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WO2007136860A1 - Alginate modifié par des polymères biocompatibles synthétiques - Google Patents

Alginate modifié par des polymères biocompatibles synthétiques Download PDF

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Publication number
WO2007136860A1
WO2007136860A1 PCT/US2007/012192 US2007012192W WO2007136860A1 WO 2007136860 A1 WO2007136860 A1 WO 2007136860A1 US 2007012192 W US2007012192 W US 2007012192W WO 2007136860 A1 WO2007136860 A1 WO 2007136860A1
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WO
WIPO (PCT)
Prior art keywords
alginate
substituted
alkyl
aryl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2007/012192
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English (en)
Inventor
Jain Krotz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MICROISLET Inc
Original Assignee
MICROISLET Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MICROISLET Inc filed Critical MICROISLET Inc
Publication of WO2007136860A1 publication Critical patent/WO2007136860A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A61K35/39—Pancreas; Islets of Langerhans

Definitions

  • polymer classes have been examined as suitable encapsulation materials. Such classes include, alginate, HEMA-MMA and other hydrogels, PAN-PVC 3 (HFMs), siliceous encapsulates, and cellulose membranes. Prakash, S. and Soe-Lin, H. Trends Biomater. Artif. Organs, 18(1), pp. 24-35 (2004) which is hereby incorporated by reference in its entirety.
  • the present invention is generally directed to materials that may be used for the encapsulation of live cells. More specifically, it is directed to modified alginate polymers that may be used for the encapsulation of live cells.
  • the present invention provides a modified alginate polymer.
  • the polymer includes an alginate backbone and a grafted polymer.
  • the grafted polymer contains one or more types of monomers.
  • the electron withdrawing group is -C(O)R2, where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; -C(O)OR2; -C(O)NR2R3, where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl and where R3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; -S(O)2OR2 where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; -S(O)2NR2R3 where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl and where R3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; or -P(O)2OR2 where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl.
  • a method of synthesizing a modified alginate polymer includes the steps of: dissolving an alginate or alginate salt and at least one monomer capable of undergoing a radical addition in a solvent; adding a radical initiator to the formed solution; and, providing conditions that initiate a radical reaction.
  • an alginate salt is used.
  • Rl is hydrogen or methyl.
  • a microcapsule composition in another composition aspect, includes a live cell that is encapsulated within a modified alginate polymer.
  • the live cell is an islet cell.
  • the islet cell is a porcine islet cell.
  • the polymer includes an alginate backbone and a grafted polymer.
  • the grafted polymer contains one or more types of monomers.
  • the monomers are capable of undergoing a radical addition.
  • the electon withdrawing group is -C(O)R 2 , where R 2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; -C(O)OR 2 ; -C(O)NR 2 R 3 , where R 2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl and where R 3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; -S(O) 2 OR 2 where R 2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; -S(O) 2 NR 2 R 3 where R 2 is hydrogen, alkyl, substituted alkyl, aryl,
  • R 1 is a hydrogen or methyl.
  • the composition exhibits diffusion of a 70k molecular weight dextran that is at least 5% less than for alginate beads. In some embodiments the composition exhibits diffusion of a 70k molecular weight dextran that is at least 20% less than for alginate beads. In some embodiments the composition exhibits diffusion of a 70k molecular weight dextran that is at least 50% less than for alginate beads. In some embodiments the composition exhibits a force at rupture (g) at least 10% greater than for alginate beads. In some embodiments the composition exhibits a force at rupture (g) at least 20% greater than for alginate beads. In some embodiments, the composition exhibits a force at rupture (g) at least 30% greater than for alginate beads.
  • the electron withdrawing group is -C(O)R2, where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; -C(O)OR2 where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; -C(O)NR2R3, where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl and where R3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; -S(O)2OR2 where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; -S(O)2NR2R3 where R2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl and where R3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; and, - P(O)2OR2 where R2 is
  • the invention is a product made by a method of the invention. In some embodiments, the invention is a product made by a process including the steps of dissolving alginate or an alginate salt and at least one monomer capable of undergoing a radical addition in a solvent; adding a radical initiator to said solvent; and providing reaction conditions that initiate a radical reaction.
  • the alginate is grafted to homopolymers or copolymers of HEMA. In some embodiments the alginate is grafted to PEG mMA. In some embodiments the alginate is grafted to polyAMPS or a copolymer of AMPS and PEG or HEMA.
  • the radical initiator is APS + riboflavin with an activator such as TEMED.
  • the present invention is the use of a compound or composition of the present invention in the manufacture of a medicament for the treatment of insulin-dependent diabetes.
  • NRS(O) 2 -substituted heterocyclic — NRS(O) 2 - NR-alkyl, — NRS(O) 2 — NR-substituted alkyl, — NRS(O) 2 - NR-aryl, — NRS(O) 2 - NR-substituted aryl, — NRS(O) 2 - NR-heteroaryl, — NRS(O) 2 - NR-substituted heteroaryl, — NRS(O) 2 - NR-heterocyclic, -NRS(O) 2 -NR- substituted heterocyclic where R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di- (substituted alkyl)amino, mono- and di-arylamino, mono- and di-substituted arylamino, mono- and di-heteroarylamino, mono- and di-sub
  • Nonlimiting examples of electon withdrawing groups include: -C(O)R 2 , where R 2 is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl; -C(O)OR 2 ; -C(O)NR 2 R 3 , where R 3 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; -S(O) 2 OR 2 ; -S(O) 2 NR 2 R 3 ; and, -P(O) 2 OR 2 .
  • R 1 is preferably hydrogen or methyl.
  • the synthesis of the alginates involves the inclusion of more than one type of monomer. Such cases result in copolymerization.
  • the grafted polymers can include a single monomer type or more than one monomer type.
  • the polymers include 2, 3, 4, 5, or 6 different monomer types.
