WO2018169950A1 - Hydrogel injectable pour administration de multiples médicaments et utilisations associés - Google Patents

Hydrogel injectable pour administration de multiples médicaments et utilisations associés Download PDF

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WO2018169950A1
WO2018169950A1 PCT/US2018/022172 US2018022172W WO2018169950A1 WO 2018169950 A1 WO2018169950 A1 WO 2018169950A1 US 2018022172 W US2018022172 W US 2018022172W WO 2018169950 A1 WO2018169950 A1 WO 2018169950A1
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peg
thermosensitive hydrogel
plga
drug
hydrogel
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PCT/US2018/022172
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English (en)
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Maziar MOHAMMADI
Kisha K. PATEL
Seyedeh P. ALAIE
Nisha HOLLINGSWORTH
Jordan J. Green
Cagri Besirli
Ronald G. LARSON
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The Johns Hopkins University
The Regents Of The University Of Michigan
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Publication of WO2018169950A1 publication Critical patent/WO2018169950A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution

Definitions

  • IOP intraocular pressure
  • corticosteroids induce IOP increase in many patients, 1 9"11 requiring additional topical treatment with ocular hypotensives, adding to the overall burden of treatment and increasing patient non-adherence.
  • Ocular drug implants can be categorized into different groups based on several characteristics including release duration, location of administration, and type of molecule delivered.
  • One of the pioneering technologies in ophthalmic therapeutics was Vitrasert (Bausch & Lomb, Rochester, NY), a non-biodegradable intravitreal implant delivering ganciclovir to treat cytomegalovirus retinitis. 12 Vitrasert uses two polymeric layers composed of poly vinyl alcohol (PVA) and ethylene vinyl alcohol (EVA) to deliver ganciclovir at a constant rate for five to eight months. 12 This system had several
  • Retisert (Bausch & Lomb, Rochester, NY) is another FDA-approved, non-biodegradable intravitreal implant that is indicated for the treatment of chronic non-infectious uveitis. This implant is composed of a PVA and silicon container and delivers fluocinolone acetonide up to 2.5 years. 12 Similar to Vitrasert, Retisert is inserted into the vitreous cavity via transscleral route during vitreoretinal surgery. Some of the implant and surgical procedure-related complications of Retisert include elevated IOP, cataract formation, and retinal detachment. 12 ' 21 22
  • Iluvien (Alimera Sciences, Alpharetta, GA) is the next generation nonbiodegradable intravitreal corticosteroid implant which was recently approved by FDA. Unlike Retisert, Iluvien does not require surgical implantation and is delivered into the vitreous cavity via transscleral injection. The implant releases fluocinolone acetonide for the treatment of diabetic macular edema up to 3 years. 12 Similar to other corticosteroids, Iluvien causes cataract formation in 82% of patients and leads to elevated IOP in 34% of cases. 23 24 While the Iluvien implant is not biodegradable, surgical removal is typically not required once the drug is depleted.
  • Ozurdex (Allergan, Irvine, CA) is an intravitreal implant for delivering dexamethasone to treat macular edema secondary to diabetes and retinal vein occlusion, as well as non-infectious posterior uveitis.
  • Ozurdex is the first biodegradable implant approved by FDA for ocular indications. 12
  • Dexamethasone is encapsulated in a poly(D,L-lactide-co- glycolide) (PLGA) matrix, and the implant is administered via intravitreal injection. Steroid is released from the implant for up to six months. 12
  • the adverse effects of Ozurdex is similar to other implants releasing corticosteroid agents and include cataract formation and elevated
  • Verisome Icon Bioscience, Sunnyvale, CA
  • This drug delivery technology encapsulates various drug molecules and can maintain drug release for up to a year after intravitreal injection.
  • Dexycu implant based on Verisome technology releases dexamethasone and is currently being tested in a phase III clinical trial to treat post-operative inflammation after cataract surgery.
  • Hirani et al. designed triamcinolone acentonide loaded PEG-PLGA nanoparticles and loaded the nanoparticles in a PLGA-PEG-PLGA hydrogel to treat age related macular degeneration (AMD). 28
  • the authors reported drug release from PLGA-PEG-PLGA hydrogel for up to 10 days, though most drug release occurred in the first 10 hours. This initial burst release of drug molecule followed by rapid reduction in drug concentration is not favorable for the treatment of ocular diseases.
  • nanoparticles for a sustained release strategy is ineffective. Drug release is governed by diffusion of molecules, thus nanoparticles are too small for the controlled release of the drug.
  • using more hydrophobic polymers that degrade slower including poly(lactic acid) and poly(caprolactone) are essential.
  • the present invention provides a novel drug delivery platform designed to release multiple drug molecules with precise temporal regulation.
  • the inventive drug delivery system is administered via intraocular or periocular injection, and is composed of biocompatible and biodegradable materials for optimal ocular safety.
  • the present invention provides a sustained drug release system comprising microparticles incorporated into a bulk hydrogel that is engineered to be in liquid form at room temperature for simple delivery into the eye or other tissue site, and form a hydrogel at physiological body temperatures (approximately 37 °C) to act as a depot release platform.
  • this novel drug delivery system immediately gels in situ to form a depot that releases a number of different drug molecules at predetermined rates and times.
  • compositions can be formed to release from 2 to 5 different biologically active agents or drugs for between 1 to 365 days.
  • the drug release system of the present invention can be used to provide optimal intraocular concentrations for effective post-operative treatment.
  • the inventive injectable, multi drug delivery system addresses the unmet need of a simple, effective, and patient-independent post-operative treatment regimen in which the daily intraocular dosage and the duration of release of each ocular agent can be adjusted based on the patient needs.
  • the inventors arrived at an ideal drug delivery system that effectively prevents immediate and late complications after ophthalmic surgery, requiring minimal patient compliance and improve post-operative success rates for ophthalmic surgeons.
  • thermos ensitive hydrogel compositions of the present invention are configured to release at least one broad-spectrum antibiotic, at least one potent corticosteroid, and at least one ocular antihypertensive, three ophthalmic therapeutic agents essential for post-operative management.
  • thermosensitive hydrogel compositions of the present invention are designed to release one or more antibiotics for up to a week, at least one corticosteroid for up to two months or more and at least one anti-hypertensive agent for at least one month.
  • the present invention provides a
  • thermosensitive hydrogel composition comprising one or more biologically compatible triblock copolymers and one or more biologically active agents.
  • the present invention provides a
  • thermosensitive hydrogel composition comprising at least two or more biologically compatible triblock copolymers and one or more biologically active agents; and wherein the composition having a gelation temperature dependent on the weight % ratio of the at least two or more triblock copolymers in said mixture.
  • the present invention provides a
  • thermosensitive hydrogel composition comprising: a) one or more biologically compatible triblock copolymers selected from the group consisting of: poly(D,L-lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-(PLGA); poly(lactic acid) (PLA)-(PEG)-(PLA); poly(lactide-co-caprolactone) (PLCL)-(PEG)-(PLCL); wherein the at least one or more triblock copolymers are combined a mixture; b) at least one or more biologically active agents; and wherein the composition having a gelation temperature dependent on the weight % ratio of the triblock copolymers in said mixture.
  • PLGA poly(D,L-lactide-co-glycolide)
  • PEG poly(ethylene glycol)
  • PLA poly(lactic acid)
  • PLA poly(lactide-co-caprolactone)
  • PLCL poly(lactide-co-caprolactone)-(
  • the present invention provides a
  • thermosensitive hydrogel composition comprising: a) two or more biologically compatible triblock copolymers selected from the group consisting of: poly(D,L-lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-(PLGA); poly(lactic acid) (PLA)-(PEG)-(PLA); poly(lactide-co-caprolactone) (PLCL)-(PEG)-(PLCL); wherein the at least two or more triblock copolymers are combined a mixture; b) at least one or more biologically active agents; and wherein the composition having a gelation temperature dependent on the weight % ratio of the at least two or more triblock copolymers in said mixture.
  • thermosensitive hydrogel composition comprising: a) three biologically compatible triblock copolymers consisting of: poly(D,L-lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-(PLGA); poly(lactic acid) (PLA)-(PEG)-(PLA); poly(lactide-co-caprolactone) (PLCL)-(PEG)-(PLCL); wherein the three triblock copolymers are combined a mixture; b) three biologically active agents; and wherein the composition having a gelation temperature dependent on the weight % ratio of the three triblock copolymers in said mixture.
  • thermosensitive hydrogel composition comprising: a) at least one, two, or more biologically compatible triblock copolymers selected from the group consisting of: poly(D,L-lactide-co- glycolide) (PLGA)-poly(ethylene glycol) (PEG)-(PLGA); poly(lactic acid) (PLA)-(PEG)- (PLA); poly(lactide-co-caprolactone) (PLCL)-(PEG)-(PLCL); wherein at least one, two, or more triblock copolymers are combined a mixture; b) at least two or more biologically active agents; and wherein the composition having a gelation temperature dependent on the weight % ratio of the at least two or more triblock copolymers in said mixture.
