of filtering.
  • Sieving is also another means by which shearing of the collagen in solution can occur.
  • Filtering of the blended solution occurs through the use of 50-100 micron filters, most typically a 50 micron filter is used.
  • the filtering results in substantially all the collagen molecules being sheared to a size of about 50-200 microns, most preferably 50 microns.
  • the filtered solution containing the collagen molecules is then treated with an alkali metal non-phosphate salt solution sufficient to reconstitute the collagen from the solution.
  • the reconstituted collagen appears as a collagen suspension and is caused by the collagen in solution reaggregating into fibrils
  • alkali metal salts include sodium hydroxide, sodium chloride and potassium chloride.
  • the filtered solution which contains the collagen molecules in solution is then treated with sodium chloride, preferably in the form of sodium chloride solution, most preferably in the form of 5M sodium chloride solution.
  • sodium chloride preferably in the form of sodium chloride solution, most preferably in the form of 5M sodium chloride solution.
  • sufficient sodium chloride is added to the filtered solution such that the filtered solution is saturated and the collagen molecules come out of solution. More typically, sufficient sodium chloride is added to the filtered solution such that a 1M concentration of sodium chloride is obtained in the final solution which results in reconstitution of the collagen molecules.
  • bovine tendon fragments of from about 0.1 -5mm in length and diameter
  • the sodium chloride is added to the filtered solution with stirring. It is also usual that the solution containing the sodium chloride is left to rest for a period of from about 1-24 hours, more usually 1-15 hours. Typically the temperature at which the resting occurs is in a range of from about 8-25°C, more typically from about 8-15°C.
  • the reconstituted collagen molecules in the form of a collagen suspension in the solution are collected by gentle batch centrifugation, the supernatant being discarded.
  • the centrifugation will also serve to remove any remaining enzyme, particularly if the solution has not been treated since digestion.
  • the collagen gel can be resuspended in buffer or water and centrifuged again, with the supernatant again being discarded.
  • a process for the preparation of a collagen composition comprising the steps of: (a) mechanically processing bovine tendons under sterile conditions to form bovine tendon fragments of from about 0.1 -5mm in both diameter and length,
  • the dialysis in undertaken using dialysis bags or tubes.
  • the collagen is dialysed against distilled water or dilute acid such as acetic acid.
  • the dialysis occurs over a period of from about 12-96 hours, more preferably over a period of from about 24-80 hours, most preferably over a period of from 48-72 hours.
  • the collagen is dialysed against between 1 to 6 changes of water or other dialysate, more typically between 1 to 4 changes of water, most typically against 3 changes of water.
  • the dialysis of the collagen occurs against 3 changes of water at 24 hour intervals.
  • the concentration of the collagen in the dialysis tubes or bags should typically reach the required range of from about 20-90 mg/ml after dialysis for a period of about 24-72 hours. More typically, the concentration is in the range of from 25-60mg/ml, most typically in the range of from 25-40 mg/ml.
  • the viscosity of the collagen solution is typically monitored such that the final collagen solution has a viscosity which allows it to be injected without blobbing through a syringe having a needle in the range of from about 30-35 gauge. Further, the viscosity is such that the collagen composition is injectable when at a temperature in the range of from about 8-18°C, more typically it is injectable when at a temperature in the range of from about 10-15°C.
  • a process for the preparation of a collagen composition comprising the steps of:
  • the anaesthetic agent is Lignocaine solution which is added to the collagen with mixing, such as in the form of gentle centrifugation, in order that any air bubbles may be removed prior to use of the collagen solution. More typically, the final
  • Lignocaine concentration of the collagen solution is from about 3-5 mg/ml, most typically 3-4mg/ml.
  • a third aspect of the present invention provides an injectable collagen composition produced by any one of the above processes.
  • a fourth aspect of the present invention provides a syringe prefilled with an injectable collagen composition comprising substantially 100% Type I collagen, said injectable composition having a pH in the range of from about 3 to 6 and a collagen concentration of from about 20-90 mg/ml and a viscosity such that said composition is injectable through at least a 30 gauge needle without blobbing.
