WO2018036523A1 - 唑类化合物眼用制剂 - Google Patents

唑类化合物眼用制剂 Download PDF

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WO2018036523A1
WO2018036523A1 PCT/CN2017/098662 CN2017098662W WO2018036523A1 WO 2018036523 A1 WO2018036523 A1 WO 2018036523A1 CN 2017098662 W CN2017098662 W CN 2017098662W WO 2018036523 A1 WO2018036523 A1 WO 2018036523A1
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ophthalmic preparation
ophthalmic
compound
preparation
eye
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PCT/CN2017/098662
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English (en)
French (fr)
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郑钦元
加帕尔责祎旦
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上海毕傲图生物科技有限公司
郑钦元
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Application filed by 上海毕傲图生物科技有限公司, 郑钦元 filed Critical 上海毕傲图生物科技有限公司
Priority to KR1020197008376A priority Critical patent/KR20190052005A/ko
Priority to CN201780051907.2A priority patent/CN109689049B/zh
Priority to SG11201901617PA priority patent/SG11201901617PA/en
Priority to CA3034766A priority patent/CA3034766A1/en
Priority to EP17842945.2A priority patent/EP3505170B1/en
Priority to AU2017317154A priority patent/AU2017317154B2/en
Priority to EA201990550A priority patent/EA201990550A1/ru
Priority to US16/327,238 priority patent/US20190192427A1/en
Priority to JP2019531514A priority patent/JP6890794B2/ja
Publication of WO2018036523A1 publication Critical patent/WO2018036523A1/zh
Priority to US17/367,863 priority patent/US20210330586A1/en

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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/41—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
    • 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
    • A61K31/41—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
    • 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
    • A61K31/41—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
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the present invention relates to the field of ocular medicines, and in particular, the invention discloses an ophthalmic preparation form of an azole compound, and the use thereof for treating or preventing an ocular lens disease such as a cataract.
  • Cataract is a common blinding eye disease with blurred vision and reduced vision. Among the 40 million to 45 million blind people in the world, 60% are blind due to cataract. Cataract occurs in the ocular lens. Due to aging, genetics, local dystrophies, immune and metabolic abnormalities, trauma, radiation and other factors, the individual's individual crystal metabolism is disordered, resulting in the wrong accumulation of lens protein denaturation, which affects the light entering the eye. The retina is ultimately characterized by blurred vision or even complete loss of vision (Bloemendal, de Jong et al. 2004).
  • cataracts The incidence of cataract is not limited to humans, and many mammalian species (horses, dogs, monkeys, etc.) can develop cataracts (Chauke, Magwebu et al. 2016; Sande, Alvarez et al. 2016). Cataracts can be divided into senile cataracts, congenital cataracts, traumatic cataracts, and complicated cataracts according to different causes. At present, there is no clinical drug that can effectively treat cataract, and the affected individual can only improve the vision by replacing the artificial lens by surgery.
  • An azole compound is a class of five-membered heterocyclic compounds including a nitrogen atom and at least one non-carbon atom. Due to the acceptable toxicity of humans, azoles have been used in mammalian antifungal treatments. As early as the 1980s, ketoconazole was used for oral treatment of systemic fungal infections. With the discovery and synthesis of more azole compounds, their antibacterial spectrum is more extensive, and the corresponding pharmacokinetic properties and safety are more suitable for clinical use (Maertens JA, 2004). To date, the FDA has approved multiple azole compounds for clinical antifungal use (http://www.fda.gov/default.htm).
  • the present invention is the first to confirm the effect of an azole compound on the treatment and prevention of ocular lens diseases such as ocular cataract in a mammal.
  • Another object of the present invention is to provide the use of the formulation, especially an ophthalmic formulation, for the treatment or prevention of cataracts in human or non-human mammals.
  • a non-invasive administration ophthalmic preparation characterized in that the ophthalmic preparation comprises: (a) a pharmaceutically acceptable carrier, and (b) An azole compound as a first active ingredient;
  • the concentration of the azole compound in the ophthalmic preparation is 0.005 to 400 ⁇ M.
  • the azole compound is selected from the group consisting of:
  • Econazole isoconazole, bifonazole, clotrimazole, aripiprazole, ketoconazole, fluconazole, phenylimidazole, miconazole, cyclosporin, triazolol, tebuconazole, Propiconazole, VFV, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof, or a combination thereof.
  • the VFV is (R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl )-4-(5-phenyl-1,3,4-oxadiazolidine-2-yl)benzamide ((R)-N-(1-(3,4'-difluorobiphenyl-4-yl)) 2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide) or a pharmaceutically acceptable salt or ester thereof.
  • all or substantially all of the azole compound is dissolved in the ophthalmic formulation.
  • the "all or substantially all” means 90-100%, preferably 95-100%, more preferably 99-100%.
  • the concentration of the azole compound in the ophthalmic preparation is from 0.01 to 200 ⁇ M, preferably from 0.025 to 100 ⁇ M, more preferably from 0.05 to 50 ⁇ M; most preferably from 0.5 to 10 ⁇ M.
  • the concentration of the azole compound is about 5-8 ⁇ M.
  • the concentration of the azole compound is 7 ⁇ M.
  • the azole compound is econazole.
  • the ophthalmic preparation is selected from the group consisting of eye drops, emulsions, gels, eye ointments, sustained release microspheres, intraocular sustained release grafts, and ocular sustained release drug films.
  • the eye drops are in the form of a solution.
  • the eye drops are in the form of an emulsion.
  • the ophthalmic formulation is a homogeneous solution.
  • the ophthalmic formulation further comprises a solid pharmaceutical dosage form reconstitutable into a liquid (ie, the dosage form can be directly reconstituted into a liquid form after the addition of a liquid pharmaceutically acceptable carrier. Ophthalmic preparation).
  • the liquid pharmaceutically acceptable carrier is water.
  • the ophthalmic preparation further comprises: (c) a second active ingredient, wherein the The second active ingredient is selected from the group consisting of steroids, glucocorticoids, antibiotics, or combinations thereof.
  • the second active ingredient is a lanosterol compound.
  • the lanosterol compound has a concentration of 10 to 200 mM, preferably 15 to 150 mM, more preferably 20 to 50 mM; most preferably 20 to 30 mM.
  • the lanosterol compound is selected from the group consisting of:
  • the lanosterol compound is lanosterol.
  • the lanosterol compound is dihydro lanosterol.
  • the lanosterol compound is a mixture of lanosterol and dihydrolanosterol.
  • the mixture of lanosterol and dihydrolanosterol has a ratio C1 to C2 of lanosterol content C1 to dihydrolanosterol content C2 of 1:500 to 500:1. Ground 5:90 to 500:1, more preferably 80:1 to 200:1, optimally 85:1 to 100:1.
  • the glucocorticoid compound is selected from the group consisting of dexamethasone, hydrocortisone, or a combination thereof.
  • the antibiotic is selected from the group consisting of tobramycin, gentamicin sulfate, chlortetracycline, chloramphenicol, or a combination thereof.
  • the second active ingredient in the ophthalmic formulation, is in a dissolved form.
  • the second active ingredient is present in the ophthalmic formulation in an amount of from 0.01 to 15% by weight, preferably from 0.5 to 3% by weight, based on the total weight of the ophthalmic preparation.
  • the pharmaceutically acceptable carrier is non-irritating to the eye.
  • the pharmaceutically acceptable carrier comprises one or more carriers selected from the group consisting of:
  • the solubilizing agent comprises: a polyhydroxy compound.
  • the ratio of the amount of the polyhydroxy compound to the first active ingredient is 1:40000-1:1.
