US20130157963A1 - Ophthalmic compositions comprising polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymers - Google Patents

Ophthalmic compositions comprising polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymers Download PDF

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US20130157963A1
US20130157963A1 US13/715,972 US201213715972A US2013157963A1 US 20130157963 A1 US20130157963 A1 US 20130157963A1 US 201213715972 A US201213715972 A US 201213715972A US 2013157963 A1 US2013157963 A1 US 2013157963A1
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composition
active agent
therapeutically active
polyvinyl
polyethylene glycol
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US13/715,972
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Anuradha V. Gore
Chetan P. Pujara
Richard S. Graham
Melissa Gulmezian
Kristin Prinn
Ramakrishnan Srikumar
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Allergan Inc
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Allergan Inc
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Priority to US13/715,972 priority Critical patent/US20130157963A1/en
Assigned to ALLERGAN, INC. reassignment ALLERGAN, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PUJARA, CHETAN P., GORE, ANURADHA V., SRIKUMAR, RAMAKRISHNAN, GRAHAM, RICHARD S, GULMEZIAN, Melissa, PRINN, KRISTIN
Publication of US20130157963A1 publication Critical patent/US20130157963A1/en
Priority to US14/152,380 priority patent/US9579385B2/en
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    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
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    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/0048—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
    • A61K9/08—Solutions
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • Topically applied formulations such as those applied to the cornea, conjunctiva, eyelid margin, etc.
  • some therapeutically active agents may have poor solubility in aqueous solutions, which may limit topical ophthalmic use. Solubility may be improved for some therapeutically active agents by using a nonionic surfactant, but further improvement may be needed.
  • Some embodiments include a topical ophthalmic composition comprising a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVA-PEG).
  • PCA-PVA-PEG polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer
  • Some embodiments include a method of solubilizing a therapeutically active agent comprising providing a composition including the therapeutically active agent and a PCA-PVA-PEG.
  • the therapeutically active agent may not be completely soluble in the composition at room temperature without the PCA-PVA-PEG.
  • Some embodiments include a method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent with a PCA-PVA-PEG to thereby improve stability of the therapeutically active agent.
  • Some embodiments include a method of solubilizing a therapeutically active agent comprising mixing the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition described herein is formed.
  • Some embodiments include a method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition described herein is formed.
  • Some embodiments include a method of treating a disease affecting an eye comprising administering a composition described herein to an eye in need thereof.
  • Polyoxyethylated surfactants such as polysorbate 80, polysorbate 20, and polyoxyl stearate 40 may suffer from disadvantages such as oxidative degradation of therapeutically active agents in a composition, degradation of the surfactant, reduced preservative effectiveness, and reduced permeability of bioavailability of the therapeutically active agent through biological membranes.
  • Use of a PCA-PVA-PEG may help to reduce or prevent these undesirable results.
  • a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer includes a polymer comprising at least one capralactam block, at least one polyvinyl acetate block, and at least one polyethylene glycol block, wherein at least one block branches from another of the type of blocks.
  • PCA-PVA-PEGs may be represented by the structure below.
  • a may be about 10 to about 10,000, about 100 to about 900, about 100 to about 500, or about 500 to about 900.
  • b may be about 20 to about 20,000, about 150 to about 1500, about 200 to about 800, or about 800 to about 1500.
  • c may be about 30 to about 30,000, about 300 to about 3000, about 300 to about 1000, about 1000 to about 2000, or about 2000 to about 3000.
  • a PCA-PVA-PEG may have an average molecular weight of about 1,000 g/mol to about 5,000,000 g/mol, about 10,000 g/mol to about 500,000 g/mol, or about 90,000 g/mol to about 140,000 g/mmol.
  • a PCA-PVA-PEG may be a polymer represented by CAS No. 402932-23-4, such as SOLUPLUS®, available from BASF.
  • PCA-PVA-PEG may improve the solubility and/or stability of a therapeutically active agent, including any of those listed below.
  • a PCA-PVA-PEG may also have minimal interference with preservatives, and thus in some compositions may allow less preservative to be used.
  • a PCA-PVA-PEG may have antimicrobial properties in some compositions, and may thus be included in a self-preserved composition that may not need a traditional preservative.
  • a PCA-PVA-PEG may also be synergistic with some preservatives such as stabilized oxychloro complexes.
  • a therapeutically active agent includes any compound or substance recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and any compound or substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals; and any substance other than food or water intended to affect the structure or any function of the body of humans or other animals.
  • Some therapeutically active agents may include antihistamines, antibiotics, beta blockers, steroids, antineoplastic agents, immunosuppressive agents, antiviral agents, and mixtures thereof.
  • antihistamines may include, but are not limited to, loradatine, hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine, cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, and derivatives thereof.
  • antibiotics may include without limitation, cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine, cefuroxime, cyclosporine, ampicillin, amoxicillin, cyclacillin, ampicillin, penicillin G, penicillin V potassium, piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin, azlocillin, carbenicillin, methicillin, nafcillin, erythromycin, tetracycline, doxycycline, minocycline, aztreonam, chloramphenicol
  • beta blockers may include acebutolol, atenolol, labetalol, metoprolol, propranolol, timolol, and derivatives thereof.
  • steroids may include corticosteroids, such as cortisone, prednisolone, fluorometholone, dexamethasone, medrysone, loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone, prednisone, methylprednisolone, riamcinolone hexacatonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, triamcinolone, derivatives thereof, and mixtures thereof.
  • corticosteroids such as cortisone, prednisolone, fluorometholone, dexamethasone, medrysone, loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone, prednisone, methylprednisolone, riamcinolone hexacatonide, paramethasone acetate,
  • antineoplastic agents may include adriamycin, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, interferons, camptothecin and derivatives thereof, phenesterine, taxol and derivatives thereof, taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen, etoposide, piposulfan, cyclophosphamide, and flutamide, and derivatives thereof.
  • immunosuppressive agents may include cyclosporine, azathioprine, tacrolimus, and derivatives thereof.
  • antiviral agents may include interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, valciclovir, dideoxycytidine, phosphonoformic acid, ganciclovir and derivatives thereof.
  • a therapeutically active agent may comprise an immunosuppressant, an alpha-adrenergic antagonist, a steroid, a prostaglandin EP2 agonist, a muscarinic, a prostaglandin, an alpha agonist, an antibiotic, an anti-infective agent, an anti-inflammatory, a beta blocker, or a combination thereof.
  • a therapeutically active agent may comprise cyclosporine A, a cyclosporine analog, phentolamine, testosterone, dexamethasone, prednisolone, bimatoprost, latanoprost, Compounds A, B, C, D, E, F, G and H of Table 8, pilocarpine, brimonidine, gatifloxacin, ketorolac, a steroid, timolol, or a combination thereof.
  • An ophthalmically acceptable liquid or solution should be tolerable to a patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid may be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
  • solutions or medicaments may be prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions may be maintained at a comfortable pH with an appropriate buffer system.
  • the formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • An ophthalmically acceptable liquid may include a buffer.
  • the buffer may vary, and may include any weak conjugate acid-base pair suitable for maintaining a desirable pH range. Examples include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, borate buffers, lactate buffers, NaOH/trolamine buffers, or a combination thereof, such as phosphate and citrate or borate and citrate. Acids or bases, such as HCl and NaOH, may be used to adjust the pH of these formulations as needed.
  • the amount of buffer used may vary. In some embodiments, the buffer may have a concentration in a range of about 1 nM to about 100 mM.
  • An ophthalmically acceptable liquid may include a preservative.
  • the preservative may vary, and may include any compound or substance suitable for reducing or preventing microbial contamination in an ophthalmic liquid subject to multiple uses from the same container.
  • Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, cationic preservatives such as quaternary ammonium compounds including benzalkonium chloride, polyquad, and the like; guanidine-based preservatives including PHMB, chlorhexidine, and the like; chlorobutanol; mercury preservatives such as thimerosal, phenylmercuric acetate and phenylmercuric nitrate; oxidizing preservatives such as stabilized oxychloro complexes (e.g.
  • a preservative may comprise benzalkonium chloride, a stabilized oxychloro complex, or a combination thereof.
  • a preservative may have a concentration of about 10 ppm to about 200 ppm, about 10 ppm to about 300 ppm, or about 50 ppm to about 150 ppm.
  • An ophthalmically acceptable liquid may include a co-solubilizer such as a surfactant.
  • the surfactant may vary, and may include any compound that is surface active or can form micelles.
  • a surfactant may be used for assisting in dissolving an excipient or an active agent, dispersing a solid or liquid in a composition, enhancing wetting, modifying drop size, stabilizing an emulsion, or a number of other purposes.
  • surfactants may include, but are not limited to, surfactants of the following classes: alcohols; amine oxides; block polymers; carboxylated alcohol or alkylphenol ethoxylates; carboxylic acids/fatty acids; ethoxylated alcohols; ethoxylated alkylphenols; ethoxylated aryl phenols; ethoxylated fatty acids; ethoxylated; fatty esters or oils (animal & veg.); fatty esters; fatty acid methyl ester ethoxylates; glycerol esters; glycol esters; lanolin-based derivatives; lecithin and lecithin derivatives; lignin and lignin derivatives; methyl esters; monoglycerides and derivatives; polyethylene glycols; polymeric surfactants; propoxylated & ethoxylated fatty acids, alcohols, or alkyl phenols; protein-based surfactants; sarcos;
  • the surfactant may include polyethylene glycol (15)-hydroxystearate (CAS Number 70142-34-6, available as SOLUTOL HS 15® from BASF), a polyoxyethylene-polyoxypropylene block copolymer (CAS No. 9003-11-6, available as PLURONIC® F-68 from BASF), polyoxyethylene 40 stearate (POE40 stearate), polysorbate 80 or polyoxyethylene (80) sorbitan monooleate (CAS No. 9005-65-6), sorbitan monostearate (CAS No. 1338-41-6, available as SPANTM 60 from Croda International PLC), or polyoxyethyleneglyceroltriricinoleate 35 (CAS No.
  • the amount of surfactant may vary. In some embodiments, the amount of any surfactant such as those listed above may be about 0.001 to about 5%, about 0.1% to about 2%, or about 0.1% to about 1%.
