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WO2011070436A2 - In situ cross linked biodegradable gel with hydrophobic pockets - Google Patents

In situ cross linked biodegradable gel with hydrophobic pockets Download PDF

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Publication number
WO2011070436A2
WO2011070436A2 PCT/IB2010/003190 IB2010003190W WO2011070436A2 WO 2011070436 A2 WO2011070436 A2 WO 2011070436A2 IB 2010003190 W IB2010003190 W IB 2010003190W WO 2011070436 A2 WO2011070436 A2 WO 2011070436A2
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WO
WIPO (PCT)
Prior art keywords
hydrophilic
hydrophobic
biodegradable gel
gel according
amine
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Application number
PCT/IB2010/003190
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French (fr)
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WO2011070436A3 (en
Inventor
Jitendra Jaikumar Gangwal
Mohan Gopalkrishna Kulkarni
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Council Of Scientific & Industrial Research
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Publication of WO2011070436A2 publication Critical patent/WO2011070436A2/en
Publication of WO2011070436A3 publication Critical patent/WO2011070436A3/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
    • C08G73/10—Polyimides; Polyester-imides; Polyamide-imides; Polyamide acids or similar polyimide precursors
    • C08G73/1092—Polysuccinimides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2379/00—Characterised by the use of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing nitrogen with or without oxygen, or carbon only, not provided for in groups C08J2361/00 - C08J2377/00
    • C08J2379/04—Polycondensates having nitrogen-containing heterocyclic rings in the main chain; Polyhydrazides; Polyamide acids or similar polyimide precursors
    • C08J2379/08—Polyimides; Polyester-imides; Polyamide-imides; Polyamide acids or similar polyimide precursors

Definitions

  • the present invention relates to in-situ biodegradable gels having hydrophobic pocket/cavity immobilized by covalent cross linking useful for delivery of an agent, with desired release profile.
  • Hydrogels are three dimensional polymer networks with unique ability to hold water mamtaining semisolid state giving them physical characteristics similar to soft tissues. In situ hydrogels have attracted considerable interest in site-specific drug-delivery systems, owing to their ability to exist as flowable aqueous solutions (or sol state) before a ⁇ iministration and immediately turn to standing gels upon a ⁇ iministration. Following gelation, these matrices would become drug delivery depots and cell- growing depots for tissue regeneration.
  • Hydrogels can be formed in situ as a result of crosslinking in presence of divalent ions, electrostatic binding between cationic and anionic charges, photo-polymerization by visible and ultraviolet light, stereo complexation between enantiomeric constituents and chemical reaction between reactive functional groups under in vivo conditions.
  • divalent ions such as PLLA, PDLA, polaxamer, PEG, Dextran, Hyaluronic acid, Heparin, Chitosan, PVA and peptides.
  • biocompatible, biodegradable polymers have been widely used in the medical field as tissue regenerative induction membranes, protective membranes for the treatment of wounds, and drug delivery systems.
  • a biodegradable polymeric drug delivery system is a system wherein a drug is contained in a biodegradable polymer matrix.
  • injectable drug delivery systems polymeric microspheres and nanospheres are known in the art.
  • those systems have disadvantages in that they require special preparation methods.
  • preparation since the biodegradable polymers used can only be dissolved in organic solvents, preparation requires the use of organic solvents that are harmful to the human body and therefore any residual solvent remaining after preparation of the microspheres must be completely removed.
  • some drugs such as polypeptides and proteins, may lose their physiological activity after contacting organic solvents.
  • U.S.5543158 describes a nanoparticle, wherein a drug is entrapped therein, formed of a block copolymer consisting of a hydrophilic polyethylene glycol block and a hydrophobic poly (lactide-co-glycolide) block.
  • Shin et al. discloses solubilization method for indomethacin using a diblock copolymer of poly (ethyleneglycol) and polycaprolactone soluble drug incorporated in a polymeric micelle.
  • drawback of these prior arts is use of organic solvents to dissolve drug and a polymer which is harmful to the human body.
  • US Patent 6616941 relates to a biodegradable polymeric composition containing a block copolymer having a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component suspended in a poly(ethylene glycol) medium, and to a method for the preparation thereof.
  • the composition can effectively solubilize a hydrophobic drug and forms a solution which can be stored as a stable liquid formulation.
  • the composition can be injected into the body undiluted or as a diluted solution in an aqueous medium, and therefore is useful for the intravenous administration of poorly water soluble drugs.
  • the potential of the system as an injectable drug delivery vehicle and as a tissue- engineering scaffold is demonstrated by using primaquine as a model drug and by encapsulation of hepatocytes inside the gel matrix, respectively.
  • object of the present invention is to develop in-situ cross linked hydro gels that can solubilize high amount of uniformly dispersed hydrophobic moiety in hydrophobic pockets.
  • Main objective of the present invention is to develop in-situ cross linked hydro gels that can solubilize high amount of uniformly dispersed hydrophobic moiety in hydrophobic pockets.
  • the present invention provides hydrophilic biodegradable gel having at least one hydrophobic pocket cavity, said pocket cavity immobilized by a cross linker, comprising a polymer backbone consisting of polyaspartic acid substituted with a hydrophobic and a hydrophilic amine.
  • hydrophobic amine comprises long chain fatty amines.
  • hydrophobic amine comprises steroidal amines.
  • fatty amines contain Cn to Ci 8 carbon atoms and steroidal amine is amino ethyl deoxycholamide.
  • degree of substitution of hydrophobic amine ranges from 10 - 60 mole %.
  • said hydrophilic substitution on polyaspartic acid is amino ethyl piperazine present in the range of 40-90 mole %.
  • the cross-linker used is water soluble.
  • the water soluble cross linker contains acrylate functionalities in the concentration range from 5 - 50 w/w %.
  • said cross linker is diacrylates and bisacrylamides.
  • the gelation time of the gel is from 1-30 minutes.
  • the degradation time ranges from 1-30 days.
  • the storage modulus ranges from 0.48-115 Kpa.
  • the present invention further provides a hydrophilic biodegradable gel having at least one hydrophobic pocket/cavity said pocket cavity immobilized by covalent cross-linker comprising a polymer backbone consisting of polyaspartic acid substituted with a hydrophobic and a hydrophilic amine, and said cavity having at least one hydrophobic moiety.
  • hydrophilic biodegradable gel provided comprises a polymer backbone, said backbone comprises polyaspartic acid substituted with a hydrophobic and a hydrophilic amine.
  • the hydrophobic amine comprises long chain fatty amines.
  • the hydrophobic amine comprises steroidal amines.
  • the fatty amines contain Cn to Ci8 carbon atoms and steroidal amine is amino ethyl deoxycholamide.