  • the polyhydroxy compound is selected from the group consisting of polyhydric alcohols, cyclodextrins, polyvinyl alcohol, or combinations thereof.
  • the polyhydroxy compound has a skeleton composed of carbon, hydrogen, and a hetero atom such as N, and the reactive group is substantially or wholly a hydroxyl group.
  • the polyhydroxy compound includes an alcohol polyhydroxy compound (such as a C2-C10 polyol), and a cyclodextrin and a cyclodextrin derivative.
  • an alcohol polyhydroxy compound such as a C2-C10 polyol
  • a cyclodextrin and a cyclodextrin derivative such as a C2-C10 polyol
  • the polyhydroxy compound is selected from the group consisting of: polyene glycol, glycerol, polyethylene glycol, ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, cyclodextrin derivative, polyvinyl alcohol (PVA), or a combination thereof.
  • the polyhydroxy compound is hydroxypropyl- ⁇ -cyclodextrin.
  • the surfactant is selected from the group consisting of an anionic surfactant, a cationic surfactant, a nonionic surfactant, a chaotropic surfactant, or a combination thereof.
  • the nonionic surfactant is selected from the group consisting of: Tween, Span, fatty acid glycerides, polyoxyethylenes, polyoxyethylene-polyoxypropylene copolymers, or combinations thereof.
  • the thickener is selected from the group consisting of chitosan, hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), povidone (PVP), gelatin, carboxymethyl Sodium cellulose (CMC-Na) or a combination thereof.
  • the thickening agent is chitosan.
  • the osmotic pressure adjusting agent is selected from the group consisting of a saccharide compound, a salt compound, or a combination thereof.
  • the saccharide compound is selected from the group consisting of sorbitol, glucose, mannitol, or a combination thereof.
  • the salt compound is selected from the group consisting of sodium chloride, potassium chloride, boric acid, or a combination thereof.
  • the buffer is selected from the group consisting of: phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, ammonium acetate buffer, or a combination thereof.
  • the preservative is selected from the group consisting of: benzalkonium bromide, chlorobutanol, a paraben, sorbic acid, an antibiotic or a combination thereof; preferably, the preservative is present in an amount of 0. -1wt%;
  • the ophthalmic formulation contains no preservatives.
  • the chelating agent is selected from the group consisting of: EDTA, EGTA, CDTA, citrate, or a combination thereof; preferably the chelating agent is present in an amount of from 0 to 0.1% by weight;
  • the ophthalmic formulation comprises: a polyhydroxy compound, an optional surfactant, and optionally a thickening agent,
  • the content of the polyhydroxy compound is from 0.1 to 50% by weight
  • the content of the surfactant is 0-2% by weight
  • the content of the thickener is from 0 to 6% by weight.
  • the content of the polyhydroxy compound is from 25 to 40% by weight.
  • the surfactant is contained in an amount of from 0.1 to 1% by weight.
  • the thickener is present in an amount of from 0.1 to 5% by weight.
  • the ophthalmic formulation has an osmotic pressure of 240 to 510 mOsm.
  • the ophthalmic formulation has a pH of from 5.5 to 8.5, preferably from 6.0 to 8.0, more preferably from 6.5 to 7.5.
  • the ophthalmic formulation is an aqueous solution for ocular administration.
  • the ophthalmic preparation is an aqueous solution for ocular administration, and the concentration of the lanosterol compound in the solution is 10 to 200 mM, preferably 15 to 150 mM, more preferably 20 to 50 mM. Optimally 20 to 30 mM.
  • the ophthalmic formulation contains the following ingredients:
  • a polyhydroxy compound preferably propylene glycol or ⁇ -cyclodextrin
  • solubilizing agent preferably polysorbate
  • 0.2-0.4 wt% thickener preferably chitosan
  • preservative preferably chloramphenicol
  • the ophthalmic preparation has a pH of about 6.5-7.5 and an osmotic pressure of 240-510 mOsm.
  • the (a) pharmaceutically acceptable carrier; and (b) the azole compound as the first active ingredient and (c) the second active ingredient are included
  • the mixing is carried out to form an ophthalmic preparation provided by the first aspect of the invention.
  • the method comprises:
  • step (ii) the remaining pharmaceutically acceptable carrier is first mixed to form a second solution or a second dispersion, and then the first dispersion and the second dispersion are The solution or the second dispersion is mixed to prepare an ophthalmic preparation provided by the first aspect of the invention.
  • the solvent of the second solution is water.
  • the solute of the second solution is selected from the group consisting of a solubilizer, a surfactant, a thickener, an osmotic pressure regulator, a buffer, a preservative, a chelating agent, a sustained release agent, or combination.
  • ophthalmic preparation provided by the first aspect of the invention, wherein the ophthalmic preparation is for the preparation of a prophylactic or therapeutic eye of a human or non-human mammal A drug for a lens disease such as cataract, presbyopia, or a combination thereof.
  • the non-human mammals include horses, dogs, cats, pandas, monkeys, orangutans, rodents, rabbits, elephants, tigers.
  • the rodent comprises a mouse or a rat.
  • the cataract is selected from the group consisting of senile cataract, congenital cataract, traumatic cataract, and complicated cataract.
  • the cataract is a traumatic cataract.
  • the patient with presbyopia is a person older than 48 years (preferably ⁇ 60 years).
  • a method of preventing or treating an ocular lens disease such as a cataract comprising: non-invasively administering an ophthalmic preparation provided by the first aspect of the invention to an eye of a subject in need thereof.
  • the ocular lens disease is selected from the group consisting of cataract, presbyopia, or a combination thereof.
  • non-invasive administration means dripping into the eye.
  • the present invention provides a method for preventing or treating an ocular lens disease such as a cataract comprising orally administering an oral preparation of the present invention to an eye of a subject in need thereof, or administering the injection form of the present invention.
  • the oral preparation or the injection form contains (a1) a pharmaceutically acceptable carrier, and (b1) the above-mentioned azole compound as a first active ingredient; wherein the azole compound in the preparation The concentration is from 0.01 to 90% by weight.
  • Figure 1 shows the therapeutic effect of an ophthalmic preparation in one embodiment of the present invention.
  • the results showed that the treatment group containing the azole compound econazole and lanosterol was far superior to the lanosterol group and the PBS solvent control group.
  • a non-invasive ophthalmic preparation containing a specific compound i.e., an azole compound
  • a specific compound i.e., an azole compound
  • an additional active ingredient such as a lanosterol compound
  • the present invention provides an ophthalmic preparation which not only successfully satisfies the special requirements of ocular medications by selecting suitable pharmaceutical compositions (such as lanosterol compounds, polyhydroxy compounds, surfactants, thickeners, etc.) (eg Osmotic pressure) also significantly increases or increases the concentration of the active ingredient.
  • suitable pharmaceutical compositions such as lanosterol compounds, polyhydroxy compounds, surfactants, thickeners, etc.
  • Osmotic pressure also significantly increases or increases the concentration of the active ingredient.
  • the ophthalmic preparation of the present invention comprises a pharmaceutically acceptable carrier and an effective amount of an azole compound as an active ingredient, and the concentration of the dissolved (i.e., free) azole compound is from 0.005 to 400 ⁇ M based on the total volume of the preparation.
  • the ophthalmic preparation of the present invention comprises water or an aqueous solvent and an active ingredient dissolved in the solvent. And the following components: lanosterol compounds, polyhydroxy compounds, optional surfactants and optionally thickeners.
  • the ophthalmic formulation may also optionally contain other pharmaceutically acceptable components including, but not limited to, osmotic pressure adjusting agents, buffering agents, preservatives, chelating agents, sustained release. Agents, etc.
