WO2009095790A1 - Preparation of terminally-sterilized collagen that is soluble at neutral ph - Google Patents
Preparation of terminally-sterilized collagen that is soluble at neutral ph Download PDFInfo
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- WO2009095790A1 WO2009095790A1 PCT/IB2009/000325 IB2009000325W WO2009095790A1 WO 2009095790 A1 WO2009095790 A1 WO 2009095790A1 IB 2009000325 W IB2009000325 W IB 2009000325W WO 2009095790 A1 WO2009095790 A1 WO 2009095790A1
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- collagen
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- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- 229940071536 silver acetate Drugs 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- 229940071575 silver citrate Drugs 0.000 description 1
- YSVXTGDPTJIEIX-UHFFFAOYSA-M silver iodate Chemical compound [Ag+].[O-]I(=O)=O YSVXTGDPTJIEIX-UHFFFAOYSA-M 0.000 description 1
- 229940045105 silver iodide Drugs 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 229960003600 silver sulfadiazine Drugs 0.000 description 1
- UEJSSZHHYBHCEL-UHFFFAOYSA-N silver(1+) sulfadiazinate Chemical compound [Ag+].C1=CC(N)=CC=C1S(=O)(=O)[N-]C1=NC=CC=N1 UEJSSZHHYBHCEL-UHFFFAOYSA-N 0.000 description 1
- LMEWRZSPCQHBOB-UHFFFAOYSA-M silver;2-hydroxypropanoate Chemical compound [Ag+].CC(O)C([O-])=O LMEWRZSPCQHBOB-UHFFFAOYSA-M 0.000 description 1
- CLDWGXZGFUNWKB-UHFFFAOYSA-M silver;benzoate Chemical compound [Ag+].[O-]C(=O)C1=CC=CC=C1 CLDWGXZGFUNWKB-UHFFFAOYSA-M 0.000 description 1
- MNMYRUHURLPFQW-UHFFFAOYSA-M silver;dodecanoate Chemical compound [Ag+].CCCCCCCCCCCC([O-])=O MNMYRUHURLPFQW-UHFFFAOYSA-M 0.000 description 1
- LTYHQUJGIQUHMS-UHFFFAOYSA-M silver;hexadecanoate Chemical compound [Ag+].CCCCCCCCCCCCCCCC([O-])=O LTYHQUJGIQUHMS-UHFFFAOYSA-M 0.000 description 1
- 239000002884 skin cream Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229960000553 somatostatin Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229940127230 sympathomimetic drug Drugs 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 229960003500 triclosan Drugs 0.000 description 1
- PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 1
- QUTYHQJYVDNJJA-UHFFFAOYSA-K trisilver;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Ag+].[Ag+].[Ag+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QUTYHQJYVDNJJA-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 230000001173 tumoral effect Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
-
- 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
- A61K38/18—Growth factors; Growth regulators
- A61K38/1875—Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
-
- 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
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/02—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using physical phenomena
- A61L2/08—Radiation
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/102—Collagen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- 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
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
-
- 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
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/16—Materials with shape-memory or superelastic properties
Definitions
- the present disclosure relates to collagen compositions and methods for their preparation. More specifically, terminally sterilized collagen which remains fully soluble at a neutral pH while maintaining most of the initial properties of native collagen, like in particular viscosity characteristics, is described.
- soluble when used with regards to collagen, it is meant that the collagen is soluble in water.
- SUMMARY Methods for making collagen preparations include chemically modifying collagen to render the collagen soluble at physiological pH, neutralizing the chemically modified collagen to a physiological pH, optionally drying the neutralized chemically modified collagen, packaging the neutralized chemically modified collagen in sealed units, and irradiating the packaged, neutralized chemically modified collagen with a dose of radiation, for example beta-radiation, equal to or lower than about 25 KGy.
- the collagen is chemically modified by reacting collagen with a water soluble aliphatic alcohol to esterify the collagen.
- methods for making collagen preparations include chemically modifying collagen to render the collagen soluble at physiological pH, neutralizing the chemically modified collagen to a physiological pH, optionally drying the neutralized chemically modified collagen, packaging the neutralized chemically modified collagen, and irradiating the packaged, neutralized chemically modified collagen with a dose of radiation, for example beta-radiation, equal to or lower than about 25 KGy.
- the dried, neutralized chemically modified collagen is stored at or below about 30 0 C before the irradiating step.