  • thermosensitive hydrogel composition comprising: a) three biologically compatible triblock copolymers consisting of: poly(D,L-lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-(PLGA); poly(lactic acid) (PLA)-(PEG)-(PLA); poly(lactide-co-caprolactone) (PLCL)-(PEG)-(PLCL); wherein the three triblock copolymers are combined a mixture; b) two or three or four biologically active agents; and wherein the composition having a gelation temperature dependent on the weight % ratio of the three triblock copolymers in said mixture.
  • the present invention provides a method for treatment of post-operative conditions of surgery of the eye comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of infection, and/or inflammation and/or intra-ocular pressure in an eye of a subject in need thereof comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of retinal edema secondary to surgery of the eye comprising
  • thermosensitive hydrogel compositions of the present invention administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of retinal edema secondary to vitreoretinal disease of the eye, including but not limited to diabetic macular edema and retinal vein occlusion, comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of abnormal retinal and/or choroidal vascularization, including but not limited to diabetic retinopathy, retinal vein occlusion, macular degeneration, choroidal neovascular membrane, comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of increased intraocular pressure secondary to glaucoma comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides for the prevention, amelioration, or treatment of a disease or condition associated with oxidative stress in an eye of a subject in need thereof, comprising administration of a therapeutically effective amount of an antioxidant agent to the eye of the subject.
  • Figure 1 depicts a phase diagram for the blended PLGA-PEG-PLGA triblock copolymer.
  • Figure 2 is a graph showing the rheological properties of a PLGA-PEG-PLGA triblock copolymer embodiment used in Experimental Study 1.
  • Figure 3 is a graph depicting the cumulative moxifloxacin release from a hydrogel embodiment used in Experimental Study 1.
  • Figure 4 shows the release profile of dexamethasone and brinzolamide from a hydrogel embodiment developed in Experimental Study 1.
  • Figures 5A-5B are SEM micrographs on A) dexamethasone and B) brinzolamide loaded microparticles made in this study. Scale bars show a distance of 2 ⁇ .
  • Figure 6 is a graph depicting cumulative release of moxifloxacin from a hydrogel of the present invention.
  • Figure 7 is a graph showing dexamethasone and brinzolamide release from the Experimental Study 2 hydrogel system.
  • Figures 8A-8B are SEM micrographs of A) dexamethasone and B) levobunolol hydrochloride loaded microparticles made in Experimental Study 3. Scale bar shows a distance of 2 ⁇ .
  • Figure 9 depicts a phase diagram for a PLCL-PEG-PLCL hydrogel embodiment.
  • Figure 10 is a graph showing the variation of rheological properties of some PLCL-PEG-PLCL hydrogels of the present invention with respect to temperature.
  • Figure 11 is a graph depicting the cumulative release of moxifloxacin in the Experimental Study 3 embodiment of the present invention.
  • Figure 12 is a graph depicting the cumulative release of dexamethasone from a hydrogel and from microparticles alone in Experimental Study 3.
  • Figure 13 is a graph depicting the cumulative release of levobunolol
  • Figures 14A-14E (fig 1 of data) SEM micrographs on a) levobunolol HCl-loaded
  • Figures 15A-15C Phase diagram for different triblock co-polymers used in this research, A) PLGA-PEG-PLGA, B) PLA-PEG-PLA, C) PLCL-PEG-PLCL.
  • FIGS 16A-16B Rheological results for different triblock copolymers; a) Storage modulus, b) Loss modulus. Results were obtained at IHz oscillation frequency.
  • the PLGA-PEG-PLGA triblock copolymer was a 3/1 blend of PLGA-PEG-PLGA
  • the PLA-PEG-PLA was P(DL)LA-PEG- P(DL)LA 1700-1500-1700DA only.
  • the PLCL-PEG-PLCL was a 6/1 blend of PLCL-PEG- PLCL MW -1600-1500-1600 DA, 75:25 CL:LA and PLCL-PEG-PLCL (-1700-1500-1700 DA, 60:40 CL:LA).
  • FIGS 17A-17B Variations of A) storage and B) loss moduli with oscillation frequency at different temperatures for PLCL-PEG-PLCL polymer solutions.
  • Figures 18A-18B (A) Comparison of release of levobunolol with levobunolol HC1 from MPs. (B) Release of dexamethasone from samples containing different levobunolol type. For these samples no hydrogel was present and drug release from MPs alone was compared. In this and all of the subsequent figures, error bars represent standard deviations between duplicate measurements and data points represent average values of duplicate measurements. [0049] Figures 19A-19B. Comparison of drug released from MP-loaded in PLCL-PEG-
  • PLCL hydrogels with that from MPs alone, (A) levobunolol, (B) dexamethasone.
  • Figure 21 Effect of polymer type on regulation of levobunolol release from the drug delivery system.
  • FIGS 22A-22C Comparison of A) moxifloxacin, B) levobunolol and C) dexamethasone release profile when the loaded drug content is decreased by a factor of 2.
  • Figure 23 A depiction of a multi-drug delivery hydrogel embodiment capable of releasing three different drug molecules at different release rates.
  • the present invention provides a novel multidrug delivery platform that temporally regulates drug release via selective thermosensitive hydrogel compositions comprising biologically active agents that can either be mixed within the hydrogel composition directly, or mixed in the composition after being made in microparticle form with biologically compatible and degradable polymers.
  • the thermosensitive hydrogel compositions are liquid at room temperature, and then become a viscous hydrogel when exposed to tissues at body temperatures. Such a platform is ideal for the treatment of many ophthalmic and other physiological conditions and diseases.
  • the present invention provides a
  • thermosensitive hydrogel composition comprising at least one, two, or more biologically compatible triblock copolymers and one or more or more biologically active agents, and wherein the composition having a gelation temperature dependent on the weight % ratio of the at least two or more triblock copolymers in said mixture.
  • the weight % ratios of the mixture of two or more triblock copolymers can be in the range from 1/1, 2/1, 3/1, 3/2, 4/1, 4/3, 5/1, 5/2, 6/1, 7/1, 7/3, 8/1, 9/1 up to 10/1 depending on the gelation temperature desired.
  • Another example is blending PLCL- PEG-PLCL copolymers PLCL-PEG-PLCL MW -1600-1500-1600 DA, 75:25 CL:LA with PLCL-PEG-PLCL (-1700-1500-1700 DA, 60:40 CL:LA) at a ratio of 6/1 gave a gelation temperature in the desired range. It will be understood by those of skill in the art that in some embodiments, one triblock copolymer may have the right gelation temperature. For example, it was found that the PLA-PEG-PLA copolymer P(DL)LA-PEG-P(DL)LA 1700-1500-1700 DA had the desired range without mixing with another copolymer.
  • triblock copolymers means a biodegradable polymer of the formula A-block-B-block-A.
  • examples of such polymers useful in the composition of the present invention include, but are not limited to, poly(D,L-lactide-co-glycolide) (PLGA)- poly(ethylene glycol) (PEG)-(PLGA); (PEG)- (PLGA)-(PEG); poly(lactic acid) (PLA)- (PEG)-(PLA); (PEG)-(PLA)-(PEG); poly(lactide-co-caprolactone) (PLCL)-(PEG)-(PLCL); (PEG)-(PLCL)-(PEG); poly(caprolactone) (PCL)-(PEG)-(PCL); (PEG)-(PCL)-(PEG);
  • poly(caprolactone)-b-poly(tetrahydrofuran)-b-poly(caprolactone) PCL)-(PTHF)-(PCL); and poly(glycolide)-b-poly(ethylene glycol)-b-poly(glycolide) (PGA)-(PEG)-(PGA); (PEG)- (PGA)-(PEG).
  • a biologically compatible polymer refers to a polymer which is functionalized to serve as a composition for creating an injectable drug.
  • the polymer is one that is a naturally occurring polymer or one that is not toxic to the host.
  • the polymer may be a homopolymer where all monomers are the same or a hetereopolymer containing two or more kinds of monomers, such as triblock copolymers.
  • biocompatible polymer refers to a polymer which is functionalized to serve as a composition for creating an injectable drug.
  • the polymer is one that is a naturally occurring polymer or one that is not toxic to the host.
  • the polymer may be a homopolymer where all monomers are the same or a hetereopolymer containing two or more kinds of monomers, such as triblock copolymers.
  • biocompatible cross-linked polymer matrix and “biocompatibility” when used in relation to the instant polymers are art-recognized and are considered equivalent to one another, including to biologically compatible polymer.
  • biocompatible polymers include polymers that are neither toxic to the host (e.g., an animal or human), nor degrade (if the polymer degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host.
  • Polymer is used to refer to molecules composed of repeating monomer units, including homopolymers, block copolymers, heteropolymers, random copolymers, graft copolymers and so on. "Polymers” also include linear polymers as well as branched polymers, with branched polymers including highly branched, dendritic, and star polymers. [0060] A monomer is the basic repeating unit in a polymer. A monomer may itself be a monomer or may be dimer or oligomer of at least two different monomers, and each dimer or oligomer is repeated in a polymer.
