WO2019024433A1 - Composition ophtalmique à base d'un composé de mononitrate d'aminoamantadine, sa préparation et son application - Google Patents

Composition ophtalmique à base d'un composé de mononitrate d'aminoamantadine, sa préparation et son application Download PDF

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Publication number
WO2019024433A1
WO2019024433A1 PCT/CN2018/000282 CN2018000282W WO2019024433A1 WO 2019024433 A1 WO2019024433 A1 WO 2019024433A1 CN 2018000282 W CN2018000282 W CN 2018000282W WO 2019024433 A1 WO2019024433 A1 WO 2019024433A1
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ophthalmic composition
ophthalmic
intraocular pressure
compound
mononitrate
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PCT/CN2018/000282
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English (en)
Chinese (zh)
Inventor
王玉强
孙业伟
张在军
张高小
于沛
易鹏
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佛山喜鹊医药有限公司
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Publication of WO2019024433A1 publication Critical patent/WO2019024433A1/fr

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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
    • A61K31/13—Amines
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the invention relates to the technical field of medicine, in particular to an aminoadamantanamine mononitrate compound ophthalmic composition, a preparation thereof and an application thereof.
  • Glaucoma refers to an eye disease in which the intraocular pressure exceeds the limits of the intraocular tissues, especially the optic nerve, and causes optic disc depression, optic atrophy, and visual field defects. If not treated in time, the visual field may be completely lost or even blind. The second leading cause of blindness in the world, about 8.4 million people worldwide are blinded by glaucoma.
  • Normal human intraocular pressure range is 10 ⁇ 21mmHg (Schitz intraocular pressure gauge), intraocular pressure exceeds 24mmHg is pathological state, high intraocular pressure can cause permanent irreversible damage of visual function, high intraocular pressure state continues The longer the time, the more serious the visual impairment.
  • Clinical application of glaucoma treatment drugs are more, are intraocular pressure drugs, including mainly pilocarpine, prostaglandin analogues, ⁇ -adrenergic receptor inhibitors, ⁇ -adrenergic receptor agonists and carbonic anhydrase inhibitors Wait.
  • intraocular pressure drugs including mainly pilocarpine, prostaglandin analogues, ⁇ -adrenergic receptor inhibitors, ⁇ -adrenergic receptor agonists and carbonic anhydrase inhibitors Wait.
  • Pilocarpine Among the various commonly used anti-glaucoma drugs, the oldest drug is pilocarpine. Since 1877, Weber first used it for the treatment of glaucoma. It has been more than 100 years old and its intraocular pressure is better. It is suitable for most glaucoma, but the eye has a large adverse reaction, such as burning eyes, stinging, blurred vision and so on.
  • Prostaglandin analogues It is the most widely used glaucoma treatment drug in clinical practice. It can reduce intraocular pressure by increasing the outflow of aqueous humor through the choroidal sclera or trabeculae. The intraocular pressure is reduced by 25% to 33%, including Latan. Prostaglandins, bimatopros and prostaglandins, common side effects are conjunctival hyperemia, eyelash growth and increased iris pigmentation.
  • Beta-adrenergic receptor inhibitors The main mechanism of action is to reduce the binding of adrenaline and norepinephrine to beta receptors, reduce cAMP levels in ciliary epithelial cells, reduce aqueous humor production, and thus reduce intraocular Pressure, intraocular pressure decreased by 20% to 25%, including timolol, carteolol and levobunolol, adverse reactions are more common in the cardiovascular system and respiratory system.
  • Alpha-adrenergic receptor stimulant The main mechanism of action is to reduce the formation of aqueous humor, reduce the iris venous pressure or increase the outflow of aqueous humor through the uveal iris, and the intraocular pressure decreases by 20% to 25%.
  • the main side effect is conjunctival hyperemia. Allergic reactions and fatigue, such as drowsiness.
  • Carbonic anhydrase inhibitor The main mechanism of action is to reduce the formation of aqueous humor, and the intraocular pressure is reduced by 15% to 20%. There are two ways of administration of eye drops and oral administration. The main side effect is atopic dermatitis/conjunctivitis. , corneal edema, etc.
  • Glaucoma optic nerve damage ultimately leads to loss of vision function, and elevated intraocular pressure is the most common risk factor, but in some patients, normal intraocular pressure is still subject to continuous damage.
  • pathogenesis of glaucomatous optic nerve damage there is evidence that when retinal ganglion cells are exposed to high intraocular pressure, they have a series of associated changes in cell downstream pathways, including mitochondrial dysfunction, proteolytic grade. Linkage reaction, endoplasmic reticulum oxidative stress, etc. Therefore, optic nerve protection therapy is an essential treatment for improving optic nerve damage in glaucoma.
  • Optic neuroprotective treatments include lowering intraocular pressure and the use of neuroprotective agents such as calcium antagonists, glutamate receptor antagonists, antioxidants, neurotrophic factors, and the like.
  • neuroprotective agents such as calcium antagonists, glutamate receptor antagonists, antioxidants, neurotrophic factors, and the like.