  • first active ingredient or “azole compound” are used interchangeably and refer to an azole compound.
  • the active ingredient of the present invention may be various crystalline forms, amorphous, anhydrate, solvate, hydrate, enantiomer of a pharmaceutically acceptable azole compound, and the azole compound in the present invention refers to the first aspect of the present invention. Active ingredient.
  • Econazole belongs to the five-membered heterocyclic compound and has the following structural formula:
  • the inventors' research has shown that the use of a specific formulation can make econazole a very effective therapeutic effect on cataracts while maintaining a high concentration in the eye.
  • second active ingredient refers to a steroid compound, a glucocorticoid compound, an antibiotic, or a combination thereof.
  • the second active ingredient may be in a dissolved form.
  • the second active ingredient is contained in an amount of from 0.01 to 20% by weight, preferably from 5 to 15% by weight, based on the total of the ophthalmic preparation.
  • the concentration thereof is preferably 10 to 200 mM, preferably 15 to 150 mM, more preferably 20 to 50 mM; most preferably 20 to 30 mM.
  • the above steroid compound is selected from the group consisting of (i) lanosterol, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof; (ii) dihydrolanosterol, or a pharmaceutically acceptable salt thereof Or a pharmaceutically acceptable ester thereof; (iii) 25-hydroxycholesterol, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable ester thereof; (iiii) the above component (i) and/or (ii) a combination of ) and / or (iii).
  • the glucocorticoid compound of the present invention is selected from the group consisting of dexamethasone, hydrocortisone, or a combination thereof.
  • the antibiotic of the present invention is selected from the group consisting of tobramycin, gentamicin sulfate, chlortetracycline, chloramphenicol, or a combination thereof.
  • polyhydroxy compound refers to a compound having two or more hydroxyl groups in the molecule.
  • the present inventors have unexpectedly discovered that when the polyhydroxy compound is used in combination with an azole compound, on the one hand, the water solubility of the azole compound and the stability of the drug can be improved, and on the other hand, the azole compound is not adversely affected. . In addition, it also helps to increase the residence time of the first active ingredient in the eye, thereby further improving the therapeutic effect of treating cataract.
  • the polyhydroxy compound preferably has a skeleton composed of carbon, hydrogen and a hetero atom such as N, and the reactive group is substantially or wholly a hydroxyl group.
  • the polyhydroxy compound includes an alcohol polyhydroxy compound (such as a C2-C10 polyol), and a cyclodextrin and a cyclodextrin derivative.
  • an alcohol polyhydroxy compound such as a C2-C10 polyol
  • a cyclodextrin and a cyclodextrin derivative such as a C2-C10 polyol
  • the polyhydroxy compound is selected from the group consisting of propylene glycol, glycerol, polyethylene glycol, modified or unmodified cyclodextrin, and derivatives thereof, or combinations thereof.
  • the polyhydroxy compound is hydroxypropyl- ⁇ -cyclodextrin.
  • the amount of the polyhydroxy compound may vary depending on the form of the preparation, the usage, and the type of the compound.
  • the amount (or content) of the polyhydroxy compound in the aqueous solution of the azole compound is generally from 0.1 to 50% by weight, as in the present invention. Between 1 and 15% by weight of propylene glycol, or 20 to 50% by weight of cyclodextrin may be used.
  • the ophthalmic preparation may further contain other pharmaceutically acceptable carriers, including, but not limited to, surfactants, thickeners, osmotic pressure adjusting agents, Buffer, preservative, chelating agent, sustained release agent.
  • other pharmaceutically acceptable carriers including, but not limited to, surfactants, thickeners, osmotic pressure adjusting agents, Buffer, preservative, chelating agent, sustained release agent.
  • the surfactant is selected from the group consisting of an anionic surfactant, a cationic surfactant, a nonionic surfactant, a chaotropic surfactant, or a combination thereof.
  • the nonionic surfactant is selected from the group consisting of: Tween, Span, fatty acid glycerides, polyoxyethylenes, polyoxyethylene-polyoxypropylene copolymers, or combinations thereof.
  • the amount (or content) of the surfactant is generally from 0 to 2% by weight, more preferably from 0.1 to 1% by weight.
  • Thickeners can be used to increase the viscosity of the system to maintain a uniform, stable suspension or turbid state.
  • the invention increases the retention time of the drug in the eye by adding an appropriate amount of thickener, thereby increasing the absorption of the effective component azole compound in the eye.
  • the thickener is preferably chitosan, hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), and povidone (PVP), gelatin, sodium carboxymethylcellulose (CMC) -Na) and so on.
  • the thickener is used in an amount (or content) of from 0 to 6 wt%, preferably from 0.1 to 5 wt%.
  • the ophthalmic formulations of the present invention may also contain additional pharmaceutically acceptable carriers including, but not limited to, osmotic pressure adjusting agents, buffering agents, preservatives, chelating agents, sustained release agents.
  • additional pharmaceutically acceptable carriers including, but not limited to, osmotic pressure adjusting agents, buffering agents, preservatives, chelating agents, sustained release agents.
  • the proper addition of a certain amount of a chelating agent, such as EDTA, can increase the stability of the formulation.
  • a chelating agent such as EDTA
  • concentration of the chelating agent ranges from 0 to 0.05% by weight.
  • the kind and amount of the additional pharmaceutically acceptable carrier are not particularly limited as long as the dissolution or therapeutic activity of the active ingredient is not affected.
  • these other pharmaceutically acceptable carriers are present in a total amount of from 0.1 to 80% by weight, preferably from 1 to 50% by weight.
  • ophthalmic formulations of the present invention can be prepared by conventional equipment and methods in accordance with the pharmaceutical compositions and ratios provided by the methods of the present invention. Including the following methods:
  • Method 1 (a) a pharmaceutically acceptable carrier; and (b) an azole compound as a first active ingredient are mixed to form an ophthalmic preparation of the present invention.
  • Method 2 (a) a pharmaceutically acceptable carrier; and (b) an azole compound as a first active ingredient and (c) a second active ingredient to form an ophthalmic preparation of the present invention.
  • the remaining pharmaceutically acceptable carrier may also be first mixed to form a second solution or a second dispersion, and then the first dispersion and the second solution or second The dispersions are mixed to form an ophthalmic preparation of the present invention.
  • eye drops it can be prepared according to any of the above three methods, pH is adjusted, and sterilized and filled in a suitable container.
  • An aqueous solution for ocular administration prepared as described above can be used for topical administration to the eye.
  • the ophthalmic preparation of the present invention can be used for the prevention or treatment of ocular lens diseases of human or non-human mammals, such as cataracts and presbyopia.
  • Representative cataracts are selected from the group consisting of senile cataracts, congenital cataracts, traumatic cataracts, and complicated cataracts.
  • the non-human mammal includes, but is not limited to, a pet (such as a dog, a cat), a domestic animal (such as a cow, a sheep, a horse, a pig), various zoo animals (a panda, a large Like).
  • a pet such as a dog, a cat
  • a domestic animal such as a cow, a sheep, a horse, a pig
  • various zoo animals a panda, a large Like.
  • the usage and amount of the preparation are not limited, and may be adjusted depending on the condition of the patient and the type of cataract.
  • the above adjustments can be made by those skilled in the art by combining the symptoms of the patient with the prior art and common knowledge in the art.
  • the drug component is stable, and it is not easy to deteriorate even after being placed for a long time, and is convenient to store, and is very suitable for being made into a commercially available drug.
  • the selected first active ingredient azole compound is an FDA approved molecular molecule, so the discovery of this use can quickly enter the clinical phase II experiment, which is beneficial to shorten the development time and reduce the research and development costs.
