CN106455567A - Compositions and methods for treatment of glaucoma - Google Patents

Compositions and methods for treatment of glaucoma Download PDF

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Publication number
CN106455567A
CN106455567A CN201480075789.5A CN201480075789A CN106455567A CN 106455567 A CN106455567 A CN 106455567A CN 201480075789 A CN201480075789 A CN 201480075789A CN 106455567 A CN106455567 A CN 106455567A
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Prior art keywords
concentration
pharmaceutical composition
dexmedetomidine
compositionss
buffer
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杰拉尔德·霍恩
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GNT LLC
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GNT LLC
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Priority claimed from US14/132,780 external-priority patent/US20140107173A1/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
    • A61K31/33—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
    • 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
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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

Abstract

The invention provides alpha-2 adrenergic receptor agonist compositions and methods for treating glaucoma and other intraocular conditions. The preferred alpha-2 agonist used in the inventive compositions and methods is dexmedetomidine.

Description

For treating compositionss and the method for glaucoma
Background of invention
Glaucoma is a kind of multi-factor disease, fills to the optic nerve blood vessel reducing including from the intraocular pressure (" IOP ") raising Note.
Although the pathogenic origin cause of formation of glaucoma is related to many factors, the existing treatment to glaucoma is reducing IOP side Face has limited effectiveness and/or with a lot of side effect, for example fatigue, calmness, eyelid allergy, local anaphylaxiss and/or Red.
Due to side effect, in glaucoma treatment, extra subject matter is patient in terms of by prescription requirements medication Compliance.It is believed that many side effect of existing treatment and suboptimum effect are by the A Er in Alpha's agonist treatment The afterclap of method -1 (" α -1 ") receptor-inducible.
Glaucoma patient more than 40% needs two or more medicines satisfactorily to control their intraocular pressure.Its In, prostaglandin/prostacyclin, including(Latanoprost；Xalatan is the registrar of Pfizer company Mark),(travoprost；Travatan is the registered trade mark of Novartis Co., Ltd) and(bimatoprost； Lumigan is the registered trade mark of Allergan company), it is key agents, because their very big reductions to IOP, generally in high eye Pressure ophthalmic (21mmHg or bigger) is more than 30%, and improvement for a long time in uveoscleral outflow.In order to obtain Maximum efficiency, two kinds of medicines should have the different mechanisms of action.
Brimonidine is a kind of known Alpha -2 (α -2) 3 adrenergic receptor agonists, generally in Bulbi hypertonia Moderate peak I OP of about 20-25% is caused to reduce and cause the moderate of 6-18% in the normal ophthalmic of blood pressure (less than 21mmHg) Peak I OP reduces.Within 2 hours instiling, the persistent period of its effect is typically smaller than 12 hours its peak effect, its moderate Effect typically requires the administration of daily 2-3 time.It is one of main two grade medicine, and the mechanism of action of water suppression is to supplement prostatitis Parathyrine/prostacyclin class strengthens uveoscleral outflow to reach significant additional effect, but is about equal to other two wires green lights Ophthalmic drug such as receptor blocking agent and carbonic anhydrase inhibitorss.At present, brimonidine is that uniquely commercially available α -2 is exciting Through comparing, agent, confirms that it includes clonidine (i.e. less systemic blood pressure is too low and/or bradycardic example than agonist before Son), Aplonidine (i.e. the example of less quick drug resistance reaction) and dexmedetomidine (i.e. less whole body calmness, more Big IOP reduces effect) safer and/or more effective.However, brimonidine can cause in the user of 10-25% in a large number Local side effects, for example conjunctival congestion (i.e. rubescent), blepharitis, allergy, chemosises, conjunctival follicle, foreign body sensation, calcination or Fuzzy.These side effect slightly can only be improved by recent brimonidine preparation, and under more alkaline pH, ophthalmic absorbs to increase and causes Make concentrations slightly reduce (P, alphagan are the registered trade marks of Allergan company).Generally speaking, α -2 agonist (including brimonidine, clonidine and dexmedetomidine) can cause significant systemic effect if be absorbed in circulation, and And especially be known be to increase fatigue, reduce blood pressure (i.e. hypopiesia) and slow down heart rate (i.e. bradycardia).Further Ground, a lot of α -2 agonist, the medicine such as clonidine and dexmedetomidine of especially more lipophilic easily propagate through blood brain screen Barrier, thus cause potent sedation effect.Particularly dexmedetomidine is a kind of potent intravenouss tranquilizer, side effect (example As sleepy, rapid breathing, dizziness, headache, hypopiesia, bradycardia and depressed) it is general to all of α -2 agonist Time, depending on the degree of systemic Absorption.Especially brimonidine produces local eyelid and conjunctiva in the patient more than 10% Allergy, dry and rubescent.These side effect cause the suboptimum compliance using brimonidine, and this has also negatively affected treatment.