  • optic neuroprotective agents such as calcium antagonists, glutamate receptor antagonists, antioxidants, neurotrophic factors, and the like.
  • Glutamate blockers glaucomatous retinal ganglion cell apoptosis studies show that excitatory amino acid receptors (NMDA, AMPA and KA receptors) are present on retinal ganglion cells when cells are ischemic or have high intraocular pressure It can cause hypoxia in ganglion cells, cause depolarization of membranes, increase glutamate release, and reduce uptake, which together lead to the accumulation of extracellular glutamate, which causes extracellular calcium ions under the action of its receptors. Influx causes high calcium load in the cells, resulting in an increase in inducible NO synthase, lipid peroxidase, aggregation of oxygen free radicals, mitochondrial degeneration, and apoptosis of optic ganglion cells.
  • Nitric oxide donor drugs Endogenous cell-derived gas signaling molecule NO plays a regulatory role in various tissues of the human body. NO activates guanylate cyclase in vascular smooth muscle cells, resulting in increased cGMP and vasodilation. Recent studies have shown that low concentrations of NO (pmol or low level of nmol) have protective effects on glaucoma retina, which is characterized by diastolic intraocular smooth muscle, trabecular meshwork, Schlemm tube, thereby reducing aqueous circulation resistance, reducing intraocular pressure; Blood vessels, increase vascular flow, reduce vascular resistance; improve the retinal microcirculation through relaxation of capillaries.
  • the NO donor drug currently in clinical research is latanoprostol, which is one of the most promising glaucoma treatments.
  • latanoprostol which is one of the most promising glaucoma treatments.
  • the average intraocular pressure of 0.024% latanoprostol was significantly higher than 0.005%.
  • Prostaglandins The drug is in clinical phase III research.
  • the simultaneous provision of intraocular pressure reduction and optic nerve protection can provide a better therapeutic effect for glaucoma and benefit patients for a long time.
  • the patent (application number: 201410235747.5) provides an amantadine nitrate compound which combines NMDA receptor antagonism and NO release, and can reduce intraocular pressure and exert optic ganglion cell protection.
  • Patent (Application No.: 20160701329) provides the use of aminoadamantane mononitrate compounds in the preparation of medicaments for the prevention and treatment of diseases, including the use in the preparation of medicaments for the prevention and treatment of glaucoma, by administering orally orally orally.
  • Alkanone mononitrate compounds can significantly reduce intraocular pressure and improve the survival rate of optic ganglion cells.
  • the main disadvantages are as follows: First, glaucoma treatment requires long-term medication, and clinical compliance of injection administration is poor. Second, after injection or oral administration, the drug is distributed throughout the body, and the drug concentration of the target site is low, and it is difficult to achieve the effective concentration. And because of the systemic exposure of the drug, the possibility of drug toxicity is increased. Based on this, we have developed an aminoadamantane mononitrate compound ophthalmic preparation.
  • the present invention provides an ophthalmic composition containing an aminoadamantane mononitrate compound and its use in the preparation of a medicament.
  • the ophthalmic composition not only can sufficiently reduce intraocular pressure, but also has an optic ganglion cell protection effect, and can obtain long-term benefits for glaucoma, as well as patients with elevated intraocular pressure or retinal ganglion cell damage.
  • the present invention provides an ophthalmic composition containing an aminoadamantanamine mononitrate compound, wherein the composition comprises aminoammonium amine mononitrate in a mass to volume ratio of 0.001% to 5.0%.
  • a compound the compound is of the formula (I) or a pharmaceutically acceptable salt thereof:
  • R is hydrogen, a linear or branched alkyl group; and n is 1-6.
  • the alkyl group is a C1-C6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, Cyclopentyl, n-hexyl or cyclohexyl.
  • aminoamantylamine mononitrate compound has the following structural formula:
  • the ophthalmic composition can be formulated as an ophthalmic gel, an ophthalmic solution, and an injectable solution that can also be formulated to be suitable for in or near the eye.
  • the ophthalmic composition can be formulated as an ophthalmic gel or ophthalmic solution. More preferably, the ophthalmic composition can be formulated as an ophthalmic gel.
  • the ophthalmic composition, as an ophthalmic gel may further comprise a gellan gum, a poloxamer 407, a carbomer, a polycarbophil, a hydroxypropyl group having a mass to volume ratio of 0.1% to 10%. Methylcellulose or a combination thereof.
  • the composition may further comprise a sustained release agent.
  • the ophthalmic composition may further comprise one or more pharmaceutically acceptable excipients.
  • the auxiliary material may be a thickener, an isotonicity adjusting agent, a tonicity adjusting agent, a mucoadhesive agent, a preservative, a complexing agent, a buffering agent, and a pH adjusting agent.
  • the ophthalmic compositions can be prepared in a conventional manner for various formulations.
