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US4582640A
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Injectable cross-linked collagen implant material
Assignee: Allergan Inc
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Filing: 1984-10-22
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Granted: 1986-04-15
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Expires: 2004-10-22
Abstract
Abstract Cross-linked atelopeptide collagen that is substantially free of residual cross-linking agent is prepared by: reconstituting atelopeptide collagen from solution by neutralizing the solution at a reduced temperature and a hypotonic ionic strength; cross-linking the reconstituted fibers in an aqueous medium at a concentration of 0.1 to 10 mg/ml with glutaraldehyde under conditions that produce cross-linked collagen that when in suspension in physiological saline at a concentration of 35 mg/ml exhibits a shear viscosity whose log varies linearly with the log of the shear rate and is approximated by the formula log eta </=-0.96 log gamma +2.3 where gamma is the shear rate in sec-1, log gamma is in the range of -6 to +2 and eta is the viscosity of the suspension in Pascal-sec; optionally quenching the cross-linking reaction with an amino acid; and separating the cross-linked atelopeptide collagen from the reaction mixture. This collagen is dispersed in an isotonic aqueous medium for use in soft tissue dermal augmentation and is injectable and forms implants that have excellent persistence.
Inventors
- 👤 Thomas L. Smestad
- 👤 John McPherson
- 👤 Donald G. Wallace
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 11:25
CPC Classifications
A; A61; A61L; A61L27/00; A61L27/14; A61L27/22; A61L27/24; C; C07; C07K; C07K14/00; C07K14/435; C07K14/78; Y; Y10; Y10S; Y10S128/00; Y10S128/08
Claims Analysis
Total Claims: 33
Claim 1
Independent Claim
115 words
A novel cross-linked atelopeptide collagen for use as an injectable aqueous suspension for augmenting soft tissue that: (a) is substantially free of residual cross-linking agent; (b) has greater than about 15 free lysine residues per 1000 amino acid residues; and (c) is composed substantially of fibrous particles which when in suspension in physiological saline at a concentration of 35 mg/ml exhibit a shear viscosity whose log varies linearly with the log of the shear rate and is approximated by the formula log η≦-0.96 log γ+2.3 where γ is the shear rate in sec -1 , log γ is in the range of -6 to +2, and η is the viscosity of the suspension in Pascal-sec.
Claim 2
Dependent Claim
115 words
A novel cross-linked atelopeptide collagen for use as an injectable aqueous suspension for augmenting soft tissue that: (a) is substantially free of residual cross-linking agent; (b) has greater than about 15 free lysine residues per 1000 amino acid residues; and (c) is composed substantially of fibrous particles which when in suspension in physiological saline at a concentration of 35 mg/ml exhibit a shear viscosity whose log varies linearly with the log of the shear rate and is approximated by the formula log η≦-0.96 log γ+2.3 where γ is the shear rate in sec -1 , log γ is in the range of -6 to +2, and η is the viscosity of the suspension in Pascal-sec.
Claim 3
Dependent Claim
12 words
The collagen of claim 1 wherein the collagen is bovine corium collagen.
Claim 4
Dependent Claim
21 words
The collagen of claim 1 wherein the amount of residual cross-linking agent in the collagen is less than about 20 ppm.
Claim 5
Dependent Claim
20 words
The collagen of claim 1 wherein the cross-linking agent is one that forms covalent bonds between itself and the collagen.
Claim 6
Dependent Claim
12 words
The collagen of claim 4 wherein the cross-linking agent is an aldehyde.
Claim 7
Dependent Claim
11 words
The collagen of claim 4 wherein the cross-linking agent is glutaraldehyde.
Claim 8
Dependent Claim
20 words
The collagen of claim 6 wherein the number of free lysine residues per 1000 residues is greater than about 20.
Claim 9
Dependent Claim
18 words
The collagen of claim 1 wherein the nominal size of the particles is less than about 750 microns.
Claim 10
Dependent Claim
18 words
The collagen of claim 8 wherein said size is in the range of about 75 to 750 microns.
Claim 11
Dependent Claim
11 words
The collagen of claim 1 wherein the cross-links are substantially intrafibrillar.
Claim 12
Dependent Claim
173 words
A process for preparing cross-linked atelopeptide collagen for use as an injectable aqueous suspension for augmenting soft tissue comprising: (a) reconstituting atelopeptide collagen from an acidic aqueous solution by neutralizing the solution at a reduced temperature and at a hypotonic ionic strength; (b) cross-linking the reconstituted atelopeptide collagen in an aqueous medium at a concentration of about 0.1 to about 10 mg/ml with a cross-linking agent at a concentration of about 0.001% to 0.05% by weight that forms covalent bonds with the collagen under conditions sufficient to produce a fibrous cross-linked collagen that has greater than about 15 free lysine residues per 1000 amino acid residues and that when in suspension in physiological saline at a concentration of 35 mg/ml exhibits a shear viscosity approximated by the formula log η≦-0.96 log γ+2.3 where γ is the shear rate in sec -1 , log γ is in the range of -6 to +2, and η is the viscosity of the suspension in Pascal-sec; and (c) separating the cross-linked collagen from the cross-linking reaction mixture.