In the rabbit with normal arterial pressure and the artificial intraocular pressure improving, have studied the phosphate buffer of pH6.4-6.5 In dexmedetomidine.U.S. Patent number 5304569 (Lammintausta) describes to use in normotensive rabbit 0.02% dexmedetomidine leads to equal pressure drop in the eyes of untreated (offside) eyes and process (100%), the known side effect instruction of high systemic Absorption.Vartiainen et al. confirms 0.05% in normotensive rabbit Dexmedetomidine leads to pressure drop and the peak effect at about 2 hours of 4.75mmHg.(Inv Oph.&Vis Sci.,Vol.33,No.6,May 1992,Dexmedetomidine-Induced Ocular Hypotension in Rabbits with Normal or Elevated Intraocular Pressures Vartiainen et.al.).In blood Press in normal rabbit and confirmed using the comparison of brimonidine tartrate 0.10% solution and dexmedetomidine, using bromine Buddhist nun does not conclude a contract or treaty the higher peak value of 6.2mm Hg, have about 3 hours peak value (comparing dexmedetomidine 2 hours) longer Persistent period, and for the relatively low systemic Absorption of brimonidine, offside (i.e. untreated eyes) compared with the eyes for the treatment of IOP reduces only about 10% (comparing dexmedetomidine about 100%), (Center for Drug Evaluation and Research Number 21-770, Pharmacology Review, brimonidine tartrate 0.1%, Allergan Pharmaceuticals).Due to compared with every other α -2 agonist attempted for this purpose, its quilt The significant IOP reduction confirming and the combination of the risk of systemic side effects greatly reducing, two during the last ten years, and brimonidine is only One commercially available α -2 agonist, although with respect to prostaglandin/prostacyclin, its be less than optimal side effect curve and in Degree effect.
Accordingly, it would be desirable to the new formulation of α -2 agonist for treating glaucoma, it will have less systemic Absorption (if any, MIN), the cross activation of α -1 receptor, the ophthalmic improving stop and more effectively IOP reduces and holds The continuous time, be substantially reduced or elimination conventional α -2 agonist side effect (such as calcination, twinge, calm and rubescent).This Outward, by reduce rubescent and eyes beauty treatment brighten the outward appearance of improvement reduction patient be not obedient to rate in terms of be important.
Content of the invention
The invention provides the therapeutically effective compositionss for glaucoma in patient in need and method.Preferably, The compositionss of the present invention are configured to prevention calmness, eliminate or reduce rubescent, elimination or reduce ocular allergies and be substantially reduced Intraocular pressure.
In some embodiments, the compositionss being provided also can have eyes whitening effect.Most preferably, described combination Thing includes all above-mentioned benefits, and also has neuroprotective benefits, can be used for optic nerve protection, including neurodegenerative diseases Treatment, for example ischemic optic neuropathy, diabetic retinopathy, optic nerve ischemia, retinal vessel ischemia and its Its optic neuropathy, especially relates in Lamina Cribrosa (nerve lamina) place or the retinal ganglial cellses near it And/or those optic neuropathy of aixs cylinder.
The present invention utilizes α -2 agonist of high selectivity to optimize α -2 agonist corneal osmosis, described α -2 agonist quilt It is formulated as the lipophile in preferred Log P 2.5 or bigger and the local lipophile scope based on pH and can be from 0.73 to 3.08 Optional preparation buffering (with respect to pH measure as Log D value) under the conditions of optimization intraocular penetration.Further, improved Preparation allows the systemic Absorption of α -1 agonist activity reducing and reduction it is allowed to α -2 agonist of more lipophilic is used for locally should With.
The preferred composition of the present invention adopts selectivity alpha-2 adrenergic receptor agonists.
Have been found that some rheological equationms of state in preferred implementation are very heavy for the safety of the present invention and effectiveness Will.Specifically it has been found that sending out within the several seconds during the preparation of the present invention each nictation cycle during medicine locally lies in Raw produces in a short time and keeps very a high proportion of low-shearing force-high viscosity and modulus of elasticity, but just rapidly turns in the twinkling of an eye It is changed into very high shearing force nictation stage-low viscosity and modulus of elasticity.
Further, suddenly, once applying, the surface thickness of tear film/preparation must be maintained at sufficiently thin putting down Weighing apparatus is to avoid blurred vision.
It has been found that described preparation preferably has following non-newtonian feature：
1) be produced as when instiling or about 150cps or bigger initial viscosity, and transient equilibrium, blurred vision is only whereby Continue tens of seconds, viscosity balance to non newtonian low-shearing force reaches high shear force difference so that highest ratio of viscosities initially instils afterwards Viscosity is little at least 2 times；
2) the viscosity increase producing after the transient equilibrium when instiling as above-mentioned 1) is poor, wherein in low-shearing force in a short time About 6 in the 1-2 second：1 or bigger ratio, declines, one in a second of some points of the beginning of the high shear force of each nictation Individual preferred embodiment in, for each nictation cycle from least 70cps to 10cps or less；
3), during the low-shearing force in a short time circulating at each, modulus of elasticity increases about 200 to 1000 within the 1-2 second Times, more preferably at least 2000 times, still more preferably at least 4000 times, and wherein during blinking, such modulus is less than 100, excellent Choosing is less than 10, more preferably from about 0；
4) produce the tear film thickness of approximately normal tear film in preferably 30 seconds in one minute when instiling, wherein each circulates Hereafter thickness in a short time under low-shearing force be about 10 μ or less, preferably from about 5 μ；
5) described preparation does not allow to cause excessive twinge or discomfort, reduces compliance or causes unacceptable ocular surface Toxicity；And
6) wherein selected composition will not otherwise interfere with drug absorption, or the work otherwise reducing active component Property.