  • the degree of substitution of hydrophobe ranges from 10 - 60 mole %.
  • hydrophilic substitution on polyaspartic acid is amine, preferably secondary amine, most preferably is amino ethyl piperazine in the range of 40-90 mole %.
  • the cross-linker used is water soluble.
  • the water soluble cross linker contains acrylate functionalities in the concentration range from 5 - 50 w/w %.
  • the hydrophilic biodegradable gel according to claim 13, wherein said cross linker is diacrylates and bisacrylamides.
  • the gelation time of the gel is from 1-30 minutes
  • the degradation time ranges from 1- 30 days.
  • the storage modulus ranges from 0.48-115 Kpa.
  • said moiety is selected from a group comprising, but not limited to oil and drug, in solution, emulsion, suspension, mixture form.
  • hydrophilic biodegradable gel incorporating hydrophobic pocket/cavity, said cavity being immobilized by a covalent cross-linker as described earlier, wherein the release of the agent is controlled instant, timed, sustained, pulsatile or delayed release pattern.
  • Figure 1 Scheme for synthesis of amino ethyl deoxycholamide or fatty amine substituted Piperazino ethyl aspartarmde synthesis.
  • Figure 2 Confocal microscopy of hydrogel prepared using examples 2, 6 and 10 polymer conjugate and PEG diacrylate.
  • Figure 3 ESEM micrograph of hydrogel prepared using example 2 polymer conjugate and PEG diacrylate.
  • Figure 4 depict Triclosan release from hydrogels in phosphate buffer saline pH -7.4.
  • 4a depicts release of Triclosan from hydrogel prepared using PEG diacrylate as cross linker and
  • 4b depicts Triclosan from hydrogel prepared using jeffamine bisacrylamide as cross linker.
  • FIG. 5 Paclitaxel release from hydrogels prepared using PEG diacrylate as cross linker.
  • the invention discloses a hydrophilic biodegradable gel having at least one hydrophobic pocket/cavity, which is immobilized by covalent cross-linker.
  • the hydrophilic biodegradable gel comprises a polymer backbone, where the backbone comprises substituted polyaspartic acid with hydrophobic and hydrophilic amine.
  • the hydrophobic substitution of the polyaspartic acid comprises long chain fatty amines.
  • the hydrophobic substitution of the polyaspartic acid comprises steroidal amines.
  • the fatty amines of the gel of the invention are selected from Ci 2 to Ci 8 amines and the steroidal amine is amino ethyl deoxycholamide.
  • the degree of hydrophobic substitution ranges from 10 - 60 mole %.
  • the hydrophilic amine of the gel is a secondary amine, preferably amino ethyl piperazine in the range of 40 - 90 mole %.
  • the cross linker for the formation of the gel of the invention comprises diacrylates and bisacrylamides selected from PEG diacrylate and jeffamine bisacrylamide.
  • the cross linkers are water soluble and present in the concentration range from 5 - 50 w/w %, preferably 5-10 w/w %.
  • the invention discloses process for preparation of the hydrophilic biodegradable gel which comprises:
  • the properties such as gelation time, degradation time and storage modulus of the hydrophilic biodegradable gel having at least one hydrophobic pocket/cavity and immobilized by covalent cross-linker are exempUfied herein.
  • the gelation time varied from 1-30 minutes.
  • the degradation time varied from 1-30 days.
  • the storage modulus for the gel 0.48-115 Kpa.
  • the degradation time of the gel of the invention is independent of the storage modulus of the gel.
  • the biodegradable gel of the instant invention is useful for delivery of an agent and tissue reconstruction.
  • the gel of the invention is useful for, but not limited to instant, timed, sustained, pulsatile and delayed release of said agent.
  • the agent is selected from drug, protein, perfumery, emollients, pigments and such like.
  • the gel of the instant invention is characterized by confocal microscopy using hydrophobic dye (Nile Red) and hydrophilic dye (FITC Dextran).
  • the photomicrograph illustrates continuous hydrogel exhibiting hydrophilic character because of green fluorescence due to staining by hydrophilic dye, while hydrophobic pockets/cavities exhibiting red orange fluorescence due to staining by hydrophobic dye were observed.
  • PSI polysuccinimide
  • PSI is dissolved in dry dimethyl formamide to which laurylamine is added and stirred at 65-70 ° C for 24 hrs under nitrogen.
  • the solution is concentrated and precipitated in acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the polymer conjugate is dissolved in dimethyl formamide and added slowly with stirring to solution of amino ethyl piperazine in dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution is dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate is then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide.
  • Polymer conjugates so obtained are dissolved in phosphate buffer pH 7.4 and then proceeded to form gel by mixing solution with PEG diacrylate or jeffamine bisacrylamide in phosphate buffer and incubating at 37 deg C.
  • the degree of hydrophobic substitution ranges from 10 - 60 mole %.
  • the hydrophilic amine of the gel is a secondary amine, preferably amino ethyl piperazine in the range of 40 - 90 mole %.
  • the cross linker for the formation of the gel of the invention comprises diacrylates and bisacrylamides selected from PEG diacrylate and jeffamine bisacrylamide.
  • the cross linkers are water soluble and present in the concentration range from 5 - 50 w/w %, preferably 5-10 w/w %.
  • the properties such as gelation time, degradation time and storage modulus of the hydrophilic biodegradable gel having at least one hydrophobic pocket cavity and immobilized by covalent cross-linker, are exemplified herein.
  • the hydrophilic biodegradable gel having hydrophobic pocket/cavity, the hydrophobic pocket/cavity immobilized by covalent cross-linker, having at least one hydrophobic moiety is disclosed.
  • the hydrophobic moiety is selected from, but not limited to drugs, a drug optionally solubilized, proteins, vitamins, nutrients, perfumes, emollients, pigments and such like.
  • hydrophobic moiety is exemplified herein as triclosan.
  • the hydrophilic biodegradable gel of the invention comprises paclitaxel solubilized in a-tocopherol.
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 0.8 g of laurylamine was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 °C and stirred for 6 hours at 20 °C.
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 1.6 g of laurylamine was added and stirred at 65 ° C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 °C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 3.2 g of laurylamine was added and stirred at 65 ° C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 4.8 g of laurylamine was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 1 g of cetylamine was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield cetyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 2 g of cetyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 4 g of cetyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield cetyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • Example 8 Synthesis of biodegradable polymer (cetyl aspartamide co amino ethyl piperazino aspartamide 60:40)
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 6 g of cetyl amine was added and stirred at 65 ° C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 ° C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield cetyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 1.12 g of stearyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield stearyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 2.24 g of stearyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 4.48 g of stearyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • PSI polysuccmimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 6.72 g of stearyl amine was added and stirred at 65 ° C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield stearyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccmimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 1.8 g of amino ethyl deoxychoamide was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield amino ethyl deoxychoamide conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccmimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 3.6 g of amino ethyl deoxychoamide was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was 4 dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 ° C.