- the irradiating is irradiating with beta-radiation, for example at a dosage from about 6 KGy to about 25 KGy, preferably at a dosage from about 6 KGy to about 15 KGy, and more preferably at a dosage from about 10 KGy to about 15 KGy.
- the irradiating with beta-radiation is at a dosage lower than about 15 KGy, preferably lower than about 10 KGy.
- irradiating is performed as multiple cycles of irradiating doses wherein the total dose of radiation is equal to or lower than about 25 KGy.
- irradiating is performed at a temperature below O 0 C.
- chemically modifying collagen comprises esterifying collagen, for example by reacting collagen with a water soluble aliphatic alcohol.
- packaging comprises sealing the neutralized chemically modified collagen in a syringe.
- a collagen preparation comprising terminally sterilized neutralized chemically modified collagen that is soluble at physiological pH.
- the collagen has at least in part an intact triple helical structure.
- the collagen is porcine.
- Another aspect of the present disclosure is a fiber formed from a collagen preparation as described above.
- Another aspect of the present disclosure is a tissue sealant or tissue adhesive comprising a collagen preparation as described above.
- the tissue sealant or tissue adhesive may further include oxidized starch.
- Another aspect of the present disclosure is a collagen preparation as described above in combination with a bioactive agent.
- Another aspect of the present disclosure is a collagen preparation as described above that is injectable and contained within a syringe.
- a bone filler comprising a collagen preparation as described above that contains one or more bone morphogenic proteins, is injectable and contained within a syringe.
- Another aspect of the present disclosure is a method comprising: combining a collagen preparation comprising terminally sterilized neutralized chemically modified collagen that is soluble at physiological pH with a sterile composition comprising a bioactive agent to provide a formulation suitable for application to tissue.
- the present disclosure relates to formulation comprising i) a collagen preparation comprising terminally sterilized neutralized chemically modified collagen that is soluble at physiological pH and ii) a sterile composition comprising a bioactive agent.
- the collagen preparations described herein are formulated to be injectable and may be packaged in syringes. In embodiments, the collagen preparations described herein are formulated to be suitable for use as a tissue sealant and a tissue adhesive. In embodiments, the collagen preparations described herein are formulated to include one or more bone morphogenic proteins to render them suitable for repair of bone or cartilage defects.
- BRIEF DESCRIPTION OF THE DRAWINGS Figure IA shows the DSC (differential scanning calorimetry) profile of non-/3- irradiated acid collagen as a control.
- Figure IB shows the DSC profile of acid collagen that has been /3-irradiated at 6 KGy.
- Figure 1 C shows the DSC profile of acid collagen that has been /3-irradiated at 10
- Figure 2 A shows the DSC profile of non-jS-irradiated esterified collagen as a control.
- Figure 2B shows the DSC profile of esterified collagen that has been /3-irradiated at 6 KGy.
- Figure 2C shows the DSC profile of esterified collagen that has been /3-irradiated at 10 KGy.
- Figure 3 A shows the DSC profile of non-jS-irradiated neutral collagen as a control.
- Figure 3B shows the DSC profile neutral collagen that has been /3-irradiated at 6
- Figure 3C shows the DSC profile neutral collagen that has been /3-irradiated at 10 KGy.
- Figure 4 shows the electrophoretic pattern of /3-irradiated collagens, specifically: /3-irradiated neutral collagen (samples RHEOOOl 5 /S-irradiated at 6 KGy and RHI00016 ⁇ - irradiated at 10 KGy); / S-irradiated acid collagen (samples RHIOOO 17 ⁇ - irradiated at 6 KGy and RHIOOO 18 /3-irradiated at 10 KGy); /3-irradiated esterified collagen (samplesRHI00019 /3-irradiated at 6 KGy RHI00020 /3-irradiated at 10 KGy); non-/3- irradiated collagen (control sample CHE00341); and non-/3-irradiated esterified collagen (control sample RHH00032).
- /3-irradiated neutral collagen samples RHEOOOl 5 /S-irradiated at 6 KGy and RHI00016 ⁇ -
- Figure 5 shows the electrophoretic pattern of ⁇ -irradiated collagens, specifically: ⁇ irradiated esterified collagen (samples RGI00008 ⁇ irradiated at 8-9 KGy, RGI00009 ⁇ - irradiated at 6-8 KGy in dry ice, RGIOOOlO -y-irradiated at 14-15 KGy, RGIOOOI l y- irradiated at 11-14 KGy in dry ice, RGI00012 - ⁇ irradiated at 29-34 KGy, and RGI00013 ⁇ -irradiated at 28-30 KGy in dry ice).