  • cyclodextrins may include ⁇ -cyclodextrin; ⁇ -cyclodextrin; ⁇ -cyclodextrin; cyclodextrin derivatives such as ether and mixed ether derivatives and those derivatives bearing sugar residues such as hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of ⁇ -, ⁇ - and ⁇ -cyclodextrin; maltosyl, glucosyl and maltotriosyl derivatives of ⁇ - and ⁇ -cyclodextrin, which may contain one or more sugar residues,
  • a co-solubilizer may comprise sorbitan monostearate, a polyoxyethylene-polyoxypropylene block copolymer, polyoxyethyleneglyceroltriricinoleate 35, a cyclodextrin, or a combination thereof.
  • An ophthalmically acceptable liquid may include a vehicle. Examples of suitable vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and acrylates (e.g. PEMULEN®).
  • An ophthalmically acceptable liquid may include an osmolality agent.
  • the osmolality agent may vary, and may include any compound or substance useful for adjusting the osmolality of an ophthalmic liquid. Examples include, but are not limited to, salts, particularly sodium chloride or potassium chloride, organic compounds such as propylene glycol, mannitol, or glycerin, or any other suitable ophthalmically acceptable osmolality adjustor.
  • an osmolality agent may comprise propylene glycol, glycerin, mannitol, sodium chloride, or a combination thereof.
  • the amount of osmolality agent may vary depending upon whether an isotonic, hypertonic, or hypotonic liquid is desired. In some embodiments, the amount of an osmolality agent such as those listed above may be at least about 0.0001% up to about 1%, about 2%, or about 5%.
  • An ophthalmically acceptable liquid may include an antioxidant.
  • the antioxidant may vary, and may include any compound or substance that is useful in reducing oxidation of any compound present in an ophthalmically acceptable liquid. Examples, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.
  • An ophthalmically acceptable liquid may include a chelating agent.
  • the chelating agent may vary, and may include any compound or substance that is capable of chelating a metal.
  • a useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • Compositions may be aqueous solutions or emulsions, or some other acceptable liquid form.
  • one or more oils may be used to form the emulsion.
  • Suitable oils include, but are not limited to anise oil, castor oil, clove oil, cassia oil, cinnamon oil, almond oil, corn oil, arachis oil, cottonseed oil, safflower oil, maize oil, linseed oil, rapeseed oil, soybean oil, olive oil, caraway oil, rosemary oil, peanut oil, peppermint oil, sunflower oil, eucalyptus oil, sesame oil, and the like.
  • compositions may comprise an ointment or a cream vehicle that may include a polymer thickener, water, preservatives, active surfactants or emulsifiers, antioxidants, and a solvent or mixed solvent system.
  • a hydrophilic thickener may comprise an acrylic acid or acrylate polymer, either cross-linked or non cross-linked such as a CARBOPOL® (B.F. Goodrich, Cleveland, Ohio), including CARBOPOL 980®. These polymers may dissolve in water and may form a clear or slightly hazy gel upon neutralization with a base such as sodium hydroxide, potassium hydroxide, triethanolamine, or other amine bases.
  • a base such as sodium hydroxide, potassium hydroxide, triethanolamine, or other amine bases.
  • KLUCEL® is a cellulose polymer that may be dispersed in water and may form a uniform gel upon complete hydration.
  • Other useful gelling polymers may include hydroxyethylcellulose, hydroxypropylcellulose, cellulose gum, MVA/MA copolymers, MVE/MA decadiene crosspolymer, PVM/MA copolymer, etc.
  • any effective amount of polymer thickener may be used, such as about 0.2% to about 4% weight/weight of the composition.
  • a useful weight/weight percent range for CARBOPOL® may be about 0.1% to about 5%, about 0.1% to about 2%, or about 0.5% to about 2%
  • a useful weight/weight percent range for NATROSOL® and KLUCEL® may be about 0.5% to about 4%
  • a useful weight/weight percent range for HYPAN® or STABILEZE® may be about 0.5% to about 4%.
  • Preservatives used in an ophthalmic ointment or cream may comprise about 0.1 to about 10%, about 1% to about 5%, about 0.05% to 0.5%, or about 0.05% to about 0.1% weight/weight of the total composition.
  • the use of preservatives may help to reduce or prevent microorganism growth.
  • Some useful preservatives may include benzyl alcohol, methylparaben, propylparaben, butylparaben, chloroxylenol, sodium benzoate, DMDM Hydantoin, 3-Iodo-2-Propylbutyl carbamate, potassium sorbate, chlorhexidine digluconate, etc.
  • Topical creams may be oil-in-water emulsions or water-in-oil emulsions.
  • An oil phase may include but is not limited to fatty alcohols, acids, or esters such as isopropyl myristate, cetyl palmitate, cetyl alcohol, stearyl alcohol, stearic acid, isopropyl stearate, glycerol stearate, mineral oil, white petrolatum, or other oils alone or in combination.
  • An oil phase may be about 1% to about 50%, about 1% to about 3%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 20% to about 30%, or about 10% to about 15% weight/weight.
  • An ophthalmic composition such as those described herein may be useful to treat or prevent ophthalmic diseases or conditions, such as one of the following: MACULOPATHIES/RETINAL DEGENERATION: Non-exudative age related macular degeneration (ARMD), exudative age related macular degeneration (ARMD), choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema.
  • MACULOPATHIES/RETINAL DEGENERATION Non-exudative age related macular degeneration (ARMD), exudative age related macular degeneration (ARMD), choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema.
  • UVEITIS/RETINITIS/CHOROIDITIS Acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome.
  • VASUCLAR DISEASES/EXUDATIVE DISEASES Retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, Eales disease.
  • CAD carotid artery disease
  • TRAUMATIC/SURGICAL Sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy.
  • PROLIFERATIVE DISORDERS Proliferative vitreal retinopathy and epiretinal membranes, proliferative diabetic retinopathy, retinopathy of prematurity (retrolental fibroplastic).
  • INFECTIOUS DISORDERS Ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, myiasis.
  • PONS presumed ocular histoplasmosis syndrome
  • GENETIC DISORDERS Retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, fundus flavimaculatus, Best's disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma elasticum, Osler Weber syndrome.
  • RETINAL TEARS/HOLES Retinal detachment, macular hole, giant retinal tear.
  • TUMORS Retinal disease associated with tumors, solid tumors, tumor metastasis, benign tumors, for example, hemangiomas, neurofibromas, trachomas, and pyogenic granulomas, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors.
  • MISCELLANEOUS Punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epithelitis, ocular inflammatory and immune disorders, ocular vascular malfunctions, corneal graft rejection, neovascular glaucoma and the like.
  • Table 1 summarizes solubility of bimatoprost in vehicles with 5 different solubilizers over a range of temperatures. Solubility of bimatoprost in vehicle containing PCA-PVA-PEG is higher than other solubilizers at room temperature (RT) and elevated temperatures.
  • PCA-PVA-PEG shows the highest solubilization for bimatoprost Solubilizer used (conc. Temperature Solubility of solubilizer is 1%) (° C.) (mg/ml) SOLUPLUS ® 5 0.427* (PCA-PVA-PEG) 25 3.513* 40 4.751* SOLUTOL ® HS 15 5 1.502** 25 1.320** 40 1.237** Polysorbate 20 5 1.242** 25 1.178** 40 1.050** POE 40 Stearate 5 1.268** 25 1.213** 40 1.149** Polysorbate 80 5 1.678** 25 1.524** 40 1.457** *Measured at 1 week only; **Measured at 8 weeks
  • Formulations containing PCA-PVA-PEG demonstrate antimicrobial activity even without use of any preservative. Formulations evaluated are listed in Table 3 along with the APET testing results. It was found that formulations containing 1% PCA-PVA-PEG and phosphate-citrate buffer (formulation 1) met USP criteria for all organisms. Replacing phosphate buffer with borate buffer and removing EDTA allows the formulations to meet PhEurB criteria for all organisms at PCA-PVA-PEG concentrations of 0.5%-1% (formulations 3-5).
  • Purite preserved formulations typically meet PhEurB criteria for APET due to lack of sufficient kill for bacteria at the 6 hour time point and mold at the 7 day time point.
  • Combination of Purite with PCA-PVA-PEG (SOLUPLUS®) it was seen that these formulations meet PhEurA criteria (Table 4). It was observed that a combination of 0.5% SOLUPLUS® with 100 ppm Purite was sufficient to meet PhEurA criteria for APET (Table 5). More importantly, excellent log-kill ratios were observed for all organisms tested at the 6 hour time point (for bacteria) and 7 day time point (for fungi).
  • Formulations containing PCA-PVA-PEG ranging from a concentration of 0.25% to 2% were evaluated in Human Corneal Epithelial Cells in-vitro. The cells were incubated with the formulations for 16 hours at 37° C. and the cell viability was measured. It was found that all the PCA-PVA-PEG formulations were non-cytotoxic. Viability of cells treated with PCA-PVA-PEG containing formulations was comparable to those without PCA-PVA-PEG or with Polysorbate 80.
  • Stability of cyclosporine analogs was evaluated in formulations using Polysorbate 80 (PS80) or PCA-PVA-PEG as solubilizer. Improved stability of the compounds was observed when either PCA-PVA-PEG or SOLUTOL® was used as the solubilizer.
  • An example for Compound H is shown in Table 8. The formulations were prepared in a vehicle containing a citrate-phosphate buffer at pH 7.2 and using PS80, SOLUTOL® or PCA-PVA-PEG at 1% concentration as the solubilizer. Samples were stored at 40° C. conditions and analyzed after 4 weeks. With either SOLUTOL® or PCA-PVA-PEG, the recovery of the drug was two-fold higher than that compared with PS80. Compound H is susceptible to degradation by oxidation. It is believed that both SOLUTOL® and PCA-PVA-PEG may improve stability for these types of compounds by reducing oxidation.
  • PCA-PVA-PEG may be used as a solubilizer or an additive to formulations with a large variety of actives. These include, but are not limited to, examples listed in Table 8.
  • Table 9 lists examples of solution formulations that may be prepared with PCA-PVA-PEG. It may be used in formulations other than aqueous solution as well. These include, but are not limited to, examples listed in Table 10.
  • formulation vehicle compositions with Soluplus® in Tables 11-17 examples include an active agent from Table 8.