In one preferred embodiment, the invention provides the novel formulation of dexmedetomidine, unexpectedly send out Existing said preparation is more much effective than brimonidine for the treatment of glaucoma.These new invention preparations have partly or entirely with Lower characteristic：
A) compare alpha-1 adrenergic receptor, the high selectivity to alpha-2 adrenergic receptor, such as 1000:1 or more Greatly；More preferably 1500:1 or bigger；Even more preferably 2000:1 or bigger；
B) the ophthalmic lipophile of height, as Log P weighs, the ophthalmic pH of balance 7.4, under physiological ph conditions, Octanol-water partition coefficient LogP between about 1.5 to 4.0；Between more preferably from about 2.50 to 3.50；And
C) include the anionic cyclodextrin of certain concentration range, for example(Captisol is Cydex drugmaker Registered trade mark), other cyclodextrin or other non-ionic surfactants such as poloxamer or alkyl Polyethylene Glycol (polyoxyl alkyl), and one or more specific viscosifier (also may be alternatively referred to as " gellant ").
In one embodiment, the invention provides a kind of pharmaceutical composition, it includes：
I. concentration is the alpha-2 adrenergic receptor agonists of about 0.0125% to about 0.125% w/v, wherein Described alpha-2 adrenergic receptor has 2.0 or bigger Log P value and has and exceed 50 times of alpha-1 adrenergic receptor 9 The adrenoreceptor of α -2 affinity；
Ii. hypotonic salt or sterilized water；
Iii. concentration is cyclodextrin or poloxamer or the alkyl Polyethylene Glycol of 2% to 2% w/v or lower；With And
Iv. viscosifier, wherein said pharmaceutical composition has the viscosity between 25 to 500cps,
The treatment of the glaucoma to patient in need for the wherein said pharmaceutical composition is effective.
Preferably alpha-2 adrenergic receptor agonists are dexmedetomidines.
Preferably, the concentration of dexmedetomidine is about 0.035% to 0.12% w/v, and more preferably concentration is about 0.035% to about 0.10%, more preferably from about 0.050% to 0.10%, between even more preferably about 0.060% to 0.087%.
In one embodiment, described salt is selected from sodium chloride, citrate, mesylate, hydrobromate/bromination Thing, acetate, fumarate, sulfate/disulfate, succinate, phosphate, maleate, nitrate, tartaric acid The group that salt, benzoate, carbonate and embonate are constituted.
Preferably, described salt is sodium chloride (such as saline solution).
In one embodiment, described viscosifier be selected from carboxymethyl cellulose, methylcellulose, hydroxymethyl cellulose, Hydroxypropyl methyl cellulose, hydroxyethyl cellulose, Polyethylene Glycol, glucosan, polyvidone, alginic acid, guar gum, Arabic tree Glue,(Veegum is the registered trade mark of Vanderbilt Minerals company limited), gelatin, shitosan,(Carbopol is the registered trade mark of Lu Borun Advanced Materials Corp.), tracasol, acid poly- card ripple Non-, glucosan, pectin, glycerol, polysorbate, povidone, polyvinyl alcohol, hyaluronic acid and combinations thereof.
In one preferred embodiment, described viscosifier are carboxymethyl celluloses.More preferably described carboxymethyl cellulose Element is that the height that concentration is 0.1% to 1.25% w/v mixes thing.
Preferably, cyclodextrin, poloxamer or alkyl Polyethylene Glycol be with 3% to 10% weight, it is highly preferred that 5% to 6% The concentration range of weight exists.
Preferably, described cyclodextrin is selected from Alpha, beta or gamma chain cyclodextrin, selected from 2 hydroxypropyl beta cyclodextrin, The sulfobutyl ether derivant of more preferably beta-schardinger dextrin-Poloxamer is selected from Poloxamer 407, poloxamer The group of 188 and combinations thereof compositions, described alkyl Polyethylene Glycol is selected from Polyethylene Glycol 40 stearate, Polyethylene Glycol 35 Oleum Ricini And/or the group that Polyethylene Glycol dehydrogenase 34 0 Oleum Ricini is constituted.
In one embodiment, described pharmaceutical composition can further include buffer agent, and described buffer agent can be selected from, But it is not limited to, citrate buffer agent, borate buffer, maleate buffer, succinate buffers, phosphate-buffered The group that agent, acetate buffer, sorbate buffer agent and carbonate buffer agent are constituted.
In one embodiment, between 1mM to 100mM, preferably 4 mMs to 10 mmoles for the concentration of described buffer agent Between you.