- ⁇ irradiated esterified collagen examples RGI00008 ⁇ irradiated at 8-9 KGy, RGI00009 ⁇ - irradiated at 6-8 KGy in dry ice, RGIOOOlO -y-irradiated at 14-15 KGy, RGIOOOI l y- irradiated
- Collagen preparations in accordance with the present disclosure are for example prepared by exposing chemically modified collagen to a dose of beta-irradiation sufficient to effect sterilization.
- the collagen material is first chemically modified, so as to obtain collagen which is soluble at a physiologic pH and at body temperature. It is then neutralized at a physiological pH and optionally dried before being terminally sterilized.
- the processes for preparing and irradiating collagen are described in greater detail below.
- Collagen of any type may be used, including, but not limited to types I, ⁇ , III, IV, and V, forms of minor collagen, or any combinations thereof.
- the collagen may be from any source, such as, for example, human, bovine, or porcine, and may be derived from the skin, tendon, muscle, connective tissues, or any other naturally occurring structural element having a high collagen content.
- Collagen may also be synthetic collagens recombinantly or otherwise produced, such as, for example, by tissue engineering.
- type I porcine or bovine collagen is used.
- type I and type III collagen from different animal origins, such as bovine, porcine, human, or mixtures in any proportions of types are used.
- Collagen refers to all forms of collagen, including those which have been processed or otherwise modified.
- Native collagen is characterized as fibrous proteins that are long, rigid rod-like structures that are made up of three polypeptide chains wound together in a triple helix configuration having non-helical terminal portions.
- the collagen used has intact triple helical structures to provide collagen preparations which display a much higher viscosity in solution and that are less prone to degradation by enzymes than thermally denatured collagens.
- thermally denatured collagens which have at least partially lost its helical structure commonly known as gelatins, may be used.
- Atelopeptide or telopeptide-containing collagen may be used. Telopeptides, the nonhelical terminal portions of collagen, extend as random coils from the amino and carboxy ends of the collagen molecules. The telopeptides serve as the primary sites for intramolecular and intermolecular cross-linking and are sites of immunogenicity. In embodiments, atelocollagens from an animal source, such as a bovine or porcine source, are used because of their reduced immunogenicity.
- telopeptides can be removed.
- Atelocollagens are produced by any technique known to those skilled in the art, including, but not limited to, methods using proteolytic enzymes.
- pepsin may be used as described by Miyata, et al. in U.S. Pat. No 4,164,559, the entire contents of which are incorporated herein by this reference. Briefly, this technique involves solubilizing a collagen material with pepsin and precipitating the soluble collagen at a pH of about 7.0 after in-activation of enzyme activity by caustic treatment at a pH of about 10.0.
- the collagen is purified by repeating re-dissolution in acidic water at a pH of about 2.0 to about 4.0 and re-precipitation at a pH of about 7.0.
- Soluble collagen at a physiological pH refers to collagen that is chemically modified in such a way that it is soluble at a physiological pH and at body temperature by any known methods, such as by acid extraction or with a proteolytic enzyme, such as pepsin, as described above.
- proteolytic enzymes which are not specific collagenases may be used to solubilize collagen without denaturation. For example, in addition to pepsin, trypsin, chymotrypsin, or papain may be used.
- Chemical modification of collagen to provide soluble collagen at a physiological pH may be accomplished by esterification of the collagen carboxyl groups by any known methods, including reaction with acidified alcohol, such as a water-soluble aliphatic alcohol such as, methanol, ethanol, and the like. Suitable techniques for chemically modifying collagen to render the collagen soluble at physiological pH are described, for example in U.S. Patent No. 4,164,559, the entire contents of which are incorporated herein by this reference. For example, ethylation of type I atelocollagen renders them soluble at a pH of about 5.5 to about 9.0 and, particularly, in the range of 7.0 to 7.5.
- the unmodified atelocollagen is soluble only in an acidic pH lower than 5.0 or in an alkaline pH above 9.0. Once collagen, soluble at a physiological pH, is obtained, it is for example neutralized at a pH from about 6.0 to about 8.0, in embodiments at a physiological pH.