  • An embodiment of the fourth aspect of the present invention provides a syringe prefilled with an injectable collagen composition comprising substantially 100% Type I collagen, said injectable composition having a pH in the range of from about 3 to 6 and a collagen concentration of from about 20-90 mg/ml and a viscosity such that said composition is injectable through at least a 30 gauge needle without blobbing when said composition is at a temperature in the range of from about 8 to 18°C.
  • a syringe prefilled with an injectable collagen composition comprising substantially 100% Type I collagen, said injectable composition having a pH in the range of from about 3 to 6 and a collagen concentration of from about 20-90 mg/ml and wherein said composition is substantially translucent to clear in appearance.
  • the pH of the composition is in the range of from about 3.5-5.5, more typically in the range of from about 4-5 and most typically in the range of from about 4.2-4.8.
  • the collagen concentration is in the range of from about 20-60 mg/ml, more typically in the range of from about 20-40mg/ml, most typically in the range of from about 22-38mg/ml.
  • a method of augmenting soft tissue which comprises injecting a composition of the present invention to a patient in need thereof.
  • Such augmentation includes the repair or correction of defects in soft tissue.
  • defects include frown lines, nasolabial creases, wrinkles and other superficial sclerodermal lines.
  • the product of the invention is translucent to clear and is not visible when injected into people having dark skin pigment.
  • the product of the invention is non turbid, non-immunogenic, injectable without blobbing through at least a 30 gauge needle and is also non crosslinked and of high purity.
  • the product is also of such viscosity that it is injectable when at a temperature in the range of about 8-18°C, and even when at a temperature of 10-12°C.
  • a temperature in the range of about 8-18°C and even when at a temperature of 10-12°C.
  • Collagen refers to all types and forms of collagen from any source, whether invivo or invitro produced, and is not limited to cross linked collagen but includes non- crosslinked collagen fibrils.
  • Collagen in solution refers to collagen which is in an acidic solution such that the collagen is in the non-fibrillar form.
  • injectable refers to compositions that can be dispensed from at least 30 gauge syringes under normal conditions and manual pressure without substantial blobbing.
  • “Clear” refers to the optical clarity wherein the product has substantially at least 90% transmittance of light at 410nm.
  • Translucent also refers to the optical clarity wherein the product has substantially at least 75% transmittance of light at 410nm.
  • “Blobbing” refers to the coagulating and/or lumping of the injectate. It also refers to the inability of a composition to be injected at a constant rate.
  • the bovine tendons or other mammalian connective tissue are processed in sterile conditions. Accordingly, the tissue is washed in bleach such as dilute hypochlorite solution as well as washed in sterile distilled water, so that the tissue and processing conditions are pyrogen free. Clean room conditions using sterile forceps and other instruments and wearing of sterile protective clothing is also observed.
  • Each tissue is differently processed according to what form of tissue it is. Typically, if the skin is being utilised as the collagen source, depilation and removal of any fat occurs. In the case of tendons, the skin is removed along with any fat and unwanted tissue.
  • Mechanical processing of the tissue takes the form of comminution by grinding, mincing or such similar physical treatment so that the tissue is finely fragmented or minced which enables collagen solubilisation to occur more effectively.
  • the collagen in the tissue is solubilised under non-denaturing conditions by dispersing the tissue fragments in an aqueous acidic medium and digesting with a proteolytic enzyme other than a collagenase.
  • the pH of the medium can be anywhere in the range of from about 1 to less than 7.
  • Mineral acids such as HC1 or carboxylic acids such as acetic and malonic, or a mixture of both carboxylic and mineral acids can be used to create the acidic medium.
  • An aqueous acidic solution comprising a mixture 5 of acetic acid with a small amount of concentrated fuming HC1 is preferred for the purposes of solubilisation.
  • the temperature at which solubilisation occurs is kept in the range of from about 4-25 °C in order to avoid denaturation.
  • the enzyme should be active at acidic pH and low temperatures and is usually o selected from such enzymes as pepsin, papain, trypsin and chymotrypsin.
  • the enzyme can be present in the acidic solution prior to the addition of the tissue, or alternatively can be added to the acidic solution after the tissue.
  • the enzyme concentration is typically in the range of from about 0.1 % to 5% by weight.
  • Digestion of the tissue with the enzyme can occur over any time from several 5 hours to weeks. At least 4 hours is preferred for digestion at lowered temperatures in the order of 5-15°C.
  • the solution is submitted to stirring in a blender which is performed in order to o help unweave the collagen fragments. Filtering and reconstitution is performed more easily and effectively on at least partly unwound collagen strands.