  • Suitable polymers for the triblock copolymers useful in the thermosensitive hydrogels could include, for example, biocompatible monomers with recurring units found in poly(phosphoesters), poly(lactides), poly(glycolides), poly(caprolactones), poly(anhydrides), poly(amides), poly(urethanes), poly(esteramides), poly(orthoesters), poly(dioxanones), poly(acetals), poly(ketals), poly(carbonates), poly(orthocarbonates), poly(phosphazenes), poly(hydroxybutyrates), poly(hydroxyl valerates), poly(alkylene oxalates), poly(alkylene succinates), poly(malic acids), poly(amino acids), polyvinylalcohol, poly(vinylpyrrolidone), poly(ethylene glycol), poly(hydroxy cellulose), copolymers, terpolymers or combinations or mixtures of the above materials.
  • the “stable” formulations of the invention retain biological activity equal to or more than 80%, 85%, 90%, 95%, 98%, 99% or 99.5% under given manufacture, preparation, transportation and storage conditions.
  • the stability of said preparation can be assessed by degrees of aggregation, degradation or fragmentation by methods known to those skilled in the art.
  • Biocompatible polymer and biocompatibility are art-recognized.
  • biocompatible polymers include polymers that are neither themselves toxic to the host (e.g., and animal or human), nor degrade (if the polymer degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host.
  • biodegradation generally involves degradation of the polymer in an organism, e.g., into its monomeric subunits, which may be known to be effectively non-toxic. Intermediate oligomeric products resulting from such degradation may have different toxicological properties, however, or biodegradation may involve oxidation or other biochemical reactions that generate molecules other than monomeric subunits of the polymer.
  • toxicology of a biodegradable polymer intended for in vivo use may be determined after one or more toxicity analyses. It is not necessary that any subject composition have a purity of 100% to be deemed biocompatible; indeed, it is only necessary that the subject compositions be biocompatible as set forth above.
  • a subject composition may comprise polymers comprising 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or even less of biocompatible polymers, e.g., including polymers and other materials and excipients described herein, and still be biocompatible.
  • a polymer or other material is biocompatible, it may be necessary to conduct a toxicity analysis.
  • assays are well known in the art, using, for example, chemical means or enzymatic means. An aliquot of the treated sample products are placed in culture plates previously seeded with the cells. The sample products are incubated with the cells. The results of the assay may be plotted as % relative growth vs. concentration of degraded sample.
  • monomers, polymers, polymer matrices, and formulations of the present invention may also be evaluated by well-known in vivo tests, such as subcutaneous implantations or intraocular/subconjunctival/subtenon/suprachoroidal injections to the eye of rodents, rabbits, mini pigs, or non-human primates, etc. to confirm that they do not cause significant levels of irritation or inflammation at the implantation/injection sites.
  • Biodegradable is art-recognized, and includes monomers, polymers, polymer matrices, gels, compositions and formulations, such as those described herein, that are intended to degrade during use, such as in vivo. Biodegradable polymers and matrices typically differ from non-biodegradable polymers in that the former may be degraded during use. In certain embodiments, such use involves in vivo use, such as in vivo therapy, and in other certain embodiments, such use involves in vitro use.
  • degradation attributable to biodegradability involves the degradation of a biodegradable polymer into its component subunits, or digestion, e.g., by a biochemical process, of the polymer into smaller, non-polymeric subunits.
  • two different types of biodegradation may generally be identified.
  • one type of biodegradation may involve cleavage of bonds (whether covalent or otherwise) in the polymer backbone.
  • monomers and oligomers typically result, and even more typically, such biodegradation occurs by cleavage of a bond connecting one or more of subunits of a polymer.
  • biodegradation may involve cleavage of a bond (whether covalent or otherwise) internal to a side chain or that connects a side chain, functional group and so on to the polymer backbone.
  • a therapeutic agent, biologically active agent, or other chemical moiety attached as a side chain to the polymer backbone may be released by biodegradation.
  • one or the other or both general types of biodegradation may occur during use of a polymer.
  • biodegradation encompasses both general types of biodegradation.
  • the degradation rate of a biodegradable polymer often depends in part on a variety of factors, including the chemical identity of the linkage responsible for any degradation, the molecular weight, crystallinity, biostability, and degree of cross-linking of such polymer, the physical characteristics of the implant, shape and size, and the mode and location of administration. For example, the greater the molecular weight, the higher the degree of crystallinity, and/or the greater the biostability, the biodegradation of any biodegradable polymer is usually slower.
  • biodegradable is intended to cover materials and processes also termed "bioerodible.”
  • the biodegradation rate of such polymer may be characterized by the presence of enzymes, for example, a chondroitinase.
  • the biodegradation rate may depend on not only the chemical identity and physical characteristics of the polymer matrix, but also on the identity of any such enzyme.
  • the present invention provides compositions comprising one or more biologically active agents incorporated into a biologically compatible microparticles, and wherein the microparticles are then incorporated into the thermosensitive hydrogel compositions comprising at least one, two, or more biologically compatible triblock copolymers and which can optionally have one or more or more biologically active agents dissolved within the hydrogel composition, and wherein the composition having a gelation temperature dependent on the weight % ratio of the at least two or more triblock copolymers in said mixture.
  • biologically compatible microparticles means biologically compatible and degradable polymers in micro or nano particle form which have been made using oil/water emulsion and solvent evaporation methods, water/oil/water emulsion and solvent evaporation methods, nanoprecipitation methods, coacervation and phase separation methods, multiorifice centrifugal methods, pan coating methods, and spray drying or spray congealing methods known in the art.
  • PLGA microparticles used in the compositions of the present invention can be made by dissolving PLGA in an organic solvent, such as dichloromethane.
  • the biologically active agents of interest such as, for example, dexamethasone
  • DMSO dimethyl methoxysulfoxide
  • the biologically active agents of interest is dissolved in DMSO, and then the two solutions are mixed together.
  • the mixture is then added to an aqueous solution of polyvinyl alcohol and agitated continuously with a high speed propeller type blade to create a high shear in the solution which results in an emulsion with small particle sizes.
  • This mixture is then allowed to evaporate the dichloromethane or placed under vacuum.
  • the microspheres are collected by ultrafiltration, centrifugation and then lyophilization.
  • the drug elution profiles of the microparticle formulations of the present invention can vary depending of the weight ratio of the components of the copolymer used in the microparticle.
  • the weight ratio of lactic acid to gly colic acid can be varied in the PLGA copolymer particles.
  • the weight ratios can vary from as much as 0%/100% lactic acid to gly colic acid, to 100%/0% lactic acid to gly colic acid, including for example, ratios of 85%/15%, 75%/25% and 50%/50%.
  • the proportion of lactic to gly colic acid is similar, the faster the drug eluted from the
  • microparticle and vice versa.
  • other types of polymers e.g. PCL, PLCL
  • PCL PCL
  • PLCL PLCL
  • hydrogel polymeric formulations of the present invention biodegrade within a period that is acceptable in the desired application.
  • such degradation occurs in a period usually less than about five years, one year, six months, three months, one month, fifteen days, five days, three days, or even one day on exposure to a physiological solution with a pH between 6 and 8 having a temperature of between about 25 and 40 °C.
  • the polymer degrades in a period of between about one hour and several weeks, depending on the desired application.
  • the polymer or polymer matrix may include a detectable agent that is released on degradation.
  • the degradation or drug eluting properties of the hydrogels can be modified by adjusting the ratios of the two or more block copolymers used in the composition. For example, by blending the ratio (PLGA)- (PEG)-(PLGA), with a triblock copolymer of same type but different properties (e.g.
  • the degradation of the block copolymers produces acidic byproducts which lower the pH of the surrounding tissue microenvironment.
  • the acidic microenvironment of the degrading hydrogel can accelerate the degradation of the microparticle polymer formulation.
  • the amount of biologically active agent added during the manufacturing of the hydrogel can be varied as well.
  • the amount of drug added can be in the range of 0.1 mg to about 100 mg, up to about 1,000 mg.
  • the drug elution profile can also be manipulated by the hydrophilicity or hydrophobicity of the biologically active agent added, its molecular weight, and/or chemical structure. In some embodiments, by choosing an agent which is more hydrophobic, the drug will elute from the composition more slowly. In some embodiments, a larger molecular weight agent may also slow the release of the agent. When the molecule has some interaction with hydrogel network, its release can favorably be slowed down.
  • hydrogels can be modified by adjusting the ratios of the two or more block copolymers used in the composition to adjust the gelation temperature profile.
  • a desired degradation and drug elution profile can be further altered by first encapsulating the drug or compound of interest in a microparticle comprised of a biodegradable and biocompatible polymer.
  • the resulting microparticles containing the drug of interest can then be incorporated into the triblock copolymer composition and mixed and then inj ected into the site of interest, such as in the eye.
  • Gel refers to a state of matter between liquid and solid, and is generally defined as a cross-linked polymer network swollen in a liquid medium.