In one embodiment, α -2 agonist of described pharmaceutical composition has between about 0.70 to about 2.98, or excellent Octanol-water partition coefficient Log D between choosing about 1.25 to 2.50.
In one embodiment, the pharmaceutical composition of the present invention can further include mucoadhesive, and it can be about Concentration between 0.05% to about 10% w/v exists.
In one embodiment, described mucoadhesive is selected fromXanthan gum and cellulose derivative structure The group becoming.
Present invention also offers being used for treating glaucoma and/or eyes Posterior pole nervus retrogression disease in patient in need Disease and/or the method for xerophthalmia, including the charge-coupled thing of medicine applying the present invention to described patient.
Unexpectedly, although employing non newtonian viscosifier carboxymethyl cellulose (wherein 1% water of very high viscosity Solution=2500cps), but highly preferred range of viscosities is, and in initial application, viscosity during instillation is only about 150cps, and tens of second balance further in about 50 to 100, so at the end of this transient equilibrium stage, high shear force is little The non-Newtonian behavior being less than in 30cps and as a rule 20cps produces；Along with the low-shearing force higher than 30cps, many It is higher than 50 to 70cps in the case of number.
Specific embodiment
Definition
Term " alpha-1 adrenergic receptor " refers to and GqThe relevant g protein coupled receptor of heterotrimeric G protein (“GPCR”).
Term " alpha-2 adrenergic receptor " refers to and GiThe relevant GPCR of heterotrimeric G protein.
Term " selectivity alpha-2 adrenergic receptor agonists " includes the affinity of α -2 adrenoceptor is exceeded To the affinity of alpha-1 adrenergic receptor 1000 times or bigger, more preferably 1500 times or bigger of all α -2 epinephrines Can receptor stimulating agent.This term also include the pharmaceutically acceptable salt of selectivity alpha-2 adrenergic receptor agonists, ester, Prodrug and other derivants.
Term " dexmedetomidine " includes, and is not limited to, dexmedetomidine salt, ester, prodrug and other derivants.
Term " prodrug " refers to be converted into the compound of biologically active cpds in physiological conditions.
As used herein, term " compositionss " is intended to the product including the special component comprising certain content, Yi Jizhi Connect or combination indirectly from the special component in certain content spawn.
Term " treatment (gerund) " and treatment (noun) " refers to disease, imbalance or disease that this term is suitable for, or such The revolution of one or more symptoms of disease, imbalance or the patient's condition, alleviation, suppression or development slow down.
Term " prevention (gerund) " and " prevention (noun) " refer to preventive use with reduce the applicable disease of this term, Imbalance or the patient's condition, or the probability of one or more symptoms of such disease, imbalance or the patient's condition.There is no need to realize 100% can The prevention of energy property；It is enough to realize reducing at least part of effect of the risk suffering from such disease, imbalance or disease.
Term " significant side effect " refers to a large amount of side effect treated, and it at least includes：A) calmness of patient, so suffers from Person feel calm and become to suffer damage or b) appreciable obvious patient the rubescent increasing that leads to because of hyperemia of eyes Plus.
Term " drug eruption " refers to the inflammatory sequelae of α -1 agonist topical remedy, especially in local eyes or nasal cavity After administration, the development of the vasodilation of such as increase and hyperemia, its less serious form is referred to as " bounce-back ".
Term poloxamer 407 HeF127 (Pluronic is the registered trade mark of BASF AG) is replaceable to be made With.
Unless otherwise stated, all of percentage ratio is all based on w/v.
The nonionic surfactant of the suitable present invention includes cyclodextrin, alkyl Polyethylene Glycol, poloxamer or a combination thereof, In addition may include and the combining of other nonionic surfactants (such as polysorbate).Preferred embodiment include poly- second Glycol 40 stearate；And optionally, Poloxamer 188, Poloxamer 407, polysorbate20, polysorbate80, (the such as anion) beta-cyclodextrin having butanoic acid salt dissolving or not having the ion live-wire of butanoic acid salt dissolving2- hydroxyl Propyl group beta cyclodextrin (" HP β CD "), Polyethylene Glycol 35 Oleum Ricini, Polyethylene Glycol 40 castor oil hydrogenated or a combination thereof.Further Ground, the sub of other nonionic surfactant compatible to ophthalmic applications can provide similar preparation effect, and it can wrap Include but be not limited to one or more non-ionic surfactants such as poloxamer, poloxamer 103, poloxamer 123 and pool Luo Shamu 