  • the present invention provides the pharmaceutical use of the aminoamantaneamine mononitrate compound ophthalmic composition described above, including the use in the preparation of a medicament, wherein the medicament can be used for the prevention and treatment of glaucoma, And other ophthalmic diseases associated with elevated intraocular pressure or retinal ganglion cell damage.
  • the aminoadamantanamine mononitrate compound ophthalmic composition provided by the present invention preferably an ophthalmic gel preparation, has a longer drug release duration and a longer lasting effect than the eye drops, and the eye coagulation is used.
  • the effect of the gel preparation on lowering the intraocular pressure is significantly stronger than that of the intravenous administration of the drug or the administration of the eye drops.
  • the aminoadamantanamine mononitrate compound ophthalmic composition provided by the invention is used for preparing a medicament, and has the advantages of being convenient for use in an ophthalmic disease patient. Compared with injection or oral preparations, the formulation is more compliant, suitable for glaucoma, and long-term medication for patients with ophthalmic diseases with elevated intraocular pressure or optic nerve cell damage;
  • the ophthalmic composition of the aminoammoniumamine mononitrate compound provided by the present invention avoids the disadvantage of systemic exposure of the drug after injection or oral administration, and increased toxicity.
  • Topical administration increases the drug concentration of the drug target site, the drug has a fast onset, the effective concentration is higher, and the patient benefit/risk ratio is higher.
  • the aminoadamantanamine mononitrate compound composition provided by the invention comprises an eye drop gel agent, and the gel agent is a liquid with good fluidity in vitro, and can be evenly spread after being dropped into the eye, in the eye.
  • the residence time is longer, it is not easy to lose, the higher local effective drug concentration can be maintained, and the bioavailability of the drug is provided.
  • Figure 1 depicts the protective effects of different concentrations of MN-08 eye drops on a transient glaucoma model in New Zealand rabbits.
  • Figure 2 depicts the protective effect of MN-08 gel (0.5%) on a New Zealand rabbit transient glaucoma model.
  • Figure 3 depicts a pharmacodynamic comparison of the protective effects of injections, eye drops, and gels on a New Zealand rabbit transient glaucoma model.
  • Figure 4 illustrates the effect of different pharmaceutical dosage forms on intraocular pressure in a New Zealand rabbit transient glaucoma model.
  • New Zealand rabbits weighing 1.5 to 2 kg were selected as model animals to produce high intraocular pressure models. New Zealand rabbits were placed in a clean animal room for 3 days, and the experiment was started after reaching the required body weight range. First, anesthesia with sodium pentobarbital (3%, 1 ml/kg) until no blink reflex; then, using compound tropicamide eye drops, local anesthesia with oxybuprocaine eye drops, card Bom eye drops prevent dry eyes, levofloxacin eye drops anti-inflammatory, iodine disinfected around the eyes; 0.1ml of 5% hypertonic saline is injected into the vitreous of the eye, using a needle of 33G needle, the injection site is the limbus After 3.5-4mm, the injection depth is 5-7mm; after the needle is withdrawn. The Tonolab intraocular pressure gauge was used to measure the intraocular pressure change 1 min after the injection of hypertonic saline to evaluate whether the model was successfully produced. The intraocular pressure was higher than 70 mmHg,
  • the MN-08 drug powder was weighed separately, and the MN-08 eye drops with a mass to volume ratio of 0.02%, 0.1%, and 0.5% were sequentially prepared by using physiological saline;
  • MN-08 drug powder and gellan gum (Gelzan TM CM) powder were weighed separately, and MN-08 gel solution containing 0.5% MN-08 and 0.6% Gelzan TM CM was prepared with physiological saline;
  • New Zealand rabbits were randomly divided into normal saline group, MN-08 eye drops group (0.02%, 0.1%, 0.5%), MN-08 gel solution group (0.5%), and positive control group (0.005% latanolide). ), 5 to 8 per group.
  • the intraocular pressure (0 min) of New Zealand rabbits before the injection of hypertonic saline was measured as the normal intraocular pressure.
  • the intraocular pressure of each experimental group was measured at the time points of 1 min, 10 min, 30 min, 60 min, 90 min and 180 min after modeling.
  • the average value of the three intraocular pressure measurements at each time point was used as the intraocular pressure at that point, and the effect of the drug on intraocular pressure changes within 3 hours after administration was observed.
  • the changes in intraocular pressure in the transient glaucoma model of New Zealand rabbits after administration of different dosage forms and concentrations of MN-08, latanoprost and saline were as shown in the list in Figure 4, and the transientity of New Zealand rabbits after administration of MN-08 eye drops.
  • the glaucoma model intraocular pressure change line diagram is shown in Figure 1.
  • the intraocular pressure of the New Zealand rabbit transient glaucoma model after MN-08 gel is shown in Figure 2.
  • MN-08 injection, eye gel solution The drug effect comparison is shown in Figure 3.
  • MN-08 injection P ⁇ 0.05
  • MN-08 eye drops P ⁇ 0.05
  • MN-08 gel P ⁇ 0.05
  • MN-08 gel 0.5%)
  • MN-08 eye drops 0.5%)
  • the MN-08 gel has a longer duration of action and more than eye drops at the same concentration. Good antihypertensive effect.