  • a gel is a two- phase colloidal dispersion containing both solid and liquid, wherein the amount of solid is greater than that in the two-phase colloidal dispersion referred to as a "sol.”
  • a "gel” has some of the properties of a liquid (i.e., the shape is resilient and deformable) and some of the properties of a solid (i.e., the shape is discrete enough to maintain three dimensions on a two-dimensional surface).
  • Hydrogels consist of hydrophilic polymers cross-linked to from a water-swollen, insoluble polymer network. Cross-linking can be initiated by many physical or chemical mechanisms.
  • the hydrogels of interest also are configured to have a viscosity that will enable the gelled hydrogel to remain affixed on or in the cell, tissue or organ, or surface. Viscosity can be controlled by the monomers and polymers used, by the level of water trapped in the hydrogel, and by incorporated thickeners, such as biopolymers, such as proteins, lipids, saccharides and the like.
  • incorporated is art-recognized when used in reference to a therapeutic agent, dye, or other material and a polymeric composition, such as a composition of the present invention. In certain embodiments, these terms include incorporating, formulating or otherwise including such agent into a composition that allows for sustained release of such agent in the desired application.
  • a therapeutic agent or other material is incorporated into a polymer matrix, including, for example, attached to a monomer of such polymer (by covalent or other binding interaction) and having such monomer be part of the polymerization to give a polymeric formulation, distributed throughout the polymeric matrix, appended to the surface of the polymeric matrix (by covalent or other binding interactions), encapsulated inside the polymeric matrix, etc.
  • co-incorporation or “co-encapsulation” refers to the incorporation of a therapeutic agent or other material and at least one other therapeutic agent or other material in a subject composition.
  • any therapeutic agent or other material is encapsulated in polymers
  • a therapeutic agent or other material may be first encapsulated in a microsphere and then combined with the polymer in such a way that at least a portion of the microsphere structure is maintained.
  • a therapeutic agent or other material may be sufficiently immiscible in the polymer of the invention that it is dispersed as small droplets, rather than being dissolved in the polymer. Any form of encapsulation or incorporation is contemplated by the present invention, in so much as the sustained release of any encapsulated therapeutic agent or other material determines whether the form of encapsulation is sufficiently acceptable for any particular use.
  • carrier refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic is administered.
  • physiological carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Saline solutions and aqueous dextrose and glycerol solutions also can be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • an active agent and a biologically active agent are used interchangeably herein to refer to a chemical or biological compound that induces a desired pharmacological and/or physiological effect, wherein the effect may be prophylactic or therapeutic.
  • the terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of those active agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, analogs and the like.
  • the active agent can be a biological entity, such as a virus or cell, whether naturally occurring or manipulated, such as transformed.
  • Pharmaceutically acceptable salts are art-recognized, and include relatively nontoxic, inorganic and organic acid addition salts of compositions of the present invention, including without limitation, therapeutic agents, excipients, other materials and the like.
  • pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric acid and sulfuric acid, and those derived from organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • suitable inorganic bases for the formation of salts include the hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and the like. Salts may also be formed with suitable organic bases, including those that are non-toxic and strong enough to form such salts.
  • the class of such organic bases may include mono-, di-, and trialkylamines, such as methylamine,
  • dimethylamine, and triethylamine mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine
  • amino acids such as arginine and lysine
  • guanidine N- methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenthylamine; (trihydroxymethyl) aminoethane; and the like, see, for example, J. Pharm. Sci., 66: 1-19 (1977).
  • the present invention provides a
  • thermosensitive hydrogel composition comprising: a) at least one, two, or more biologically compatible triblock copolymers selected from the group consisting of: poly(D,L-lactide-co- glycolide) (PLGA)-poly(ethylene glycol) (PEG)-(PLGA); poly(lactic acid) (PLA)-(PEG)- (PLA); poly(lactide-co-caprolactone) (PLCL)-(PEG)-(PLCL); wherein the at least one, two, or more triblock copolymers are combined a mixture; b) at least two or more biologically active agents; and wherein the composition having a gelation temperature dependent on the weight % ratio of the at least one, two, or more triblock copolymers in said mixture.
  • thermosensitive hydrogel composition comprising: a) three biologically compatible triblock copolymers consisting of: poly(D,L-lactide-co-glycolide) (PLGA)-poly(ethylene glycol) (PEG)-(PLGA); poly(lactic acid) (PLA)-(PEG)-(PLA); poly(lactide-co-caprolactone) (PLCL)-(PEG)-(PLCL) and the like; wherein the three triblock copolymers are combined a mixture; b) three biologically active agents; and wherein the composition having a gelation temperature dependent on the weight % ratio of the three triblock copolymers in said mixture.
  • the biologically active agents can be incorporated into the same or different triblock copolymers of the composition, and can also be incorporated into a microparticle prior to being incorporated into the triblock copolymers of the inventive thermosensitive hydrogel.
  • the biologically active agent may vary widely with the intended purpose for the composition.
  • active is art-recognized and refers to any moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject.
  • biologically active agents that may be referred to as "drugs” are described in well-known literature references such as the Merck Index, the Physicians' Desk Reference, and The Pharmacological Basis of Therapeutics, and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • Various forms of a biologically active agent may be used which are capable of being released the subject composition, for example, into adjacent tissues or fluids upon administration to a subject.
  • a biologically active agent may be used in the
  • thermosensitive hydrogels of this invention to treat, ameliorate, inhibit, or prevent a disease or symptom, in conjunction with, for example, promoting ocular healing, reducing inflammation, fighting infection, and reducing intra-ocular pressure.
  • biologically active agents include, without limitation, enzymes, receptor antagonists or agonists, hormones, growth factors, peptides, antibiotics, antimicrobial agents, antibodies, proteins and antibody-drug conjugates.
  • the subject compositions comprise about 1% to about 75% or more by weight of the total composition, alternatively about 2.5%, 5%, 10%, 20%, 30%, 40%, 50%, 60% or 70%, of a biologically active agent.
  • Non-limiting examples of biologically active agents include following: adrenergic blocking agents, anabolic agents, androgenic steroids, anti-allergenic materials, anticholinergics and sympathomimetics anti-hypertensive agents, anti-infective agents, antiinflammatory agents such as steroids, non-steroidal anti-inflammatory agents, anti-pyretic and analgesic agents, antihistamines, benzophenanthridine alkaloids, biologicals, decongestants, diagnostic agents, estrogens, mucolytic agents, growth factors, peripheral vasodilators, progestational agents, prostaglandins, vitamins and prodrugs.
  • steroids used in the compositions described herein include dexamethasone, betamethasone, fluocinolone, fluocinolone acetonide, difluprednate, fluorometholone, loteprednol, prednisolone, medrysone, triamcinolone, triamcinolone acetonide, and rimexolone.
  • ophthalmic antibiotics used in the compositions described herein include levofloxacin, natamycin, tobramycin, polymyxin b/trimethoprim, ciprofloxacin, trifiuridine, moxifloxacin, gatifloxacin, besifloxacin, ganciclovir, azithromycin,
  • chloramphenicol erythromycin, gentamicin, vancomycin, ceftazidime, amikacin, and ofloxacin.
  • ophthalmic hypotensive agents used in the compositions described herein include timolol, brimonidine, apraclonidine, zioptan, pilocarpine, brinzolamide, bimatoprost, dorzolamide, levobunolol, betimol, betaxolol, lopidine, betagan, metipranol, carteolol, travoprost, latanoprost and tafluprost.
  • any form of the biologically active agents may be used. These include, without limitation, such forms as uncharged or charged molecules, molecular complexes, salts, ethers, esters, amides, prodrug forms and the like, which are biologically activated when implanted, injected or otherwise placed into a subject.
  • Buffers, acids and bases may be incorporated in the compositions to adjust pH.
  • Agents to increase the diffusion distance of agents released from the composition may also be included.
  • the charge, lipophilicity or hydrophilicity of a composition may be modified by employing an additive.
  • surfactants may be used to enhance miscibility of poorly miscible liquids.
  • suitable surfactants include dextran, polysorbates and sodium lauryl sulfate.
  • surfactants are used in low concentrations, generally less than about 5%.
  • Buffering agents help to maintain the pH in the range which approximates physiological conditions. Buffers are preferably present at a concentration ranging from about 2 mM to about 50 mM.
  • Suitable buffering agents for use with the instant invention include both organic and inorganic acids, and salts thereof, such as citrate buffers (e.g., monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture etc.), succinate buffers (e.g., succinic acid monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid- potassium tartrate mixture, tartaric acid-sodium hydroxide mixture etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, fumaric acid-mon
  • Preservatives may be added to retard microbial growth, and may be added in amounts ranging from 0.2%-l % (w/v).
  • Suitable preservatives for use with the present invention include phenol, benzyl alcohol, m-cresol, octadecyldimethylbenzyl ammonium chloride, benzyaconium halides (e.g., chloride, bromide and iodide), hexamethonium chloride, alkyl parabens, such as, methyl or propyl paraben, catechol, resorcinol,
  • compositions of the instant invention and include polhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol.