Claim 13
Dependent Claim
173 words
A process for preparing cross-linked atelopeptide collagen for use as an injectable aqueous suspension for augmenting soft tissue comprising: (a) reconstituting atelopeptide collagen from an acidic aqueous solution by neutralizing the solution at a reduced temperature and at a hypotonic ionic strength; (b) cross-linking the reconstituted atelopeptide collagen in an aqueous medium at a concentration of about 0.1 to about 10 mg/ml with a cross-linking agent at a concentration of about 0.001% to 0.05% by weight that forms covalent bonds with the collagen under conditions sufficient to produce a fibrous cross-linked collagen that has greater than about 15 free lysine residues per 1000 amino acid residues and that when in suspension in physiological saline at a concentration of 35 mg/ml exhibits a shear viscosity approximated by the formula log η≦-0.96 log γ+2.3 where γ is the shear rate in sec -1 , log γ is in the range of -6 to +2, and η is the viscosity of the suspension in Pascal-sec; and (c) separating the cross-linked collagen from the cross-linking reaction mixture.
Claim 14
Dependent Claim
23 words
The process of claim 11 wherein said concentration of reconstituted atelopeptide collagen in the cross-linking reaction mixture is about 1 to 5 mg/ml.
Claim 15
Dependent Claim
12 words
The process of claim 11 wherein the cross-linking agent is an aldehyde.
Claim 16
Dependent Claim
19 words
The process of claim 11 wherein the cross-linked atelopeptide collagen contains less than about 20 ppm reactive cross-linking agent.
Claim 17
Dependent Claim
48 words
The process of claim 11 wherein the temperature of step (a) is about 10° C. to about 25° C., the ionic strength of step (a) is about 0.03 to about 0.1, and the final pH of step (a) is in the range of about 4.9 and about 10.0.
Claim 18
Dependent Claim
18 words
The process of claim 15 wherein said final pH is in the range of about 5 and 8.
Claim 19
Dependent Claim
30 words
The process of claim 11 wherein the cross-linking agent is glutaraldehyde, and the free lysine content of the cross-linked collagen is greater than about 20 lysine residues per 1000 residues.
Claim 20
Dependent Claim
23 words
The process of claim 17 wherein the cross-linking reaction of step (b) is carried out for about one-half hour to about one week.
Claim 21
Dependent Claim
21 words
The process of claim 11 wherein the cross-linking reaction is quenched with a quenching agent that reacts with the cross-linking agent.
Claim 22
Dependent Claim
11 words
The process of claim 19 wherein the quenching agent is glycine.
Claim 23
Dependent Claim
25 words
The process of claim 11 wherein the separation of step (c) includes washing the cross-linked atelopeptide collagen to remove other reaction products and unreacted reactants.
Claim 24
Dependent Claim
11 words
The process of claim 11 wherein the cross-links are substantially intrafibrillar.
Claim 25
Dependent Claim
128 words
The process of claim 11 wherein: the collagen is bovine corium collagen: the temperature of step (a) is about 10° C. to about 25° C.; the ionic strength of step (a) is about 0.03 to about 0.1; the final pH of step (a) is in the range of about 5 and about 8; the cross-linking agent is glutaraldehyde; the concentration of collagen in the cross-linking reaction mixture is about 1 to 5 mg/ml; the cross-linking reaction is carried out for about one-half hour to about one week; the separation includes washing the cross-linked atelopeptide collagen to remove other reaction products and unreacted reactants; and the cross-linked atelopeptide collagen contains less than about 20 ppm reactive aldehyde and has greater than about 20 free lysine residues per 1000 residues.
Claim 26
Dependent Claim
10 words
Cross-linked atelopeptide collagen prepared by the process of claim 11.
Claim 27
Dependent Claim
10 words
Cross-linked atelopeptide collagen prepared by the process of claim 23.
Claim 28
Dependent Claim
24 words
A collagen implant material for use in augmenting soft tissue in mammals comprising an aqueous suspension of the cross-linked atelopeptide collagen of claim 1.
Claim 29
Dependent Claim
24 words
A collagen implant material for use in augmenting soft tissue in mammals comprising an aqueous suspension of the cross-linked atelopeptide collagen of claim 24.
Claim 30
Dependent Claim
24 words
A collagen implant material for use in augmenting soft tissue in mammals comprising an aqueous suspension of the cross-linked atelopeptide collagen of claim 25.
Claim 31
Dependent Claim
24 words
The collagen implant material of claim 26 wherein the concentration of cross-linked atelopeptide collagen in the suspension is about 20 to about 65 mg/ml.
Claim 32
Dependent Claim
26 words
A method for augmenting soft tissue in a living mammal comprising injecting the collagen implant material of claim 26 into the mammal at the augmentation site.
Claim 33
Dependent Claim
26 words
A method for augmenting soft tissue in a living mammal comprising injecting the collagen implant material of claim 29 into the mammal at the augmentation site.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1989-04-14 | 1989-10-14 | 1990-04-15 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1993-04-14 | 1993-10-14 | 1994-04-15 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1997-04-14 | 1997-10-14 | 1998-04-15 | $7700.00 | Window Closed / Lapsed |