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 7.2 g of amino ethyl deoxychoamide was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield amino ethyl deoxychoamide conjugated piperazino ethyl aspartamide (Scheme in figure 1)
  • PSI polysuccinimide
  • 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 10.8 g of amino ethyl deoxychoamide was added and stirred at 65 0 C for 24 hrs under nitrogen.
  • the solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate.
  • the 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C.
  • the solid was then dissolved in 200 ml of dichloromethane and washed 3 times with acidified brine solution (50 ml). The dichloromethane solution was then washed with sodium bicarbonate solution followed by brine and then dried over anhydrous sodium sulfate and concentrated to yield Jeffamine ® ED 600 bisacrylamide. The product was stored at -20 ° C under argon.
  • Triclosan 0.01 g was solubilized in 0.5 ml of polymer conjugate solution obtained in example 18. The solution was mixed with 0.5 ml of PEG diacrylate (Mn 700) solution in phosphate buffer. (20 wt %) (Molar ratio of amine to unsaturated groups was kept at 1.1) and incubated at 37 deg C to form the gel.
  • Triclosan 0.01 g was solubilized in 0.5 ml of polymer conjugate solution obtained in example 18. The solution was mixed with 0.5 ml of Jeffamine diacrylamide as exemplified in example 17 solution in phosphate buffer.(20 wt %) (Molar ratio of amine to unsaturated groups was kept at 1.1) and incubated at 37 deg C to form the gel.
  • paclitaxel and 0.5 g of alpha tocopherol were solubilized in 20 ml of ethanol and concentrated to form paclitaxel solution in alpha tocopherol.
  • the 0.1 g of this solution was added to 0.5 ml of polymer conjugate solution obtained in example 18 and mixed and sonicated for 30 minutes to form a mixture.
  • the mixture was mixed with 0.5 ml of PEG diacrylate in phosphate buffer (20 wt %) (Molar ratio of amine to unsaturated groups was kept at 1.1) and incubated at 37 deg C to form the gel.
  • Example 11 No gel 345 - 3
  • Example 12 No gel No gel - -
  • 0.1 g gel of example 20 prepared using polymer conjugates of examples 2,6,10 and 14 were studied for triclosan release in 10 ml Phosphate buffer (pH 7.4) . After each time interval 1 ml release medium was withdrawn and same amount was replaced with phosphate buffer in order to maintain sink condition. To 1 ml of release medium, 0.25 ml of acetonitrile was added, vortexed and analyzed using UV spectrophotometer at 280 nm. (Refer table 3)
  • Example 14 Example 14
  • 0.1 g gel of example 20 prepared using polymer conjugates of examples 2,6,10 and 14 were studied for triclosan release in 10 ml Phosphate buffer (pH 7.4) with 2% sodium dodecyl sulphate. After each time interval 1 ml release medium was withdrawn and same amount was replaced with phosphate buffer in order to maintain sink condition. To 1 ml of release medium, 0.25 ml of acetonitrile was added, vortexed and analyzed using UV spectrophotometer at 280 nm. (Refer table 4)
  • Example 14 Example 14
  • the 0.1 ggel of paclitaxel as exemplified in example 20 prepared using conjugates of example 2 and 14 and studied for release of paclitaxel in 10 ml phosphate buffer and release was monitored over 30 hours. After each hour, 0.2 ml aliquot was withdrawn and same volume replaced in the release medium in order to maintain sink condition. The aliquots were diluted to 1 ml using ethanol, centrifuged and analyzed by HPLC [Ci8 column, Mobile phase - Acetonitrile : water (55:45), 23 lnm]. (Refer table 5)
  • Main advantage of the present invention is to provide in-situ cross linked hydro gels that can solubilize high amount of uniformly dispersed hydrophobic moiety in hydrophobic pockets.
  • Another advantage of the present invention is to provide gel useful for drug or protein delivery systems e.g. for slow release of agents or medications and also in tissue reconstruction.

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Abstract

Hydrophilic biodegradable gel incorporating hydrophobic pocket/cavity immobilized by a cross linker where the gel comprises a polymer backbone of polyaspartic acid substituted with a hydrophobic and a hydrophilic amine is disclosed. The pocket/cavity comprises at least one hydrophobic moiety, and is useful for drug delivery and tissue reconstruction.

Description

IN SITU CROSS LINKED BIODEGRADABLE GEL WITH HYDROPHOBIC
POCKETS
FIELD OF THE INVENTION
The present invention relates to in-situ biodegradable gels having hydrophobic pocket/cavity immobilized by covalent cross linking useful for delivery of an agent, with desired release profile.
BACKGROUND AND PRIOR ART OF THE INVENTION
Hydrogels are three dimensional polymer networks with unique ability to hold water mamtaining semisolid state giving them physical characteristics similar to soft tissues. In situ hydrogels have attracted considerable interest in site-specific drug-delivery systems, owing to their ability to exist as flowable aqueous solutions (or sol state) before a<iministration and immediately turn to standing gels upon a<iministration. Following gelation, these matrices would become drug delivery depots and cell- growing depots for tissue regeneration.
Hydrogels can be formed in situ as a result of crosslinking in presence of divalent ions, electrostatic binding between cationic and anionic charges, photo-polymerization by visible and ultraviolet light, stereo complexation between enantiomeric constituents and chemical reaction between reactive functional groups under in vivo conditions. Recently several research groups have reported preparation of hydrogels from various polymers such as PLLA, PDLA, polaxamer, PEG, Dextran, Hyaluronic acid, Heparin, Chitosan, PVA and peptides.
The traditional synthetic methods of hydrogel synthesis based on crosslinking copolymerization, crosslinking of polymeric precursors, and polymer-polymer reactions, however, lack in precise control of chain length, sequence and three- dimensional arrangement. In addition, side reactions may occur, influencing their physico-chemical properties and performance in the biological environment such as low degree of cross linking, high rate of biodegradation thereby unable to uniformly load hydrophobic drug and subsequent release in solubilized form.
Further, biocompatible, biodegradable polymers have been widely used in the medical field as tissue regenerative induction membranes, protective membranes for the treatment of wounds, and drug delivery systems. One example of a biodegradable polymeric drug delivery system is a system wherein a drug is contained in a biodegradable polymer matrix. These systems have the disadvantage of having to be surgically implanted. In the form of injectable drug delivery systems, polymeric microspheres and nanospheres are known in the art. However, those systems have disadvantages in that they require special preparation methods. In addition, since the biodegradable polymers used can only be dissolved in organic solvents, preparation requires the use of organic solvents that are harmful to the human body and therefore any residual solvent remaining after preparation of the microspheres must be completely removed. Furthermore, some drugs, such as polypeptides and proteins, may lose their physiological activity after contacting organic solvents.