  • Polyhydric alcohols can be present in an amount of between about 0.1 % to about 25%, by weight, preferably 1 % to 5% taking into account the relative amounts of the other ingredients.
  • Stabilizers refer to a broad category of excipients which can range in function from a bulking agent to an additive which solubilizes the therapeutic agent or helps to prevent denaturation or adherence to the container wall.
  • Typical stabilizers can be polyhydric sugar alcohols; amino acids, such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine etc.
  • organic sugars or sugar alcohols such as lactose, trehalose, stachyose, arabitol, erythritol, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol and the like, including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, a-monothioglycerol and sodium thiosulfate; low molecular weight polypeptides (i.e., ⁇ 10 residues); proteins, such as human serum albumin, bovine serum albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone, saccharides, monosaccharides, such as x
  • Additional miscellaneous excipients include bulking agents, (e.g., starch), chelating agents (e.g., EDTA), antioxidants (e.g., ascorbic acid, methionine or vitamin E) and cosolvents.
  • bulking agents e.g., starch
  • chelating agents e.g., EDTA
  • antioxidants e.g., ascorbic acid, methionine or vitamin E
  • cosolvents e.g., ascorbic acid, methionine or vitamin E
  • Non-ionic surfactants or detergents may be added to help solubilize the therapeutic agent, as well as to protect the therapeutic protein against agitation-induced aggregation, which also permits the formulation to be exposed to shear surface stresses without causing denaturation of the protein.
  • Suitable non-ionic surfactants include polysorbates (20, 80 etc.), polyoxamers (184, 188 etc.), Pluronic® polyols and polyoxyethylene sorbitan monoethers (TWEEN-20®, TWEEN-80® etc.).
  • Non-ionic surfactants may be present in a range of about 0.05 mg/ml to about 1.0 mg/ml, preferably about 0.07 mg/ml to about 0.2 mg/ml.
  • the instant invention encompasses formulations, such as, liquid formulations having stability at temperatures found in a commercial refrigerator and freezer found in the office of a physician or laboratory, such as from about 20 °C to about 2 °C, said stability assessed, for example, by microscopic analysis, for storage purposes, such as for about 60 days, for about 120 days, for about 180 days, for about a year, for about 2 years or more.
  • the liquid formulations of the present invention also exhibit stability, as assessed, for example, by particle analysis, at room temperatures, for at least a few hours, such as one hour, two hours or about three hours or more prior to use.
  • the formulations to be used for in vivo administration must be sterile. That can be accomplished, for example, by filtration through sterile filtration membranes.
  • the formulations of the present invention may be sterilized by filtration.
  • thermosensitive hydrogel compositions will be formulated, dosed and administered in a manner consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the "therapeutically effective amount" of the biopolymer to be administered will be governed by such considerations, and can be the minimum amount necessary to prevent, ameliorate or treat a disorder of interest.
  • the term "effective amount" is an equivalent phrase refers to the amount of a therapy (e.g., a prophylactic or therapeutic agent), which is sufficient to reduce the severity and/or duration of a disease, ameliorate one or more symptoms thereof, prevent the advancement of a disease or cause regression of a disease, or which is sufficient to result in the prevention of the development, recurrence, onset, or progression of a disease or one or more symptoms thereof, or enhance or improve the prophylactic and/or therapeutic effect(s) of another therapy (e.g., another therapeutic agent) useful for treating a disease.
  • a therapy e.g., a prophylactic or therapeutic agent
  • an effective amount of a therapeutic or a prophylactic agent of interest reduces the symptoms of a disease, such as a post-operative inflammation, infection, or increased intraocular pressure, by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. Also used herein as an equivalent is the term, "therapeutically effective amount.”
  • the term “treat,” as well as words stemming there from, includes preventative as well as disorder remitative treatment.
  • the terms “reduce,” “suppress,” “prevent,” and “inhibit,” as well as words stemming there from, have their commonly understood meaning of lessening or decreasing. These words do not necessarily imply 100% or complete treatment, reduction, suppression, or inhibition.
  • Embodiments of the invention also include a process for preparing pharmaceutical products comprising the inventive thermosensitive hydrogel compositions.
  • pharmaceutical product means a composition suitable for pharmaceutical use
  • compositions as defined herein.
  • Pharmaceutical compositions formulated for particular applications comprising the compounds of the present invention are also part of this invention, and are to be considered an embodiment thereof.
  • Examples of such products can include hydrogel compositions incorporating drugs or other biologically active agents, and also the hydrogel compositions comprising microparticles having drugs or other biologically active agents encapsulated within the microparticles in the hydrogel
  • hydrogel compositions of the present invention can be used to deliver a multitude of FDA approved agents for ocular and intraocular indications.
  • drugs or biologically active agents that can be formulated with the hydrogel compositions of the present invention include, but are not limited to, naphazoline; amikacin; amphotericin B; besifloxacin; ofloxacin; vancomycin; ketorolac tromthamine; pemirolast potassium; cidofovir; azithromycin; gangcyclovir;
  • valgancyclovir travaprost; bimatoprost; cyclosporine; pegaptanib; ranbizumab;
  • difluprednate difluprednate; dexamethasone; triamcinolone acetonide; foscarnet; methotrexate; bepotastine besilate; ceftazidime; voriconazole; aflibercept; tafluprost; ocriplasmin; cysteamine HC1; phenylephrine; adalimumab; lifitegrast; carbachol; and epinephrine.
  • thermosensitive hydrogel compositions useful for the treatment of the disorders described above comprises a container and a label.
  • Suitable containers include, for example, bottles, vials, syringes and test tubes.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the container holds a composition which is effective for preventing or treating, for example, a wound or a joint disease and may have a sterile access port (for example, the container may be a vial having a stopper pierceable by a hypodermic injection needle).
  • the label on or associated with the container indicates that the composition is used for treating the condition of choice.
  • the article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as phosphate- buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes and package inserts with instructions for use.
  • a pharmaceutically acceptable buffer such as phosphate- buffered saline, Ringer's solution and dextrose solution.
  • buffers, diluents, filters, needles, syringes and package inserts with instructions for use including buffers, diluents, filters, needles, syringes and package inserts with instructions for use.
  • the present invention provides a method for treatment of post-operative conditions of surgery of the eye comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of infection, and/or inflammation and/or elevation of intra-ocular pressure in an eye of a subject in need thereof comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the term "administering" means that the compounds of the present invention are introduced into a subject, preferably a subject receiving treatment for a inflammatory related disease of the eye, infection related disease of the eye, hypertension related disease of the eye, etc. and the compounds are allowed to come in contact with the one or more disease related cells or population of cells in vivo, using one or more known routes of administration.
  • the preferred route of administration is injection.
  • the present invention provides a method for treatment of post-operative conditions of surgery of the eye comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of retinal edema secondary to vitreoretinal disease of the eye, including but not limited to diabetic macular edema and retinal vein occlusion, comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of increased intraocular pressure secondary to glaucoma comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides a method for treatment of abnormal retinal and/or choroidal vascularization, including but not limited to diabetic retinopathy, retinal vein occlusion, macular degeneration, choroidal neovascular membrane, comprising administering to a subject in need thereof, an effective amount of the thermosensitive hydrogel compositions of the present invention.
  • the present invention provides for the prevention, amelioration, or treatment of a disease or condition associated with oxidative stress in an eye of a subject in need thereof, comprising administration of a therapeutically effective amount of an antioxidant agent to the eye of the subject.
  • a disease or condition associated with oxidative stress in an eye include, but are not limited to, retinitis pigmentosa, macular degeneration including age related macular degeneration (AMD) both wet and dry, diabetic retinopathy, Lebers optic neuropathy, and optic neuritis.
  • AMD age related macular degeneration
  • RP Retinitis pigmentosa
  • Retinitis pigmentosa comprises a large group of inherited vision disorders that cause progressive loss of photoreceptor cells of the retina, leading to severe vision impairment and often incurable blindness.
  • the most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades.
  • rod photoreceptors die early, whereas light-insensitive, morphologically altered cone photoreceptors persist longer.
  • Glutathione is a tripeptide, c-L-glutamyl-L-cysteinyl-glycine, found in all mammalian tissues. It has several important functions including detoxification of
  • GSH is the dominant non-protein thiol in mammalian cells; as such it is essential in maintaining the intracellular redox balance and the essential thiol status of proteins. Also, it is necessary for the function of some antioxidant enzymes such as the glutathione peroxidases.
  • Intracellular GSH levels are determined by the balance between production and loss. Production results from de novo synthesis and regeneration of GSH from GSSG by GSSG reductase. Generally there is sufficient capacity in the GSSG reductase system to maintain all intracellular GSH in the reduced state, so little can be gained by ramping up that pathway. The major source of loss of intracellular GSH is transport out of cells. Intracellular GSH levels range from 1-8 mM while extracellular levels are only a few ⁇ ; this large concentration gradient essentially precludes transport of GSH into cells and once it is transported out of cells, it is rapidly degraded by ⁇ -glutamyltranspeptidase.