  • Emulsion Vehicles with Soluplus Preserved with Purite, Benzalkonium chloride or combination. Any of the vehicles in Table 6 with the following ingredients as preservatives Concentration Ingredients Range Examples Purite 50-200 ppm 50 100 200 50 50 100 100 0 0 0 Benzalkonium 10-200 ppm 0 0 0 20 50 20 200 50 100 200 chloride Any of the QS to 100% w/v or % w/w vehicles from Table 6
  • compositions comprise a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer.
  • the polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer has an average molecular weight of about 10,000 g/mol to about 500,000 g/mol.
  • compositions of Example 8 or 9 further comprise a therapeutically active agent.
  • the therapeutically active agent comprises an immunosuppressant.
  • the therapeutically active agent comprises an alpha-adrenergic antagonist.
  • the therapeutically active agent comprises a prostaglandin EP2 agonist.
  • the therapeutically active agent comprises a muscarinic.
  • the therapeutically active agent comprises a prostaglandin.
  • the therapeutically active agent comprises an alpha agonist.
  • the therapeutically active agent comprises an antibiotic.
  • the therapeutically active agent comprises an anti-infective agent.
  • the therapeutically active agent comprises an anti-inflammatory.
  • the therapeutically active agent comprises a beta blocker.
  • the therapeutically active agent comprises cyclosporine A.
  • the therapeutically active agent comprises a cyclosporine analog.
  • the therapeutically active agent comprises phentolamine.
  • the therapeutically active agent comprises testosterone.
  • the therapeutically active agent comprises dexamethasone.
  • the therapeutically active agent comprises prednisolone.
  • the therapeutically active agent comprises bimatoprost.
  • the therapeutically active agent comprises latanoprost.
  • the therapeutically active agent comprises Compounds A or B of Table 8.
  • the therapeutically active agent comprises pilocarpine.
  • the therapeutically active agent comprises brimonidine.
  • the therapeutically active agent comprises Compound C of Table 8.
  • the therapeutically active agent comprises Compound D of Table 8.
  • the therapeutically active agent comprises Compound E of Table 8.
  • the therapeutically active agent comprises Compound F or G of Table 8.
  • the therapeutically active agent comprises gatifloxacin.
  • the therapeutically active agent comprises ketorolac.
  • the therapeutically active agent comprises a steroid.
  • the therapeutically active agent comprises timolol.
  • compositions of Example 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39, the composition is a solution.
  • compositions of Example 40 further comprise a co-solubilizer.
  • the co-solubilizer comprises sorbitan monostearate.
  • the co-solubilizer comprises a polyoxyethylene-polyoxypropylene block copolymer.
  • the co-solubilizer comprises polyoxyethyleneglyceroltriricinoleate 35.
  • the co-solubilizer comprises a cyclodextrin.
  • compositions of Example 40, 41, 42, 43, 44, or 45 further comprise an osmolality agent.
  • the osmolality agent comprises propylene glycol.
  • the osmolality agent comprises glycerin.
  • the osmolality agent comprises mannitol.
  • the osmolality agent comprises sodium chloride.
  • compositions of Example, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 further comprise a buffer.
  • the buffer comprises phosphate.
  • the buffer comprises phosphate and citrate.
  • the buffer comprises trolamine.
  • the buffer comprises lactate.
  • the buffer comprises borate.
  • the buffer comprises borate and citrate.
  • compositions of Example, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57 further comprise a preservative.
  • the preservative comprises benzalkonium chloride.
  • the preservative comprises a stabilized oxychloro complex.
  • a method of solubilizing a therapeutically active agent comprising mixing the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition according to any of Examples 10-60 is formed.
  • a method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent with a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer to thereby improve stability of the therapeutically active agent.
  • a method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition according to any of Examples 10-60 is formed.
  • a method of treating a disease affecting an eye comprising administering a composition according to any Examples 8-60 to an eye in need thereof.
  • a 65 year old Caucasian male suffering from elevated intraocular pressure applies one drop per day of Formula 2 of Table 18 in each eye for a period of 60 days.
  • the patient experiences a significant drop in IOP almost immediately which persists for the entire 60 days of treatment wherein his intraocular pressure levels drop to acceptable levels.
  • a 71 year old African American woman suffering from elevated intraocular pressure and open-angle glaucoma applies one drop daily in each eye of Formula 4 from Table 19. After 30 days, her symptoms of glaucoma improve significantly and her intraocular pressure falls to normal levels and without significant side effects so long as she continued daily application of Formula 4 of Table 19.
  • a 41 year old Caucasian female is suffering from symptoms of dry eye, applies twice daily Formulation 2 in Table 20 in each eye. After two days of application, the symptoms of dry eye improve significantly.

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Abstract

Compositions and methods related to ophthalmic use of polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymers and therapeutic uses are described herein.

Description

    RELATED APPLICATION
  • This application claims the benefit of U.S. Provisional Application Ser. No. 61/576,453, filed Dec. 16, 2011, which is incorporated herein by reference in its entirety.
    • BACKGROUND
  • Topically applied formulations, such as those applied to the cornea, conjunctiva, eyelid margin, etc., are frequently used in ophthalmology to treat acute and chronic conditions because they may be safer than systemically delivered formulations. However, some therapeutically active agents may have poor solubility in aqueous solutions, which may limit topical ophthalmic use. Solubility may be improved for some therapeutically active agents by using a nonionic surfactant, but further improvement may be needed.
    • SUMMARY
  • Some embodiments include a topical ophthalmic composition comprising a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVA-PEG).
  • Some embodiments include a method of solubilizing a therapeutically active agent comprising providing a composition including the therapeutically active agent and a PCA-PVA-PEG. In some embodiments, the therapeutically active agent may not be completely soluble in the composition at room temperature without the PCA-PVA-PEG.
  • Some embodiments include a method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent with a PCA-PVA-PEG to thereby improve stability of the therapeutically active agent.
  • Some embodiments include a method of solubilizing a therapeutically active agent comprising mixing the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition described herein is formed.
  • Some embodiments include a method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition described herein is formed.
  • Some embodiments include a method of treating a disease affecting an eye comprising administering a composition described herein to an eye in need thereof.
  • Other embodiments of the invention include:
      • 1) A topical ophthalmic composition comprising a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer.
      • 2) The composition of paragraph 1, wherein the polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer has an average molecular weight of about 10,000 g/mol to about 500,000 g/mol.
      • 3) The composition of paragraphs 1 or 2, further comprising a therapeutically active agent.
      • 4) The composition of paragraph 3, wherein the therapeutically active agent comprises an immunosuppressant, an alpha-adrenergic antagonist, a steroid, a prostaglandin EP2 agonist, a muscarinic, a prostaglandin, an alpha agonist, an antibiotic, an anti-infective agent, an anti-inflammatory, a beta blocker, or a combination thereof.
      • 5) The composition of paragraph 3, wherein the therapeutically active agent comprises cyclosporine A, a cyclosporine analog, phentolamine, testosterone, dexamethasone, prednisolone, bimatoprost, latanoprost, Compounds A, B, C, D, E, F, G and H of Table 8, pilocarpine, brimonidine, gatifloxacin, ketorolac, a steroid, timolol, or a combination thereof.
      • 6) The composition of paragraph 5, wherein the composition is a solution.
      • 7) The composition of paragraph 6, further comprising a co-solubilizer.
      • 8) The composition of paragraph 7, wherein the co-solubilizer comprises sorbitan monostearate, a polyoxyethylene-polyoxypropylene block copolymer, polyoxyethyleneglyceroltriricinoleate 35, a cyclodextrin, or a combination thereof.
      • 9) The composition of paragraph 6, further comprising an osmolality agent.
      • 10) The composition of paragraph 9, wherein the osmolality agent comprises propylene glycol, glycerin, mannitol, sodium chloride, or a combination thereof.
      • 11) The composition of paragraph 10, further comprising a buffer.
      • 12) The composition of paragraph 11, wherein the buffer comprises phosphate, phosphate and citrate, trolamine, lactate, borate, borate and citrate, or a combination thereof.
      • 13) The composition of paragraph 10 further comprising a preservative.
      • 14) The composition of paragraph 13, wherein the preservative comprises benzalkonium chloride, a stabilized oxychloro complex, or a combination thereof.
      • 15) A method of solubilizing a therapeutically active agent comprising providing a composition comprising the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein the therapeutically active agent is not completely soluble in the composition at room temperature without the polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer.
      • 16) A method of solubilizing a therapeutically active agent comprising mixing the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition according to claim 5 is formed.
      • 17) A method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent with a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer to thereby improve stability of the therapeutically active agent.
      • 18) A method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition according to claim 5 is formed.
      • 19) A method of treating a disease affecting an eye comprising administering a composition according to paragraph11 to an eye in need thereof wherein one of the active agents is bimatoprost.
      • 20) The method of paragraph19 further comprising the active agent brimonidine.
    DETAILED DESCRIPTION
  • Polyoxyethylated surfactants such as polysorbate 80, polysorbate 20, and polyoxyl stearate 40 may suffer from disadvantages such as oxidative degradation of therapeutically active agents in a composition, degradation of the surfactant, reduced preservative effectiveness, and reduced permeability of bioavailability of the therapeutically active agent through biological membranes. Use of a PCA-PVA-PEG may help to reduce or prevent these undesirable results.
  • A polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCA-PVA-PEG) includes a polymer comprising at least one capralactam block, at least one polyvinyl acetate block, and at least one polyethylene glycol block, wherein at least one block branches from another of the type of blocks. For example, some PCA-PVA-PEGs may be represented by the structure below.
  • Figure US20130157963A1-20130620-C00001
  • In the structure above, a may be about 10 to about 10,000, about 100 to about 900, about 100 to about 500, or about 500 to about 900.
  • In the structure above, b may be about 20 to about 20,000, about 150 to about 1500, about 200 to about 800, or about 800 to about 1500.
  • In the structure above, c may be about 30 to about 30,000, about 300 to about 3000, about 300 to about 1000, about 1000 to about 2000, or about 2000 to about 3000. In some embodiments, a PCA-PVA-PEG may have an average molecular weight of about 1,000 g/mol to about 5,000,000 g/mol, about 10,000 g/mol to about 500,000 g/mol, or about 90,000 g/mol to about 140,000 g/mmol.