124, Poloxamer 407, Poloxamer 188 and Pluronic/Lutrol F 108, any poloxamer analog or derivant, poly- Sorbitol ester, polysorbate20, polysorbate40, polysorbate60, polysorbate80, any polysorbate esters Like thing or derivant, cyclodextrin, HP-β-CD, hydropropyl-y-cyclodextrin, any methylated β-cyclodextrin, β-ring Dextrin sulfobutyl ether, gamma-cyclodextrin sulfobutyl ether or glucosyl-ss-cyclodextrin, any cyclodextrin analog or derivant, poly- Ethylene glycol, polyoxypropyleneglycol, polysorbate ester analogs or derivant, Cremophor RH40 60, Polyethylene Glycol (200), polyoxypropyleneglycol (70), Cremophor RH40, Cremophor RH40 60, Polyethylene Glycol (polyoxol), polyglycol distearate, nonoxynolum, OPEO, NPE, propylene glycol Single caprylate (capryols), propylene glycol glyceryl monolaurate, PEG,35th, glyceryl laurate ester, lauryl glucose Glycosides, decyl glucoside or spermol；Or zwitterionic surfactant such as palmitoyl carnitine, coconut oleoyl amine DEA, cocos nucifera oil acyl Amine DEA derivant cocamido propyl betaine (" CAPB ") or trimethyl glycine glycine betaine (trimethyl glycine Betaine), N-2 (2- acetamido) -2- aminoethane sulphonic acid (ACES), N-2- acetamidoiminodiacetic acid (ADA), N, N- double (2- ethoxy) -2- aminoethane sulphonic acid (BES), 2- [double-(2- ethoxy)-amino] -2- methylol-propane -1, 3- glycol (Bis-Tris), 3- Cyclohexylamino -1- propane sulfonic acid (CAPS), 2- Cyclohexylamino -1- ethane sulfonic acid (CHES), N, N- double (2- ethoxy) -3- amino -2- hydroxypropane sulfonic acid (DIPSO), 4- (2- ethoxy) -1- piperazinepropanesulfonic acid (EPPS), N-2- hydroxyethyl piperazine-N ' -2 ethane sulfonic aicd (HEPES), 2- (N- morpholino)-ethane sulfonic acid (MES), 4- (N- Quinoline generation)-butane sulfonic acid (MOBS), 2- (N- morpholino)-propane sulfonic acid (MOPS), 3- morpholino -2- hydroxypropanesulfonic acid (MOPSO), 1,4- piperazine-bis--(ethane sulfonic acid) (PIPES), piperazine-N, N '-bis- (2- hydroxypropane sulfonic acid) (POPSO), N- tri- (methylol) methyl-2-amino propane sulfonic acid (TAPS), N- [three (methylol) methyl] -3- amino -2- hydroxypropanesulfonic acid (TAPSO), N- tri- (methylol) methyl-2-amino ethane sulfonic acid (TES), 2- amino -2- methylol-propane -1,3- glycol (Tris), tyloxapol and20-80 (Span is the registered trade mark of Uniqema Americas limited company).? In some embodiments, anion surfactant such as sodium lauryl tri(oxyethyl) sulfate (sodium lauryl ether Sulfate), the interpolation of sodium lauryl sulfate (" SLS ") or a combination thereof is preferred.
Embodiments of the present invention
The invention provides the therapeutically effective compositionss to glaucoma in patient in need and method.Preferably, originally The compositionss of invention by formula manufacture with prevent calmness, elimination or reduce rubescent, eliminate or reduce ocular allergies and significantly subtracting Little intraocular pressure.
In one embodiment, described salt be selected from sodium chloride, citrate, mesylate, hydrobromate/bromide, Acetate, fumarate, sulfate/disulfate, succinate, phosphate, maleate, nitrate, tartrate, benzene The group that formates, carbonate and embonate are constituted.
Preferably, described salt is sodium chloride (as saline solution).
In one embodiment, described viscosifier be selected from carboxymethyl cellulose, methylcellulose, hydroxymethyl cellulose, Hydroxypropyl methyl cellulose, hydroxyethyl cellulose, Polyethylene Glycol, glucosan, polyvidone, alginic acid, guar gum, Arabic tree Glue,Gelatin, shitosan,Tracasol, acid polycarbophil, glucosan, pectin, polyvidone, poly- The group that vinylpyridine ketone, polyvinyl alcohol and hyaluronic acid are constituted.
In one preferred embodiment, described viscosifier are carboxymethyl celluloses.
Preferably, cyclodextrin, poloxamer or alkyl Polyethylene Glycol are with 3% to 10% weight；It is highly preferred that 5% to 6% The concentration range of weight exists.
Preferably, cyclodextrin is selected from Alpha, beta or gamma chain cyclodextrin, more preferably 2 hydroxypropyl beta cyclodextrin, also The sulfobutyl ether derivant of more preferably beta-schardinger dextrin-Poloxamer is selected from Poloxamer 407, poloxamer 188；Alkyl Polyethylene Glycol is selected from Polyethylene Glycol 40 stearate, Polyethylene Glycol 35 Oleum Ricini and/or Polyethylene Glycol dehydrogenase 34 0 Semen Ricini Oil.However, for the purposes of the present invention, it is possible to use other poloxamers, alkyl Polyethylene Glycol and/or a combination thereof.
It should be appreciated that the target of the part of the present invention and optimal formulation in this is：Maximize dextrorotation U.S. support miaow The cornea time of staying of pyridine and permeability are absorbed with realizing maximized ophthalmic, minimize systemic circulation and side effect simultaneously.This A little side effect include but is not limited to calm, blurred vision and/or uncomfortable (such as twinge).