  • the physical solubilization means such as ultrasonic, heating, etc. can be used in the preparation process.
  • the above 7 ⁇ M econazole eye drops were administered three times a day, morning, and evening, at intervals of at least 5 hours.
  • the drug was administered to a cataract dog caused by trauma.
  • a total of 9 cataract patients were involved in the test.
  • the administration method was direct addition of the eye to ensure that the drug was completely dripped into the eye.
  • the ophthalmic solution of the invention is uniform, non-suspension, white liquid, completely aqueous phase, the co-solvent is cyclodextrin, preferably hydroxypropyl- ⁇ -cyclodextrin, the concentration of econazole is 7 ⁇ M, and the whole eye drops are internal No white particles insoluble in the aqueous phase were observed.
  • the physical solubilization means such as ultrasonic, heating, etc. can be used in the preparation process.
  • the above pharmaceutical preparations are administered three times a day, morning, and evening, at intervals of at least 5 hours.
  • the drug is administered to a dog that causes cataract for various reasons, and the administration method is direct addition of the eye to ensure that the drug is completely dropped into the eye.
  • Each treated dog received one drop per eye, about 50 microliters, for 8 weeks. give Do not take statin molecules at the same time.
  • the opacity of the lens is observed using a slit lamp, and the lens opacity is generally classified into a 0-V phase.
  • Phase 0 - the lens is transparent
  • Stage I the surrounding cortex of the lens is scattered in small vacuoles
  • Stage III another part of the cortical opacity
  • Stage IV lens nucleus and perinuclear cortical opacity
  • Stage V - the lens is completely turbid.
  • the cataract clear eye drops formulated according to the present invention can reduce the number of eyes of stage IV or V cataract by 2-4 after treatment without the need for surgery or intraocular injection of the eye, only by the method of administration of ocular drops. grade. Especially for traumatic cataracts, it can be completely cured after 2 weeks of administration. No dog had any discomfort or allergic reaction throughout the treatment.
  • the above examples show that the addition of a polyhydroxy compound can significantly increase the aqueous phase solubility of the active ingredient in the eye drops.
  • the addition of a suitable thickening agent can increase the stability of the preparation, promote the absorption of the drug during ocular administration, and improve the administration effect.
  • the ophthalmic preparation provided by the invention has low irritation and good therapeutic effect, and is particularly suitable for preventing or treating human or non-human mammal cataract.
  • the physical solubilization means such as ultrasonic, heating, etc. can be used in the preparation process.
  • Rat model of cataract was made: Wistar rats were selected 12 days after birth, male or female, modeled with sodium selenite (senile cataract), each rat was injected subcutaneously in the back and neck according to 20 ⁇ mol/kg body weight; Acupuncture is used to model adult rats (traumatic cataract).
  • the opacity of the lens is observed using a slit lamp, and the lens opacity is generally classified into a 0-V phase.
  • Phase 0 - the lens is transparent
  • Stage I the surrounding cortex of the lens is scattered in small vacuoles
  • Stage III another part of the cortical opacity
  • Stage IV lens nucleus and perinuclear cortical opacity
  • Stage V - the lens is completely turbid.