  • In some embodiments, a PCA-PVA-PEG may be a polymer represented by CAS No. 402932-23-4, such as SOLUPLUS®, available from BASF.
  • Use of a PCA-PVA-PEG may improve the solubility and/or stability of a therapeutically active agent, including any of those listed below. A PCA-PVA-PEG may also have minimal interference with preservatives, and thus in some compositions may allow less preservative to be used. Furthermore, a PCA-PVA-PEG may have antimicrobial properties in some compositions, and may thus be included in a self-preserved composition that may not need a traditional preservative. A PCA-PVA-PEG may also be synergistic with some preservatives such as stabilized oxychloro complexes.
  • A therapeutically active agent includes any compound or substance recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and any compound or substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals; and any substance other than food or water intended to affect the structure or any function of the body of humans or other animals.
  • Some therapeutically active agents may include antihistamines, antibiotics, beta blockers, steroids, antineoplastic agents, immunosuppressive agents, antiviral agents, and mixtures thereof.
  • Examples of antihistamines may include, but are not limited to, loradatine, hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine, cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine, diphenylpyraline, phenindamine, azatadine, tripelennamine, dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimprazine doxylamine, pheniramine, pyrilamine, chiorcyclizine, thonzylamine, and derivatives thereof.
  • Examples of antibiotics may include without limitation, cefazolin, cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan, cefutoxime, cefotaxime, cefadroxil, ceftazidime, cephalexin, cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone, cefadroxil, cephradine, cefuroxime, cyclosporine, ampicillin, amoxicillin, cyclacillin, ampicillin, penicillin G, penicillin V potassium, piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin, azlocillin, carbenicillin, methicillin, nafcillin, erythromycin, tetracycline, doxycycline, minocycline, aztreonam, chloramphenicol, ciprofloxacin hydrochloride, clindamycin, metronidazole, gentamicin, lincomycin, tobramycin, vancomycin, polymyxin B sulfate, colistimethate, colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim, gatifloxacin, ofloxacin, and derivatives thereof.
  • Examples of beta blockers may include acebutolol, atenolol, labetalol, metoprolol, propranolol, timolol, and derivatives thereof.
  • Examples of steroids may include corticosteroids, such as cortisone, prednisolone, fluorometholone, dexamethasone, medrysone, loteprednol, fluazacort, hydrocortisone, prednisone, betamethasone, prednisone, methylprednisolone, riamcinolone hexacatonide, paramethasone acetate, diflorasone, fluocinonide, fluocinolone, triamcinolone, derivatives thereof, and mixtures thereof.
  • Examples of antineoplastic agents may include adriamycin, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, interferons, camptothecin and derivatives thereof, phenesterine, taxol and derivatives thereof, taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen, etoposide, piposulfan, cyclophosphamide, and flutamide, and derivatives thereof.
  • Examples of immunosuppressive agents may include cyclosporine, azathioprine, tacrolimus, and derivatives thereof.
  • Examples of antiviral agents may include interferon gamma, zidovudine, amantadine hydrochloride, ribavirin, acyclovir, valciclovir, dideoxycytidine, phosphonoformic acid, ganciclovir and derivatives thereof.
  • In some embodiments, a therapeutically active agent may comprise an immunosuppressant, an alpha-adrenergic antagonist, a steroid, a prostaglandin EP2 agonist, a muscarinic, a prostaglandin, an alpha agonist, an antibiotic, an anti-infective agent, an anti-inflammatory, a beta blocker, or a combination thereof. In some embodiments, a therapeutically active agent may comprise cyclosporine A, a cyclosporine analog, phentolamine, testosterone, dexamethasone, prednisolone, bimatoprost, latanoprost, Compounds A, B, C, D, E, F, G and H of Table 8, pilocarpine, brimonidine, gatifloxacin, ketorolac, a steroid, timolol, or a combination thereof.
  • An ophthalmically acceptable liquid or solution should be tolerable to a patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid may be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
  • For ophthalmic application, solutions or medicaments may be prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions may be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
  • An ophthalmically acceptable liquid may include a buffer. The buffer may vary, and may include any weak conjugate acid-base pair suitable for maintaining a desirable pH range. Examples include, but are not limited to, acetate buffers, citrate buffers, phosphate buffers, borate buffers, lactate buffers, NaOH/trolamine buffers, or a combination thereof, such as phosphate and citrate or borate and citrate. Acids or bases, such as HCl and NaOH, may be used to adjust the pH of these formulations as needed. The amount of buffer used may vary. In some embodiments, the buffer may have a concentration in a range of about 1 nM to about 100 mM.
  • An ophthalmically acceptable liquid may include a preservative. The preservative may vary, and may include any compound or substance suitable for reducing or preventing microbial contamination in an ophthalmic liquid subject to multiple uses from the same container. Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, cationic preservatives such as quaternary ammonium compounds including benzalkonium chloride, polyquad, and the like; guanidine-based preservatives including PHMB, chlorhexidine, and the like; chlorobutanol; mercury preservatives such as thimerosal, phenylmercuric acetate and phenylmercuric nitrate; oxidizing preservatives such as stabilized oxychloro complexes (e.g. PURITE®); and other preservatives such as benzyl alcohol. In some embodiments, a preservative may comprise benzalkonium chloride, a stabilized oxychloro complex, or a combination thereof. In some embodiments, a preservative may have a concentration of about 10 ppm to about 200 ppm, about 10 ppm to about 300 ppm, or about 50 ppm to about 150 ppm.
  • An ophthalmically acceptable liquid may include a co-solubilizer such as a surfactant. The surfactant may vary, and may include any compound that is surface active or can form micelles. A surfactant may be used for assisting in dissolving an excipient or an active agent, dispersing a solid or liquid in a composition, enhancing wetting, modifying drop size, stabilizing an emulsion, or a number of other purposes. Examples of surfactants may include, but are not limited to, surfactants of the following classes: alcohols; amine oxides; block polymers; carboxylated alcohol or alkylphenol ethoxylates; carboxylic acids/fatty acids; ethoxylated alcohols; ethoxylated alkylphenols; ethoxylated aryl phenols; ethoxylated fatty acids; ethoxylated; fatty esters or oils (animal & veg.); fatty esters; fatty acid methyl ester ethoxylates; glycerol esters; glycol esters; lanolin-based derivatives; lecithin and lecithin derivatives; lignin and lignin derivatives; methyl esters; monoglycerides and derivatives; polyethylene glycols; polymeric surfactants; propoxylated & ethoxylated fatty acids, alcohols, or alkyl phenols; protein-based surfactants; sarcosine derivatives; sorbitan derivatives; sucrose and glucose esters and derivatives. In some embodiments, the surfactant may include polyethylene glycol (15)-hydroxystearate (CAS Number 70142-34-6, available as SOLUTOL HS 15® from BASF), a polyoxyethylene-polyoxypropylene block copolymer (CAS No. 9003-11-6, available as PLURONIC® F-68 from BASF), polyoxyethylene 40 stearate (POE40 stearate), polysorbate 80 or polyoxyethylene (80) sorbitan monooleate (CAS No. 9005-65-6), sorbitan monostearate (CAS No. 1338-41-6, available as SPAN™ 60 from Croda International PLC), or polyoxyethyleneglyceroltriricinoleate 35 (CAS No. 61791-12-6, available as CREMOPHOR EL® from BASF), ethoxylated castor oil, such as Cremophor EL (CAS Number 61791-12-6). The amount of surfactant may vary. In some embodiments, the amount of any surfactant such as those listed above may be about 0.001 to about 5%, about 0.1% to about 2%, or about 0.1% to about 1%.
  • Other compounds, such as a cyclodextrin, may be used as a co-solubilizer. Examples of cyclodextrins may include α-cyclodextrin; β-cyclodextrin; γ-cyclodextrin; cyclodextrin derivatives such as ether and mixed ether derivatives and those derivatives bearing sugar residues such as hydroxyethyl, hydroxypropyl (including 2- and 3-hydroxypropyl) and dihydroxypropyl ethers, their corresponding mixed ethers and further mixed ethers with methyl or ethyl groups, such as methyl-hydroxyethyl, ethyl-hydroxyethyl and ethyl-hydroxypropyl ethers of α-, β- and γ-cyclodextrin; maltosyl, glucosyl and maltotriosyl derivatives of β- and γ-cyclodextrin, which may contain one or more sugar residues, e.g. glucosyl or diglucosyl, maltosyl or dimaltosyl, as well as various mixtures thereof, e.g. a mixture of maltosyl and dimaltosyl derivatives; cyclodextrin derivatives comprising anionic functional groups such as sulfobutylether derivatives, sulfonates, phosphates, and the like, such as hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether-γ-cyclodextrin, as well as hydroxyethyl-β-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin and dimaltosyl-β-cyclodextrin, and mixtures thereof such as maltosyl-β-cyclodextrin/dimaltosyl-β-cyclodextrin. Cyclodextrins may be present at a concentration of about 0.01% to about 30%, about 0.01% to about 10%, or about 1% to about 10%.
  • In some embodiments, a co-solubilizer may comprise sorbitan monostearate, a polyoxyethylene-polyoxypropylene block copolymer, polyoxyethyleneglyceroltriricinoleate 35, a cyclodextrin, or a combination thereof. An ophthalmically acceptable liquid may include a vehicle. Examples of suitable vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose, and acrylates (e.g. PEMULEN®).
  • An ophthalmically acceptable liquid may include an osmolality agent. The osmolality agent may vary, and may include any compound or substance useful for adjusting the osmolality of an ophthalmic liquid. Examples include, but are not limited to, salts, particularly sodium chloride or potassium chloride, organic compounds such as propylene glycol, mannitol, or glycerin, or any other suitable ophthalmically acceptable osmolality adjustor. In some embodiments, an osmolality agent may comprise propylene glycol, glycerin, mannitol, sodium chloride, or a combination thereof.
  • The amount of osmolality agent may vary depending upon whether an isotonic, hypertonic, or hypotonic liquid is desired. In some embodiments, the amount of an osmolality agent such as those listed above may be at least about 0.0001% up to about 1%, about 2%, or about 5%.
