US4324683A
Expired / Lapsed
US
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Encapsulation of labile biological material
Assignee: Abbott Biotech Inc
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Filing: 1975-08-20
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Granted: 1982-04-13
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Expires: 1995-08-20
Abstract
Abstract A two step interfacial polymerization process for encapsulating operative chemically active substances in high quality semipermeable membranes. An emulsion is formed wherein the discontinuous phase contains the substance to be encapsulated and a first monomer. When a second monomer is added to the continuous phase, an imperfect membrane forms about the droplets of the discontinuous phase. Removal of the continuous phase, followed by resuspension of the raw microcapsules and addition of a second portion of second monomer, causes further polymerization strengthening the membranes and "patching" macroporous defects in them. The choice of solvents and control of reaction conditions such as pH, maximize the yield of operable labile substance encapsulated. A method of encapsulating a very high concentration of hemoglobin is also disclosed. Adaption of the two step process provides a method for forming and controlling the pore sizes in the membranes of a number of known prior art encapsulation processes.
Inventors
- 👤 Franklin Lim
- 👤 Richard D. Moss
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 06:48
CPC Classifications
B; B01; B01D; B01D67/00; B01D67/0002; B01D67/0006; A; A61; A61K; A61K38/00; A61K38/16; A61K38/41; A61K38/42; A61K38/43; A61K38/44; A61K38/443; A61K38/45; A61K38/46; A61K38/47; A61K38/50; A61K9/00; A61K9/48; A61K9/50; A61K9/5005; A61K9/5021; A61K9/5031; A61K9/5089; B01D67/0081; B01D67/0088; B01D69/00; B01D69/02; B01D69/14; B01D69/141; B01J; B01J13/00; B01J13/02; B01J13/06; B01J13/14; B01J13/16; C; C08; C08G; C08G69/00; C08G69/02; C08G69/26; C08G69/28; C12; C12N; C12N11/00; C12N11/02; C12N11/04; Y; Y10; Y10T; Y10T428/00; Y10T428/29; Y10T428/2982; Y10T428/2989
Claims Analysis
Total Claims: 43
Claim 1
Independent Claim
179 words
A process for encapsulating a chemically active core material in a porous capsule membrane from which the active core material cannot diffuse, said membrane comprising a polymer selected from the group consisting of polyamides, polyesters, polyureas, polycarbonates, and polysulfonamides, said process comprising the steps of: 1. preparing a solution of a first monomer and said core material in a first solvent selected from the group consisting of water and hydrophilic solvents, said first monomer being selected from the group consisting of polyols and diamines; 2. emulsifying said solution in a hydrophobic solvent in which the first monomer is slightly soluble to produce a hydrophilic discontinuous phase; 3. adding a second monomer selected from the group consisting of diacids, diacid halides, diisocyanates, and multifunctional sulfonyl halides to said emulsion to cause an interfacial polymerization reaction between the first and second monomers at the interface of the phases of the emulsion to form macroporous polymeric capsule membranes about the members of the discontinuous phase; 4. separating the capsules produced in step 3 from the hydrophobic solvent to terminate the polymerization reaction;
Claim 2
Dependent Claim
179 words
A process for encapsulating a chemically active core material in a porous capsule membrane from which the active core material cannot diffuse, said membrane comprising a polymer selected from the group consisting of polyamides, polyesters, polyureas, polycarbonates, and polysulfonamides, said process comprising the steps of: 1. preparing a solution of a first monomer and said core material in a first solvent selected from the group consisting of water and hydrophilic solvents, said first monomer being selected from the group consisting of polyols and diamines; 2. emulsifying said solution in a hydrophobic solvent in which the first monomer is slightly soluble to produce a hydrophilic discontinuous phase; 3. adding a second monomer selected from the group consisting of diacids, diacid halides, diisocyanates, and multifunctional sulfonyl halides to said emulsion to cause an interfacial polymerization reaction between the first and second monomers at the interface of the phases of the emulsion to form macroporous polymeric capsule membranes about the members of the discontinuous phase; 4. separating the capsules produced in step 3 from the hydrophobic solvent to terminate the polymerization reaction;
Claim 3
Dependent Claim
66 words
resuspending the capsules in a liquid, said liquid being selected to be less soluble with said first monomer than said hydrophobic solvent; 6. adding a second portion of said second monomer to the resuspension to cause further polymerization at said capsule membranes to strengthen said membranes and to render them microporous yet impermeable to said core material; and 7. quenching the polymerization reaction in the resuspension.