- Physiological pH refers to a pH that is in a relatively narrow range as normally encountered in the fluids of the human body, generally in the range of about 7.0 to about 7.5.
- the soluble collagen at a physiological pH is then optionally dried by any known relevant methods, including, but not limited to, drying in an oven under vacuum, freeze drying, and dehydration by solvents such as acetone.
- the optionally dried collagen is packaged under any suitable known sealed or closed units relevant to the final use of such collagens.
- Packaging units include syringes, vials, pouches, plates, jars, tubes, and any other casing appropriate for the ultimate use of product.
- the terminally packaged collagen may then be stored at a temperature below 3O 0 C until it is sterilized by beta-irradiation.
- Sterilization is generally performed on the terminally packaged collagen by irradiation.
- Sterilization refers to collagen that is treated via a single procedure or a combination of procedures which reduce the number of microorganisms capable of growing in the collagen under conditions at which the collagen is stored and/or distributed and is below a level determined by a standardized sterilization protocol and/or validation test.
- Terminal sterilization refers to collagen that is sterilized as defined above, in its final packaging for storage and distribution prior to use.
- the sterilization process is for example performed at room temperature or any temperature lower than room temperature according to any known suitable methods.
- Room temperature refers to the temperature generally recorded in irradiation facilities, in embodiments, room temperature is less than 50 0 C, more generally 25 0 C ⁇ 5 0 C.
- sterilization is effected on dry ice at a temperature below 0 0 C.
- Sterilization is performed at a sterilizing total dose equal to or lower than 25 KGy.
- the sterilization is performed by beta-irradiation at a sterilizing total dose lower than 15 KGy.
- the sterilization is performed by beta- irradiation at a sterilizing total dose lower than 10 KGy.
- Sterilizing doses may include one or more cycles of irradiation except that the total cumulative dose should by lower than or equal to values mentioned above.
- Collagen soluble at physiological pH is not extensively degraded by the beta-irradiation sterilization treatment.
- the collagen keeps most of its initial properties (e.g. molecular weight profile, viscosity, thermal properties, etc).
- ethylated type I atelocollagen remains soluble at a physiological pH after its sterilization by beta-irradiation.
- a solution of ethylated type I atelocollagen is as viscous as it is before beta-irradiation.
- type I collagen is degraded to such an extent that it is no longer soluble.
- beta-irradiated esterif ⁇ ed collagen can be unlimitedly envisaged wherever specialists in relevant fields might advantageously consider using terminally sterilized collagens with features similar to native collagen.
- Non-limiting examples of how beta- irradiated esterified collagen may be used include, but are not limited to, as a component of sealants, adhesives, matrices for healing and regeneration of tissues and organs, wound dressings, osteogenic formulations, chondrogenic formulations, matrices for drug delivery, hemostatic products, cosmetic formulations, fillers for wrinkles and lips, skin creams, as well as, a medium for cell cultures, medium for microorganism cultures, and a reagent for in vitro and in vivo tests.
- beta-irradiated esterified collagen can be used in the formation of fibers and devices made from such fibers.
- Matrices, scaffolds, and meshes made from the collagen of the present disclosure and produced in accordance with the methods described herein have properties particularly useful in medical and surgical applications.
- applications include, but are not limited to, surgical sutures, blood vessel grafts, catheters, and in general, the fabrication of surgical prostheses and artificial organs.
- Techniques for making fibers from collagen are within the purview of those skilled in the art and include, but are not limited to the techniques disclosed in U.S. Paten Nos. 6,997,231 and 6,361,551 the entire disclosures of which are incorporated herein by this reference.
- Beta-irradiated esterified collagen after some handling and just before use, can be used in the form of pastes, gels, solutions, or suspensions, homogeneous or heterogeneous, which are contained in syringes, tubes, or other containers equipped with appropriate plungers, sprayers, or systems designed to extrude the collagen content, such as through a needle or a nozzle.
- the collagen may be injected, surgically applied through a trocar, or directly applied on a wound surface.
- the collagen paste, gel, solution, or suspension is of a similar viscosity before and after its terminal sterilization as it remains fully soluble.
- bioactive agent may be combined with the collagen for use in the present compositions.
- the collagen preparation can also serve as a vehicle for delivery of the bioactive agent.