  • An ophthalmically acceptable liquid may include an antioxidant. The antioxidant may vary, and may include any compound or substance that is useful in reducing oxidation of any compound present in an ophthalmically acceptable liquid. Examples, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.
  • An ophthalmically acceptable liquid may include a chelating agent. The chelating agent may vary, and may include any compound or substance that is capable of chelating a metal. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
  • Compositions may be aqueous solutions or emulsions, or some other acceptable liquid form. For an emulsion, one or more oils may be used to form the emulsion. Suitable oils include, but are not limited to anise oil, castor oil, clove oil, cassia oil, cinnamon oil, almond oil, corn oil, arachis oil, cottonseed oil, safflower oil, maize oil, linseed oil, rapeseed oil, soybean oil, olive oil, caraway oil, rosemary oil, peanut oil, peppermint oil, sunflower oil, eucalyptus oil, sesame oil, and the like.
  • Some ophthalmically acceptable compositions may comprise an ointment or a cream vehicle that may include a polymer thickener, water, preservatives, active surfactants or emulsifiers, antioxidants, and a solvent or mixed solvent system.
  • Any polymer thickeners suitable for ophthalmic application may be used, such as hydrophilic thickeners frequently used in the pharmaceutical industries. For example, a hydrophilic thickener may comprise an acrylic acid or acrylate polymer, either cross-linked or non cross-linked such as a CARBOPOL® (B.F. Goodrich, Cleveland, Ohio), including CARBOPOL 980®. These polymers may dissolve in water and may form a clear or slightly hazy gel upon neutralization with a base such as sodium hydroxide, potassium hydroxide, triethanolamine, or other amine bases. Other commercially available thickeners may include HYPAN® (Kingston Technologies, Dayton, N.J.), NATROSOL® (Aqualon, Wilmington, Del.), KLUCEL® (Aqualon, Wilmington, Del.), or STABILEZE® (ISP Technologies, Wayne, N.J.). KLUCEL® is a cellulose polymer that may be dispersed in water and may form a uniform gel upon complete hydration. Other useful gelling polymers may include hydroxyethylcellulose, hydroxypropylcellulose, cellulose gum, MVA/MA copolymers, MVE/MA decadiene crosspolymer, PVM/MA copolymer, etc.
  • Any effective amount of polymer thickener may be used, such as about 0.2% to about 4% weight/weight of the composition. A useful weight/weight percent range for CARBOPOL® may be about 0.1% to about 5%, about 0.1% to about 2%, or about 0.5% to about 2%, a useful weight/weight percent range for NATROSOL® and KLUCEL® may be about 0.5% to about 4%, and a useful weight/weight percent range for HYPAN® or STABILEZE® may be about 0.5% to about 4%.
  • Preservatives used in an ophthalmic ointment or cream and may comprise about 0.1 to about 10%, about 1% to about 5%, about 0.05% to 0.5%, or about 0.05% to about 0.1% weight/weight of the total composition. The use of preservatives may help to reduce or prevent microorganism growth. Some useful preservatives may include benzyl alcohol, methylparaben, propylparaben, butylparaben, chloroxylenol, sodium benzoate, DMDM Hydantoin, 3-Iodo-2-Propylbutyl carbamate, potassium sorbate, chlorhexidine digluconate, etc.
  • An ophthalmic composition may be applied in a topical cream. Topical creams may be oil-in-water emulsions or water-in-oil emulsions. An oil phase may include but is not limited to fatty alcohols, acids, or esters such as isopropyl myristate, cetyl palmitate, cetyl alcohol, stearyl alcohol, stearic acid, isopropyl stearate, glycerol stearate, mineral oil, white petrolatum, or other oils alone or in combination. An oil phase may be about 1% to about 50%, about 1% to about 3%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 20% to about 30%, or about 10% to about 15% weight/weight.
  • An ophthalmic composition such as those described herein may be useful to treat or prevent ophthalmic diseases or conditions, such as one of the following: MACULOPATHIES/RETINAL DEGENERATION: Non-exudative age related macular degeneration (ARMD), exudative age related macular degeneration (ARMD), choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema.
  • UVEITIS/RETINITIS/CHOROIDITIS: Acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (MEWDS), ocular sarcoidosis, posterior scleritis, serpignous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-Harada syndrome.
  • VASUCLAR DISEASES/EXUDATIVE DISEASES: Retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, Eales disease.
  • TRAUMATIC/SURGICAL: Sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, laser, PDT, photocoagulation, hypoperfusion during surgery, radiation retinopathy, bone marrow transplant retinopathy.
  • PROLIFERATIVE DISORDERS: Proliferative vitreal retinopathy and epiretinal membranes, proliferative diabetic retinopathy, retinopathy of prematurity (retrolental fibroplastic).
  • INFECTIOUS DISORDERS: Ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associated with HIV infection, uveitic disease associated with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, myiasis.
  • GENETIC DISORDERS: Retinitis pigmentosa, systemic disorders with associated retinal dystrophies, congenital stationary night blindness, cone dystrophies, fundus flavimaculatus, Best's disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, pseudoxanthoma elasticum, Osler Weber syndrome.
  • RETINAL TEARS/HOLES: Retinal detachment, macular hole, giant retinal tear.
  • TUMORS: Retinal disease associated with tumors, solid tumors, tumor metastasis, benign tumors, for example, hemangiomas, neurofibromas, trachomas, and pyogenic granulomas, congenital hypertrophy of the RPE, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of the ocular fundus, retinal astrocytoma, intraocular lymphoid tumors.
  • MISCELLANEOUS: Punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, acute retinal pigment epithelitis, ocular inflammatory and immune disorders, ocular vascular malfunctions, corneal graft rejection, neovascular glaucoma and the like.
    • Example 1
  • Table 1 summarizes solubility of bimatoprost in vehicles with 5 different solubilizers over a range of temperatures. Solubility of bimatoprost in vehicle containing PCA-PVA-PEG is higher than other solubilizers at room temperature (RT) and elevated temperatures.
  • TABLE 1
    Bimatoprost Solubility in five different formulation vehicles at
    different temperatures. At room temperature and elevated
    temperatures, PCA-PVA-PEG shows the highest solubilization for
    bimatoprost
    Solubilizer used (conc. Temperature Solubility
    of solubilizer is 1%) (° C.) (mg/ml)
    SOLUPLUS ® 5 0.427*
    (PCA-PVA-PEG) 25 3.513*
    40 4.751*
    SOLUTOL ® HS 15 5 1.502**
    25 1.320**
    40 1.237**
    Polysorbate 20 5 1.242**
    25 1.178**
    40 1.050**
    POE 40 Stearate 5 1.268**
    25 1.213**
    40 1.149**
    Polysorbate 80 5 1.678**
    25 1.524**
    40 1.457**
    *Measured at 1 week only;
    **Measured at 8 weeks
    • Example 2 Data in Support of Improved BAK Efficacy
  • Preservative titration studies were performed to compare the efficacy of BAK in formulations using different solubilizers. Typically, it is seen that in the presence of surfactants, the preservative efficacy of BAK is significantly reduced. As a result, higher levels of BAK may be required to meet the preservative criteria for ophthalmic products as defined in USP <51> and European Pharmacopeial 5.1.3 chapters. It was seen that when PCA-PVA-PEG was used as a solubilizer, the preservative criteria were met at lower levels of BAK as compared to all other surfactants tested as summarized in Table 2. In fact, formulations containing PCA-PVA-PEG met PhEurA criteria with as low as 50 ppm BAK, which is similar to formulations containing no solubilizers.
  • TABLE 2
    Summary of Preservative Titration to Failure results for
    formulations containing different solubilizers.
    APET Criteria Met1
    1% PS80 1% SOLUTOL ® 1% PS20 1% POE40
    BAK 1% F1 Solution F2 Solution F3 Solution F4 Solution
    (ppm) SOLUPLUS ® Series Series Series Series
    50 Ph Eur-A USP Ph Eur-B USP USP
    75 Not tested Ph Eur-B Ph Eur-B Ph Eur-B USP
    100 Ph Eur-A Ph Eur-B Ph Eur-A Ph Eur-B Ph Eur-B
    120 Ph Eur-A Ph Eur-B Ph Eur-A Ph Eur-B Ph Eur-B
    140 Ph Eur-A Ph Eur-A Ph Eur-A Ph Eur-A Ph Eur-B
    160 Ph Eur-A Ph Eur-A Ph Eur-A Ph Eur-A Ph Eur-B
    Expt # 22955 22358 22839 22861 22861
    1APET criteria as defined in USP <51> and European Pharmacopeia (Ph Eur) 5.1.3.
    • Example 3 Use of PCA-PVA-PEG in a Self-Preserved System
  • Formulations containing PCA-PVA-PEG demonstrate antimicrobial activity even without use of any preservative. Formulations evaluated are listed in Table 3 along with the APET testing results. It was found that formulations containing 1% PCA-PVA-PEG and phosphate-citrate buffer (formulation 1) met USP criteria for all organisms. Replacing phosphate buffer with borate buffer and removing EDTA allows the formulations to meet PhEurB criteria for all organisms at PCA-PVA-PEG concentrations of 0.5%-1% (formulations 3-5).
  • TABLE 3
    Effect of PCA-PVA-PEG Level and
    Boric Acid Buffer in APET testing
    Concentration (% w/v)
    Formulation 1 2 3 4 5 6 7
    SOLUPLUS ® 1.0 1.0 1.0 0.75 0.5 0.25 0.1
    (PCA-PVA-PEG)
    Edetate Disodium 0.01 0.01 0 0 0 0 0
    Boric Acid 0 0.6 0.6 0.6 0.6 0.6 0.6
    Sodium Phosphate 0.268 0 0 0 0 0 0
    Dibasic Heptahydrate
    Citric Acid 0.014 0 0 0 0 0 0
    Monohydrate
    Glycerin 1.2 1.2 1.2 1.2 1.2 1.2 1.2
    Mannitol 2.0 0 0 0 0 0 0
    1N NaOH/1N HCl 7.4 7.4 7.4 7.4 7.4 7.4 7.4
    Purified Water QS QS QS QS QS QS QS
    APET results (Expt # 22994)
    PhEurA Fail Fail Fail Fail Fail Fail Fail
    PhEurB Fail Fail Pass Pass Pass Fail Fail
    USP Pass Pass Pass Pass Pass Pass Pass
    • Example 4 Synergistic Effect of PCA-PVA-PEG on Antimicrobial Efficacy of Purite as Preservative
  • Purite preserved formulations typically meet PhEurB criteria for APET due to lack of sufficient kill for bacteria at the 6 hour time point and mold at the 7 day time point. Combination of Purite with PCA-PVA-PEG (SOLUPLUS®), it was seen that these formulations meet PhEurA criteria (Table 4). It was observed that a combination of 0.5% SOLUPLUS® with 100 ppm Purite was sufficient to meet PhEurA criteria for APET (Table 5). More importantly, excellent log-kill ratios were observed for all organisms tested at the 6 hour time point (for bacteria) and 7 day time point (for fungi).