Although prior art has confirmed that dexmedetomidine can reduce IOP, (the example of being free from side effects to applicant As calmness) the concentration of dexmedetomidine and the knowledge of formula also do not confirm.
It is critical to the invention that nictation height and low-shearing force during preparation viscosity transition because its need provide Sufficient cornea release and stop, do not have systemic Absorption simultaneously.In the composition of the preparation of this example and concentration best known to Embodiment, but it is not including all.
Have been found that the preparation of the present invention preferably has following non-newtonian feature：
1) producing ratio in low-shearing force in a short time 1-2 second is at least about 5-20:1 viscosity increases, and blinks each A second of some points of the beginning of high shear force in decline, in one preferred embodiment, each is blinked cycle From at least 50cps to 10cps or less；
2), during the low-shearing force in a short time circulating at each, coefficient of elasticity increases about 100 to 1000 within the 1-2 second Times, more preferably at least 2000 times, and wherein during blinking, such modulus is less than 100, preferably smaller than 10, more preferably from about 0；
3) produce the tear film thickness of approximately normal tear film in preferably 30 seconds in one minute when instiling, wherein each circulates Hereafter thickness in a short time under low-shearing force be about 10 μ or less, preferably from about 5 μ；
4) described preparation does not allow to cause excessive twinge or discomfort, reduces compliance or causes unacceptable ocular surface Toxicity；
5) wherein selected composition will not otherwise interfere with drug absorption, or the work otherwise reducing active component Property；And
6) in one preferred embodiment, by about 3% to about 10%, preferably from about 5-6%Pool Lip river is husky Nurse 407 or the high mixed thing carboxymethyl cellulose (CMC) of Polyethylene Glycol 40 stearate, NaCl 0.025%, 0.75% to 1.25% The solution of composition produces corneal stop, cornea drug release and systemic Absorption and suppresses necessary rheology condition, to allow Under than the low concentration of Alpha 2 agonist agent before any, greatly IOP reduces, simultaneously not before the local that finds Or whole body adverse events.
Especially it is surprising that above-mentioned preparation produces instillation high viscosity and is less than in high shear force within tens of seconds 30cps and the at low shear balance viscosity higher than 30cps.Result is suddenly and period, to subtract during instillation every time The nose tear pump of little nose tear passage and minimizing and passage, wherein in one preferred embodiment, CMC is really 1%= 2500cps, and be about 0.80%w/v.
Equally wonderful, unexpected and to optimal cornea absorb and systemic Absorption reduce importantly, UseWhen, CMC is increased preferably to about 0.90% to about 1.2%w/v scope, to be maintained at the dense of 0.80%w/v The similar rheological property finding when being used together to poloxamer or alkyl Polyethylene Glycol under degree.
It is not intended to confine or be limited to specifically theoretical it is believed that when instiling 150cps or higher, tens of seconds inner equilibriums be extremely (reverse each other from a relatively high in suddenly property by non newtonian property less than the high viscosity of non newtonian property after 100cps To at a fairly low；In a short time viscosity and modulus of elasticity suddenly high increase and nictation during some points of high shear force of one second phase Between unexpected He extremely low reduction)：1) produce the most optimal retention time on cornea；2) lead to provide the thin of splendid vision Tear film thickness；3) allow during blinking every time to provide the about 20cps of splendid vision or less viscosity；With 4) because of suppression when instiling Normally high nose tear absorbs and produces initial high viscosity when instiling, and postpones the suction of nose tear and the nose reducing during the nictation cycle After tear absorption, the viscosity of the relatively high magnification numbe of non newtonian increases in a short time.Low-shearing force fast transition within the several seconds is very high Viscosity and high modulus of elasticity, it is sufficient to stop medicine from being administered into concha nasalis by nasolacrimal duct in addition to increasing the cornea time of staying And return circulation, do not damage vision during the nictation cycle.It is not intended to confine in specifically theoretical it is further believed that highly parent What the medicine of fat such as dexmedetomidine or other similar α -2 agonist were embedded in the preparation of the present invention has micelle balance Micelle in nonpolar inner cell in, by by polarity housing shroud therefore in such construction, with respect in the solution from By the medicine floating, decrease the absorption of lipotropy blood vessel endothelium.These characteristics of opthalmological delivery vehicles should be suitable for appointing What solvable therapeutic or Palliative ophthalmology active medicine, to realize optimal vision, comfortableness, effect and safety.