  • GSH transporters could theoretically increase intracellular GSH levels, but is potentially problematic because the transporters are not specific for GSH and their suppression could lead imbalance of other amino acids and peptides. Thus, intracellular GSH levels are modulated primarily by changes in synthesis.
  • amelioration or treatment is understood as meaning to lessen or decrease at least one sign, symptom, indication, or effect of a specific disease or condition.
  • amelioration or treatment of retinitis pigmentosa can be to reduce, delay, or eliminate one or more signs or symptoms of RP including, but not limited to, a reduction in night vision, a reduction in overall visual acuity, a reduction in visual field, a reduction in the cone density in one or more quadrants of the retina, thinning of retina, particularly the outer nuclear layer, reduction in a- or b-wave amplitudes on scotopic or photopic
  • electroretinograms EMGs
  • Amelioration and treatment can require the administration of more than one dose of an agent, either alone or in conjunction with other therapeutic agents and interventions. Amelioration or treatment does not require that the disease or condition be cured.
  • Antioxidant as used herein is understood as a molecule capable of slowing or preventing the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons from a substance to an oxidizing agent. Such reactions can be promoted by or produce superoxide anions or peroxides. Oxidation reactions can produce free radicals, which start chain reactions that damage cells. Antioxidants terminate these chain reactions by removing free radical intermediates, and inhibit other oxidation reactions by being oxidized themselves. As a result, antioxidants are often reducing agents such as thiols, ascorbic acid or polyphenols.
  • Antioxidants include, but are not limited to, a-tocopherol, ascorbic acid, Mn(III)tetrakis (4-benzoic acid) porphyrin, a-lipoic acid, n-acetylcysteine, and n- acetylcysteineamide.
  • Co-administration is understood as administration of one or more agents to a subject such that the agents are present and active in the subject at the same time. Co-adminsitration does not require a preparation of an admixture of the agents or
  • antioxidants examples include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, a-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin
  • the term "subject” refers to any mammal, including, but not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Logomorpha, such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swines (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human.
  • mammals of the order Rodentia such as mice and hamsters
  • mammals of the order Logomorpha such as rabbits. It is preferred that the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is
  • a dosing regimen used in the inventive methods can be any length of time sufficient to provide a reduction in the inflammatory, infection and/or hypertension disease in the eyes of the subject.
  • the term "chronic" as used herein, means that the length of time of the dosage regimen can be hours, days, weeks, months, or possibly years.
  • the multidrug delivery platform of the present invention which temporally regulates drug release is ideal for the treatment of many ophthalmic conditions, including post-operative management requiring multiple topical agents for inflammation, infection, and elevated IOP.
  • ophthalmic conditions including post-operative management requiring multiple topical agents for inflammation, infection, and elevated IOP.
  • IOP irritable irritable irritable irritable irritable irritable irritable irritable irritable s, and associated with multiple topical agents for inflammation, infection, and elevated IOP.
  • combination therapy is more effective than single drug therapy in many patients. 12 29
  • the inventive drug delivery system is administered via intraocular injection, and is composed of biocompatible and biodegradable materials for optimal ocular safety.
  • the present inventors designed the inventive drug delivery system to address the challenges of multi-drug treatment during postoperative management of cataract surgery.
  • topical antibiotics are administered for 7 days to reduce risk of infection, whereas topical corticosteroids are applied up to a month with decreasing frequency to reduce inflammation.
  • 6"8 Often an ocular hypotensive is added to the post-operative treatment regimen to reduce IOP increase secondary to inflammation and/or corticosteroid use.
  • 1 9"11 The inventors designed the present novel drug delivery platform to replace this topical treatment paradigm.
  • a broad-spectrum antibiotic the 4 th generation
  • fluoroquinolone moxifloxacin
  • a potent corticosteroid dexamethasone
  • an ocular hypotensive agent such as the carbonic anhydrase inhibitor brinzolamide, 30 ' 1 or beta-blocker levobunolol hydrochloride, 32 3 is delivered intraocularly to control ocular pressure.
  • the anti-inflammatory and hypotensive drugs are encapsulated in PLGA microparticles, which act as barriers through which drug release can be controlled. It will be understood by those of skill in the art that other biocompatible and degradable polymers known in the art can be used to manufacture the microparticles.
  • the particles are then embedded into the inventive thermosensitive hydrogel compositions of the present invention to further regulate the control of drug release. With the innovative design, drug release rate and time for each agent can be individually controlled to for specific ocular indications or other diseases by changing the amount and loading of microparticles, composition of the polymer used to synthesize the particles as well as the hydrogels. Since the drug delivery platform is in liquid phase at room temperature, implantation can be accomplished through direct injection into the anterior chamber or vitreous cavity after surgical procedure or in office.
  • PLGA Resomer 503H, molecular weight: 24-38 kDa, lactic acid (LA) to gly colic acid (GA) ratio of 50/50
  • 5 mg PEGylated PLGA Polyscitech, PEG and PLGA molecular weights: 5 and 20 kDa respectively.
  • DCM dichloromethane
  • DMSO dimethyl sulfoxide
  • the polymer-drug solutions were mixed and sonicated at an amplitude of 60% for 45 seconds and quickly transferred to a 50 ml of 1% PVA solution that was homogenized at a speed of 15,000 rpm for 1 minute.
  • the resulting microparticles (MPs) were transferred to a larger bath of PVA (volume: 100 ml) at a concentration of 0.5% that was being stirred at a speed of 500 rpm for 3.5 hrs.
  • the MPs were pelleted by centrifugation at a speed of 4000 rpm for 5 mins, and washed thrice with miliQ water, and lyophilized for later use.
  • Brinozolamide loaded MPs were made using the same protocol except 3 mg of Brinzolamide was used at a concentration of 10 mg/ml in DMSO.
  • PLGA-PEG-PLGA with MWs of 1000: 1000: 1000 Da
  • PLGA-PEG-PLGA with MWs of 1500: 1500: 1500 Da
  • LA/GA 6/1.
  • the triblock copolymers were dissolved in milliQ water at a concentration of 28.57 wt% by shaking for 3 days.
  • the drug release experiments in the Experimental Study 1 were done with a hydrogel made up of the following compositions.
  • the resulting blend gels at 37 ° C. By blending different amounts of triblock copolymers, gelation temperature can be finely tuned.
  • PBS phosphate buffered saline
  • antibiotic moxifloxacin
  • Expected duration of release of moxifloxacin is approximately one week.
  • the antibiotics are directly added to the hydrogel to maintain the planned shorter drug release duration.
  • the final inventive hydrogel composition had a total volume of 180 ⁇ and was kept in a 1.5 ml centrifuge tube. 1.2 ml of PBS was poured on it as the release media. 1 ml of PBS was replaced with fresh PBS at certain intervals.
  • the release samples taken from hydrogels or microparticles were lyophilized and drug molecules were dissolved in the DMSO-methanol (1-27 or 1-10 ratios).
  • the samples were analyzed with the high performance liquid chromatography (HPLC) to quantify the amount of drug release.
  • HPLC high performance liquid chromatography
  • the mobile phase for HPLC was composed of mixture of acetonitrile (24%) and water (76%) for the first 11 minutes.
  • the proportion of acetonitrile was raised to 36% during the last 9 minutes to elute dexamethasone, which was a more hydrophobic compound compared to other drugs studied.
  • the flow rate of solvent system was set to 1 ml/min, and injection volume of the drug solution was 25 ⁇ .
  • Figure 1 illustrates the phase diagram for the blended PLGA-PEG-PLGA triblock copolymers.
  • copolymer was incubated at each set temperature point for 15 minutes. Subsequently, the vial was placed upside-down for 30 seconds. If the polymer solution was not able to flow during this time, it was considered as a gel. Otherwise, it was a liquid or precipitate.
  • Figure 2 depicts the variation of storage and loss moduli for the PLGA-PEG- PLGA triblock blended copolymers.
  • the polymer solution was formulated at 20% wt/vol in IX PBS.
  • Figure 2 shows that the resulting blend of triblock copolymers had a low value for both the storage and loss moduli at room temperature, indicating liquid like behavior.
  • Figure 3 depicts moxifloxacin release from the drug delivery platform developed in Experimental Study 1. The duration of moxifloxacin release shown in Fig. 3 is as expected.
  • particles have a monodispersed size distribution and the particle size is between 1-2 ⁇ .
  • Hydrogel was kept in a 1.5 ml centrifuge tube. 1.1 ml of PBS (at IX).
  • Target drug loading for dexamethasone and levobunolol hydrochloride was increased to 25 and 15% wt% respectively.
  • the polymer concentration in DCM was raised to about 68 mg/ml.
  • the PVA volume and concentration were decreased to 40 ml and 0.75% wt% for homogenization step.