  • The combination of Purite, Boric acid and PCA-PVA-PEG would be of utility in over-the-counter (OTC) products. Addition of 0.5% PCA-PVA-PEG in Allergan products such as REFRESH®, REFRESH PLUS®, REFRESH DRYEYE®, OPTIVE® and Next Generation Emulsion would allow these products to meet PhEurA criteria for APET testing. Similarly, for drug products such as ALPHAGAN P®, addition of PCA-PVA-PEG and meeting PhEurA criteria would make this product suitable for filing in the EU.
  • TABLE 4
    Effect of PCA-PVA-PEG and boric acid in
    combination with Purite on APET
    Concentration (% w/v)
    Formulation Control 1 2 3 4 5
    SOLUPLUS ®® 1.0 1.0 1.0 1.0 1.0 1.0
    (Polyvinyl caprolactam-
    polyvinyl acetate-
    polyethylene glycol graft
    copolymer)
    Purite 0 0.002 0.004 0.006 0.008 0.010
    Boric Acid 0.6 0.6 0.6 0.6 0.6 0.6
    Glycerin 1.2 1.2 1.2 1.2 1.2 1.2
    1N NaOH/1N HCl 7.4 7.4 7.4 7.4 7.4 7.4
    Purified Water QS QS QS QS QS QS
    APET results (Expt # 22994)
    PhEurA Fail Pass Pass Pass Pass Pass
    PhEurB Pass Pass Pass Pass Pass Pass
    USP Pass Pass Pass Pass Pass Pass
  • TABLE 5
    Effect of different levels of PCA-PVA-PEG with Purite on APET
    Concentration (% w/v)
    Formulation 1 2 3 4 5 6
    SOLUPLUS ®® 1.0 0.75 0.5 0.25 0.1 0
    (Polyvinyl caprolactam-
    polyvinyl acetate-
    polyethylene glycol graft
    copolymer)
    Purite 0.01 0.01 0.01 0.01 0.01 0.01
    Boric Acid 0.6 0.6 0.6 0.6 0.6 0.6
    Glycerin 1.5 1.5 1.5 1.5 1.5 1.5
    1N NaOH/1N HCl 7.4 7.4 7.4 7.4 7.4 7.4
    Purified Water QS QS QS QS QS QS
    APET 14 day results (Expt #23017)
    PhEurA Pass Pass Pass Fail Fail Fail
    PhEurB Pass Pass Pass Pass Pass Pass
    USP Pass Pass Pass Pass Pass Pass
    • Example 5 Cytotoxicity Testing of PCA-PVA-PEG Formulations
  • Formulations containing PCA-PVA-PEG ranging from a concentration of 0.25% to 2% were evaluated in Human Corneal Epithelial Cells in-vitro. The cells were incubated with the formulations for 16 hours at 37° C. and the cell viability was measured. It was found that all the PCA-PVA-PEG formulations were non-cytotoxic. Viability of cells treated with PCA-PVA-PEG containing formulations was comparable to those without PCA-PVA-PEG or with Polysorbate 80.
  • TABLE 6
    Cytotoxicity testing of Formulations containing PCA-PVA-PEG
    Concentration (% w/v)
    Formulation 1 2 3 4 5 6 7
    Solubilizer: SOLUPLUS ® 1.0 0.75 0.5 0.25 0.1 0.0 0.0
    Polyvinyl caprolactam-
    polyvinyl acetate-
    polyethylene glycol graft
    copolymer
    Polysorbate 80 0.0 0.0 0.0 0.0 0.0 0.0 1.0
    Boric Acid 0.6 0.6 0.6 0.6 0.6 0.6 0.6
    Glycerin 1.5 1.5 1.5 1.5 1.5 1.5 1.5
    Mannitol 0 0 0 0 0 0 0
    1N NaOH/1N HCl 7.4 7.4 7.4 7.4 7.4 7.4 7.4
    Purified Water QS QS QS QS QS QS QS
    Results for in-vitro cytotoxicity
    % Viability compared to 84 ± 3 83 ± 3 92 ± 3 89 ± 6 90 ± 2 92 ± 1 90 ± 4
    normal saline
    • Example 6 Data Showing Improved Stability of Drug Substances in Formulations Containing PCA-PVA-PEG
  • Stability of cyclosporine analogs was evaluated in formulations using Polysorbate 80 (PS80) or PCA-PVA-PEG as solubilizer. Improved stability of the compounds was observed when either PCA-PVA-PEG or SOLUTOL® was used as the solubilizer. An example for Compound H is shown in Table 8. The formulations were prepared in a vehicle containing a citrate-phosphate buffer at pH 7.2 and using PS80, SOLUTOL® or PCA-PVA-PEG at 1% concentration as the solubilizer. Samples were stored at 40° C. conditions and analyzed after 4 weeks. With either SOLUTOL® or PCA-PVA-PEG, the recovery of the drug was two-fold higher than that compared with PS80. Compound H is susceptible to degradation by oxidation. It is believed that both SOLUTOL® and PCA-PVA-PEG may improve stability for these types of compounds by reducing oxidation.
  • TABLE 7
    Stability of Compound H at 0.01% in MP500 bottles at 40° C.
    Vehicle % Recovery at 4-weeks at 40° C.
    1% PS80 33.9
    1% SOLUTOL ® 72.3
    1% SOLUPLUS ® 69.6
    Other components of the vehicle: citrate/phosphate buffer and NaCl at pH~7.2
    • Example 7 Examples of Classes of APIs and Formulations that May be Formulated with PCA-PVA-PEG for Ophthalmic Use
  • PCA-PVA-PEG may be used as a solubilizer or an additive to formulations with a large variety of actives. These include, but are not limited to, examples listed in Table 8. Table 9 lists examples of solution formulations that may be prepared with PCA-PVA-PEG. It may be used in formulations other than aqueous solution as well. These include, but are not limited to, examples listed in Table 10.
  • TABLE 8
    Examples of APIs that may be formulated using PCA-PVA-PEG
    Typical
    concentration range
    in Ophthalmic
    Drug class Examples products
    Immuno- Cyclosporine A, Cyclosporine analogs 0.001-0.4%
    suppressant
    Alpha- Phentolamine 0.001-2%  
    adrenergic
    antagonist
    Steroids Testosterone, Dexamethasone, 0.001-5%  
    Prednisolone
    EP-2 agonists Compound A (below) 0.001-0.1%
    Compound B (below) 0.0002-0.05%
    Compound E (below) 0.001-0.1%
    Muscarinics Pilocarpine  0.1-6.0%
    Prostaglandins Bimatoprost, Latanoprost 0.001-0.1   
    Alpha-agonists Brimonidine, Compounds C, D, E and F 0.001-1%  
    (below)
    Antibiotics/anti- Gatifloxicin  0.1-1%  
    infectives
    Anti- Ketorolac 0.01-1% 
    inflammatory Steroids
    Beta Blockers Timolol  0.05-0.5%
    Compound A
    Figure US20130157963A1-20130620-C00002
         		IUPAC Name: isopropyl 5-((((R)-1- (4-((S)-1- hydroxyhexyl)phenyl)- 5-oxopyrrolidin-2- yl)methoxy)methyl) thiophene-2- carboxylate
    Compound B
    Figure US20130157963A1-20130620-C00003
         		IUPAC Name: isopropyl 5-(3-((S)-1- (4-((S)-1- hydroxyhexyl)phenyl)- 5-oxopyrrolidin-2- yl)propyl)thiophene-2- carboxylate
    Compound C
    Figure US20130157963A1-20130620-C00004
         		IUPAC Name: 3-[(1S)-1-(1H- imidazol- 4-yl)ethyl]-2- methylbenzyl 2- methylpropanoate
    Compound D
    Figure US20130157963A1-20130620-C00005
         		IUPAC Name: 3-[(1S)- 1-(1H-imidazol-4- yl)ethyl]-2- methylbenzyl pivalate
    Compound E
    Figure US20130157963A1-20130620-C00006
         		IUPAC Name: 4- bromo-N-imidazolidin- 2-ylidene-1H- benzimidazol-5-amine
    Compound F
    Figure US20130157963A1-20130620-C00007
         		IUPAC Name: (S)-(+)-7-(1H- Imidazol- 4-ylmethyl)-5,6,7,8- tetrahydro-quinoline
    Compound G
    Figure US20130157963A1-20130620-C00008
         		IUPAC Name: 2-hydroxyethyl 5-(3- {(2S)-1-[4-(1- hydroxyhexyl)phenyl]- 5-oxopyrrolidin-2- yl}propyl)thiophene-2- carboxylate
    Compound H
    Figure US20130157963A1-20130620-C00009
         		Cyclosporine Analog
    Figure US20130157963A1-20130620-C00010
  • TABLE 9
    Examples of Solution Formulations using PCA-PVA-PEG
    Examples
    of typical
    Ingredient conc. range
    type Ingredient % (w/w)
    Active Any one or more of the drug Any concentration
    Ingredients substances listed in Table 8 of drug substances
    in ranges listed
    in Table 8
    Solubilizer/ PCA-PVA-PEG 0.001-5%
    Preservative/
    Co-preservative
    Secondary SPAN ™ 60    0-1%
    solubilizer/ Pluronic F68    0-5%
    Co-solubilizer POE40Stearate    0-1%
    (may or may not CREMOPHOR EL ®    0-1%
    be required) Cyclodextrins   0-10%
    Osmolality Propylene glycol    0-2%
    agents (any one Glycerin  0-2.5%
    or two or more in Mannitol    0-5%
    combinations) Sodium chloride    0-1%
    Buffers (Any one Phosphate buffer 1-100 mM
    of the buffers Phosphate citrate buffer 1-100 mM
    listed) NaOH/Trolamine 1-100 mM
    Lactate buffer 1-100 mM
    Borate buffer 1-100 mM
    Borate citrate 1-100 mM
    NaOH or HCl for pH adjustment Q.S
    Preservatives None—Non preserved NA
    (Any one or in BAK 10-200 ppm
    combination) Purite 10-300 ppm
    Water QS
  • TABLE 10
    Examples of formulations containing PCA-PVA-PEG with non-
    aqueous components
    Ointment Micro-
    Examples Cream Examples emulsion
    Active Ingredients % (w/w)
    Any one or more of the drug Any concentration of drug substances
    substances listed in Table 8 in ranges listed in Table 8
    Excipients % (w/w)
    SOLUPLUS ® 0.1-5   0.1-3   0.1-3   0.67
    Water QSAD QSAD QSAD qs 100%
    Propylene glycol 10-15  5-20 — 2
    Glycerin — —  8-12
    Benzyl alcohol (preservative) 1-5 — —
    Isopropyl myristate — 10-25 —
    Carbopol 980 — 0.1-2% 0.1-2  
    NaOH/ — QS pH QS pH
    Trolamine 5.5-6.0 5.5-6.0
    SPAN ™ 60 1-5 — —
    Petrolatum 20-30 — —
    Stearyl alcohol 10-30 — 1-3
    Pluronic F68 — 0.1-2   —
    Stearic Acid — — 10-15
    Cetyl Alcohol — — 1-3
    Methyl/Propylparabens — — PP 0.05
    MP 0.1 
    Capmul 0.67
    CREMOPHOR EL ® 0.67
    Lipid
    Nanoparticle Emulsion
    Ingredients % (w/w)
    Active Ingredients Any concentration of drug substances in
    Any one or more of the drug ranges listed in
    substances listed in Table 8 Table 8
    Excipients % (w/w)
    Medium chain triglyceride 10-40 —
    Oleic acid      0-0.5% —
    Water QS —
    Castor Oil — 1.25
    SOLUPLUS ® 0.01-5   0.01-2
    Glycerin — 2
    Carbopol 980      0.1-1%  0.1-1
    Trolamine Qs ad Qs ad
  • Examples of formulation vehicle compositions with Soluplus® in Tables 11-17. All of the formulations disclosed in Tables 11-17 may include an active agent from Table 8.