  • the blending occurs at a speed in the range of from about 3500 to 22000 rpm. Conveniently, blending can occur at a temperature in the range of from about 15-25 °C, and usually at around 20° C.
  • Filtering provides a preferred starting material by breaking up any fibrillar aggregates in the solution.
  • the solution which has been chilled is mechanically filtered through a 50 micron filter at temperatures, in the order of 5-25°C. This results in the collagen having improved flow characteristics and enhanced 0 injectability through fine gauge needles.
  • the aim of reconstitution is to reaggregate collagen fibrils such that they precipitate out of the filtered collagen solution in the form of a suspension.
  • This can be effected by raising the ionic strength and/or pH of the solution by such means as 5 adding a nonphosphate buffer and/or a non phosphate salt solution (which may or may not be buffered, but if buffered, a non-phosphate buffer is used) to a level where the collagen in solution re-aggregates into fibrils.
  • the pH is preferably in the range of from about 2-8, and most preferably in the range of from about 3.5 to about 7.5.
  • Sterile NaCl typically in the form of a solution is added in accordance with the present invention with stirring, to the solution.
  • the addition can occur at temperatures in the range of from about 4-25°C, usually around 20°C. Temperatures are preferably kept low to avoid crosslinking of the collagen fibrils.
  • the addition of the salt solution which can be buffered, but with non-phosphate buffers, results in the collagen in solution re-aggregating into atelopeptide fibrils. Fibril formation can take any time from 30 mins through to more than 24 hours.
  • the reaggregated collagen fibrils can be collected by centrifugation. Centrifugation preferably occurs for at least 30 minutes at an approximate speed of about 20,000-40,000 g.
  • the precipitated collagen gel can be resuspended in water or other buffer if required and the centrifugation process repeated. This acts to remove any remaining enzyme and also is a further purification step. The collagen gel is then transferred to sterile dialysis tubes or bags.
  • Dialysis Dialysis in sterile dialysis tubes or bags against three changes of distilled sterile water, with each dialysis period lasting for approximately 20-24 hours is typical.
  • the dialysis preferably occurs at such temperatures to avoid crosslinking of the collagen fibrils.
  • dialysis occurs at temperatures in the range of about 5-25°C, usually around 20°C.
  • the dialysis tubes preferably have a molecular weight cut off in the 5 range of about 5,000-10,000.
  • the concentration of the collagen in the dialysis tubes/bags can be monitored until the desired concentration is reached.
  • a variety of methods are available for the characterisation of soluble collagen, including gel electrophoresis (SDS-PAGE), which demonstrates the purity of the collagen and the collagen types present, and amino acid analysis which further distinguishes the collagen o types present.
  • a local anaesthetic agent preferably Lignocaine
  • Lignocaine is added to the collagen to a concentration of about 0.2-0.5% by weight to reduce local pain upon injection.
  • the collagen is then loaded into syringes having at least a 30 gauge needle, preferably a 31, 5 32 or 33 gauge needle.
  • All equipment is sterile and all sterile manipulations are performed in a Class A laminar air flow cabinet in a Class C clean room. 5 All non-self sterilising process fluids are sterile filtered (0.2 ⁇ ).
  • LAF Laminar Air Flow cabinet Class A
  • Waring Blender 0 Disposable 0.2 ⁇ capsule filters
  • the tendons are thawed and 1 cm of the ends removed with sterile scalpel.
  • the tendons are chemically sterilised in dilute (250 ppm) sodium 5 hypochlorite solution.
  • the tendons are minced and the mince collected in the LAF. 5.
  • the mince is weighed and transferred to sterile carboys containing per each lOOg of mince, 30 litres of 10% acetic acid, 20 ml of fuming HCl and lg of Pepsin.
  • the mixture is then blended in the Waring blender in batches and recombined in a carboy.
  • the solution is chilled for a period of time (can be up to 24 hours) and then filtered through a 50 ⁇ filter and collected in a carboy.
  • the collagen is centrifuged as before and the supernatant discarded.
  • the gel is transferred to sterile dialysis tubes of about 30 cm in length and dialysed against 3 changes of water at 24 hour intervals. 13. A representative sample of gel is analysed to determine collagen concentration.
  • the collagen is concentrated in the dialysis bag to above the required concentration.
  • the collagen gel is collected and the appropriate amount of lignocaine HCL solution is added to give the concentration of collagen as about 20-90mg/ml and the concentration of lignocaine HCl as about l-5mg/ml.
  • the product is thoroughly mixed, preferably by gentle centrifugation, to remove any air prior to filling the syringes fitted with 30-35 gauge needles with the collagen product.

