EP0668081A2
Expired / Lapsed
EP
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Collagen-synthetic polymer conjugates having controlled fiber size distributions
Assignee: Collagen Aesthetics Inc
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Filing: 1995-02-13
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Granted: —
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Expires: 2015-02-13
Abstract
Abstract Current commercially available fibrillar collagen compositions tend to have heterogeneous fiber size populations, including very large fibers, which are not conducive to efficient crosslinking using chemical crosslinking agents. The present invention discloses preferred methods for producing collagens having relatively homogeneous, controlled fiber size populations, which are then covalently conjugated to synthetic hydrophilic polymers, such as functionally activated polymeric glycols, to produce collagen-synthetic polymer conjugates having unique physical and chemical characteristics. The resulting conjugates are used to prepare formed implants or injectable formulations for use in a variety of therapeutic applications. Compositions of the conjugates may include additional components, such as pharmaceutically acceptable fluid carriers and/or biologically active molecules such as growth factors or cytokines.
Inventors
- 👤 Woonza M. Rhee
Bibliographic Details
Application Number
—
Jurisdiction
EP
Data Source
google_patents
Last Synchronized
2026-10-23 11:48
CPC Classifications
C; C08; C08H; C08H1/00; C08H1/06; A; A61; A61L; A61L27/00; A61L27/14; A61L27/22; A61L27/24; C08G; C08G81/00; C08L; C08L89/00; C08L89/04; C08L89/06; A61F; A61F2310/00; A61F2310/00005; A61F2310/00365
Claims Analysis
Total Claims: 45
Claim 1
Independent Claim
33 words
A conjugate comprising collagen covalently bound to a synthetic hydrophilic polymer, wherein the collagen comprises fibers, at least 80% of which collagen fibers have a fiber size of about 10 µm or less.
Claim 2
Dependent Claim
33 words
A conjugate comprising collagen covalently bound to a synthetic hydrophilic polymer, wherein the collagen comprises fibers, at least 80% of which collagen fibers have a fiber size of about 10 µm or less.
Claim 3
Dependent Claim
35 words
An optically clear conjugate comprising collagen covalently bound to a synthetic hydrophilic polymer, wherein the collagen comprises fibers, at least 80% of which collagen fibers have a fiber size of about 8.0 µm or less.
Claim 4
Dependent Claim
35 words
An optically clear conjugate comprising collagen covalently bound to a synthetic hydrophilic polymer, wherein the collagen comprises fibers, at least 80% of which collagen fibers have a fiber size of about 8.0 µm or less.
Claim 5
Dependent Claim
28 words
A conjugate comprising collagen covalently bound to a synthetic hydrophilic polymer, wherein the collagen comprises fibers having a mean fiber size between about 5.0 and about 8.0 µm.
Claim 6
Dependent Claim
28 words
A conjugate comprising collagen covalently bound to a synthetic hydrophilic polymer, wherein the collagen comprises fibers having a mean fiber size between about 5.0 and about 8.0 µm.
Claim 7
Dependent Claim
15 words
The conjugate of any one of the preceding claims, wherein the collagen is atelopeptide collagen.
Claim 8
Dependent Claim
24 words
The conjugate of any one of the preceding claims, wherein the synthetic hydrophilic polymer is a functionally activated, preferably a difunctionally activated, polyethylene glycol.
Claim 9
Dependent Claim
41 words
The conjugate of any one of the preceding claims, wherein the collagen and the synthetic hydrophilic polymer are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.
Claim 10
Dependent Claim
33 words
The conjugate of any one of the preceding claims, wherein 80% of the collagen fibers have a fiber size of about 8.5 /1.m or less, and preferably of about 8.0 /1.m or less.
Claim 11
Dependent Claim
14 words
The conjugate of any one of the preceding claims, wherein the conjugate is translucent.
Claim 12
Dependent Claim
16 words
The conjugate of any one of claims 1 to 7, wherein the conjugate is optically clear.
Claim 13
Dependent Claim
37 words
An implant composition comprising a conjugate comprising collagen covalently bound to a synthetic hydrophilic polymer, wherein the collagen comprises fibers, at least 80% of which collagen fibers have a fiber size of about 10 µm or less.