  • TABLE 11
    Soluplus ® containing formulation vehicles with
    Boric acid buffer (Preservative-free)
    Concentration (% w/v)
    Ingredients Range Examples
    Soluplus ® 0.1-10  10.0 2.0 1.0 1.0 0.75 0.5 0.25 0.1
    (Polyvinyl
    caprolactame-
    polyvinyl acetate-
    polyethylene
    glycol graft
    copolymer)
    Boric Acid 0.1-1   0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
    Glycerin 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2
    1N NaOH/1N 5.0-8.2 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4
    HCl Qs to pH
    Water QS QS QS QS QS QS QS QS QS
  • TABLE 12
    Soluplus ® containing formulation vehicles with Boric acid buffer
    and Purite ® as preservative
    Concentration (% w/v)
    Ingredients Range Examples
    Soluplus ® 0.1-10 10.0 2.0 1.0 1.0 0.75 0.5 0.25 0.1
    (Polyvinyl caprolactame-
    polyvinyl acetate-
    polyethylene glycol graft
    copolymer)
    Boric Acid 0.1-1  0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6
    Glycerin 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2
    Purite ® 0.002-0.02  50 50 100 100 100 100 100 100
    1N NaOH/1N HCl pH 5.0-8.2 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4
    Qs to pH
    Water QS QS QS QS QS QS QS QS QS
  • TABLE 13
    Soluplus ® containing formulation vehicles with citrate-phosphate
    buffer (preservative-free)
    Concentration (% w/v)
    Ingredients Range Examples
    Soluplus ® 0.1-10  1.0 1.0 1.0 2.0 2.0 5.0 0.5 0.5
    (Polyvinyl caprolactame-
    polyvinyl acetate-
    polyethylene glycol graft
    copolymer)
    Sodium Phosphate 0.03-3   0.268 0.268 0.268 0.268 0.268 0.268 0.268 0.268
    Dibasic Heptahydrate
    Citric Acid 0.001-0.15  0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014
    Monohydrate
    Glycerin 0-3 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2
    Mannitol 0-5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
    1N NaOH/1N HCl 5.0-8.2 7.3 7.4 7.4 7.4 7.4 7.4 7.4 7.4
    Qs to pH
    Water QS QS QS QS QS QS QS QS
  • TABLE 14
    Soluplus ® containing formulation vehicles with citrate-phosphate
    buffer and Benzalkonium chloride (BAK) as preservative
    Concentration (% w/v)
    Ingredients Range Examples
    Soluplus ® 0.1-10  1.0 1.0 1.0 2.0 2.0 5.0 0.5 0.5
    (Polyvinyl caprolactame-
    polyvinyl acetate-
    polyethylene glycol graft
    copolymer)
    Benzalkonium Chloride 0.003-0.02  0.005 0.010 0.020 0.012 0.014 0.016 0.01 0.020
    Sodium Phosphate 0.03-3   0.268 0.268 0.268 0.268 0.268 0.268 0.268 0.268
    Dibasic Heptahydrate
    Citric Acid 0.001-0.15  0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014
    Monohydrate
    Glycerin 0-3 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2
    Mannitol 0-5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
    1N NaOH/1N HCl 5.0-8.2 7.3 7.4 7.4 7.4 7.4 7.4 7.4 7.4
    Qs to pH
    Water QS QS QS QS QS QS QS QS
  • TABLE 15
    Soluplus ® containing formulation vehicles with citrate-phosphate
    buffer, Benzalkonium chloride (BAK) as preservative and EDTA
    Concentration (% w/v)
    Ingredients Range Examples
    Soluplus ® 0.1-10  1.0 1.0 1.0 2.0 2.0 5.0 0.5 0.5
    (Polyvinyl caprolactame-
    polyvinyl acetate-
    polyethylene glycol graft
    copolymer)
    Benzalkonium Chloride 0.003-0.02  0.005 0.010 0.020 0.012 0.014 0.016 0.01 0.020
    Edetate Disodium   0-0.05 0.01 0.01 0.01 0.01 0.01 0.01 0.005 0.005
    Sodium Phosphate 0.03-3   0.268 0.268 0.268 0.268 0.268 0.268 0.268 0.268
    Dibasic Heptahydrate
    Citric Acid 0.001-0.15  0.014 0.014 0.014 0.014 0.014 0.014 0.014 0.014
    Monohydrate
    Glycerin 0-3 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2
    Mannitol 0-5 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
    1N NaOH/1N HCl 5.0-8.2 7.3 7.4 7.4 7.4 7.4 7.4 7.4 7.4
    Qs to pH
    Water QS QS QS QS QS QS QS QS
  • TABLE 16
    Examples of Emulsion Vehicles with Soluplus (Preservative-Free)
    Concentration (% w/v or % w/w)
    Ingredients Range Examples
    Castor Oil 0.1-10  0.25 0.5 1.25 1.25 0.25 0.5 1.25 0.25 0.5 1.25
    Polysorbate 80 0-2 0 0 0 0 0.25 0.5 0.5 0 0 0
    Solutol ® 0-5 0 0.5 0.5 1 0.25 0.5 0.5 0 0 0
    Polyoxyethylene 0-5 0.25 0.5 0.5 1 0 0 0 0.5 1 2
    40 Stearate
    Soluplus ® 0.01-2   0.25 0.5 2 2 0.5 0.5 1.0 1 2 2
    (Polyvinyl
    caprolactame-
    polyvinyl acetate-
    polyethylene glycol
    graft copolymer)
    Glycerin 0.5-3   2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
    Carbopol 980 0.1-1   0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1
    Trolamine or QS QS to pH 6 to 8
    NaOH
    Water QS to QS QS QS QS QS QS QS QS QS QS
    100%
  • TABLE 17
    Examples of Emulsion Vehicles with Soluplus (Preserved with
    Purite, Benzalkonium chloride or combination). Any of the vehicles in Table 6
    with the following ingredients as preservatives
    Concentration
    Ingredients Range Examples
    Purite 50-200 ppm 50 100 200 50 50 100 100 0 0 0
    Benzalkonium 10-200 ppm 0 0 0 20 50 20 200 50 100 200
    chloride
    Any of the QS to 100% w/v or % w/w
    vehicles from
    Table 6
    • Example 8
  • Some topical ophthalmic compositions comprise a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer.
    • Example 9
  • In some compositions of Example 8, the polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer has an average molecular weight of about 10,000 g/mol to about 500,000 g/mol.
    • Example 10
  • Some compositions of Example 8 or 9 further comprise a therapeutically active agent.
    • Example 11
  • In some compositions of Example 10, the therapeutically active agent comprises an immunosuppressant.
    • Example 12
  • In some compositions of Example 10, the therapeutically active agent comprises an alpha-adrenergic antagonist.
    • Example 13
  • In some compositions of Example 10, the therapeutically active agent comprises a prostaglandin EP2 agonist.
    • Example 14
  • In some compositions of Example 10, the therapeutically active agent comprises a muscarinic.
    • Example 15
  • In some compositions of Example 10, the therapeutically active agent comprises a prostaglandin.
    • Example 16
  • In some compositions of Example 10, the therapeutically active agent comprises an alpha agonist.
    • Example 17
  • In some compositions of Example 10, the therapeutically active agent comprises an antibiotic.
    • Example 18
  • In some compositions of Example 10, the therapeutically active agent comprises an anti-infective agent.
    • Example 19
  • In some compositions of Example 10, the therapeutically active agent comprises an anti-inflammatory.
    • Example 20
  • In some compositions of Example 10, the therapeutically active agent comprises a beta blocker.
    • Example 21
  • In some compositions of Example 10, the therapeutically active agent comprises cyclosporine A.
    • Example 22
  • In some compositions of Example 10, the therapeutically active agent comprises a cyclosporine analog.
    • Example 23
  • In some compositions of Example 10, the therapeutically active agent comprises phentolamine.