Many important known drugs are hydrophobic in nature and have limited solubility in water. In order to attain the expected therapeutic effect from these drugs it is usually required that a solubilized form of the drug need to be administered to a patient. U.S.5543158 describes a nanoparticle, wherein a drug is entrapped therein, formed of a block copolymer consisting of a hydrophilic polyethylene glycol block and a hydrophobic poly (lactide-co-glycolide) block.
Shin et al. discloses solubilization method for indomethacin using a diblock copolymer of poly (ethyleneglycol) and polycaprolactone soluble drug incorporated in a polymeric micelle. However, drawback of these prior arts is use of organic solvents to dissolve drug and a polymer which is harmful to the human body.
US Patent 6616941 relates to a biodegradable polymeric composition containing a block copolymer having a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component suspended in a poly(ethylene glycol) medium, and to a method for the preparation thereof. The composition can effectively solubilize a hydrophobic drug and forms a solution which can be stored as a stable liquid formulation. Furthermore, the composition can be injected into the body undiluted or as a diluted solution in an aqueous medium, and therefore is useful for the intravenous administration of poorly water soluble drugs.
An article titled "Self-cross-linking biopolymers as injectable in-situ forming biodegradable scaffolds'''' by Biji Balakrishnan and A. Jayakrishnan published in Biomaterials Volume 26, Issue 18, June 2005, Pages 3941-3951 discloses an injectable polymer scaffolds which are biocompatible and biodegradable and are important biomaterials for tissue engineering and drug delivery. Hydrogels derived from natural proteins and polysaccharides are ideal scaffolds for tissue engineering since they resemble the extracellular matrices of the tissue comprised of various amino acids and sugar-based macromolecules. A new class of hydrogels derived from oxidized alginate and gelatin are reported.
The potential of the system as an injectable drug delivery vehicle and as a tissue- engineering scaffold is demonstrated by using primaquine as a model drug and by encapsulation of hepatocytes inside the gel matrix, respectively.
Hence there is a need for biocompatible, biodegradable hydrogel system with hydrophobic pockets having higher hydrophobe solubilization capacity which can thus provide uniform hydrophobic drug loading and its subsequent release.
Therefore, object of the present invention is to develop in-situ cross linked hydro gels that can solubilize high amount of uniformly dispersed hydrophobic moiety in hydrophobic pockets.
OBJECTIVE OF THE INVENTION
Main objective of the present invention is to develop in-situ cross linked hydro gels that can solubilize high amount of uniformly dispersed hydrophobic moiety in hydrophobic pockets.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides hydrophilic biodegradable gel having at least one hydrophobic pocket cavity, said pocket cavity immobilized by a cross linker, comprising a polymer backbone consisting of polyaspartic acid substituted with a hydrophobic and a hydrophilic amine.
In an embodiment of the present invention, hydrophobic amine comprises long chain fatty amines.
In another embodiment of the present invention, hydrophobic amine comprises steroidal amines.
In yet another embodiment of the present invention, fatty amines contain Cn to Ci8 carbon atoms and steroidal amine is amino ethyl deoxycholamide. In yet another embodiment of the present invention, degree of substitution of hydrophobic amine ranges from 10 - 60 mole %.
In yet another embodiment of the present invention, said hydrophilic substitution on polyaspartic acid is amino ethyl piperazine present in the range of 40-90 mole %.
In yet another embodiment of the present invention, the cross-linker used is water soluble.
In yet another embodiment of the present invention, the water soluble cross linker contains acrylate functionalities in the concentration range from 5 - 50 w/w %.
In yet another embodiment of the present invention, said cross linker is diacrylates and bisacrylamides.
In yet another embodiment of the present invention, the gelation time of the gel is from 1-30 minutes.
In yet another embodiment of the present invention, the degradation time ranges from 1-30 days.
In yet another embodiment of the present invention, the storage modulus ranges from 0.48-115 Kpa.
The present invention further provides a hydrophilic biodegradable gel having at least one hydrophobic pocket/cavity said pocket cavity immobilized by covalent cross-linker comprising a polymer backbone consisting of polyaspartic acid substituted with a hydrophobic and a hydrophilic amine, and said cavity having at least one hydrophobic moiety.
In a further embodiment of the present invention, hydrophilic biodegradable gel provided comprises a polymer backbone, said backbone comprises polyaspartic acid substituted with a hydrophobic and a hydrophilic amine.
In yet further embodiment of the present invention, the hydrophobic amine comprises long chain fatty amines.
In yet further embodiment of the present invention, the hydrophobic amine comprises steroidal amines.
In yet another further embodiment of the present invention, the fatty amines contain Cn to Ci8 carbon atoms and steroidal amine is amino ethyl deoxycholamide.
In yet further embodiment of the present invention, the degree of substitution of hydrophobe ranges from 10 - 60 mole %. In yet further embodiment of the present invention, hydrophilic substitution on polyaspartic acid is amine, preferably secondary amine, most preferably is amino ethyl piperazine in the range of 40-90 mole %.
In yet embodiment of the present invention, the cross-linker used is water soluble. In yet further embodiment of the present invention, the water soluble cross linker contains acrylate functionalities in the concentration range from 5 - 50 w/w %.
In yet further embodiment of the present invention, the hydrophilic biodegradable gel according to claim 13, wherein said cross linker is diacrylates and bisacrylamides. In yet further embodiment of the present invention, the gelation time of the gel is from 1-30 minutes
In yet further embodiment of the present invention, the degradation time ranges from 1- 30 days.
In yet further embodiment of the present invention, the storage modulus ranges from 0.48-115 Kpa.
In yet further embodiment of the present invention, said moiety is selected from a group comprising, but not limited to oil and drug, in solution, emulsion, suspension, mixture form.
In yet further embodiment of the present invention, hydrophilic biodegradable gel incorporating hydrophobic pocket/cavity, said cavity being immobilized by a covalent cross-linker as described earlier, wherein the release of the agent is controlled instant, timed, sustained, pulsatile or delayed release pattern.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Scheme for synthesis of amino ethyl deoxycholamide or fatty amine substituted Piperazino ethyl aspartarmde synthesis.
Figure 2: Confocal microscopy of hydrogel prepared using examples 2, 6 and 10 polymer conjugate and PEG diacrylate.
Figure 3: ESEM micrograph of hydrogel prepared using example 2 polymer conjugate and PEG diacrylate.