  • Drug loading was found to depend on polymer mass used to make MPs. Two homogenization steps were performed to make MPs each for 50 mg of polymer mass. To avoid escape of levobunolol hydrochloride, a more hydrophobic version of PLGA was used with the LA/GA ratio of 85/15. In a separate synthesis, polycaprolactone as a slower degrading polymer was used to make MPs too. However, due to the very low loading of levobunolol hydrochloride in the synthesized MPs, the resultant loading of levobunolol was insignificant.
  • Figure 8 illustrates the SEM images taken from the microparticles made in this Experimental Study.
  • size of dexamethasone loaded microparticles ranges from 1 to 3 microns.
  • levobunolol loaded microparticles are bigger in size (between 2-8 microns). It will be shown how larger particle size for levobunolol hydrochloride will enable a more sustained drug release compared to brinzolamide hydrogel system developed in Experimental Study 2.
  • Poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone) (PLCL-PEG-PLCL with MWs of 1700 and 1500 Da for PLCL and PEG, respectively).
  • the ratio of caprolactone to lactic acid was 60/40.
  • PBS phosphate buffered saline
  • the hydrogel was kept in a 1.5 ml centrifuge tube. About 1.1 ml of PBS (at IX concentration) was poured on it as the release media. About 1 ml of PBS was replaced with fresh PBS at certain intervals. The PBS samples were lyophilized, reconstituted in DMSO- methanol and analyzed with high performance liquid chromatography (HPLC) to determine daily release of drug molecules from the hydrogels. The release of dexamethasone and levobunolol hydrochloride from the hydrogel was compared with their release from MPs alone.
  • HPLC high performance liquid chromatography
  • Figure 9 depicts the phase diagram for PLCL-PEG-PLCL hydrogels. For each polymer concentration, Fig. 9 indicates the temperatures where the polymer solution is a liquid, gel and precipitate. This figure also indicates that the polymer solution is a hydrogel at body temperatures.
  • Figure 10 illustrates the rheological properties of PLCL-PEG-PLCL hydrogels. Qualitative observations for phase diagram are backed by quantitative rheological measurements shown in Fig. 10. This figure also indicates that the current hydrogel formulation has high mechanical properties at body temperature.
  • MPs alone have a huge burst release of dexamethasone on day 1.
  • daily dexamethasone release is decreased over time, and most of the drug is released in 10 days.
  • burst drug release is eliminated and daily release of dexamethasone is constant up to 3 weeks.
  • the hydrogel has been able to release the dexamethasone for more than 37 days. The hydrogel is still releasing the dexamethasone on physiologically relevant concentrations.
  • An outstanding feature of the hydrogel system developed in this invention is enhancement in the release of levobunolol hydrochloride after 3 weeks. Because the anti- glaucoma drug is embedded in the hydrogel to prevent the side effect of releasing steroids and elevating ocular pressure, increase in daily release of anti-glaucoma drugs after 3 weeks is extremely desirable.
  • PLGA-PEG-PLGA (with MWs of 1000: 1000: 1000 Da, ratio of lactic to glycolic acid (LA/GA): 1/1);
  • PLGA-PEG-PLGA (with MWs of 1500: 1500: 1500 Da, LA/GA: 6/1);
  • PLA-PEG-PLA (with MWs of 1700: 1500: 1700 Da);
  • PLCL-PEG-PLCL (with MWs of 1600: 1500: 1600 Da, caprolactone (CL)/LA: 3/1); and PLCL-PEG-PLCL (with MWs of 1700: 1500: 1700 Da, CL/LA: 3/2).
  • PLGA Different types were used to make drug loaded MPs.
  • PLGA with LA/GA of 60/40 (Product number: AP43), 75/25 (Product number: AP18), or 85/15 (Product number: AP 87), all with number averaged molecular weight of 45- 55kDa) was purchased from PolySciTech.
  • PLGA Resomer 503H with LA/GA ratio of 50/50 and weight averaged molecular weight of 24-38 kDa
  • Evonik Corporation Essen, Germany
  • Dexamethasone (Product number: 46165) and moxifloxacin (Product number: PHR1542) were obtained from Sigma Aldrich (St. Louis, MO), while levobunolol hydrochloride (HC1) (Product number: 1359801) was purchased from United States Pharmacopeia (Rockville, MD).
  • Poly(vinyl alcohol) (PVA, with molecular weight of 13-23 kDa, product number: 363170) was obtained from Sigma Aldrich. All other materials were obtained from Sigma Aldrich. Unless noted otherwise, the materials were used as received without further purification.
  • DMSO dimethyl sulfoxide
  • TAA triethylamine
  • the resulting MPs were transferred to a larger bath of PVA (80 ml at a concentration of 0.5%) while stirring at a speed of 990 rpm for 3.5 hours.
  • the MPs were pelleted by centrifugation at a speed of 3300 RCF for 5 mins, and washed thrice with miliQ water.
  • the MPs were then lyophilized and stored at -20 °C.
  • Dexamethasone-loaded MPs were made following the same protocol as described for levobunolol, except that PLGA (50/50) was dissolved in DCM at a higher concentration of 68 mg/ml. In addition, 20 mg of dexamethasone was dissolved in DMSO at a
  • thermogels To make the thermogels, the polymer solution is dissolved at a higher
  • the triblock co-polymers were dissolved in milliQ water at a concentration of 28.6 % wt/vol by shaking while cold (2-8°C) for 3 days.
  • the triblock co-polymer solutions were then diluted to reach the intended polymer concentration by addition of excess water and 10X PBS.
  • the volume of 10X PBS addition was chosen so that the final formulations were at IX PBS concentration to minimize any osmotic pressure difference with the biological environment (isotonic concentration).
  • PLGA-PEG-PLGA PLA-PEG-PLA
  • PLCL-PEG-PLCL hydrogels by blending them with different triblock co-polymers.
  • the ideal triblock co-polymer solution is one that is a liquid at room
  • the PLGA-PEG-PLGA was a 3/1 blend of PLGA-PEG-PLGA Mw 1,500: 1,500: 1,500 Da, 6: 1 LA:GA (86%/14% LA/GA) (w:w) and PLGA-PEG-PLGA LG 50:50 (w:w) (M n -1,000: 1,000: 1,000 Da) triblock co-polymer solutions.
  • the PLA-PEG-PLA hydrogel was made with P(DL)LA-PEG-P(DL)LA 1700-1500-1700 DA triblock co-polymer solution only, as its gelation temperature was in the right range. Furthermore, PLCL-PEG- PLCL hydrogels were a 6/1 blend of PLCL-PEG-PLCL MW -1600-1500-1600 DA, 75:25 CL:LA/PLCL-PEG-PLCL (-1700-1500-1700 DA, 60:40 CL:LA) triblock co-polymer solutions. By blending different amounts of triblock co-polymers, the gelation temperature can be finely tuned.
  • levobunolol release should be low initially and increase later to suppress any ocular pressure increase in the postoperative treatment period.
  • these small drug molecules are encapsulated in MPs first and then these MPs are loaded in the hydrogel network. This provides two barriers against burst release and premature escape of the drug molecules.
  • 7 mg of dexamethasone-loaded MPs and 17 mg of levobunolol-loaded MPs were loaded into the hydrogel network for drug release studies.
  • Hydrogels were made with 200 ⁇ triblock co-polymer solution and were kept in a 1.5 ml centrifuge tube. After incubation of hydrogel at 37 °C for half an hour, 1.2 ml of "pre- warmed" PBS was poured on it as the release media and the drug release was initiated. 1 ml of PBS was replaced with fresh PBS at certain intervals to make sure hydrogel was exposed to an effectively infinite-volume bath to release the drugs and to determine the released amount over time.
  • the release media taken from hydrogels or MP-containing samples were lyophilized and drug molecules were reconstituted in DMSO/methanol (at 1/10 volumetric ratio) and were analyzed with high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the mobile phase for HPLC was composed of mixture of acetonitrile (20%) and water (80%) for the first 9.5 minutes to elute levobunolol (peak position: between 3.8 to 4.6 minutes) and
  • moxifioxacin peak position: between 5.6 to 7.5 minutes. Then a linear compositional ramp was induced and the proportion of acetonitrile was raised to 34% in 1 minute. The acetonitrile was then kept at 34% for 6.5 minutes to elute dexamethasone (peak position: between 13.6 and 14.1 minutes), which was a more hydrophobic compound than the other drugs studied.
  • Levobunolol, moxifioxacin and dexamethasone signals were read at 221, 295 and 240 nm, respectively. Peak position for each drug could shift slightly from one day to another, but the drug content would always be checked with its UV absorption spectra. The flow rate of solvent was set to 1 ml/min, and injection volume of the drug solution was 25 ⁇ .
  • Figures 14A-14E illustrate the SEM micrographs taken from the MPs loaded with levobunolol or dexamethasone in this invention.
  • Figure 14 confirms the presence of spherical particles after loading different drug molecules and using different polymer types.