  • econazole eye drops were administered three times a day, morning, and evening, at intervals of at least 5 hours.
  • the cataract patients involved in the test were enrolled in 10 eyes in each group.
  • the mode of administration was direct eye drops, ensuring that the drug was completely instilled into the eye.
  • One eye drop per administration about 20 microliters, was administered for 10 weeks. All eyes of all cataract patients in different treatment groups were observed and judged for signs of symptom relief or symptom relief.
  • the results show that the cataract-recovery eye drops containing only econazole formulated according to the present invention can treat or prevent cataract very effectively without the need for surgery or intraocular injection of the eye, only by the administration of ocular drops. Especially for traumatic cataracts. No rats have any discomfort or eye over the entire course of treatment. Sensitive reaction.
  • Example 4 different components of eye drops soaking cataract crystals
  • the physical solubilization means such as ultrasonic, heating, etc. can be used in the preparation process.
  • the above-mentioned eye drops of the invention are uniform, non-suspended, white liquid, completely aqueous phase
  • the co-solvent is cyclodextrin, preferably hydroxypropyl- ⁇ -cyclodextrin, and the concentration of econazole can be From 2 ⁇ M to 40 ⁇ M, no white particles insoluble in the aqueous phase were observed inside the entire eye drop.
  • the cataract rat model (sodium selenite modeling) 30-40 days after birth was taken out, randomly divided, anesthetized and euthanized, and the lens was carefully removed under a microscope, and the cortex was intact.
  • These lenses with the same level of cataract were randomly divided into PBS solvent group (A), a solution containing only lanosterol (Formula B above) and a solution containing both econazole and lanosterol (Formula C above) Medium, shelter at room temperature 7 Day, go to the cortex and observe the changes in the crystal nucleus.
  • the ophthalmic preparation of the present invention e.g., eye drops
  • lanosterol lanosterol

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Abstract

一种包含唑类化合物的眼用药物组合物及其制备方法以及该药物组合物在制备用于预防和治疗眼科疾病的眼用制剂中的用途，所述眼用制剂包含浓度为0.005-400µM的唑类化合物。

Description

唑类化合物眼用制剂 技术领域
本发明涉及眼部药物领域，具体地，本发明公布了一种唑类化合物的眼用制剂形式，及其用于治疗或预防白内障等眼部晶状体疾病的用途。
背景技术
白内障是一种以视力模糊、视力减退为主要症状的常发性致盲眼病，在全球4000万至4500万盲人中，因白内障致盲者占60％。白内障发生于眼部晶体上，由于老化、遗传、局部营养障碍、免疫与代谢异常、外伤、辐射等因素，患者个体的晶体代谢紊乱，导致晶状体蛋白变性发生错误堆积，从而影响光线进入眼内到达视网膜，最终表现为视力模糊甚至视力完全丧失的症状(Bloemendal,de Jong et al.2004)。
白内障发病不仅限于人类，很多哺乳动物物种(马、狗、猴等)都可发生白内障(Chauke,Magwebu et al.2016；Sande,Alvarez et al.2016)。白内障根据不同的病因可分为老年性白内障、先天性白内障、外伤性白内障和并发性白内障。目前，尚无临床药物能够对白内障进行有效治疗，患病个体只能通过手术更换人工晶体来改善视力。
唑类化合物是一类包括一个氮原子和至少含一个非碳原子的五元杂环化合物。由于人体可接受的毒性，唑类化合物一直被用于哺乳动物抗真菌的治疗。早在20世纪80年代，酮康唑就被用于口服治疗全身系统性真菌感染。随着更多唑类化合物的发现、合成，其本身的抗菌谱更加广泛，而相应的药代动力学性质和安全性也更适用于临床使用(Maertens JA,2004)。迄今为止，FDA已批准多个唑类化合物用于临床抗真菌使用(http://www.fda.gov/default.htm)。
本发明为首次确认唑类化合物对哺乳动物眼部白内障等眼部晶状体疾病有治疗和预防的作用。
发明内容
本发明的目的在于提供一种高浓度，具有合适的渗透压，眼部耐受性好，适合用于眼部给药的唑类化合物眼用制剂。
本发明的另一目的是提供所述制剂(尤其是眼用制剂)在治疗或预防人或非人哺乳动物白内障方面的应用。
在本发明的第一方面，提供了一种非创(non-invasive)给药的眼用制剂，其特征在于，所述眼用制剂包括：(a)药学上可接受的载体，以及(b)作为第一活性成分的唑类化合物；
其中，所述眼用制剂中唑类化合物的浓度为0.005～400μM。
在另一优选例中，所述的唑类化合物选自下组：
益康唑、异康唑、联苯苄唑、克霉唑、阿立哌唑、酮康唑、氟康唑、苯基咪唑、咪康唑、环菌唑、三唑醇、戊唑醇、丙环唑、VFV，或其药学上可接受的盐、或其药学上可接受的酯，或其组合。
在另一优选例中，所述的VFV为(R)-N-(1-(3,4'-二氟联苯-4-基)-2-(1H-咪唑-1-基)乙基)-4-(5-苯基-1,3,4-恶二唑吡啶-2-基)苯甲酰胺((R)-N-(1-(3,4'-difluorobiphenyl-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)或其药学上可接受的盐或酯。
在另一优选例中，所述眼用制剂中，所有或基本上所有的唑类化合物是溶解的。
在另一优选例中，所述的“所有或基本上所有的”指90-100％，较佳地95-100％，更佳地99-100％。
在另一优选例中，所述眼用制剂中，唑类化合物的浓度为0.01～200μM，较佳地0.025～100μM，更佳地0.05～50μM；最佳地0.5～10μM。