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  • Gastroenterology & Hepatology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

L'invention concerne une composition de collagène injectable, qui contient sensiblement 100 % de collagène de type I, et qui a un pH compris entre 3 et 6 environ et une concentration en collagène comprise entre 20 et 90 mg/ml environ.
EP98912152A 1997-04-03 1998-04-03 Procede ameliore pour fabriquer du collagene Withdrawn EP0969740A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AUPO5998A AUPO599897A0 (en) 1997-04-03 1997-04-03 Clear collagen for facial implants
AUPO599897 1997-04-03
PCT/AU1998/000226 WO1998044809A1 (fr) 1997-04-03 1998-04-03 Procede ameliore pour fabriquer du collagene

Publications (1)

Publication Number Publication Date
EP0969740A1 true EP0969740A1 (fr) 2000-01-12

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP98912152A Withdrawn EP0969740A1 (fr) 1997-04-03 1998-04-03 Procede ameliore pour fabriquer du collagene

Country Status (6)

Country Link
EP (1) EP0969740A1 (fr)
JP (1) JP2001519695A (fr)
AU (1) AUPO599897A0 (fr)
CA (1) CA2285235A1 (fr)
NZ (1) NZ500666A (fr)
WO (1) WO1998044809A1 (fr)

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RU2273489C1 (ru) * 2004-08-17 2006-04-10 Андрей Федорович Панасюк Способ получения коллагена из костной ткани
RU2342162C1 (ru) * 2005-10-27 2008-12-27 Саващук Дмитрий Алексеевич Способ получения биоматериалов из костной ткани и полученный этим способом материал для остеопластики и тканевой инженерии
WO2007049988A1 (fr) * 2005-10-27 2007-05-03 Savaschuk, Dmitry Alekseevich Procede de fabrication de materiaux biologiques a partir de tissus osseux et materiau d'osteoplastie et d'ingenierie de tissus obtenu au moyen de ce procede
US8685092B2 (en) 2005-10-27 2014-04-01 Andrey Fedorovich Panasyuk Material for osteoplasty and tissue engineering
BR112013026200A2 (pt) 2011-04-14 2019-08-27 Lifecell Corp método para preparar uma composição de matriz de tecido, e matriz de tecido
CN105979912B (zh) * 2013-12-03 2021-08-20 康奈尔大学 修复环的方法和胶原凝胶组合物
KR101669478B1 (ko) * 2015-11-23 2016-10-26 세원셀론텍(주) 콜라겐의 수득율을 높이는 방법
CA3015685A1 (fr) * 2016-03-16 2017-09-21 Phoenix Tissue Repair, Inc. Procedes de purification de collagene 7
JP7297739B2 (ja) 2017-10-18 2023-06-26 ライフセル コーポレーション 脂肪組織製品および製造方法
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CA2285235A1 (fr) 1998-10-15

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