Claim 14
Dependent Claim
37 words
An implant composition comprising a conjugate comprising collagen covalently bound to a synthetic hydrophilic polymer, wherein the collagen comprises fibers, at least 80% of which collagen fibers have a fiber size of about 10 µm or less.
Claim 15
Dependent Claim
11 words
The implant of claim 10, wherein the collagen is atelopeptide collagen.
Claim 16
Dependent Claim
22 words
The implant of claim 10 or 11, wherein the synthetic hydrophilic polymer is a functionally activated, preferably a difunctionally activated, polyethylene glycol.
Claim 17
Dependent Claim
42 words
The implant of any one of claims 10 to 12, wherein the collagen and the synthetic hydrophilic polymer are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.
Claim 18
Dependent Claim
29 words
The implant of claim 20, wherein 80% of the collagen fibers have a fiber size of about 8.5 µm or less, and preferable of about 8.0 µm or less.
Claim 19
Dependent Claim
15 words
The implant of any one of claims 10 to 14, wherein the conjugate is translucent.
Claim 20
Dependent Claim
16 words
The imlant of any one of claims 10 to 14, wherein the conjugate is optically clear.
Claim 21
Dependent Claim
65 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension comprising collagen fibers, at least 80% of which collagen fibers have a fiber size of about 10 µm or less; providing a solution of a synthetic hydrophilic polymer; mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 22
Dependent Claim
65 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension comprising collagen fibers, at least 80% of which collagen fibers have a fiber size of about 10 µm or less; providing a solution of a synthetic hydrophilic polymer; mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 23
Dependent Claim
16 words
The process of claim 17, wherein the collagen suspension is prepared by reprecipitation of fibrillar collagen.
Claim 24
Dependent Claim
18 words
The process of claim 17, wherein the collagen suspension is prepared by addition of salt to fibrillar collagen.
Claim 25
Dependent Claim
56 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of reprecipitated collagen having a pH of about 6 or less; providing a solution of a synthetic hydrophilic polymer; mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 26
Dependent Claim
56 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of reprecipitated collagen having a pH of about 6 or less; providing a solution of a synthetic hydrophilic polymer; mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 27
Dependent Claim
38 words
The process of claim 20, additionally comprising the step of adjusting the pH of the reprecipitated collagen to within the range of between about 6 and about 9 prior to mixing the collagen with the synthetic hydrophilic polymer.
Claim 28
Dependent Claim
143 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of fibrillar collagen having a pH within the range of between about 6 and about 9; adjusting the pH of the collagen suspension to about 5 or less; allowing the collagen suspension to incubate for a sufficient time to effect fiber disassembly of the collagen; adjusting the pH of the collagen suspension to between about 5 and about 6 to produce reprecipitated collagen; allowing the reprecipitated collagen to incubate for a sufficient time to achieve the desired fiber size; providing a solution of a synthetic hydrophilic polymer; adjusting the pH of the reprecipitated collagen to within the range of between about 6 and about 9; immediately mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 29
Dependent Claim
143 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of fibrillar collagen having a pH within the range of between about 6 and about 9; adjusting the pH of the collagen suspension to about 5 or less; allowing the collagen suspension to incubate for a sufficient time to effect fiber disassembly of the collagen; adjusting the pH of the collagen suspension to between about 5 and about 6 to produce reprecipitated collagen; allowing the reprecipitated collagen to incubate for a sufficient time to achieve the desired fiber size; providing a solution of a synthetic hydrophilic polymer; adjusting the pH of the reprecipitated collagen to within the range of between about 6 and about 9; immediately mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 30
Dependent Claim
124 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of fibrillar collagen having a pH within the range of between about 6 and about 9; adjusting the pH of the collagen suspension to about 5 or less; allowing the collagen suspension to incubate for a sufficient time to effect fiber disassembly of the collagen; adjusting the pH of the collagen suspension to between about 5 and about 6 to produce reprecipitated collagen; allowing the reprecipitated collagen to incubate for a sufficient time to achieve the desired fiber size; providing a solution of a synthetic hydrophilic polymer; mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 31
Dependent Claim
124 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of fibrillar collagen having a pH within the range of between about 6 and about 9; adjusting the pH of the collagen suspension to about 5 or less; allowing the collagen suspension to incubate for a sufficient time to effect fiber disassembly of the collagen; adjusting the pH of the collagen suspension to between about 5 and about 6 to produce reprecipitated collagen; allowing the reprecipitated collagen to incubate for a sufficient time to achieve the desired fiber size; providing a solution of a synthetic hydrophilic polymer; mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 32
Dependent Claim
125 words
A process for preparing an optically clear nonfibrillar collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of fibrillar collagen having a pH within the range of between about 6 and about 9; adjusting the pH of the collagen suspension to about 5 or less; allowing the collagen suspension to incubate for a sufficient time at a temperature within the range of between about 0 ° C and about 8 ° C to produce nonfibrillar collagen; providing a solution of a synthetic hydrophilic polymer; mixing the nonfibrillar collagen with the synthetic hydrophilic polymer solution at a temperature within the range of between about 0 ° C and about 8 ° C; and allowing the synthetic hydrophilic polymer to covalently bind with the nonfibrillar collagen.