- bioactive agent is used in its broadest sense and includes any substance or mixture of substances that have clinical use. Consequently, bioactive agents may or may not have pharmacological activity per se, e.g., a dye, or fragrance.
- a bioactive agent could be any agent which provides a therapeutic or prophylactic effect, a compound that affects or participates in tissue growth, cell growth, cell differentiation, an anti-adhesive compound, a compound that may be able to invoke a biological action such as an immune response, or could play any other role in one or more biological processes.
- the bioactive agent is added to irradiated, esterified collagen immediately prior to use.
- the bioactive agent can be separately provided in a sterile package of known types, such as within a syringe.
- the contents of a syringe of sterile collagen can be mixed with the contents of a syringe containing sterile bone morphogenic protein (BMP) to provide a formulation suitable for bone repair.
- BMP bone morphogenic protein
- one or more bioactive agents are added to the collagen preparation prior to sterilization of the collagen.
- bioactive agents examples include anti-adhesives, antimicrobials, analgesics, antipyretics, anesthetics, antiepileptics, antihistamines, antiinflammatories, cardiovascular drugs, diagnostic agents, sympathomimetics, cholinomimetics, antimuscarinics, antispasmodics, hormones, growth factors, muscle relaxants, adrenergic neuron blockers, antineoplastics, immunogenic agents, immunosuppressants, gastrointestinal drugs, diuretics, steroids, lipids, lipopolysaccharides, polysaccharides, and enzymes. It is also intended that combinations of bioactive agents may be used.
- Anti-adhesive agents can be used to prevent adhesions from forming between implantable medical devices and the surrounding tissues opposite the target tissue.
- Some examples of these agents that may be included in the present compositions include, but are not limited to poly(vinyl pyrrolidone), carboxymethyl cellulose, hyaluronic acid, polyethylene oxide, poly vinyl alcohols and combinations thereof.
- Suitable antimicrobial agents which may be included as a bioactive agent in the compositions of the present disclosure include triclosan, also known as 2,4,4'-trichloro-2'- hydroxydiphenyl ether, chlorhexidine and its salts, including chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, and chlorhexidine sulfate, silver and its salts, including silver acetate, silver benzoate, silver carbonate, silver citrate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein, and silver sulfadiazine, polymyxin, tetracycline, aminoglycosides, such as tobramycin and gentamicin, rifampicin, bacitracin, neomycin, chloramphenicol, miconazole, quinolones such as oxolinic acid, norfloxacin
- antimicrobial proteins and peptides such as bovine lactoferrin and lactoferricin B and antimicrobial polysaccharides such as fucans and derivatives may be included as a bioactive agent in the bioactive coating of the present disclosure.
- bioactive agents which may be included as a bioactive agent in the compositions in accordance with the present disclosure include: local anesthetics; nonsteroidal antifertility agents; parasympathomimetic agents; psychotherapeutic agents; tranquilizers; decongestants; sedative hypnotics; steroids; sulfonamides; sympathomimetic agents; vaccines; vitamins; antimalarials; anti-migraine agents; anti- parkinson agents such as L-dopa; anti-spasmodics; anticholinergic agents (e.g.
- oxybutynin antitussives
- bronchodilators cardiovascular agents such as coronary vasodilators and nitroglycerin
- alkaloids analgesics
- narcotics such as codeine, dihydrocodeinone, meperidine, morphine and the like
- non-narcotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like
- opioid receptor antagonists such as naltrexone and naloxone
- anti-cancer agents anti-convulsants; anti-emetics
- antihistamines anti-inflammatory agents such as hormonal agents, hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, indomethacin, phenylbutazone and the like
- prostaglandins and cytotoxic drugs estrogens; antibacterials; antibiotics; anti-fungals; anti-virals; anticoagulants;
- bioactive agents include viruses and cells, peptides, polypeptides and proteins, analogs, muteins, and active fragments thereof, such as immunoglobulins, antibodies, cytokines (e.g.