在另一优选例中，所述唑类化合物的浓度约5-8μM。
在另一优选例中，所述唑类化合物的浓度为7μM。
在另一优选例中，所述的唑类化合物为益康唑。
在另一优选例中，所述的眼用制剂选自下组：滴眼液、乳剂、凝胶、眼药膏、缓释微球、眼内缓释植片、眼部缓释药膜。
在另一优选例中，所述的滴眼液为溶液形式。
在另一优选例中，所述的滴眼液为乳液形式。
在另一优选例中，所述的眼用制剂是均匀的溶液。
在另一优选例中，所述的眼用制剂还包括可重构为液体的固态药物剂型(即所述剂型在添加液态的药学上可接受的载体后，可直接重构(reconstruct)成液态眼用制剂)。
在另一优选例中，所述的液态的药学上可接受的载体为水。
在另一优选例中，所述的眼用制剂还包括：(c)第二活性成分，其中所述的第 二活性成分选自下组：类固醇类化合物、糖皮质激素类化合物、抗生素、或其组合。
在另一优选例中，所述的第二活性成分为羊毛甾醇类化合物。
在另一优选例中，所述的羊毛甾醇类化合物的浓度为10～200mM，较佳地15～150mM，更佳地20～50mM；最佳地20～30mM。
在另一优选例中，所述的羊毛甾醇类化合物选自下组：
(i)羊毛甾醇、或其或其药学上可接受的盐、或其药学上可接受的酯；
(ii)二氢羊毛甾醇、或其或其药学上可接受的盐、或其药学上可接受的酯；
(iii)上述组分(i)和(ii)的组合。
在另一优选例中，所述的羊毛甾醇类化合物为羊毛甾醇。
在另一优选例中，所述的羊毛甾醇类化合物为二氢羊毛甾醇。
在另一优选例中，所述的羊毛甾醇类化合物为羊毛甾醇和二氢羊毛甾醇的混合物。
在另一优选例中，所述的羊毛甾醇和二氢羊毛甾醇的混合物中，羊毛甾醇的含量C1与二氢羊毛甾醇的含量C2之比C1/C2为1:500至500：1，较佳地5：90至500：1，更佳地为80：1至200：1，最佳地为85：1至100：1。
在另一优选例中，所述的糖皮质激素化合物选自下组：地塞米松、氢化可的松、或其组合。
在另一优选例中，所述的抗生素选自下组：妥布霉素、硫酸庆大霉素、金霉素、氯霉素、或其组合。
在另一优选例中，在所述眼用制剂中，所述的第二活性成分为溶解形式。
在另一优选例中，在所述眼用制剂中，所述的第二活性成分的含量为0.01-15wt％，较佳地为0.5-3wt％，按眼用制剂的总重量计。
在另一优选例中，所述的药学上可接受的载体是对眼睛无刺激性的。
在另一优选例中，所述的药学上可接受的载体包括选自下组的一种或多种载体：
(a1)水；
(a2)增溶剂；
(a3)表面活性剂；
(a4)增稠剂。
(a5)渗透压调节剂；
(a6)缓冲剂或所述缓冲剂构成的缓冲液；
(a7)防腐剂；
(a8)螯合剂；
(a9)缓释剂。
在另一优选例中，所述的增溶剂包括：多羟基化合物。
在另一优选例中，所述的多羟基化合物与第一活性成分的用量之比为：1：40000－1：1。
在另一优选例中，所述的多羟基化合物选自下组：多羟基的醇类、环糊精、聚乙烯醇、或其组合。
在另一优选例中，所述的多羟基化合物具有碳、氢和杂原子(如N)构成的骨架，并且活性基团基本上或全部是羟基。
在另一优选例中，所述的多羟基化合物包括醇类多羟基化合物(如C2-C10多元醇)、和环糊精及环糊精衍生物。
在另一优选例中，所述的多羟基化合物选自：丙二醇(polyene glycol)、丙三醇(glycerol)、聚乙二醇(polyethylene glycol)，α-环糊精、β-环糊精、γ-环糊精、环糊精衍生物、聚乙烯醇(polyvinyl alcohol,PVA)，或其组合。
在另一优选例中，所述的多羟基化合物为羟丙基-β-环糊精。
在另一优选例中，所述表面活性剂选自：阴离子表面活性剂、阳离子表面活性剂、非离子表面活性剂、离液型(chaotropic)表面活性剂或其组合。
在另一优选例中，所述非离子表面活性剂选自：吐温、司盘、脂肪酸甘油酯、聚氧乙烯类，聚氧乙烯-聚氧丙烯共聚物，或其组合。
在另一优选例中，所述增稠剂选自：壳聚糖、羟丙基甲基纤维素(HPMC)、甲基纤维素(MC)、聚维酮(PVP)，明胶、羧甲基纤维素钠(CMC-Na)或其组合。
在另一优选例中，所述的增稠剂为壳聚糖。
在另一优选例中，所述渗透压调节剂选自：糖类化合物，盐类化合物或其组合。
在另一优选例中，所述糖类化合物选自山梨醇，葡萄糖、甘露醇或其组合。
在另一优选例中，所述盐类化合物选自氯化钠、氯化钾、硼酸或其组合。
在另一优选例中，所述的缓冲液选自：磷酸盐缓冲液，硼酸盐缓冲液，柠檬酸盐缓冲液，酒石酸缓冲液，醋酸铵盐缓冲液，或其组合。
在另一优选例中，所述防腐剂选自：苯扎溴铵、三氯叔丁醇、对羟基苯甲酸酯类、山梨酸，抗生素或其组合；较佳地，防腐剂的含量为0-1wt％；
在另一优选例中，所述的眼用制剂不含防腐剂。
在另一优选例中，所述的螯合剂选自：EDTA、EGTA、CDTA、柠檬酸盐，或其组合；较佳地鳌合剂的含量为0-0.1wt％；
在另一优选例中，所述眼用制剂含有：多羟基化合物、任选的表面活性剂和任选的增稠剂，
其中，按所述眼用制剂的总重量计，
多羟基化合物的含量为0.1-50wt％；
表面活性剂的含量为0-2wt％；
增稠剂的含量为0-6wt％。
在另一优选例中，多羟基化合物的含量为25-40wt％。
在另一优选例中，表面活性剂的含量为0.1-1wt％。
在另一优选例中，增稠剂的含量为0.1-5wt％。
在另一优选例中，所述眼用制剂的渗透压为240～510mOsm。
在另一优选例中，所述眼用制剂pH值为5.5～8.5，较佳地6.0～8.0，更佳地6.5-7.5。
在另一优选例中，所述的眼用制剂是用于眼部给药的水溶液。
在另一优选例中，所述的眼用制剂是用于眼部给药的水溶液，且溶液中羊毛甾醇类化合物的浓度为10～200mM，较佳地15～150mM，更佳地20～50mM；最佳地20～30mM。
在另一优选例中，所述眼用制剂含有以下成分：
0.05～40μM唑类化合物；
10～50mM羊毛甾醇类化合物；
0.1-50wt％的多羟基化合物，优选丙二醇或β环糊精；
0-1wt％增溶剂，优选聚山梨酯；
0.2-0.4wt％增稠剂，优选壳聚糖；
0-0.5wt％防腐剂，优选氯霉素；
和余量的水，
并且所述眼用制剂pH值约6.5-7.5，且渗透压为240～510mOsm。
在本发明的第二方面，提供了一种本发明第一方面所提供的眼用制剂的制备方法，其特征在于，包括以下步骤：
(1)将(a)药学上可接受的载体；和(b)作为第一活性成分的唑类化合物进行混 合，从而形成本发明第一方面所提供的眼用制剂。
在另一优选例中，在步骤(1)中，包括将(a)药学上可接受的载体；和(b)作为第一活性成分的唑类化合物和(c)所述的第二活性成分进行混合，从而形成本发明第一方面所提供的眼用制剂。
在另一优选例中，所述的方法包括：
(i)将作为第一活性成分的唑类化合物和任选的第二活性成分分散于多羟基化合物中，形成第一分散体；
(ii)将所述第一分散体与余下的药学上可接受的载体的进行混合，从而形成本发明第一方面所提供的眼用制剂。
在另一优选例中，在步骤(ii)中，先将余下的药学上可接受的载体进行混合，形成第二溶液或第二分散体，然后将所述第一分散体与所述第二溶液或第二分散体混合，从而制成本发明第一方面所提供的眼用制剂。
在另一优选例中，所述第二溶液的溶剂为水。
在另一优选例中，所述第二溶液的溶质选自下组：增溶剂、表面活性剂、增稠剂、渗透压调节剂、缓冲剂、防腐剂、螯合剂、缓释剂、或其组合。
在本发明的第三方面，提供了一种本发明第一方面所提供的眼用制剂的用途，其特征在于，所述眼用制剂用于制备预防或治疗人或非人哺乳动物的眼部晶状体疾病(如白内障、老花眼、或其组合)的药物。
在另一优选例中，所述的非人哺乳动物包括马、狗、猫、熊猫、猴、猩猩、啮齿动物、兔、象、虎。
在另一优选例中，所述的啮齿动物包括小鼠、大鼠。
在另一优选例中，所述白内障选自下组：老年性白内障、先天性白内障、外伤性白内障、和并发性白内障。
在另一优选例中，所述白内障为外伤性白内障。
在另一优选例中，所述的老花眼的患者为年龄大于48岁(较佳地≥60岁)的人。
在本发明的第四方面，提供了一种预防或治疗白内障等眼部晶状体疾病的方法，包括：给需要的对象的眼睛非创地施用本发明的第一方面提供的眼用制剂。
在另一优选例中，所述的眼部晶状体疾病选自下组：白内障、老花眼、或其组合。在另一优选例中，所述的“非创地施用”指滴加于眼睛。
另外，本发明还提供了一种预防或治疗白内障等眼部晶状体疾病的方法，包括：给需要的对象的眼睛口服施用本发明的口服制剂，或者施用本发明的注射剂型。