In one preferred embodiment, the invention provides a kind of pharmaceutical composition, it includes：
I. dexmedetomidine, concentration is about 0.0125% to about 0.125%w/v, and more preferably from about 0.035% to about 0.10%w/v, most preferably from about 0.060% to about 0.087%w/v；
Ii. surfactant, selected from concentration be about 1% to about 15%w/v Polyethylene Glycol 40 stearate, cyclodextrin, Gamma cyclodextrin andMore preferably concentration be about 5.5%w/v Polyethylene Glycol 40 stearate or
Iii. carboxymethyl cellulose ((1%=2500 centipoise)), concentration is about 0.10% to about 1.25%w/v, if table Face activating agent is Polyethylene Glycol 40 stearate, more preferably from about 0.80%w/v, or if surfactant isMore Preferably 0.90% to about 1.2%w/v；
Iv. sodium chloride, concentration is about 0.025% to about 0.90%w/v, more preferably from about 0.25% to about 0.50%w/v, Preferably from about 0.037%w/v；
V. benzalkonium chloride (" BAK "), concentration is about 0.007% to about 0.02%w/v；Preferably 0.02%w/v；
Vi. optionally, concentration is about 0.005% to about 0.05%w/v, preferably the antioxidant of 0.015%w/v it is preferable that Described antioxidant is the sodium ethylene diamine tetracetate that concentration is about 0.015%w/v；
Vii. optionally, concentration is about 1 mM to about 100 mMs of buffer agent；Preferably from about 1 to about 5 mM Phosphate or borate buffer, more preferably concentration are about 2 to about 4 mMs of phosphatic buffer agents；And
Viii.pH about 4.0 to about 8.0, preferably from about 6.0 to about 7.0.
Wherein said pharmaceutical composition is effective to the treatment of glaucoma in patient in need.
Another preferred embodiment in, the invention provides a kind of pharmaceutical composition, it includes：
I. dexmedetomidine, concentration is about 0.060% to about 0.087%w/v；
Ii. Polyethylene Glycol 40 stearate, concentration is about 5.5%w/v；
Iii. carboxymethyl cellulose (1%=2500 centipoise), concentration is about 0.80%w/v；
Iv. sodium chloride, concentration is about 0.037%w/v；
V. benzalkonium chloride, concentration is about 0.02%w/v；
Vi. sodium lauryl sulfate, concentration is about 0.01% to about 5.0%w/v, preferably 0.50%w/v；
Vii. optionally, EDTA, concentration is about 0.015%w/v；And
Viii. optionally, phosphate buffer, concentration is about 1 to about 5 mM,
The pH of wherein said compositionss is about 6.0 to about 7.0.
Another preferred embodiment in, the invention provides a kind of pharmaceutical composition, it includes：
I. dexmedetomidine, concentration is about 0.06% to 0.087%w/v；
ii.Concentration is about 5.5%w/v；
Iii. carboxymethyl cellulose (1%=2500 centipoise), concentration is about 0.90% to about 1.1%w/v；
Iv. sodium chloride, concentration is about 0.037%w/v；
V. benzalkonium chloride, concentration is about 0.02%w/v；
V. sodium lauryl sulfate, concentration is about 0.1% to about 1.0%w/v, preferably 0.50%w/v；
Vi. optionally, antioxidant, concentration is about 0.015%w/v；And
Vii. optionally, phosphate buffer, concentration is about 1 to about 5 mM；
The pH of wherein said compositionss is about 6.0 to about 7.0.
Another preferred embodiment in, the invention provides a kind of pharmaceutical composition, it includes：
I. dexmedetomidine, concentration is about 0.080%w/v；
iiConcentration is about 5.5%w/v；
Ii. sodium lauryl sulfate, concentration is about 0.5%w/v；
Iii. cocamido propyl betaine, concentration is about 0.05% to about 0.5%w/v；
Iii. carboxymethyl cellulose (1%=2500 centipoise), concentration is about 0.90% to about 1.1%w/v, preferably 1.05% w/v；
Iv. sodium chloride, concentration is about 0.037%w/v；
V. sodium ethylene diamine tetracetate, concentration is about 0.015%w/v；
Vi. benzalkonium chloride, concentration is about 0.02%w/v；And
Wherein w/v represents w/v, the treatment to glaucoma in patient in need for the wherein said pharmaceutical composition Effectively.
In one embodiment, described pharmaceutical composition can further include that concentration is about 1 mM to about 5 mMs Buffer agent, described buffer agent is selected from citrate buffer agent, borate buffer, maleate buffer, succinate Buffer agent, phosphate buffer, acetate buffer, sorbate buffer agent and carbonate buffer agent, preferably from about 2 mMs extremely About 4 mMs, and pH is about 5.5 to about 7.5.
In one embodiment, the overall pH of described pharmaceutical composition is about 6.0 to 7.0.
In one embodiment, α -2 agonist of described pharmaceutical composition has between about 0.70 to about 2.20, excellent It is selected in the octanol-water partition coefficient Log D between about 1.25 to 2.00.
In one embodiment, the pharmaceutical composition of the present invention can further include mucoadhesive, and it is selected fromXanthan gum and cellulose derivative.However, for the purposes of the present invention, it is possible to use other natural gum and/or glue Solidifying agent and/or viscosifier.
In one embodiment, the concentration of described mucoadhesive is about 0.5% to about 1.0% w/v.
The preparation of the present invention also optionally includes other compositions, for example corneal osmosis reinforcing agent and other.
Present invention also offers treating the side of glaucoma and/or the eyes Posterior pole neural degeneration patient's condition in patient in need Method, including the pharmaceutical composition applying the present invention to described patient.
Additionally, the compositionss of the present invention can provide optic nerve protection, retinal ganglial cellses optic nerve protection, retina The increase of α -2 agonist concentration and other neuroprotective benefits in inner molecular layer.They also can increase endotheliocyte filling And be considered with the discharge at the trabecular reticulum of the α -2a receptor of mankind filling.