- lymphokines monokines, chemokines
- blood clotting factors hemopoietic factors, interleukins (LL-2, EL-3, IL-4, EL-6), interferons ((3-EFN, (a-EFN and y-IFN), erythropoietin, nucleases, tumor necrosis factor, colony stimulating factors (e.g., GCSF, GM-CSF, MCSF), insulin, anti-tumor agents and tumor suppressors, blood proteins, gonadotropins (e.g., FSH, LH, CG, etc.), hormones and hormone analogs (e.g., growth hormone), vaccines (e.g., tumoral, bacterial and viral antigens); somatostatin; antigens; blood coagulation factors; growth factors (e.g., nerve growth factor, insulin-like growth factor); factors useful in the repair of bone or cartilage such as bone morphogenic proteins (BMPs); protein inhibitors, protein antagonists, and protein
- the following non-limiting examples show properties of beta-irradiated esterif ⁇ ed collagen as well as a comparison data of the beta-irradiated esterified collagen with the beta-irradiated acid and neutral collagens, as well as with gamma-irradiated esterified collagen.
- Type I porcine collagen is solubilized at an acidic pH or by pepsin digestion and then purified by saline precipitation using conventional techniques. Dry collagen fibers are obtained by the precipitation of an acid solution of collagen by adding NaCl, and then washing and drying the precipitate obtained with an aqueous solution of acetone having an increasing concentration from 80% to 100%. 2°) Neutral Collagen
- Type I porcine collagen obtained as described above at 1°) is solubilized in water at a concentration of 30 g/1.
- the pH of the subsequent collagen preparation is neutralized with the addition of dilute sodium hydroxide solution, at a pH between 7.0 and 7.5.
- the collagen is then dried either by acetone washing or by freeze-drying. 3°)
- Esterified Collagen Twenty grams of dry collagen fibers as obtained at 1°) above are immersed in one liter of dehydrated ethanol containing 0.1 N HCl for seven days at room temperature in a closed vessel. Dehydration of ethanol containing HCl prior to the addition of collagen is carried out by intermittent stirring with excess of anhydrous sodium sulphate. After ethylation, the solvent is removed.
- the esterified collagen fibers are then washed several times with acetone. They are then dried and solubilized in water at a final concentration of 1% w/v. The pH of the solution is adjusted between 7.0 and 7.5 and the collagen is freeze-dried. Sterilization of Collagen The acid collagen, neutral collagen, and esterified collagen obtained as described above are individually filled in syringes. The syringes are then packed in sealed bags. The collagen syringes are sterilized by beta-irradiation at different doses ranging from 6 KGy to 25 KGy.
- the esterified collagen as described above is also sterilized by beta-irradiation at different doses, ranging from 6KGy to 25 KGy, on dry ice, at a temperature lower than O 0 C.
- beta-irradiated coHagens Properties of the beta-irradiated coHagens are shown individually for beta- irradiated esterified collagen and comparatively for beta-irradiated acid collagen, neutral collagen, and esterified collagen.
- Beta-irridated esterified collagen was evaluated as follows: Collagen was first solubilized by incorporating 150 mg of dry collagen (assumed residual water content: 10 %) in 100 ml of water, at a neutral pH. The preparation was centrifuged at 10 000 rpm, during 4 min. The total amount of collagen in the supernatant was dosed by the Biuret method and was compared to the total amount of collagen initially present in the preparation, before its centrifugation. As shown in Table 2, irradiated esterified collagens were as soluble as non-irradiated esterified collagens. TABLE 2
- the plastic viscosity and yield stress of different batches of beta-irradiated esterified collagen were measured at +25 0 C, in solution, at a concentration of 2% w/v, according to Bingham's model. Values were acquired with the TVe-05 Lamy viscosimeter, between 300 and 600 rpm. As shown in Table 3, values were in the same range before and after beta-irradiation, at 6 KGy and 10 KGy. Irradiated esterified collagen remained fully soluble when beta- irradiated at 6KGy and 10 KGy, and only partially soluble at 25 KGy.
- the viscosity of the different batches of beta-irradiated esterified collagen and beta-irradiated acid collagen were measured at +25°C, in solution, at a concentration of 2% w/v, as described above. Viscosity measurements were also carried out on neutral collagen, after heating to a temperature of +50 0 C, so as to obtain gelatin.
- Beta-irradiated neutral collagen was not soluble, whatever the dose of beta- irradiation, either at an acid pH or after heating at +42 0 C at a neutral pH. After heating, the solution did not form a gel at room temperature, even at a concentration up to 4% w/v whereas non-irradiated neutral collagen, after heating, gave a gel at a concentration lower than 1% w/v at room temperature. Irradiated acid collagen was soluble, but did not gelify after heating at +42°C. Irradiated esterified collagen was as soluble as the esterified collagen that had not been irradiated. TABLE 4
- Thermal properties were not substantially modified for esterified collagen after beta-irradiation up to 10 KGy, whereas they were degraded for irradiated acid and neutral collagens, degraded to a larger extent for the latter.