Claim 4
Dependent Claim
66 words
resuspending the capsules in a liquid, said liquid being selected to be less soluble with said first monomer than said hydrophobic solvent; 6. adding a second portion of said second monomer to the resuspension to cause further polymerization at said capsule membranes to strengthen said membranes and to render them microporous yet impermeable to said core material; and 7. quenching the polymerization reaction in the resuspension.
Claim 5
Dependent Claim
22 words
The process of claim 1 further characterized by the step of adding an emulsifying agent to said system before said emulsifying step.
Claim 6
Dependent Claim
18 words
The process of claim 2 further characterized by the step of adding an emulsifying agent to said liquid.
Claim 7
Dependent Claim
11 words
The process of claim 1 wherein said first solvent is water.
Claim 8
Dependent Claim
16 words
The process of claim 1 wherein said hydrophobic solvent is a solution of cyclohexane and chloroform.
Claim 9
Dependent Claim
14 words
The process of claim 5 wherein said solution comprises 80% cyclohexane and 20% chloroform.
Claim 10
Dependent Claim
10 words
The process of claim 1 wherein said liquid is cyclohexane.
Claim 11
Dependent Claim
12 words
The process of claim 1 wherein said first monomer is a polyamine.
Claim 12
Dependent Claim
13 words
The process of claim 8 wherein said second monomer is a diacid halide.
Claim 13
Dependent Claim
13 words
The process of claim 9 wherein said diacid halide is a diacid chloride.
Claim 14
Dependent Claim
30 words
The process of claim 10 wherein the ratio of the concentration of said polyamine and said diacid chloride in their respective solvents is on the order of 100 to 1.
Claim 15
Dependent Claim
31 words
The process of claim 11 wherein the ratio of the concentration of said polyamine and said diacid chloride in their respective solvents in said resuspension is less than 60 to 1.
Claim 16
Dependent Claim
27 words
The process of claim 10 wherein the quantity of said acid chloride used is added in fractions at regular time intervals over the duration of the polymerization.
Claim 17
Dependent Claim
37 words
The process of claim 9 wherein said polyamine is chosen from the group consisting of 1,6 hexanediamine, lysine, 4,4' diamino, 2,2' biphenyl disulfonic acid, 4,4' diamino stilbene 2,2' disulfonic acid, 2,5 diaminobenzenesulfonic acid, tetraethylenepentamine, and mixtures thereof.
Claim 18
Dependent Claim
23 words
The process of claim 9 wherein said diacid chloride is chosen from the group consisting of sebacyl chloride, terephthaloyl chloride, and mixtures thereof.
Claim 19
Dependent Claim
23 words
The process of claim 1 wherein the pH of the phase containing said chemically active core material is maintained between 5 and 9.
Claim 20
Dependent Claim
16 words
The process of claim 16 wherein said chemically active core material is a labile biological substance.
Claim 21
Dependent Claim
52 words
The process of claim 17 wherein said substance is hemoglobin, said hemoglobin being prepared by removing water from red blood cells by exposing said cells to hypertonic saline solution, said saline solution being on the order of 1.5% salt by weight, to enable hemoglobin concentrations up to 30 g/dl to be prepared.
Claim 22
Dependent Claim
11 words
The process of claim 17 wherein said substance is an enzyme.
Claim 23
Dependent Claim
20 words
The process of claim 19 wherein said enzyme is chosen from the group consisting of LDH, GOT, urease, and β-glucuronidase.
Claim 24
Dependent Claim
180 words
A process for encapsulating a labile biological material within a semipermeable membrane, said process comprising the steps of: 1. preparing an aqueous phase having a pH between 5 and 9 and containing an operative biological material and a diamine monomer; 2. emulsifying the aqueous phase in a hydrophobic solvent in which the diamine is slightly soluble to produce an aqueous discontinuous phase; 3. adding a diacid halide to said emulsion to cause a polymerization reaction at the interface of the phases of the emulsion and to form macroporous polymeric capsule membranes about the members of the discontinuous phase; 4. separating the capsules produced in step 3 form the hydrophobic solvent to terminate the polymerization reaction; 5. resuspending the capsules in a liquid, said liquid being selected to be less soluble with said diamine than said hydrophobic solvent; 6. adding a second portion of diacid halide to the resuspension to cause further polymerization at said capsule membranes to strengthen said membranes and to render them microporous yet impermeable to said biological material; and 7. quenching the polymerization reaction in the resuspension.