Figure 4: These figures depict Triclosan release from hydrogels in phosphate buffer saline pH -7.4. 4a depicts release of Triclosan from hydrogel prepared using PEG diacrylate as cross linker and 4b depicts Triclosan from hydrogel prepared using jeffamine bisacrylamide as cross linker.
Figure 5: Paclitaxel release from hydrogels prepared using PEG diacrylate as cross linker.
DETAIL DESCRIPTION OF THE INVENTION
The invention discloses a hydrophilic biodegradable gel having at least one hydrophobic pocket/cavity, which is immobilized by covalent cross-linker. The hydrophilic biodegradable gel comprises a polymer backbone, where the backbone comprises substituted polyaspartic acid with hydrophobic and hydrophilic amine. The hydrophobic substitution of the polyaspartic acid comprises long chain fatty amines. Optionally the hydrophobic substitution of the polyaspartic acid comprises steroidal amines. The fatty amines of the gel of the invention are selected from Ci2 to Ci8 amines and the steroidal amine is amino ethyl deoxycholamide. The degree of hydrophobic substitution ranges from 10 - 60 mole %. The hydrophilic amine of the gel is a secondary amine, preferably amino ethyl piperazine in the range of 40 - 90 mole %. The cross linker for the formation of the gel of the invention comprises diacrylates and bisacrylamides selected from PEG diacrylate and jeffamine bisacrylamide. The cross linkers are water soluble and present in the concentration range from 5 - 50 w/w %, preferably 5-10 w/w %.
In another aspect, the invention discloses process for preparation of the hydrophilic biodegradable gel which comprises:
a. Preparing solution of polyaspartic acid having hydrophobic and hydrophilic amine in phosphate buffer;
b. Preparing solution of PEG diacrylate and jeffamine bisacrylamide in phosphate buffer;
c. Mixing solutions of steps a and b and incubating at 37 °C to form gel.
The properties such as gelation time, degradation time and storage modulus of the hydrophilic biodegradable gel having at least one hydrophobic pocket/cavity and immobilized by covalent cross-linker, are exempUfied herein. The gelation time varied from 1-30 minutes. The degradation time varied from 1-30 days. The storage modulus for the gel 0.48-115 Kpa. The degradation time of the gel of the invention is independent of the storage modulus of the gel. The biodegradable gel of the instant invention is useful for delivery of an agent and tissue reconstruction. The gel of the invention is useful for, but not limited to instant, timed, sustained, pulsatile and delayed release of said agent. The agent is selected from drug, protein, perfumery, emollients, pigments and such like.
The gel of the instant invention is characterized by confocal microscopy using hydrophobic dye (Nile Red) and hydrophilic dye (FITC Dextran). The photomicrograph illustrates continuous hydrogel exhibiting hydrophilic character because of green fluorescence due to staining by hydrophilic dye, while hydrophobic pockets/cavities exhibiting red orange fluorescence due to staining by hydrophobic dye were observed.
Aspartic acid is polymerized by dehydro polycondensation to yield polysuccinimide (PSI).PSI is dissolved in dry dimethyl formamide to which laurylamine is added and stirred at 65-70 ° C for 24 hrs under nitrogen. The solution is concentrated and precipitated in acetone and dried in vacuum desiccators to obtain the polymer conjugate. The polymer conjugate is dissolved in dimethyl formamide and added slowly with stirring to solution of amino ethyl piperazine in dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution is dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate is then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide.
Jeffamine® ED600 is dried by azeotropic distillation of toluene under vacuum followed by addition of anhydrous Tetrahydrofuran. Triethylamine is added to it and stirred for 30 minutes. Acryloyl chloride in dichloromethane is added drop wise to above solution over 1 hr. The reaction is allowed to proceed overnight in the dark under argon. The solution is filtered and concentrated. The solid is then dissolved in dichloromethane and washed 3 times with acidified brine solution. The dichloromethane solution is then washed with sodium bicarbonate solution followed by brine and then dried over anhydrous sodium sulfate and concentrated to yield Jeffamine® ED 600 bisacrylamide. The product is stored at -20 ° C under argon.
Polymer conjugates so obtained are dissolved in phosphate buffer pH 7.4 and then proceeded to form gel by mixing solution with PEG diacrylate or jeffamine bisacrylamide in phosphate buffer and incubating at 37 deg C. The degree of hydrophobic substitution ranges from 10 - 60 mole %. The hydrophilic amine of the gel is a secondary amine, preferably amino ethyl piperazine in the range of 40 - 90 mole %.
The cross linker for the formation of the gel of the invention comprises diacrylates and bisacrylamides selected from PEG diacrylate and jeffamine bisacrylamide. The cross linkers are water soluble and present in the concentration range from 5 - 50 w/w %, preferably 5-10 w/w %.
The properties such as gelation time, degradation time and storage modulus of the hydrophilic biodegradable gel having at least one hydrophobic pocket cavity and immobilized by covalent cross-linker, are exemplified herein.
In one more aspect of the invention, the hydrophilic biodegradable gel having hydrophobic pocket/cavity, the hydrophobic pocket/cavity immobilized by covalent cross-linker, having at least one hydrophobic moiety is disclosed. The hydrophobic moiety is selected from, but not limited to drugs, a drug optionally solubilized, proteins, vitamins, nutrients, perfumes, emollients, pigments and such like.
The hydrophobic moiety is exemplified herein as triclosan. In another preferred embodiment, the hydrophilic biodegradable gel of the invention comprises paclitaxel solubilized in a-tocopherol.