在另一优选例中，所述的口服制剂或注射剂型含有(a1)药学上可接受的载体，以及(b1)作为第一活性成分的上述唑类化合物；其中，所述制剂中唑类化合物的浓度为0.01-90wt％。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了本发明一个实施中眼用制剂的治疗效果。结果显示，含有唑类化合物益康唑和羊毛甾醇的药剂组，对大鼠的白内障患眼的治疗效果要远优于单独羊毛甾醇药剂组和PBS溶剂对照组。
具体实施方式
本发明人经过长期而深入的研究，意外地发现，含一类特定的化合物(即唑类化合物)作为活性成分的非创(non-invasive)给药的眼用制剂，居然能够极其有效地减轻哺乳动物的白内障症状，甚至完全消除哺乳动物的白内障症状。此外，通过加入特定的药学上可接受的载体(尤其是多羟基化合物)和额外的活性成分(如羊毛甾醇类化合物)，能够制得刺激性小、眼耐受性高、药物在眼内的滞留时间更长且疗效更佳的眼用制剂。在上述基础上，发明人完成了本发明。
眼用制剂
本发明提供了一种眼用制剂，通过选用合适的药物组合物(如羊毛甾醇类化合物，多羟基化合物、表面活性剂、增稠剂等)，不仅成功满足了眼部用药的特殊要求(如渗透压)，还显著提高或增加了活性成分的浓度。
本发明的眼用制剂包括药学上可接受的载体和作为活性成分的有效量的唑类化合物，并且按制剂的总体积计，溶解的(即游离的)唑类化合物的浓度为0.005～400μM。
通常，本发明的眼用制剂包括水或水性溶剂以及溶解于所述溶剂中的活性成分 和以下组分：羊毛甾醇类化合物，多羟基化合物，任选的表面活性剂和任选的增稠剂。所述眼用制剂还可任选地添加药学上可接受的其他组分，上述其他药学上可接受的组分包括但不限于，渗透压调节剂、缓冲剂、防腐剂、螯合剂、缓释剂等。
第一活性成分
如本文所用，术语“第一活性成分”或“唑类化合物”可互换使用，指唑类化合物。本发明的活性成分可以为药学上可接受的唑类化合物的各种晶型、无定形、脱水物、溶剂化物、水合物、对映体，本发明中唑类化合物即指本发明的第一活性成分。
益康唑属于五元杂环类化合物，结构式如下：
Figure PCTCN2017098662-appb-000001
本发明人的研究表明，采用特定的制剂配方，可以在保持眼内较高浓度下，使益康唑对白内障有非常有效的治疗效果。
第二活性成分
如本文所用，术语“第二活性成分”是指类固醇类化合物、糖皮质激素类化合物、抗生素、或其组合。在本发明中的眼用制剂中，第二活性成分可以是溶解形式。在本发明的眼用制剂中，第二活性成分的含量为0.01-20wt％，较佳地为5-15wt％，按眼用制剂的总重量计。
本发明的“第二活性成分”是羊毛甾醇类化合物时，其浓度优选为10～200mM，较佳地15～150mM，更佳地20～50mM；最佳地20～30mM。
上述类固醇类化合物选自(i)羊毛甾醇、或其或其药学上可接受的盐、或其药学上可接受的酯；(ii)二氢羊毛甾醇、或其或其药学上可接受的盐、或其药学上可接受的酯；(iii)25-羟基胆固醇、或其药学上可接受的盐、或其药学上可接受的酯；(iiii)上述组分(i)和/或(ii)和/或(iii)的组合。
本发明中的糖皮质激素化合物选自下组：地塞米松、氢化可的松、或其组合。
本发明中的抗生素选自下组：妥布霉素、硫酸庆大霉素、金霉素、氯霉素、或其组合。
多羟基化合物
如本文所用，术语“多羟基化合物”指分子中具有二个或多个羟基的化合物。本发明人意外地发现，当将所述多羟基化合物与唑类化合物组合使用时，一方面可以提高唑类化合物的水溶性及药物的稳定性，另一方面不会对唑类化合物产生不利影响。此外，还有助于提高第一活性成分在眼内的滞留时间，进而进一步提高治疗白内障的疗效。
所述的多羟基化合物优选具有碳、氢和杂原子(如N)构成的骨架，并且活性基团基本上或全部是羟基。
在另一优选例中，所述的多羟基化合物包括醇类多羟基化合物(如C2-C10多元醇)、和环糊精及环糊精衍生物。
在另一优选例中，所述的多羟基化合物选自下组：丙二醇、丙三醇、聚乙二醇、改性或未改性的环糊精及其衍生物，或其组合。
在另一优选例中，所述的多羟基化合物为羟丙基-β-环糊精。
多羟基化合物的用量可以根据制剂形式、用法和化合物类型而变化，在本发明中，多羟基化合物在唑类化合物水溶液中的用量(或含量)一般为0.1-50wt％，如，在本发明中，可使用1-15wt％的丙二醇，或20-50wt％的环糊精。
其他药学上可接受的载体
在本发明中，除了多羟基化合物之外，所述眼用制剂还可含有其他药学上可接受的载体，代表性的来自包括但不限于：表面活性剂、增稠剂，渗透压调节剂、缓冲剂、防腐剂、螯合剂、缓释剂。
表面活性剂
在本发明中，表面活性剂选自阴离子表面活性剂、阳离子表面活性剂、非离子表面活性剂、离液型(chaotropic)表面活性剂或其组合。其中非离子表面活性剂选自：吐温、司盘、脂肪酸甘油酯、聚氧乙烯类，聚氧乙烯-聚氧丙烯共聚物，或其组合。一般表面活性剂的用量(或含量)为0-2wt％，更佳地0.1-1wt％。
增稠剂
增稠剂可用于提高物系粘度，使物系保持均匀的稳定的悬浮状态或乳浊状态。本发明通过添加适量增稠剂，增加药物在眼部的滞留时间，从而增加眼部对于有效成分唑类化合物的吸收。
本发明中，增稠剂优选为壳聚糖、羟丙基甲基纤维素(HPMC)，甲基纤维素(MC)，和聚维酮(PVP)，明胶、羧甲基纤维素钠(CMC-Na)等。
一般，增稠剂的用量(或含量)为0～6wt％，较佳地为0.1-5wt％。
此外，本发明的眼用制剂还可含有额外的药学上可接受的载体，其中包括(但并不限于)：渗透压调节剂、缓冲剂、防腐剂、螯合剂、缓释剂。
例如，适当加入一定量的螯合剂，如EDTA，可增加制剂的稳定性。通常，螯合剂的浓度范围为0～0.05wt％。
通常，对于额外的药学上可接受的载体的种类和用量没有特别限制，只要不影响活性成分的溶解或治疗活性即可。
通常，这些其他药学上可接受的载体的总含量为0.1-80wt％，较佳地为1-50wt％。
眼用制剂的制备
本发明眼用制剂可用常规的设备和方法，按照本发明方法所提供的药物组分和配比进行制备。包括下面几种方法：
方法1：将(a)药学上可接受的载体；和(b)作为第一活性成分的唑类化合物进行混合，从而形成本发明的眼用制剂。
方法2：将(a)药学上可接受的载体；和(b)作为第一活性成分的唑类化合物和(c)所述的第二活性成分进行混合，从而形成本发明的眼用制剂。
方法3：
(i)将作为第一活性成分的唑类化合物和任选的第二活性成分分散于多羟基化合物中，形成第一分散体；
(ii)将所述第一分散体与余下的药学上可接受的载体的进行混合，从而形成本发明的眼用制剂。
在步骤(i i)中，也可以先将余下的药学上可接受的载体进行混合，形成第二溶液或第二分散体，然后将所述第一分散体与所述第二溶液或第二分散体混合，从而形成本发明的眼用制剂。
就滴眼液而言，可按照上述3种方法中任意一种进行制备，调节pH，并灭菌灌装于合适的容器内。
按所述方法配制的用于眼部给药的水溶液，可以用于局部给药至眼部。
用途
本发明的眼用制剂可用于预防或治疗人或非人哺乳动物的眼部晶状体疾病，例如白内障和老花眼等。代表性的白内障选自：老年性白内障、先天性白内障、外伤性白内障和并发性白内障。
在另一优选例中，所述的非人哺乳动物包括(但并不限于)：宠物(如狗、猫)、家畜(如牛、羊、马、猪)、各种动物园动物(熊猫、大象)等。
所述的制剂的用法和用量没有一定限制，根据患者的情况和白内障的种类而有所调整，上述调整可由本领域的熟练技术人员通过患者的症状结合本领域现有技术和公知常识得出。
本发明的主要优点在于：
1)可直接对眼部施用，易给药，耐受性好，且在眼内的滞留时间长，具有较好的疗效。
2)药物组分稳定，即使长时间放置也不易变质，储存方便，非常适合制成市售药品。
3)药物对眼部刺激性小，患者依从性好。
4)显著提高了活性成分的浓度(可以提高到mM级)，使浓度达到了临床眼部给药要求。
5)治疗白内障无需手术或者玻璃腔内注射药物。
6)选择的第一活性成分唑类化合物为FDA已批准上市分子，所以该用途的发现可以快速进入临床Ⅱ期实验，有利于缩短研发时间和降低研发费用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York: Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1
配制滴眼液：
益康唑             0.0003％
壳聚糖               1％
羟丙基-β-环糊精     40％
PBS溶液定容至100mL
注：制备过程中可以借助常规的超声、加热等物理促溶手段。