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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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Abstract

L'invention concerne une composition ophtalmique comprenant un composé de mononitrate d'aminoamantadine dans un rapport poids/volume de 0,001 à 5 % et une application de ladite composition ophtalmique dans la préparation d'un médicament destiné à prévenir ou à traiter le glaucome, une pression intraoculaire élevée, ou une maladie oculaire impliquant une lésion des cellules ganglionnaires de la rétine.
PCT/CN2018/000282 2017-08-04 2018-08-01 Composition ophtalmique à base d'un composé de mononitrate d'aminoamantadine, sa préparation et son application WO2019024433A1 (fr)

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CN201710660958.7A CN107412211A (zh) 2017-08-04 2017-08-04 氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用
CN201710660958.7 2017-08-04

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CN107412211A (zh) * 2017-08-04 2017-12-01 佛山喜鹊医药有限公司 氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用
CN109172560B (zh) * 2018-10-15 2022-08-16 佛山喜鹊医药有限公司 氨基金刚烷硝酸酯类化合物或其药学上可接受的盐在预防和/或治疗肺部疾病中的应用
CN116725997A (zh) * 2022-03-01 2023-09-12 广州喜鹊医药有限公司 氨基金刚烷单硝酸酯类化合物在制药领域中的应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101536974A (zh) * 2009-04-08 2009-09-23 南京医科大学 醋甲唑胺眼用温度敏感原位凝胶制剂及其制备方法
CN105294450A (zh) * 2014-05-29 2016-02-03 广州喜鹊医药有限公司 具有神经保护作用的金刚烷胺硝酸酯化合物及其制备和医药应用
CN106344551A (zh) * 2016-08-22 2017-01-25 广州喜鹊医药有限公司 氨基金刚烷单硝酸酯类化合物在制备预防和治疗疾病药物中的应用
CN107412211A (zh) * 2017-08-04 2017-12-01 佛山喜鹊医药有限公司 氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101536974A (zh) * 2009-04-08 2009-09-23 南京医科大学 醋甲唑胺眼用温度敏感原位凝胶制剂及其制备方法
CN105294450A (zh) * 2014-05-29 2016-02-03 广州喜鹊医药有限公司 具有神经保护作用的金刚烷胺硝酸酯化合物及其制备和医药应用
CN106344551A (zh) * 2016-08-22 2017-01-25 广州喜鹊医药有限公司 氨基金刚烷单硝酸酯类化合物在制备预防和治疗疾病药物中的应用
CN107412211A (zh) * 2017-08-04 2017-12-01 佛山喜鹊医药有限公司 氨基金刚烷胺单硝酸酯类化合物眼用组合物及其制剂和应用

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