EXAMPLES
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
Example 1: Synthesis of biodegradable polymer (lauryl aspartamide co amino ethyl piperazino aspartamide 10:90)
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 0.8 g of laurylamine was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 °C and stirred for 6 hours at 20 °C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1) Example 2: Synthesis of biodegradable polymer (lauryl aspartamide co amino ethyl piperazino aspartamide 20:80) [LmC1220]
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 1.6 g of laurylamine was added and stirred at 65 ° C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 °C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 3: Synthesis of biodegradable polymer (lauryl aspartamide co amino ethyl piperazino aspartamide 40:60)
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 3.2 g of laurylamine was added and stirred at 65 ° C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 4: Synthesis of biodegradable polymer (lauryl aspartamide co amino ethyl piperazino aspartamide 60:40)
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 4.8 g of laurylamine was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield lauryl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 5: Synthesis of biodegradable polymer (cetyl aspartamide co amino ethyl piperazino aspartamide 10:90)
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 1 g of cetylamine was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield cetyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 6: Synthesis of biodegradable polymer (cetyl aspartamide co amino ethyl piperazino aspartamide 20:80)
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 2 g of cetyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield cetyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1) Example 7: Synthesis of biodegradable polymer (cetyl aspartamide co amino ethyl piperazino aspartamide 40:60)
Aspartic acid was polymerized by dehydropolycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 4 g of cetyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield cetyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 8: Synthesis of biodegradable polymer (cetyl aspartamide co amino ethyl piperazino aspartamide 60:40)
Aspartic acid was polymerized by dehydropolycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 6 g of cetyl amine was added and stirred at 65 ° C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 ° C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield cetyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 9: Synthesis of biodegradable polymer (stearyl aspartamide co amino ethyl piperazino aspartamide 10:90)
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 1.12 g of stearyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield stearyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 10: Synthesis of biodegradable polymer (stearyl aspartamide co amino ethyl piperazino aspartamide 20:80)
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 2.24 g of stearyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield stearyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1) Example 11: Synthesis of biodegradable polymer (stearyl aspartamide co amino ethyl piperazino aspartamide 40:60)
Aspartic acid was polymerized by dehydropolycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 4.48 g of stearyl amine was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield stearyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1) Example 12: Synthesis of biodegradable polymer (stearyl aspartamide co amino ethyl piperazino aspartamide 60:40)
Aspartic acid was polymerized by dehydropolycondensation to yield polysuccmimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 6.72 g of stearyl amine was added and stirred at 65 ° C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield stearyl amine conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 13: Synthesis of biodegradable polymer (deoxycholamido ethyl aspartamide co amino ethyl piperazino aspartamide 10:90)
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccmimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 1.8 g of amino ethyl deoxychoamide was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield amino ethyl deoxychoamide conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 14: Synthesis of biodegradable polymer (deoxycholamido ethyl aspartamide co amino ethyl piperazino aspartamide 20:80) [BmDOCA20|
Aspartic acid was polymerized by dehydro polycondensation to yield polysuccmimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 3.6 g of amino ethyl deoxychoamide was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was 4 dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 ° C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield amino ethyl deoxychoamide conjugated piperazino ethyl aspartamide (Scheme in figure 1) Example 15: Synthesis of biodegradable polymer (deoxycholamido ethyl aspartamide co amino ethyl piperazino aspartamide 40:60)
Aspartic acid was polymerized by dehydropolycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 7.2 g of amino ethyl deoxychoamide was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with intermittent change of water outside. Dialyzate was then freeze dried to yield amino ethyl deoxychoamide conjugated piperazino ethyl aspartamide (Scheme in figure 1)
Example 16: Synthesis of biodegradable polymer (deoxycholamido ethyl aspartamide co amino ethyl piperazino aspartamide 60:40)
Aspartic acid was polymerized by dehydropolycondensation to yield polysuccinimide (PSI). 4 g of PSI was dissolved in 40 ml dry dimethyl formamide to which 10.8 g of amino ethyl deoxychoamide was added and stirred at 65 0 C for 24 hrs under nitrogen. The solution was concentrated and precipitated in 250 ml acetone and dried in vacuum desiccators to obtain the polymer conjugate. The 5 g of polymer conjugate was dissolved in 50 ml dimethyl formamide and added slowly with stirring to solution of 15 ml of amino ethyl piperazine in 15 ml of dimethyl formamide at 10 0 C and stirred for 6 hours at 20 0 C. The solution was dialyzed against distilled water for 24 hours with mtermittent change of water outside. Dialyzate was then freeze dried to yield amino ethyl deoxychoamide conjugated piperazino ethyl aspartamide (Scheme in figure 1) Example 17
Jeffarnine® ED600 biscrylamide. Jeffamine® ED 600 (20 g, 66.66 mmol of amine) was dried by azeotropic distillation of 300 ml of toluene under vacuum. 200 ml of anhydrous Tetrahydrofuran (Aldrich) was added. Triemylamine (11.12 ml, 80 mmol) was added to it and stirred for 30 minutes. Acryloyl chloride (7.25g, 80 mmol) in 20 ml of Dichloromethane was added drop wise to above solution over 1 hr. The reaction proceeded overnight in the dark under argon. The solution was filtered and concentrated. The solid was then dissolved in 200 ml of dichloromethane and washed 3 times with acidified brine solution (50 ml). The dichloromethane solution was then washed with sodium bicarbonate solution followed by brine and then dried over anhydrous sodium sulfate and concentrated to yield Jeffamine® ED 600 bisacrylamide. The product was stored at -20 ° C under argon.
Example 18: Preparation of polymer conjugate dispersions
0.1 g of polymer conjugates obtained in examples 1-16 were dissolved in 0.5 ml phosphate buffer pH 7.4
Example 19: Preparation of Triclosan gel
0.01 g of Triclosan was solubilized in 0.5 ml of polymer conjugate solution obtained in example 18. The solution was mixed with 0.5 ml of PEG diacrylate (Mn 700) solution in phosphate buffer. (20 wt %) (Molar ratio of amine to unsaturated groups was kept at 1.1) and incubated at 37 deg C to form the gel.
Example 20: Preparation of Triclosan gel
0.01 g of Triclosan was solubilized in 0.5 ml of polymer conjugate solution obtained in example 18. The solution was mixed with 0.5 ml of Jeffamine diacrylamide as exemplified in example 17 solution in phosphate buffer.(20 wt %) (Molar ratio of amine to unsaturated groups was kept at 1.1) and incubated at 37 deg C to form the gel.
Example 21: Preparation of paclitaxel gel
0.05 g of paclitaxel and 0.5 g of alpha tocopherol were solubilized in 20 ml of ethanol and concentrated to form paclitaxel solution in alpha tocopherol. The 0.1 g of this solution was added to 0.5 ml of polymer conjugate solution obtained in example 18 and mixed and sonicated for 30 minutes to form a mixture. The mixture was mixed with 0.5 ml of PEG diacrylate in phosphate buffer (20 wt %) (Molar ratio of amine to unsaturated groups was kept at 1.1) and incubated at 37 deg C to form the gel.
