US5807581A
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Collagen-based injectable drug delivery system and its use
Assignee: Angiotech Pharmaceuticals Inc
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Filing: 1995-09-29
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Granted: 1998-09-15
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Expires: 2015-09-29
Abstract
Abstract Drugs are delivered in a sustained manner from an in vivo depot which is formed from a collagen-based injectable composition. The injectable composition is fluid when injected but undergoes crosslinking in situ to form a crosslinked collagen matrix which encloses the drug to be released. The composition also includes a flexible chain polymer which is similarly charged to the precrosslinked collagen. This flexible chain polymer is enclosed in the matrix as well when the matrix forms and alters the effective porosity of the matrix. The drug diffuses out of the matrix at a rate which depends upon the matrix's effective porosity.
Inventors
- 👤 Joel S. Rosenblatt
- 👤 Richard A. Berg
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-04 17:56
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/0012; A61K9/0019; A61K9/0024; A61K9/20; A61K9/2004; A61K9/2022; A61K9/205; A61K9/2063
Claims Analysis
Total Claims: 53
Claim 1
Independent Claim
141 words
An injectable pharmaceutically acceptable sustained-release drug delivery formulation comprising: i) collagen; ii) a crosslinking agent capable of forming covalent bonds with the collagen in situ following injection with the collagen; iii) a flexible chain polymer, wherein the flexible chain polymer is hydrophilic and has a molecular weight of at least about 100 kDa, a persistence length of less than about 10% of the persistence length of the collagen, and a charge similar in sign to that of the collagen; iv) a drug; and v) a pharmaceutically acceptable injectable carrier; wherein upon injection of the formulation into a patient, the crosslinking agent is capable of crosslinking the collagen in situ to form a porous matrix having both the drug and the flexible chain polymer entrapped therein, and wherein the crosslinked matrix is capable of sustained diffusion of the drug from the matrix.
Claim 2
Dependent Claim
141 words
An injectable pharmaceutically acceptable sustained-release drug delivery formulation comprising: i) collagen; ii) a crosslinking agent capable of forming covalent bonds with the collagen in situ following injection with the collagen; iii) a flexible chain polymer, wherein the flexible chain polymer is hydrophilic and has a molecular weight of at least about 100 kDa, a persistence length of less than about 10% of the persistence length of the collagen, and a charge similar in sign to that of the collagen; iv) a drug; and v) a pharmaceutically acceptable injectable carrier; wherein upon injection of the formulation into a patient, the crosslinking agent is capable of crosslinking the collagen in situ to form a porous matrix having both the drug and the flexible chain polymer entrapped therein, and wherein the crosslinked matrix is capable of sustained diffusion of the drug from the matrix.
Claim 3
Dependent Claim
17 words
The formulation of claim 1, wherein the collagen and the flexible chain polymer are each positively charged.
Claim 4
Dependent Claim
16 words
The formulation of claim 1, wherein the flexible chain polymer is a synthetic flexible chain polymer.
Claim 5
Dependent Claim
30 words
The formulation of claim 3, wherein the synthetic flexible chain polymer is selected from the group consisting of: poly(acrylic acid), poly(vinyl alcohol), poly(acrylamide), poly(N-isopropylacrylamide),poly(methacrylate), poly(hydroxyethylmethacrylate), poly(vinyl acetate), and copolymers thereof.
Claim 6
Dependent Claim
15 words
The formulation of claim 1, wherein the flexible chain polymer is a naturally occurring material.
Claim 7
Dependent Claim
24 words
The formulation of claim 5, wherein the naturally occurring flexible chain polymer is selected from the group consisting of glycosaminoglycans, celluloses, and poly(nucleic acid)s.
Claim 8
Dependent Claim
15 words
The formulation of claim 6, wherein the naturally occurring flexible chain polymer is a glycosaminoglycan.
Claim 9
Dependent Claim
35 words
The formulation of claim 7, wherein the naturally occurring flexible chain polymer is a glycosaminoglycan selected from the group consisting of: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B, chondroitin sulfate C, chitin, and chitosan.
Claim 10
Dependent Claim
11 words
The formulation of claim 1, wherein the collagen is fibrillar collagen.
Claim 11
Dependent Claim
11 words
The formulation of claim 1, wherein the collagen is atelopeptide collagen.
Claim 12
Dependent Claim
12 words
The formulation of claim 1, wherein the collagen is fibrillar atelopeptide collagen.
Claim 13
Dependent Claim
12 words
The formulation of claim 1, wherein the collagen is nonfibrillar atelopeptide collagen.
Claim 14
Dependent Claim
17 words
The formulation of claim 1, wherein the collagen has available at least one lysine residue for crosslinking.
Claim 15
Dependent Claim
17 words
The formulation of claim 9, wherein the fibrillar collagen is prepared by grinding or shredding collagenous tissue.
Claim 16
Dependent Claim
22 words
The formulation of claim 11, wherein the fibrillar atelopeptide collagen is prepared by dissolving tissue in aqueous acid followed by enzymatic digestion.