  • Figures 15A-15C illustrate the phase diagram for different triblock co-polymers used in this study. All the formulations tested were at IX PBS concentration. For PLGA- PEG-PLGA and PLCL-PEG-PLCL, two different triblock co-polymers with different molecular weight and ratio of lactic-to-caprolactone (as discussed above) were blended to make sure that the resulting polymer solution was a liquid at room temperature and a gel at body temperature. PLA-PEG-PLA polymer solutions already possessed this property.
  • Figure 15 confirms this and shows that at lower temperatures all of the polymer solutions are liquid. However, they will change into the gel form at body temperature. Figure 15 also indicates that at very high temperatures, the polymers precipitate out of solution and can no longer form a gel network. According to Fig. 15, for each triblock co-polymer concentration, there is a gelation temperature window. When the polymer concentration is increased, this gelation window becomes wider. At very high polymer concentrations, there are enough micelles associated with each other that the triblock co-polymer solution could form a hydrogel network even at room temperature. On the other hand, at lower polymer concentrations, the gelation window is too narrow to work with.
  • the polymer concentration for all the hydrogels was set to 20% wt/vol.
  • PLCL- PEG-PLCL polymer solutions have a much wider gelation window at each concentration, compared to PLGA-PEG-PLGA and PLA-PEG-PLA polymer solutions.
  • Figures 16A-16B depict the variation of storage and loss moduli for the different triblock co-polymers blended in this study.
  • the polymer solution was formulated at 20% wt/vol in IX PBS.
  • Figure 16 shows that the resulting blend of triblock co-polymers had a low value for both the storage and loss moduli at room temperature, indicating liquid-like behavior.
  • the mechanical properties of the gels shift as gelation occurs and the moduli are maximized near body temperature (37 °C).
  • the polymer precipitates and the desirable mechanical properties decrease.
  • Figures 17A-17B depict the variations of the moduli with frequency at different temperatures for the PLCL-PEG-PLCL triblock co-polymer solution. According to Fig. 17, regardless of oscillation frequency, the moduli are maximum at body temperature.
  • dexamethasone is constant for at least a week. Beyond the first week, daily drug release decreases over time (which is greatly favorable for the clinical application). Dexamethasone release from MPs was detectable for up to 36 days, while for MPs in the hydrogel, the drug release was detectable for up to 51 days. As will be described in the subsequent section, if required, the drug release profile could be manipulated by varying the hydrophobicity of the polymer encapsulating the drug molecules. However, throughout the first month, daily release of dexamethasone was enough to have a biologically significant effect.
  • the amount of dexamethasone released to the vitreous cavity by implants should be between 0.2- 1.2 ⁇ g daily in the first week, and the amount of drug should decrease gradually over time for postoperative management following cataract surgeries.
  • the mechanism behind sustaining the dexamethasone release by the hydrogel mainly stems from their chemical interaction.
  • Dexamethasone has a fluorine and several hydroxyl and double bonded oxygen groups that could form hydrogen bonds with excess water content in the hydrogel or with its PEG block.
  • levobunolol does not have as many groups capable of forming hydrogen bonds.
  • dexamethasone is very hydrophobic compared to levobunolol, and the tendency of dexamethasone to diffuse out of the hydrogel network and go into release media is therefore low.
  • A-B-A triblock co-polymers form a hydrogel network with large pore sizes (-50-100 ⁇ ), 7 and therefore can't physically avoid or slow down the release of small drug molecules studied in this research.
  • the mechanical properties of the hydrogel network do not seem to effect drug release kinetics, since drug release kinetics were found to be similar in hydrogels with significantly different moduli (Fig. 20A).
  • Figures 20A-20C depict the effect of different hydrogel types on the release kinetics of moxifioxacin, dexamethasone and levobunolol, respectively.
  • Moxifloxacin is hydrophilic (water solubility: 24 mg/ml), and was added directly to the polymer solution, and upon hydrogel formation, it will be held “loosely” within the hydrogel network.
  • Its release profile as shown in Fig. 20A contains a high burst release followed by gradual decrease in daily drug release amount with the majority of the drug being released within a week.
  • we suggest that there might be some chemical interactions between the drug and hydrogel network such as hydrogen bonding between fluorine, hydroxyl and double- bonded oxygen groups in Moxifloxacin with excess water content in hydrogel or its PEG part that has slowed down the release of this drug.
  • the drug delivery platform should have the ability to finely tune the drug release profile.
  • One way to achieve this goal is to vary the type of polymer encapsulating the drug molecule.
  • deprotonated levobunolol loaded MPs were made out of PLGA with differing hydrophobicity and degradation rate with LA/GA ratios of 60/40, 75/25, and 85/15. A higher ratio of lactic to gly colic acid leads to greater hydrophobicity and slower degradation rate.
  • Fig. 21 Evident in Fig. 21 is the ability of the drug delivery platform to finely tune the drug release profile by variation of polymer used to encapsulate the drug molecule.
  • PLGA with a LA/GA ratio of 60/40 degrades faster and thus enables rapid and linear drug release kinetics.
  • the majority of levobunolol release happens within 25 days.
  • 85/15 PLGA is the most hydrophobic polymer and releases the drug molecule more slowly and sustain the drug release for up to 60 days.
  • an increase in the drug release content was observable on the fourth week of drug release.
  • Figure 23 depicts the variation in percent drug release over time for three different drug molecules loaded in the present multi-drug delivery platform. To determine the percent of drug release, drug release at each time point is divided by the maximum detected drug release from the hydrogel.
  • Conspicuous in Fig. 23 is the ability of the present drug delivery system to release different drug molecules regardless of their hydrophobicity over different durations chosen according to the application.
  • moxifloxacin was the most hydrophilic (water solubility: 24 mg/ml) and dexamethasone was the most hydrophobic drug (water solubility: ⁇ 100 ⁇ g/ml).
  • 8 Drug release duration could be adjusted on demand depending on the direct addition of drug to the polymer network (rapid drug release) or encapsulating the drug molecules in MPs and embedding the MPs in the hydrogel network (slow drug release).
  • the drug release profile could be modified depending on the polymer used to encapsulate the drug molecules.
  • very hydrophobic polymer 85/15
  • more drugs could be released early on during the course of treatment.
  • Fluocinolone Acetonide implant for noninfectious posterior uveitis: thirty -four- week results of a multicenter randomized clinical study. Ophthalmology 113, 1020-1027 (2006).
  • Campochiaro P. A., Brown, D. M., Pearson, A., Ciulla, T., Boyer, D., Holz, F. G, Tolentino, M., Gupta, A., Duarte, L., Madreperla, S., Gonder, J., Kapik, B., Billman, K., Kane, F., and FAME Study Group. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology 118, 626-635 (2011).

Abstract

La présente invention porte sur un nouveau système de libération prolongée de médicament comprenant des microparticules incorporées dans un hydrogel en masse qui est modifié pour être sous forme liquide à température ambiante pour une administration simple dans l'œil ou un autre site tissulaire, et former un hydrogel à des températures corporelles physiologiques (environ 37 °C) pour servir de plateforme de libération de dépôt. Lors de l'injection ou de l'implantation, ce nouveau système d'administration de médicament gélifie immédiatement in situ formant un dépôt qui libère un certain nombre de différentes molécules de médicament à des taux et des moments prédéterminés pour fournir des concentrations intraoculaires ou intra-tissulaires optimales pour un traitement efficace.
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CN110559255A (zh) * 2019-09-06 2019-12-13 南京医科大学 Zl006 温敏凝胶及其制备方法
WO2022069799A1 (fr) * 2020-10-01 2022-04-07 Turku University of Applied Sciences Ltd Matériau hydrogel
AU2021353103B2 (en) * 2020-10-01 2023-05-18 Standard Millox Pharmaceuticals Oy A hydrogel material
WO2022192425A1 (fr) * 2021-03-10 2022-09-15 Pacira Therapeutics, Inc. Gels thermodurcissables à libération prolongée comprenant des médicaments anesthésiques et leurs procédés de fabrication
WO2022251468A3 (fr) * 2021-05-26 2023-01-05 Georgia Tech Research Corporation Hydrogels dégradables par hydrolyse et leurs utilisations
CN113350268A (zh) * 2021-06-17 2021-09-07 复旦大学附属眼耳鼻喉科医院 一种用于眼结膜下植入的药物缓释凝胶及其制备方法
CN113350268B (zh) * 2021-06-17 2023-09-05 复旦大学附属眼耳鼻喉科医院 一种用于眼结膜下植入的药物缓释凝胶及其制备方法
WO2023012357A1 (fr) * 2021-08-05 2023-02-09 Medincell Composition pharmaceutique
CN115364046A (zh) * 2022-08-16 2022-11-22 上海交通大学医学院附属第九人民医院 一种用于治疗血管痉挛的温敏溶胶及其制备方法与应用
CN115364046B (zh) * 2022-08-16 2024-04-30 上海交通大学医学院附属第九人民医院 一种用于治疗血管痉挛的温敏溶胶及其制备方法与应用
WO2024061673A1 (fr) * 2022-09-19 2024-03-28 Universiteit Utrecht Holding B.V. Hydrogel injectable pour l'administration de médicament

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