  • monomer composition for the grafted polymers are as follows (using abbreviations shown above): Al; Bl; Cl; Dl; El; AlBl; AlCl; AlDl; AlEl; BlCl; BlDl; BlEl; ClDl; DlEl; AlBlCl; AlBlDl; AlBlEl; AlClDl; AlClEl; AlDlEl; BlClDl; BlClEl; and, ClDlEl.
  • the monomer composition is either Al or Bl.
  • the alginate polymers are used to encapsulate live cells, typically islet cells.
  • islet cells and a modified alginate or a salt thereof is placed in a droplet generator. Droplets generated from islets suspended in the modified alginate solution are collected and then gelled using a crosslinking agent (e.g., CaCk). This accordingly forms microencapsulated islet cells.
  • a crosslinking agent e.g., CaCk
  • Microcapsule crosslinking can be accomplished using either non-covalent or covalent bonds between the modified alginate chains.
  • non-covalent crosslinking is accomplished through the addition of a divalent cation, such as Ca +2 , Ba +2 or Sr +2 .
  • covalent crosslinking can be achieved when the monomer used for polymer grafting is difunctional.
  • Both ends of the monomer are radical acceptors, which means initiating a radical reaction can lead to the addition of an alginate to the two different termini of the monomer.
  • microcapsules of the present invention exhibit superior properties to those consisting of unmodified alginates.
  • the present microcapsules usually provide for a decrease in diffusion of molecules from the external surface of the capsule to the internal surface. Diffusion measurements are oftentimes made in reference to the diffusion of a particular compound through the surface of an unmodified alginate bead, in other words a control.
  • the diffusion of a 20k molecular weight dextran for microcapsules of the present invention is at least 5% less than for control alginate beads; preferably it is at least 10% less and more preferably at least 15% less.
  • the diffusion of a 70k molecular weight dextran for microcapsules of the present invention is at least 5% less than for control alginate beads; preferably it is at least 20% and more preferably at least 30% less; most preferably it is at least 50% less.
  • the diffusion of a 150k molecular weight dextran for microcapsules of the present invention is typically at least 5% less than for control alginate beads; preferably it is at least 20% and more preferably at least 30% less; most preferably it is at least 50% less.
  • the present microcapsules are typically more mechanically stable than control alginate beads.
  • the force at rupture (g) for microcapsules of the present invention is oftentimes at least 10% greater than for control alginate beads. In other embodiments, the force at rupture is at least 20%, 30%, 40% or even 50% greater.
  • Encapsulated islet cells produced according to the present invention may be transplanted into subjects as a treatment for insulin-dependent diabetes. Such transplantation can be into any part of the subject's body that allows for stable transplantation, In some embodiments, the transplantation may be into the peritoneal cavity of the subject. An amount of encapsulated islet cells to produce sufficient insulin to control glycemia in the subject is provided by any suitable means, including but not limited to surgical implantation and intraperitoneal injection.
  • the International Islet Transplant Registry has recommended transplants of at least 6,000 islets, equivalent to 150 ⁇ m in size, per kilogram of recipient body weight, to achieve euglycemia.
  • microcapsules transplanted depends on the ability of the microcapsules to provide insulin in vivo, in response to glucose stimulation.
  • One skilled in the art will be able to determine suitable transplantation quantities of microcapsules, using techniques as are known in the art.
  • Table 1 A summary of modified alginate formulations.
  • ID refers to Identification Number
  • AIg refers to ml of an aqueous alginate solution
  • APS refers to ⁇ l of an aqueous ammonium persulfate solution (10 wt%)
  • Rib refers to ⁇ l of an aqueous riboflavin solution (0.1% w/v)
  • TEMED refers to ⁇ l of tetramethylethylene diamine
  • H 2 O refers to ⁇ l of water
  • HEMA refers to ⁇ l of hydroxyethyl methacrylate
  • MAA refers to ⁇ l of methacrylic acid
  • DMAEMA refers to ⁇ l of dimethylaminoethyl methacrylate
  • AMPS refers to ⁇ l of an aqueous solution of acrylamido methylpropane sulfonic acid (50 wt%)
  • PEGmMA refers to ⁇ l of an aqueous solution of polyethylene glycol
  • M+ for dimethylamino methacrylate
  • M- for methacrylic acid
  • HEMA for 2-hydroxyethyl methacrylate
  • PEG polyethylene glycol
  • PEGMMA for polyethylene glycol mono methacrylate
  • EGDMA for ethylene glycol dimethacrylate
  • AMPS 2-acrylamido-2-methyl-2-propane sulfonic acid
  • Islets were suspended in 1.4% of modified alginate and placed in a droplet generator adapted from that of Walters et al., J. Appl. Biomater. 3:281 (1992) which is hereby incorporated by reference in its entirety.
  • Droplets generated from islets suspended in the modified alginate solution were collected in a funnel containing 1.1% CaCl 2 , where they gelled.
  • the resulting microcapsules were washed with normal saline (NS), incubated with 0.05% poly- L-lysine, washed again with NS, incubated with modified alginate, and washed a final time with NS.
  • NS normal saline
  • the porosity change in modified alginate formulations was quantified by determining the relative decrease/increase in diffusion of a particular weight dextran with respect to control alginate beads. Relative decrease in porosity as quantified for various formulations is shown in Table 2 below. Table 2. Porosity comparison of modified alginate formulations (% decrease from alginate).
  • HEMA modified alginate formulation
  • the backbone has been modified through the addition of a HEMA monomer followed by monomer polymerization.
  • the modified polymer contains copolymers comprising the various monomers.
  • modified alginate microcapsules were quantified using a texture analyzer. Force rupture and AUC for various modified alginates is shown in Table 3. Force may be related to bead strength, while AUC may be related to bead toughness.
  • Islets encapsulated in modified alginate formulations exhibited comparable viability to islets encapsulated in unmodified alginate. Data from viability studies is shown in Table 4 below.
  • alginate modified with polyHEMA exhibited 75% graft function at approximately 100 days post transplantation and 50% graft function more than 400 days post transplantation.
  • the alginate control exhibited 25% graft function at less than 100 days post transplantation and 100% graft failure at about 200 days post translation.
  • Alginate modified with PEG performed even better than the polyHEMA-modified alginate.
  • polyHEMA-modified alginate maintained graft function. 80% longer than an alginate control.
  • PEG-modified alginate maintained graft function 33% longer than the alginate control in the same model.