Example 22: Determination of gelation time
To determine the gelation time, 250 μΐ solutions formed in example 18 and 250 μΐ PEG diacrylate solution (molar ratio of amine to unsaturated groups was kept at 1.1) in isotonic Phosphate buffer (pH 7.4) was mixed by vortexing and held at 37 °C. The gelation time was determined by the vial tilting method. When the sample showed no flow on tilting and holding for 5 sec, it was regarded as a gel. (Refer Table : 1)
Example 23 : ESEM of gel
250 μΐ solutions formed in example 18 and 250 μΐ PEG diacrylate solution or jeffamine bisacrylamide solution (molar ratio of amine to unsaturated groups was kept at 1.1) in isotonic Phosphate buffer (pH 7.4) was mixed by vortexing and held at 37 °C and placed in cup / sample holder of ESEM and field was applied for evaluation of surface morphology and nanoaggregate distribution inside hydrogel as shown in Figure 2
Example 24: Determination of degradation time
The samples prepared for gelation time determination were weighed and kept for degradation at 37 0 C in 3 ml 0.1M isotonic Phosphate buffer pH 7.4. For determining the weight loss of gel, buffer was removed after every 24 hrs, sample vials were inverted and allowed to dry on tissue paper and weighed. The same sample vial was then refilled with 3 ml buffer and kept at 37 0 C. This procedure was repeated till the gel was degraded completely. The time required for complete disappearance of gel in isotonic phosphate buffer at 37 0 C, pH = 7.4 was taken as complete degradation time.(Refer to Table 1 and 2)
Table 1: Gelation and degradation time of PEG diacrylate (700) cross-linked gels
Polymer Gelation time (Sec) Degradation time (days) conjugate 5% 10% 5% 10%
Example 1 442 241 1 2
Example 2 613 275 1 3
Example 3 No gel 315 2
Example 4 No gel No gel -
Example 5 327 66 1 3
Example 6 431 45 1 3
Example 7 No gel 210 3
Example 8 No gel No gel -
Example 9 406 90 1 3
Example 10 440 146 1 3
Example 11 No gel 345 - 3 Example 12 No gel No gel - -
Example 13 602 253 1 2
Example 14 779 310 1 2
Example 15 No gel No gel - -
Example 16 No gel No gel - -
Table 2: Gelation and degradation time of Jeffamine diacrylate cross-linked gels
Polymer conjugate Gelation time (Sec) Degradation time (days)
Example 1 1215 26
Example 2 1536 21
Example 3 1730 17
Example 4 No gel -
Example 5 1380 28
Example 6 1630 21
Example 7 1790 18
Example 8 No gel -
Example 9 1318 21
Example 10 1680 16
Example 11 No gel -
Example 12 No gel -
Example 13 1536 25
Example 14 1734 19
Example 15 No gel -
Example 16 No gel -
Example 25: Storage modulus measurement
Small amplitude oscillatory experiments were performed at 37 ° C on a MCR301 rheometer (Anton Paar) using cone and plate geometry. Polymer conjugate dispersions as described in example 18 and PEG diacrylate were dissolved separately in isotonic phosphate buffer (pH 7.4). These two solutions were mixed at molar ratio of amine to unsaturated groups of PEGDA of 1.1:1 and quickly introduced in the plate of rheometer. The storage modulus were measured at constant amplitude of 2 % with angular frequency of 1 rad / sec as a function of time. (Please refer to table 3)
Table 3: Storage modulus of hydrogels prepared using PEG diacrylate and polymer conjugates of examples as tabulated
Figure imgf000019_0001
Example 26: Triclosan release profile
0.1 g gel of example 20 prepared using polymer conjugates of examples 2,6,10 and 14 were studied for triclosan release in 10 ml Phosphate buffer (pH 7.4) . After each time interval 1 ml release medium was withdrawn and same amount was replaced with phosphate buffer in order to maintain sink condition. To 1 ml of release medium, 0.25 ml of acetonitrile was added, vortexed and analyzed using UV spectrophotometer at 280 nm. (Refer table 3)
Table 3 Triclosan release profile from hydrogels prepared using PEG diacrylate 700 as crosslinker
Polymer conjugates
Time in hrs Example 2 Example 6 Example 10 Example 14
1 4.88 2.12 4.20 2.20
2 8.20 4.32 6.65 6.59
3 9.13 5.62 8.67 10..25 4 12.02 6.34 10.35 13.35
5 11.80 7.16 11.00 15.27
6 12.30 8.81 12.41 14.87
7 13.21 8.54 13.17 15.22
8 13.69 9.10 13.57 15.58
9 13.66 9.28 13.66 15.43
10 14.13 9.52 13.69 15.67
11 15.02 9.53 13.86 15.55
12 16.58 10.20 13.93 18.39
16 49.24 61.30 61.10 77.21
24 100 100 100 100
Example 27
Triclosan release profile
0.1 g gel of example 20 prepared using polymer conjugates of examples 2,6,10 and 14 were studied for triclosan release in 10 ml Phosphate buffer (pH 7.4) with 2% sodium dodecyl sulphate. After each time interval 1 ml release medium was withdrawn and same amount was replaced with phosphate buffer in order to maintain sink condition. To 1 ml of release medium, 0.25 ml of acetonitrile was added, vortexed and analyzed using UV spectrophotometer at 280 nm. (Refer table 4)
Table 4: Triclosan release profile from gels prepared using Jeffamine ED 600 bisacrylamide as a cross linker
Polymer conjugates
Time in hrs Example 2 Example 6 Example 10 Example 14
6 30.20 15.63 17.40 22.29
12 36.96 25.91 30.37 51.64
18 41.75 28.15 32.99 63.43
24 46.30 30.51 38.71 70.21
30 50.33 36.21 42.06 65.44
36 53.05 39.46 44.50 72.65
42 49.36 36.96 43.87 71.16 48 51.97 37.95 47.19 67.28
72 56.80 47.08 53.61 81.91
96 64.53 60.19 61.38 103.72
120 62.70 65.17 72.63 93.54
144 64.49 66.87 69.53 100
168 100 82.94 94.48 91.58
192 92.88 91.03 99.50 95.12
216 91.16 90.09 99.54 94.93
240 94.65 95.02 98.87 98.66
264 90.25 100 100 98.03
Example 28: Release study of paclitaxel
The 0.1 ggel of paclitaxel as exemplified in example 20 prepared using conjugates of example 2 and 14 and studied for release of paclitaxel in 10 ml phosphate buffer and release was monitored over 30 hours. After each hour, 0.2 ml aliquot was withdrawn and same volume replaced in the release medium in order to maintain sink condition. The aliquots were diluted to 1 ml using ethanol, centrifuged and analyzed by HPLC [Ci8 column, Mobile phase - Acetonitrile : water (55:45),
Figure imgf000021_0001
23 lnm]. (Refer table 5)
Table 5: Paclitaxel release profile
Time in hrs Example 2 polymer conjugate Example 14 polymer conjugate
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
6 0 0
7 0 0
8 0 0
9 0 0
10 0 0
11 0.72 0.41 12 3.39 0.16
13 3.29 4.87
14 5.48 23.57
15 6.72 30.42
16 17.18 30.24
17 21.94 31.83
18 23.71 38.94
19 28.22 39.40
20 38.98 38.54
21 39.92 53.62
22 40.55 59.02
23 71.69 63.96
24 100 75.02
26 101.23 93.58
30 97.86 100.28
ADVANTAGES OF THE INVENTION
• Main advantage of the present invention is to provide in-situ cross linked hydro gels that can solubilize high amount of uniformly dispersed hydrophobic moiety in hydrophobic pockets.