- Electrophoretic Properties of Beta-irradiated CoUagens Electrophoresis of collagen was carried out on CriterionTM XT 7% Tris Acetate precast gels, by using the running buffer XT Tricine Running Buffer 2Ox (BioRad). Sample preparation included XT Reducing Agent (BioRad). Gels were stained with Bio- Safe Coomassie (BioRad), according to BioRad instructions.
- Beta-irradiated neutral collagen showed a deeply altered electrophoretic profile, with no visible bands, but with an extended trail. Electrophoretic properties of esterified collagen and acid collagen were not substantially modified after beta-irradiation, at doses up to 10KGy.
- Adhesive collagen based compositions for surgical and/or therapeutic use may be prepared as described by Tardy et al. in U.S. Patent No. 6,165,488, the entire contents of which are incorporated herein by this reference. Briefly, the composition generally contains an aqueous solution of oxidized starch, a biodegradable polysaccharide, and an aqueous solution of heated collagen (i.e. gelatine).
- the composition is obtained by mixing together oxidized starch and collagen, by incorporating air bubbles, or not, at a neutral pH.
- the mixing provides a gel which is rapidly applied to tissues and/or biomaterials to achieve binding.
- the adhesiveness is the result of the combination of the chemical reaction of oxidized starch aldehydes with the free amino groups of collagen as well as the unique properties of collagen (e.g., viscosity or hydropathic properties).
- the heated collagen was replaced with esterified collagen beta-irradiated at a dose of 6 KGy.
- Beta-irradiated esterified collagen - batch RGK00026 - was solubilized at a concentration of 4% w/v.
- Two ml of the corresponding solution in a first syringe were mixed with 0.7ml of 1.5% w/v oxidized starch - batch ZFE00523 x2 - diluted in a second syringe, by transferring the products from one syringe to another one, back and forth, several times.
- Beta-irradiated esterified collagen - batch RGK00026 - was also used alone, without oxidized starch at a concentration of 8% w/v.
- Sample C PrevadhTM foam was prepared from instructions for use from a SOFRADIM commercial kit Two ml of heated collagen at a concentration of 16% w/v - batch SCC23330 - were crosslinked with 0.7 ml of oxidized starch at a concentration of 3% w/v - batch SA024016. Adhesion strength
- Esterified collagen when compared to acid and neutral collagen, was the only one to be safely sterilized by beta-irradiation at doses lower than 25 KGy. Analytical results have shown that irradiated esterified properties were similar to the non-irradiated counterpart.
- Collagen was prepared as described above in Example 1 for esterified collagen. Sterilization of Collagen
- Esterified collagen syringes were prepared as described above in Example 1, but were sterilized by gamma-irradiation at different doses ranging from 6 KGy to 30 KGy, either at room temperature or at a temperature below 0 0 C, in dry ice. Analysis of gamma-irradiated collagen Esterified collagen gave translucent solutions showing some viscosity, but increasing the dose of y irradiation clearly decreased the viscosity, except for collagens irradiated at doses above 25 KGy which are presumed to be completely degraded, This was correlated with electrophoretic analysis showing more obvious signs of degradation with increasing gamma-irradiation dose.
- Gamma irradiation was less effective than beta-irradiation in keeping initial properties of esterified collagen. Even, at low doses, around 10 KGy, esterified collagens were obviously altered when sterilized by gamma-irradiation. Gamma-irradiation for the preparation of sterile preparation of esterified collagen is less advantageous than beta- irradiation.