Claim 17
Dependent Claim
22 words
The formulation of claim 12, wherein the nonfibrillar atelopeptide collagen is prepared by dissolving tissue in aqueous acid followed by enzymatic digestion.
Claim 18
Dependent Claim
14 words
The formulation of claim 1, wherein the crosslinking agent is a synthetic hydrophilic polymer.
Claim 19
Dependent Claim
14 words
The formulation of claim 17, wherein the synthetic hydrophilic polymer is functionalized polyethylene glycol.
Claim 20
Dependent Claim
12 words
The formulation of claim 18, wherein the functionalized polyethylene glycol is difunctionalized.
Claim 21
Dependent Claim
15 words
The formulation of claim 19, wherein the difunctionalized polyethylene glycol is succinimidyl glutaryl polyethylene glycol.
Claim 22
Dependent Claim
19 words
The formulation of claim 1, wherein the drug has an apparent molecular weight of at least about 10 kDa.
Claim 23
Dependent Claim
12 words
The formulation of claim 1, wherein the drug is encapsulated in liposomes.
Claim 24
Dependent Claim
12 words
The formulation of claim 1, wherein the drug is a growth factor.
Claim 25
Dependent Claim
11 words
The formulation of claim 1, wherein the drug is a cytokine.
Claim 26
Dependent Claim
12 words
The formulation of claim 1, wherein the drug is Clotting Factor 9.
Claim 27
Dependent Claim
11 words
The formulation of claim 1, wherein the drug is PEGylated TGF-beta.
Claim 28
Dependent Claim
10 words
The formulation of claim 1, wherein the drug is erythropoietin.
Claim 29
Dependent Claim
15 words
The formulation of claim 1, wherein the drug is covalently attached to a carrier molecule.
Claim 30
Dependent Claim
15 words
The formulation of claim 28, wherein the carrier molecule is a glycosaminoglycan or a protein.
Claim 31
Dependent Claim
11 words
The formulation of claim 28, wherein the carrier molecule is starch.
Claim 32
Dependent Claim
11 words
The formulation of claim 28, wherein the carrier molecule is glycogen.
Claim 33
Dependent Claim
11 words
The formulation of claim 28, wherein the carrier molecule is fibrinogen.
Claim 34
Dependent Claim
12 words
The formulation of claim 28, wherein the carrier molecule is human albumin.
Claim 35
Dependent Claim
12 words
The formulation of claim 28, wherein the carrier molecule is monofunctional PEG.
Claim 36
Dependent Claim
11 words
The formulation of claim 28, wherein the carrier molecule is fibronectin.
Claim 37
Dependent Claim
12 words
The formulation of claim 28, wherein the carrier molecule is a lipid.
Claim 38
Dependent Claim
11 words
The formulation of claim 28, wherein the drug is an enzyme.
Claim 39
Dependent Claim
12 words
The formulation of claim 28, wherein the drug is a PEGylated protein.
Claim 40
Dependent Claim
12 words
The formulation of claim 28, wherein the drug is Clotting Factor 8.
Claim 41
Dependent Claim
133 words
A sustained-release drug delivery depot, for administration of a drug to an environment in a patient, comprising a drug and a flexible chain polymer wherein both the drug and the flexible chain polymer are entrapped within a porous matrix of collagen crosslinked with a crosslinking agent, wherein the pore size is less than 200 nanometers; wherein the flexible chain polymer is hydrophilic and has a molecular weight of at least about 100 kDa, a persistence length of less than about 10% of the persistence length of the collagen, and a charge similar in sign to that of the collagen; and wherein the flexible chain polymer alters the effective pore size of a matrix of crosslinked collagen to a size capable of sustaining the diffusion of the drug from the matrix into surrounding tissues.
Claim 42
Dependent Claim
133 words
A sustained-release drug delivery depot, for administration of a drug to an environment in a patient, comprising a drug and a flexible chain polymer wherein both the drug and the flexible chain polymer are entrapped within a porous matrix of collagen crosslinked with a crosslinking agent, wherein the pore size is less than 200 nanometers; wherein the flexible chain polymer is hydrophilic and has a molecular weight of at least about 100 kDa, a persistence length of less than about 10% of the persistence length of the collagen, and a charge similar in sign to that of the collagen; and wherein the flexible chain polymer alters the effective pore size of a matrix of crosslinked collagen to a size capable of sustaining the diffusion of the drug from the matrix into surrounding tissues.
Claim 43
Independent Claim
166 words
A method for preparing an injectable pharmaceutically acceptable composition capable of forming a sustained-release drug delivery depot in situ comprising the steps of. i) providing: a) a drug; b) collagen; c) at least one crosslinking agent capable of forming bonds with the collagen; d) at least one flexible chain polymer, wherein the flexible chain polymer is hydrophilic and has a molecular weight of at least about 100 kDa, a persistence length of less than about 10% of the persistence length of the collagen, and a charge similar in sign to that of the collagen; and e) a pharmaceutically acceptable injectable medium; and ii) forming a pharmaceutically acceptable formulation comprising the components provided in (i); wherein upon injection of the formulation into a patient, the crosslinking agent is capable of crosslinking the collagen in situ to form a porous matrix having both the drug and the flexible chain polymer entrapped therein, and wherein the crosslinked matrix is capable of sustained diffusion of the drug from the matrix.