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Abstract

La présente invention concerne d'une manière générale des composés pouvant être utilisés pour encapsuler des cellules vivantes, des procédés de production de composés pouvant être utilisés pour encapsuler des cellules vivantes, des procédés d'encapsulation de cellules vivantes, des compositions comprenant des cellules vivantes encapsulées et l'utilisation de tels composés dans le traitement du diabète.
PCT/US2007/012192 2006-05-17 2007-05-17 Alginate modifié par des polymères biocompatibles synthétiques Ceased WO2007136860A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US80111406P 2006-05-17 2006-05-17
US60/801,114 2006-05-17
US74996207A 2007-05-17 2007-05-17
US11/749,962 2007-05-17

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WO2007136860A1 true WO2007136860A1 (fr) 2007-11-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011086328A2 (fr) 2010-01-15 2011-07-21 L'oreal Procédé de traitement cosmétique des cheveux

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5788988A (en) * 1991-11-25 1998-08-04 Vivorx, Inc. Method for making cytoprotective, biocompatible, retrievable microcapsule containment systems

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5788988A (en) * 1991-11-25 1998-08-04 Vivorx, Inc. Method for making cytoprotective, biocompatible, retrievable microcapsule containment systems

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KLOCK ET AL.: "Biocompatibility of mannuronic acid-rich alginates", BIOMATERIALS, vol. 18, no. 10, May 1997 (1997-05-01), pages 707 - 713, XP004063784 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011086328A2 (fr) 2010-01-15 2011-07-21 L'oreal Procédé de traitement cosmétique des cheveux

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