上述7μM益康唑滴眼液每天早、中、晚三次给药，给药间隔至少5小时。给药对象是外伤造成的白内障狗，参与测试的白内障患眼共9例，给药方式是眼部直接滴加，保证药物完全滴入眼内。每例接受治疗的患眼每次给药一滴，约50微升，连续给药12周。观察并评判所有9例白内障患眼有无症状减轻或症状缓解迹象。
实施例2
本发明滴眼液均一、非悬浊、白色液体，完全水相，助溶剂为环糊精，优选为羟丙基-β-环糊精，益康唑的浓度为7μM，整个滴眼液内部未见不溶于水相的白色颗粒。
滴眼液配方:
Figure PCTCN2017098662-appb-000002
注：制备过程中可以借助常规的超声、加热等物理促溶手段。
给药方式：
上述药物制剂每天早、中、晚三次给药，给药间隔至少5小时。给药对象是各种原因造成白内障的狗，给药方式是眼部直接滴加，保证药物完全滴入眼内。每只接受治疗的犬每侧患眼每次给药一滴，约50微升，连续给药8周。给 药期间不得同时服用他汀类分子。
评价指标：
使用裂隙灯观察晶状体混浊度，一般可将晶状体混浊分为0-Ⅴ期。
0期-晶状体透明；
Ⅰ期-晶状体周边皮质散在细小空泡；
Ⅱ期-晶状体周边皮质成环状密集中等空泡；
Ⅲ期-另外部分皮质片状混浊；
Ⅳ期-晶状体核及核周皮质混浊；
Ⅴ期-晶状体完全混浊。
治疗效果：
依照本发明配制的白内障复明滴眼液可以在无需手术或眼部玻璃腔注射，仅通过眼部滴用的给药方式，使IV期或V期白内障患眼在治疗后降低了2-4个等级。特别对于外伤性白内障，给药2周即可完全治愈。整个疗程无任何一只狗有不适或过敏反应。
上述实施例表明，多羟基化合物的加入，可以显著提高滴眼液内有效成分的水相溶解度。而适当的增稠剂的加入，则可以增加制剂稳定性，并促进眼部给药时药物的吸收，改善给药效果。本发明提供的眼部制剂刺激性小，具有良好的治疗效果，尤其适合用于预防或治疗人或非人哺乳动物白内障。
实施例3益康唑滴眼液治疗白内障
配制滴眼液：
益康唑            0.0003％
吐温-80               0.1％
羟丙基-β-环糊精     40％
PBS溶液定容至100mL
注：制备过程中可以借助常规的超声、加热等物理促溶手段。
制造大鼠白内障模型：选出生后12天的Wistar大鼠，雌雄不限，用亚硒酸钠造模(老年性白内障)，每只大鼠按照20μmol/kg体重，于背颈部皮下注射；针刺法对成年大鼠造模(外伤性白内障)。
评价指标：
使用裂隙灯观察晶状体混浊度，一般可将晶状体混浊分为0-Ⅴ期。
0期-晶状体透明；
Ⅰ期-晶状体周边皮质散在细小空泡；
Ⅱ期-晶状体周边皮质成环状密集中等空泡；
Ⅲ期-另外部分皮质片状混浊；
Ⅳ期-晶状体核及核周皮质混浊；
Ⅴ期-晶状体完全混浊。
造模3天后，益康唑滴眼液每天早、中、晚三次给药，给药间隔至少5小时。参与测试的白内障患眼每组10例，给药方式是眼部直接滴加，保证药物完全滴入眼内。每例接受治疗的患眼每次给药一滴，约20微升，连续给药10周。观察并评判不同处理组所有白内障患眼有无症状减轻或症状缓解迹象。
治疗效果：
白内障治疗效果如表1和2所示。
表1 核型白内障治疗效果
处理组 0期 I期 II期 III期 Ⅳ期 Ⅴ期
益康唑 6 0 0 0 4 0
PBS组 0 0 0 0 8 2
对照组 2 0 0 0 6 2
表2外伤性白内障治疗效果
处理组 0期 I期 II期 III期 Ⅳ期 Ⅴ期
益康唑 4 5 1 0 0 0
PBS组 0 0 1 1 6 2
对照组 0 0 1 1 5 3
结果表明，依照本发明配制的只含有益康唑的白内障复明滴眼液可以在无需手术或眼部玻璃腔注射，仅通过眼部滴用的给药方式，非常有效地治疗或预防白内障。特别对于外伤性白内障。整个疗程无任何一只大鼠有不适或眼部过 敏反应。
实施例4不同组分滴眼液浸泡白内障晶体
滴眼液C配方:
Figure PCTCN2017098662-appb-000003
滴眼液B配方:
羊毛甾醇           1.1364％
吐温-80                0.1％
羟丙基-β-环糊精     40％
PBS溶液定容至100mL
滴眼液A配方:
羊毛甾醇              0％
吐温-80                0.1％
羟丙基-β-环糊精     40％
PBS溶液定容至100mL
注：制备过程中可以借助常规的超声、加热等物理促溶手段。
上述本发明滴眼液(配方B和C)均一、非悬浊、白色液体，完全水相，助溶剂为环糊精，优选为羟丙基-β-环糊精，益康唑的浓度可以为2μM-40μM，整个滴眼液内部未见不溶于水相的白色颗粒。
取出生后30-40天的白内障大鼠模型(亚硒酸钠造模)，随机分组，麻醉并安乐死后，于显微镜下小心取出晶状体，皮质完整。将这些白内障等级相同(IV期)的晶状体随机分组，浸泡于PBS溶剂组(A)，只含有羊毛甾醇的溶液(上述配方B)以及同时含有益康唑和羊毛甾醇的溶液(上述配方C)中，室温避光放置7 天，去皮质，观察晶体核的变化。
结果如图1所示，分别经三种配方处理的晶状体，其透明度如下：配方C优于配方B，且配方B显著优于配方A。这表明，同时含有益康唑和羊毛甾醇的C组溶液在治疗核性白内障方面效果最好，只含有羊毛甾醇的滴眼液组分(B)配方次之，PBS对照组(A)对白内障无任何治疗效果。
上述各实验的综合结果表明，本发明的眼用制剂(如滴眼液)(不含羊毛甾醇)对动物的白内障有显著的治疗效果。无论是老年性(核型)白内障还是外伤性白内障都可以被本发明的含唑类化合物的药物制剂有效干预。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (13)

  1. 一种非创(non-invasive)给药的眼用制剂，其特征在于，所述眼用制剂包括：(a)药学上可接受的载体，以及(b)作为第一活性成分的唑类化合物；
    其中，所述眼用制剂中唑类化合物的浓度为0.005～400μM。
  2. 如权利要求1所述眼用的制剂，其特征在于，所述的眼用制剂选自下组：滴眼液、乳剂、凝胶、眼药膏、缓释微球、眼内缓释植片、眼部缓释药膜。
  3. 如权利要求1所述的眼用制剂，其特征在于，所述的眼用制剂还包括：(c)第二活性成分，其中所述的第二活性成分选自下组：类固醇类化合物、糖皮质激素类化合物、抗生素、或其组合。
  4. 如权利要求1所述的制剂，其特征在于，所述的药学上可接受的载体是对眼睛无刺激性的。
  5. 如权利要求1所述的制剂，其特征在于，所述眼用制剂含有：多羟基化合物、任选的表面活性剂和任选的增稠剂，
    其中，按所述眼用制剂的总重量计，
    多羟基化合物的含量为0.1-50wt％；
    表面活性剂的含量为0-2wt％；
    增稠剂的含量为0-6wt％。
  6. 如权利要求1所述的制剂，其特征在于，所述眼用制剂pH值为5.5～8.5，较佳地6.0～8.0，更佳地6.5-7.5。
  7. 如权利要求1所述的制剂，其特征在于，所述的眼用制剂是用于眼部给药的水溶液。
  8. 如权利要求1所述的眼用制剂，其特征在于，所述眼用制剂含有以下成分：
    0.05～40μM唑类化合物；
    10～50mM羊毛甾醇类化合物；
    0.1-50wt％的多羟基化合物，优选丙二醇或β环糊精；
    0-1wt％增溶剂，优选聚山梨酯；
    0.2-0.4wt％增稠剂，优选壳聚糖；
    0-0.5wt％防腐剂，优选氯霉素；
    和余量的水，
    并且所述眼用制剂pH值约6.5-7.5，且渗透压为240～510mOsm。
  9. 一种如权利要求1所述的眼用制剂的制备方法，其特征在于，包括以下步骤：
    (1)将(a)药学上可接受的载体；和(b)作为第一活性成分的唑类化合物进行混合，从而形成权利要求1所述的眼用制剂。
  10. 如权利要求1所述的眼用制剂的用途，其特征在于，所述眼用制剂用于制备预防或治疗人或非人哺乳动物眼部晶状体疾病的药物。
  11. 一种预防或治疗眼部晶状体疾病的方法，其特征在于，给需要的对象的眼睛非创地施用权利要求1所述的眼用制剂。
  12. 如权利要求11所述的方法，其特征在于，所述的眼部晶状体疾病选自下组：白内障、老花眼、或其组合。
  13. 一种预防或治疗眼部晶状体疾病的方法，其特征在于，包括步骤：给需要的对象的眼睛口服施用一口服制剂，或者施用注射剂型，其中，所述口服制剂或注射剂型含有(a1)药学上可接受的载体，以及(b1)作为第一活性成分的唑类化合物；其中，所述制剂中唑类化合物的浓度为0.01-90wt％。
PCT/CN2017/098662 2016-08-24 2017-08-23 唑类化合物眼用制剂 WO2018036523A1 (zh)

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