Claim 33
Dependent Claim
125 words
A process for preparing an optically clear nonfibrillar collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of fibrillar collagen having a pH within the range of between about 6 and about 9; adjusting the pH of the collagen suspension to about 5 or less; allowing the collagen suspension to incubate for a sufficient time at a temperature within the range of between about 0 ° C and about 8 ° C to produce nonfibrillar collagen; providing a solution of a synthetic hydrophilic polymer; mixing the nonfibrillar collagen with the synthetic hydrophilic polymer solution at a temperature within the range of between about 0 ° C and about 8 ° C; and allowing the synthetic hydrophilic polymer to covalently bind with the nonfibrillar collagen.
Claim 34
Dependent Claim
102 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of fibrillar collagen having a pH within the range of between about 6 and about 9; adding salt to the collagen suspension in an amount sufficient to reduce the fiber size of the collagen such that at least 80% of the collagen fibers in the collagen suspension have a fiber size of about 10 µm or less; providing a solution of a synthetic hydrophilic polymer; mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 35
Dependent Claim
102 words
A process for preparing an improved collagen-synthetic polymer conjugate comprising the steps of: providing a suspension of fibrillar collagen having a pH within the range of between about 6 and about 9; adding salt to the collagen suspension in an amount sufficient to reduce the fiber size of the collagen such that at least 80% of the collagen fibers in the collagen suspension have a fiber size of about 10 µm or less; providing a solution of a synthetic hydrophilic polymer; mixing the collagen with the synthetic hydrophilic polymer solution; and allowing the synthetic hydrophilic polymer to covalently bind with the collagen.
Claim 36
Dependent Claim
13 words
The process of claim 19 or 25, wherein the salt is sodium chloride.
Claim 37
Dependent Claim
22 words
The process of any one of claims 22 to 26, wherein the suspension of fibrillar collagen has a pH of approximately 7.
Claim 38
Dependent Claim
30 words
The process of any one of claims 22 to 24, wherein the pH of the collagen is adjusted to approximately 7 prior to mixing with the synthetic hydrophilic polymer solution.
Claim 39
Dependent Claim
29 words
The process of any one of claims 20 to 28, wherein the solution of synthetic hydrophilic polymer has a pH within the range of about 8 to about 9.5.
Claim 40
Dependent Claim
30 words
The process of any one of claims 22 to 24, wherein the pH of the collagen suspension is adjusted to between about 3 and about 5 to effect fiber disassembly.
Claim 41
Dependent Claim
38 words
The process of claim 24, additionally comprising the step of adjusting the pH of the nonfibrillar collagen to within the range of between about 6 and about 9 prior to mixing the collagen with the synthetic hydrophilic polymer.
Claim 42
Dependent Claim
18 words
The process of any one of claims 17 to 31, wherein the collagen is an atelopeptide fibrillar collagen.
Claim 43
Dependent Claim
30 words
The process of any one of claims 17 to 32, wherein the collagen suspension has a collagen concentration within the range of between about 10 mg/ml and about 120 mg/ml.
Claim 44
Dependent Claim
25 words
The process of any one of claims 17 to 33, wherein the synthetic hydrophilic polymer is a functionally activated, preferably a difunctionally activated, polyethylene glycol.
Claim 45
Dependent Claim
42 words
The process of any one of claims 17 to 34, wherein the collagen and the synthetic hydrophilic polymer are covalently bound by means of a linkage selected from the group consisting of an ether linkage, an ester linkage, and a urethane linkage.
References Cited (Backward Citations)
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