Claim 44
Independent Claim
166 words
A method for preparing an injectable pharmaceutically acceptable composition capable of forming a sustained-release drug delivery depot in situ comprising the steps of. i) providing: a) a drug; b) collagen; c) at least one crosslinking agent capable of forming bonds with the collagen; d) at least one flexible chain polymer, wherein the flexible chain polymer is hydrophilic and has a molecular weight of at least about 100 kDa, a persistence length of less than about 10% of the persistence length of the collagen, and a charge similar in sign to that of the collagen; and e) a pharmaceutically acceptable injectable medium; and ii) forming a pharmaceutically acceptable formulation comprising the components provided in (i); wherein upon injection of the formulation into a patient, the crosslinking agent is capable of crosslinking the collagen in situ to form a porous matrix having both the drug and the flexible chain polymer entrapped therein, and wherein the crosslinked matrix is capable of sustained diffusion of the drug from the matrix.
Claim 45
Dependent Claim
16 words
The method of claim 41, wherein at least one crosslinking agent functions only to crosslink collagen.
Claim 46
Independent Claim
176 words
A method for administering a drug to a patient comprising the steps of: i) forming a pharmaceutically acceptable formulation comprising: a) the drug; b) collagen; c) at least one crosslinking agent capable of forming covalent bonds with the collagen; d) at least one flexible chain polymer, wherein the flexible chain polymer is hydrophilic and has a molecular weight of at least about 100 kDa, a persistence length of less than about 10% of the persistence length of the collagen, and a charge similar in sign to that of the collagen; and e) a pharmaceutically acceptable injectable medium; and ii) injecting the pharmaceutically acceptable formulation into the patient under conditions which limit the immediate dispersion of the formulation, and permitting the crosslinking agent to crosslink the collagen in situ to form a porous matrix comprising the drug and capable of sustained release of the drug, wherein the pores of the matrix are limited in size by the presence of the flexible chain polymer, and wherein the drug is able to diffuse through the pores to the patient.
Claim 47
Independent Claim
176 words
A method for administering a drug to a patient comprising the steps of: i) forming a pharmaceutically acceptable formulation comprising: a) the drug; b) collagen; c) at least one crosslinking agent capable of forming covalent bonds with the collagen; d) at least one flexible chain polymer, wherein the flexible chain polymer is hydrophilic and has a molecular weight of at least about 100 kDa, a persistence length of less than about 10% of the persistence length of the collagen, and a charge similar in sign to that of the collagen; and e) a pharmaceutically acceptable injectable medium; and ii) injecting the pharmaceutically acceptable formulation into the patient under conditions which limit the immediate dispersion of the formulation, and permitting the crosslinking agent to crosslink the collagen in situ to form a porous matrix comprising the drug and capable of sustained release of the drug, wherein the pores of the matrix are limited in size by the presence of the flexible chain polymer, and wherein the drug is able to diffuse through the pores to the patient.
Claim 48
Dependent Claim
33 words
The formulation of claim 1 wherein the formulation includes about 1 to 5% collagen by weight, about 0.1 to 1 % crosslinker by weight, and about 0.5 to 5% flexible polymer by weight.
Claim 49
Dependent Claim
23 words
The formulation of claim 1 wherein the weight ratio of flexible polymer to collagen plus crosslinker is between about 0.02:1 to about 5:1.
Claim 50
Dependent Claim
22 words
The formulation of claim 1 wherein the weight ratio of flexible polymer to collagen plus crosslinker is between about 0.1:1 to 1:1.
Claim 51
Dependent Claim
15 words
The method of claim 43 wherein size of the pores is less than 200 nanometers.
Claim 52
Dependent Claim
14 words
The method of claim 43 wherein the crosslinking agent comprises a synthetic hydrophilic polymer.
Claim 53
Dependent Claim
16 words
The drug delivery depot of claim 40 wherein the crosslinking agent comprises a synthetic hydrophilic polymer.
References Cited (Backward Citations)
US4179337A
Cited
US3949073A
Cited
US4488911A
Cited
US4165599A
Cited
US4164559A
Cited
US4358442A
Cited
US4424208A
Cited
US4582640A
Cited
US4820857A
Cited
WO1985004413A1
Cited
US4925924A
Cited
US4703108A
Cited
US4970298A
Cited
EP0160266A2
Cited
US4557764A
Cited
US4689399A
Cited
US4642117A
Cited
US4861714A
Cited
US4863856A
Cited
US4997753A
Cited
US4938763B1
Cited
US4938763A
Cited
US5162430A
Cited
DE3912693A1
Cited
DE4028622A1
Cited
WO1992014447A1
Cited
WO1992014445A1
Cited
EP0509338A1
Cited
US5198465A
Cited
US5318780A
Cited
WO1994001483A1
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2001-09-14 | 2002-03-16 | 2002-09-15 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2005-09-14 | 2006-03-16 | 2006-09-15 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2009-09-14 | 2010-03-16 | 2010-09-15 | $7700.00 | Window Closed / Lapsed |