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AU2009208729A AU2009208729A1 (en) | 2008-01-31 | 2009-01-30 | Preparation of terminally-sterilized collagen that is soluble at neutral pH |
US12/865,039 US20100331257A1 (en) | 2008-01-31 | 2009-01-30 | Preparation of terminally-sterilized collagen that is soluble at neutral ph |
EP09706664A EP2238163A1 (en) | 2008-01-31 | 2009-01-30 | Preparation of terminally-sterilized collagen that is soluble at neutral ph |
JP2010544815A JP2011510971A (en) | 2008-01-31 | 2009-01-30 | Production of terminally sterilized collagen soluble at neutral pH |
CA2713358A CA2713358A1 (en) | 2008-01-31 | 2009-01-30 | Preparation of terminally-sterilized collagen that is soluble at neutral ph |
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US8273725B2 (en) | 2009-09-10 | 2012-09-25 | Genzyme Corporation | Stable hyaluronan/steroid formulation |
JP2014507135A (en) * | 2011-01-19 | 2014-03-27 | セウォン セロンテック カンパニー リミテッド | Radiation-crosslinked collagen gel and method for producing and using the same |
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FR3015050B1 (en) * | 2013-12-18 | 2017-02-17 | Inst De Radioprotection Et De Surete Nucleaire | RADICAL SPECIES AND METHOD FOR MEASURING RECEIVED DOSES |
US10173375B2 (en) | 2014-03-05 | 2019-01-08 | Bacterin International, Inc. | Shaped fiber-based products and method of manufacture thereof |
US10821004B2 (en) | 2015-06-30 | 2020-11-03 | Bacterin Interational, Inc. | Expandable bone grafts and methods of manufacture thereof |
JP2020031668A (en) * | 2016-12-28 | 2020-03-05 | 公益財団法人神戸医療産業都市推進機構 | Medical adhesive |
WO2020004646A1 (en) * | 2018-06-29 | 2020-01-02 | 国立研究開発法人量子科学技術研究開発機構 | Hydrogel for cell culture, gel kit, method for producing cell culture, and method for producing hydrogel for cell culture |
CN113736841A (en) * | 2021-10-09 | 2021-12-03 | 广州俪灵生物科技有限公司 | Preparation method of soluble type I collagen and application of soluble type I collagen in cosmetics |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US4164559A (en) * | 1977-09-21 | 1979-08-14 | Cornell Research Foundation, Inc. | Collagen drug delivery device |
US5674290A (en) * | 1995-04-05 | 1997-10-07 | Li; Shu-Tung | Water-stabilized biopolymeric implants |
US6706684B1 (en) * | 1998-11-30 | 2004-03-16 | Imedex Biomateriaux | Method for preparing a collagen material with controlled in vivo degradation |
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NZ527014A (en) * | 2001-01-04 | 2005-06-24 | Osteotech Inc | Method for sterilizing bioactive materials by irradiating in the presence of hydrogen gas |
US7371345B2 (en) * | 2002-12-23 | 2008-05-13 | Closure Medical Corporation | Sterilization of medical adhesive kits |
MX2007014480A (en) * | 2005-05-19 | 2008-04-22 | Albiorex Llc | Terminal sterilization of injectable collagen products. |
-
2009
- 2009-01-30 WO PCT/IB2009/000325 patent/WO2009095790A1/en active Application Filing
- 2009-01-30 CA CA2713358A patent/CA2713358A1/en not_active Abandoned
- 2009-01-30 JP JP2010544815A patent/JP2011510971A/en active Pending
- 2009-01-30 US US12/865,039 patent/US20100331257A1/en not_active Abandoned
- 2009-01-30 EP EP09706664A patent/EP2238163A1/en not_active Withdrawn
- 2009-01-30 AU AU2009208729A patent/AU2009208729A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4164559A (en) * | 1977-09-21 | 1979-08-14 | Cornell Research Foundation, Inc. | Collagen drug delivery device |
US5674290A (en) * | 1995-04-05 | 1997-10-07 | Li; Shu-Tung | Water-stabilized biopolymeric implants |
US6706684B1 (en) * | 1998-11-30 | 2004-03-16 | Imedex Biomateriaux | Method for preparing a collagen material with controlled in vivo degradation |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8273725B2 (en) | 2009-09-10 | 2012-09-25 | Genzyme Corporation | Stable hyaluronan/steroid formulation |
US8680073B2 (en) | 2009-09-10 | 2014-03-25 | Genzyme Corporation | Stable hyaluronan/steroid formulation |
JP2014507135A (en) * | 2011-01-19 | 2014-03-27 | セウォン セロンテック カンパニー リミテッド | Radiation-crosslinked collagen gel and method for producing and using the same |
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EP2238163A1 (en) | 2010-10-13 |
AU2009208729A1 (en) | 2009-08-06 |
CA2713358A1 (en) | 2009-08-06 |
US20100331257A1 (en) | 2010-12-30 |
JP2011510971A (en) | 2011-04-07 |
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