• Another advantage of the present invention is to provide gel useful for drug or protein delivery systems e.g. for slow release of agents or medications and also in tissue reconstruction.

Claims

We Claim
1. Hydrophilic biodegradable gel having at least one hydrophobic pocket/cavity, said pocket.cavity immobilized by a cross linker, comprising a polymer backbone consisting of polyaspartic acid substituted with a hydrophobic and a hydrophilic amine.
2. The hydrophilic biodegradable gel according to claim 1, wherein the hydrophobic amine comprises long chain fatty amines.
3. The hydrophilic biodegradable gel according to claim 1, wherein the hydrophobic amine comprises steroidal amines.
4. The hydrophilic biodegradable gel according to claim 1, wherein the fatty amines contain Ci2 toCi8 carbon atoms and steroidal amine is amino ethyl deoxycholamide.
5. The hydrophilic biodegradable gel according to claim 1, wherein the degree of substitution of hydrophobic amine ranges from 10 - 60 mole %.
6. The hydrophilic biodegradable gel according to claim 1, wherein said hydrophilic substitution on polyaspartic acid is amino ethyl piperazine present in the range of 40-90 mole %.
7. The hydrophilic biodegradable gel according to claim 1, wherein the cross-linker is water soluble.
8. The hydrophilic biodegradable gel according to claim 1, wherein the water soluble cross linker contains acrylate functionalities in the concentration range from 5 - 50 w/w %.
9. The hydrophilic biodegradable gel according to claim 1, wherein said cross linker is diacrylates and bisacrylamides.
10. The hydrophilic biodegradable gel according to claim 1, wherein the gelation time of the gel is from 1-30 minutes.
11. The hydrophilic biodegradable gel according to claim 1, wherein the degradation time ranges from 1-30 days.
12. The hydrophilic biodegradable gel according to claim 1, wherein the storage modulus ranges from 0.48-115 Kpa.
13. Hydrophilic biodegradable gel having at least one hydrophobic pocket cavity said pocket/cavity immobilized by covalent cross-linker comprising a polymer backbone consisting of polyaspartic acid substituted with a hydrophobic and a hydrophilic amine, and said cavity having at least one hydrophobic moiety.
14. The hydrophilic biodegradable gel according to claim 13, wherein the gel comprises a polymer backbone, said backbone comprises polyaspartic acid substituted with a hydrophobic and a hydrophilic amine.
15. The hydrophilic biodegradable gel according to claim 13, wherein the hydrophobic amine comprises long chain fatty amines.
16. The hydrophilic biodegradable gel according to claim 13, wherein the hydrophobic amine comprises steroidal amines.
17. The hydrophilic biodegradable gel according to claim 13, wherein the fatty amines contain Ci2 to C18 carbon atoms and steroidal amine is amino ethyl deoxycholamide.
18. The hydrophilic biodegradable gel according to claim 13, wherein the degree of substitution of hydrophobic amine ranges from 10 - 60 mole %.
19. The hydrophiUc biodegradable gel according to claim 13, wherein said hydrophilic substitution on polyaspartic acid is amine, preferably secondary amine, most preferably is amino ethyl piperazine in the range of 40-90 mole %.
20. The hydrophilic biodegradable gel according to claim 13, wherein the cross-linker is water soluble.
21. The hydrophilic biodegradable gel according to claim 13, wherein the water soluble cross linker contains acrylate functionalities in the concentration range from 5 - 50 w/w %.
22. The hydrophilic biodegradable gel according to claim 13, wherein said cross linker is diacrylates and bisacrylamides.
23. The hydrophilic biodegradable gel according to claim 13, wherein the gelation time of the gel is from 1-30 minutes.
24. The hydrophiUc biodegradable gel according to claim 13, wherein the degradation time ranges from 1-30 days.
25. The hydrophilic biodegradable gel according to claim 13, wherein the storage modulus ranges from 0.48-115 Kpa.
26. The hydrophobic moiety as claimed in claim 13, wherein said moiety is selected from a group comprising, but not limited to oil and drug, in solution, emulsion, suspension, mixture form.
27. Hydrophilic biodegradable gel incorporating hydrophobic pocket/cavity, said cavity immobilized by covalent cross-linker as claimed in any of the preceding claims wherein the release of the agent is controlled instant, timed, sustained, pulsatile or delayed release pattern.
PCT/IB2010/003190 2009-12-11 2010-12-10 In situ cross linked biodegradable gel with hydrophobic pockets WO2011070436A2 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015130877A1 (en) 2014-02-26 2015-09-03 University Of Massachusetts Medical School Amphiphilic degradable polymers for immobilization and sustained delivery of biomolecules
EP2890804A4 (en) * 2013-05-17 2016-10-05 Xyleco Inc Processing biomass

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5543158A (en) 1993-07-23 1996-08-06 Massachusetts Institute Of Technology Biodegradable injectable nanoparticles
US6616941B1 (en) 1999-08-14 2003-09-09 Samyang Corporation Polymeric composition for solubilizing poorly water soluble drugs and process for the preparation thereof

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5998492A (en) * 1994-09-13 1999-12-07 Donlar Corporation Super-absorbing polymeric networks
JPH10292044A (en) * 1997-02-07 1998-11-04 Mitsui Chem Inc Water-absorbent film and sheet, and production of them
US5998491A (en) * 1998-01-27 1999-12-07 Donlar Corporation Super-absorbing polymeric networks
JP4541598B2 (en) * 2001-07-03 2010-09-08 三井化学株式会社 Continuous production method of crosslinked polysuccinimide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5543158A (en) 1993-07-23 1996-08-06 Massachusetts Institute Of Technology Biodegradable injectable nanoparticles
US6616941B1 (en) 1999-08-14 2003-09-09 Samyang Corporation Polymeric composition for solubilizing poorly water soluble drugs and process for the preparation thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIJI BALAKRISHNAN; A. JAYAKRISHNAN: "Self-cross-linking biopolymers as injectable in-situ forming biodegradable scaffolds", BIOMATERIALS, vol. 26, no. 18, June 2005 (2005-06-01), pages 3941 - 3951

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2890804A4 (en) * 2013-05-17 2016-10-05 Xyleco Inc Processing biomass
WO2015130877A1 (en) 2014-02-26 2015-09-03 University Of Massachusetts Medical School Amphiphilic degradable polymers for immobilization and sustained delivery of biomolecules
EP3110451A4 (en) * 2014-02-26 2018-06-20 University of Massachusetts Medical School Amphiphilic degradable polymers for immobilization and sustained delivery of biomolecules

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