Claim 25
Dependent Claim
180 words
A process for encapsulating a labile biological material within a semipermeable membrane, said process comprising the steps of: 1. preparing an aqueous phase having a pH between 5 and 9 and containing an operative biological material and a diamine monomer; 2. emulsifying the aqueous phase in a hydrophobic solvent in which the diamine is slightly soluble to produce an aqueous discontinuous phase; 3. adding a diacid halide to said emulsion to cause a polymerization reaction at the interface of the phases of the emulsion and to form macroporous polymeric capsule membranes about the members of the discontinuous phase; 4. separating the capsules produced in step 3 form the hydrophobic solvent to terminate the polymerization reaction; 5. resuspending the capsules in a liquid, said liquid being selected to be less soluble with said diamine than said hydrophobic solvent; 6. adding a second portion of diacid halide to the resuspension to cause further polymerization at said capsule membranes to strengthen said membranes and to render them microporous yet impermeable to said biological material; and 7. quenching the polymerization reaction in the resuspension.
Claim 26
Dependent Claim
13 words
The process of claim 21 wherein said labile biological material is an enzyme.
Claim 27
Dependent Claim
12 words
The process of claim 21 wherein said labile biological material is hemoglobin.
Claim 28
Dependent Claim
48 words
The process of claim 23 wherein said hemoglobin is prepared by removing water from red blood cells by exposing said cells to hypertonic saline solution, said saline solution being on the order of 1.5% salt by weight, to enable hemoglobin concentrations up to 30 g/dl to be prepared.
Claim 29
Dependent Claim
36 words
The process of claim 21 wherein said diamine is chosen from the group consisting of 1,6 hexanediamine, lysine, 4,4' diamino, 2,2' biphenyl disulfonic acid, 4,4' diamino stilbene 2,2' disulfonic acid, 2,5 diaminobenzenesulfonic acid, and mixtures thereof.
Claim 30
Dependent Claim
13 words
The process of claim 21 wherein said diacid halide is a diacid chloride.
Claim 31
Dependent Claim
23 words
The process of claim 26 wherein said diacid chloride is chosen from the group consisting of sebacyl chloride, terephthaloyl chloride and mixtures thereof.
Claim 32
Dependent Claim
21 words
The process of claim 21 further characterized by the step of adding an emulsifying agent to said hydrophobic solvent before emulsifying.
Claim 33
Dependent Claim
12 words
The process of claim 28 wherein said emulsifying agent is sorbitan trioleate.
Claim 34
Dependent Claim
19 words
The process of claim 21 wherein the pH of said aqueous phase is set by passing CO 2 therethrough.
Claim 35
Dependent Claim
16 words
The process of claim 21 wherein said hydrophobic solvent is a mixture of cyclohexane and chloroform.
Claim 36
Dependent Claim
20 words
The process of claim 31 wherein said hydrophobic solvent is a mixture, by volume, of 80% cyclohexane and 20% chloroform.
Claim 37
Dependent Claim
10 words
The process of claim 21 wherein said liquid is cyclohexane.
Claim 38
Dependent Claim
27 words
The process of claim 21 wherein the quenching step is accomplished by adding sorbitan monolaurate in a hypertonic solution buffered to have a pH close to 7.
Claim 39
Dependent Claim
19 words
The process of claim 21 wherein a polyamine is added to said diamine monomer before adding the hydrophobic solvent.
Claim 40
Dependent Claim
10 words
The process of claim 36 wherein said polyamine is tetraethylenepentamine.
Claim 41
Dependent Claim
26 words
The process of claim 35 wherein said polyamine is adjusted to have a pH between 5 and 9 before it is added to said diamine monomer.
Claim 42
Dependent Claim
19 words
The process as set forth in claim 21 wherein the hydrophobic solvent is relatively non-denaturing to said biological material.
Claim 43
Dependent Claim
25 words
The process as set forth in claim 21 wherein the diacid halide added in step 3 is added in increments as the polymerization reaction proceeds.
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) | 1985-04-12 | 1985-10-12 | 1986-04-13 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1989-04-12 | 1989-10-12 | 1990-04-13 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1993-04-12 | 1993-10-12 | 1994-04-13 | $7700.00 | Window Closed / Lapsed |