    • Example 24
  • In some compositions of Example 10, the therapeutically active agent comprises testosterone.
    • Example 25
  • In some compositions of Example 10, the therapeutically active agent comprises dexamethasone.
    • Example 26
  • In some compositions of Example 10, the therapeutically active agent comprises prednisolone.
    • Example 27
  • In some compositions of Example 10, the therapeutically active agent comprises bimatoprost.
    • Example 28
  • In some compositions of Example 10, the therapeutically active agent comprises latanoprost.
    • Example 29
  • In some compositions of Example 10, the therapeutically active agent comprises Compounds A or B of Table 8.
    • Example 30
  • In some compositions of Example 10, the therapeutically active agent comprises pilocarpine.
    • Example 31
  • In some compositions of Example 10, the therapeutically active agent comprises brimonidine.
    • Example 32
  • In some compositions of Example 10, the therapeutically active agent comprises Compound C of Table 8.
    • Example 33
  • In some compositions of Example 10, the therapeutically active agent comprises Compound D of Table 8.
    • Example 34
  • In some compositions of Example 10, the therapeutically active agent comprises Compound E of Table 8.
    • Example 35
  • In some compositions of Example 10, the therapeutically active agent comprises Compound F or G of Table 8.
    • Example 36
  • In some compositions of Example 10, the therapeutically active agent comprises gatifloxacin.
    • Example 37
  • In some compositions of Example 10, the therapeutically active agent comprises ketorolac.
    • Example 38
  • In some compositions of Example 10, the therapeutically active agent comprises a steroid.
    • Example 39
  • In some compositions of Example 10, the therapeutically active agent comprises timolol.
    • Example 40
  • In some compositions of Example 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, or 39, the composition is a solution.
    • Example 41
  • Some compositions of Example 40 further comprise a co-solubilizer.
    • Example 42
  • In some compositions of Example 41, the co-solubilizer comprises sorbitan monostearate.
    • Example 43
  • In some compositions of Example 41, the co-solubilizer comprises a polyoxyethylene-polyoxypropylene block copolymer.
    • Example 44
  • In some compositions of Example 41, the co-solubilizer comprises polyoxyethyleneglyceroltriricinoleate 35.
    • Example 45
  • In some compositions of Example 41, the co-solubilizer comprises a cyclodextrin.
    • Example 46
  • Some compositions of Example 40, 41, 42, 43, 44, or 45 further comprise an osmolality agent.
    • Example 47
  • In some compositions of Example 46, the osmolality agent comprises propylene glycol.
    • Example 48
  • In some compositions of Example 46, the osmolality agent comprises glycerin.
    • Example 49
  • In some compositions of Example 46, the osmolality agent comprises mannitol.
    • Example 50
  • In some compositions of Example 46, the osmolality agent comprises sodium chloride.
    • Example 51
  • Some compositions of Example, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 further comprise a buffer.
    • Example 52
  • In some compositions of Example 51, the buffer comprises phosphate.
    • Example 53
  • In some compositions of Example 51, the buffer comprises phosphate and citrate.
    • Example 54
  • In some compositions of Example 51, the buffer comprises trolamine.
    • Example 55
  • In some compositions of Example 51, the buffer comprises lactate.
    • Example 56
  • In some compositions of Example 51, the buffer comprises borate.
    • Example 57
  • In some compositions of Example 51, the buffer comprises borate and citrate.
    • Example 58
  • Some compositions of Example, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, or 57 further comprise a preservative.
    • Example 59
  • In some compositions of Example 58, the preservative comprises benzalkonium chloride.
    • Example 60
  • In some compositions of Example 58, the preservative comprises a stabilized oxychloro complex.
    • Example 61
  • A method of solubilizing a therapeutically active agent comprising mixing the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition according to any of Examples 10-60 is formed.
    • Example 62
  • A method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent with a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer to thereby improve stability of the therapeutically active agent.
    • Example 63
  • A method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition according to any of Examples 10-60 is formed.
    • Example 64
  • A method of treating a disease affecting an eye comprising administering a composition according to any Examples 8-60 to an eye in need thereof.
    • Example 65
  • A 65 year old Caucasian male suffering from elevated intraocular pressure applies one drop per day of Formula 2 of Table 18 in each eye for a period of 60 days. The patient experiences a significant drop in IOP almost immediately which persists for the entire 60 days of treatment wherein his intraocular pressure levels drop to acceptable levels.
  • TABLE 18
    Formulation #
    1 2 8
    Ingredient (% w/v)
    Bimatoprost 0.01 0.01 0.01
    Brimonidine (190342-LF) 0.1 0.1 0.1
    Soluplus 1 1 1
    Sodium phosphate 0.268 0.268
    dibasic heptahydrate
    Citric acid monohydrate 0.014 0.014
    Sodium borate 0.095
    decahydrate
    Boric acid 0.229
    NaCl 0.8
    Glycerin 2.3 2.3
    BAK 0.005 0.01
    Purite 0.01
    Target pH pH 7.7 ± 0.3
    Purified Water Q.S. to 100
    APET Criteria Met
    USP Pass Pass Pass
    Ph Eur B Pass Pass Pass
    Ph Eur A Pass Fail Pass
    • Example 66
  • A 71 year old African American woman suffering from elevated intraocular pressure and open-angle glaucoma applies one drop daily in each eye of Formula 4 from Table 19. After 30 days, her symptoms of glaucoma improve significantly and her intraocular pressure falls to normal levels and without significant side effects so long as she continued daily application of Formula 4 of Table 19.
  • TABLE 19
    Active Formulation #
    1 2 3 4 5 6
    Ingredient (% w/v)
    Compound D Of Table 8 0.4 0.4 0.4 0.4 0.4 0.4
    Soluplus 1 1 1 1 1 2
    BAK 0 0.005 0.010 0.015 0.020 0.020
    Edetate Disodium 0.01 0.01 0.01 0.01 0.01 0.01
    Citric Acid Monohydrate 0.13 0.13 0.13 0.13 0.13 0.13
    Sodium Phosphate Dibasic 0.2 0.2 0.2 0.2 0.2 0.2
    Heptahydrate
    Glycerin 2.2 2.2 2.2 2.2 2.2 2.2
    Target pH pH 5.4
    Purified Water Q.S. to 100
    APET Criteria Met
    USP Pass Pass Pass Pass Pass Pass
    Ph Eur B Pass Pass Pass Pass Pass Pass
    Ph Eur A Fail Fail Fail Fail Pass Pass
  • A 41 year old Caucasian female is suffering from symptoms of dry eye, applies twice daily Formulation 2 in Table 20 in each eye. After two days of application, the symptoms of dry eye improve significantly.
  • TABLE 20
    Formulation #
    1 2
    Ingredient (% w/v)
    Soluplus 2 5
    Boric Acid 0.6 0.6
    Glycerin 2 2
    Target pH pH 7.4
    Purified Water Q.S. to 100
    APET Criteria Met
    USP Pass Pass
    Ph Eur B Pass Pass
    Ph Eur A Fail Fail
  • Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
  • The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of any claim. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
  • Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
  • Certain embodiments are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than specifically described herein. Accordingly, the claims include all modifications and equivalents of the subject matter recited in the claims as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is contemplated unless otherwise indicated herein or otherwise clearly contradicted by context.
  • In closing, it is to be understood that the embodiments disclosed herein are illustrative of the principles of the claims. Other modifications that may be employed are within the scope of the claims. Thus, by way of example, but not of limitation, alternative embodiments may be utilized in accordance with the teachings herein. Accordingly, the claims are not limited to embodiments precisely as shown and described.

Claims (20)

What is claimed is:
1. A topical ophthalmic composition comprising a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer.
2. The composition of claim 1, wherein the polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer has an average molecular weight of about 10,000 g/mol to about 500,000 g/mol.
3. The composition of claim 1 or 2, further comprising a therapeutically active agent.
4. The composition of claim 3, wherein the therapeutically active agent comprises an immunosuppressant, an alpha-adrenergic antagonist, a steroid, a prostaglandin EP2 agonist, a muscarinic, a prostaglandin, an alpha agonist, an antibiotic, an anti-infective agent, an anti-inflammatory, a beta blocker, or a combination thereof.
5. The composition of claim 3, wherein the therapeutically active agent comprises one selected from the group consisting of cyclosporine A, a cyclosporine analog, phentolamine, testosterone, dexamethasone, prednisolone, bimatoprost, latanoprost, Compounds A. B, C, D, E, F, G, or H of Table 8, pilocarpine, brimonidine, gatifloxacin, ketorolac, a steroid, timolol, or a combination thereof.
6. The composition of claim 5, wherein the composition is a solution.
7. The composition of claim 6, further comprising a co-solubilizer.
8. The composition of claim 7, wherein the co-solubilizer comprises sorbitan monostearate, a polyoxyethylene-polyoxypropylene block copolymer, polyoxyethyleneglyceroltriricinoleate 35, a cyclodextrin, or a combination thereof.
9. The composition of claim 6, further comprising an osmolality agent.
10. The composition of claim 9, wherein the osmolality agent comprises propylene glycol, glycerin, mannitol, sodium chloride, or a combination thereof.
11. The composition of claim 10, further comprising a buffer.
12. The composition of claim 11, wherein the buffer comprises phosphate, phosphate and citrate, trolamine, lactate, borate, borate and citrate, or a combination thereof.
13. The composition of claim 10 further comprising a preservative.
14. The composition of claim 13, wherein the preservative comprises benzalkonium chloride, a stabilized oxychloro complex, or a combination thereof.
15. A method of solubilizing a therapeutically active agent comprising providing a composition comprising the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer, wherein the therapeutically active agent is not completely soluble in the composition at room temperature without the polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer.
16. A method of solubilizing a therapeutically active agent comprising mixing the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition according to claims 5 is formed.
17. A method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent with a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer to thereby improve stability of the therapeutically active agent.
18. A method of stabilizing a therapeutically active agent comprising combining the therapeutically active agent and a polyvinyl capralactam-polyvinyl acetate-polyethylene glycol graft copolymer so that a composition according to claim 5 is formed.
19. A method of treating a disease affecting an eye comprising administering a composition according to claim 11 to an eye in need thereof wherein one of the active agents is bimatoprost.
20. The method of claim 19 further comprising the active agent brimonidine.
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