Additionally, the method for the present invention and compositionss can be used for, and in experimenter in need, reduction eyes are rubescent and/or increase Plus eyes whiteness.
Unexpected technique effect using the particular combination of composition
It is surprising that the scope being found and combination be found to be maximally effective.Based on prior art, people will be pre- Expect that dexmedetomidine is the worse glaucoma medicine of weaker brimonidine or Aplonidine than lipotropy, find with The lipotropy of dexmedetomidine α -2 agonist clonidine is similar.
Further on, it has been found that, single poloxamer, no matter concentration, not only for the purposes of the present invention Enhanced both effectiveness aspect invalid, and also create moderate in local application to serious twinge, no matter whether it exist In buffer or in non-buffered liquid, also no matter its pH is how many.
Have contemplated that, the concentration of poloxamer, alkyl Polyethylene Glycol or cyclodextrin should be in 15% to 25% scope Interior, within the range it is known that there is the gelatification under room temperature, cornea is stopped and is extended by this gelatification, but adjoint The several minutes being obviously prolonged when instiling or longer obscuring, and/or the physiological range in tension-elevating agent.However, having sent out Existing, when with 12% or less, preferably greater than 3% but in the presence of being less than 10%, poloxamer, alkyl Polyethylene Glycol or cyclodextrin In the combination providing effectively.When poloxamer, alkyl Polyethylene Glycol or cyclodextrin are with 15% or bigger or more much smaller than 2% In the presence of concentration, described compositionss astoundingly poor effect or invalid.
Also wonderful and unforeseeable be, test embodiment in, other gels, for example954 and/or xanthan gum it is impossible to replace poloxamer, alkyl Polyethylene Glycol or cyclodextrin.People will expect this A little medicaments are interchangeable.
Further, using low concentration viscosifier lead to wonderful more side effect and reduce effect, And viscosity is reduced to or is more than 100 times, so that the 1%CMC aqueous solution of 2500cps will be initial in the preparation of the present invention The preferred implementation of about 100 to 250cps during instillation.Also find (that is, there is no poloxamer, alkyl using viscosifier itself Polyethylene Glycol or cyclodextrin) produce the worse preparation of effectiveness, and fuzzy along with the instillation extending, larger systemic Absorption And typically less effect and more side effect.It is surprising that such high viscosity example of preferred viscosity agent Balance drastically and non newtonian benefit as led in CMC 0.80%w/v (wherein 1%=2500cps), during strengthening stop Between, the nose tear passage that simultaneously reduces, from preparation about 100cps when instiling to about 15cps after lower tens seconds of high shear force (nictation) With about 50-70cps under low-shearing force (suddenly).
Further it has surprisingly been found that the tension force working as the preparation providing is 0 to 200mOsm/kg, preferably During 50 to 150mOsm/kg, lasting moistening/lubricant effect will provide least confusion and more preferable comfortableness for patient.Generally, Eye vector requires 280-310mOsm/kg, to realize by using electrolyte or polyhydric alcohol (such as Mannitol).
Further it has surprisingly been found that the sulfobutyl ether derivant of cyclodextrin, more preferably beta-schardinger dextrin-Enhance the rubescent minimizing in local and the whitening effect of α -2 agonist especially dexmedetomidine；This is excellent whereby The cyclodextrin of choosing improves the reduction of intraocular pressure further.
Further it has indeed surprisingly been found that, sodium lauryl tri(oxyethyl) sulfate and/or similar anion surface active Agent includes but is not limited to the interpolation of sodium lauryl sulfate, and the intraocular pressure further enhancing the preparation of the present invention reduces.Meaning The outer preparation being the discovery that invention largely minimize using this analog anion surfactants be generally found any Twinge；Wherein it may also happen that such twinge fully and it has been unexpectedly found that cation surface activating by little concentration The interpolation of agent such as cocamido propyl betaine reduces or essentially eliminates.
The compositionss providing and the advantage of method
The compositionss providing and method are effective for the treatment of glaucoma.Preferably, the compositionss of the present invention are by joining Side manufactures to prevent calmness, elimination or to reduce rubescent, can increase persistent period of therapeutical effect and reduce bounce-back congested and/or its His anaphylactoid incidence rate, and significantly more reduce intraocular pressure than the preparation of α -2 agonist of prior art.
Have discovered unexpectedly that similar dexmedetomidine preparation (such as phosphoric acid is compared in the combination of the composition of offer Dexmedetomidine in salt buffer agent pH 6.4 6.5) produce for dexmedetomidine and reach twice raising and continue Effect, about twice or bigger peak I OP reduce.They additionally provide compares homonymy (eye effect for the treatment of) and (non-controls in offside The eyes treated) five to six times of IOP reduction aspect reduction, reflect the systemic Absorption significantly reducing to the eyes of non-treatment Impact.Dexmedetomidine preparation (0.025% to 0.05% right side in phosphate buffer pH 6.4-6.5 in non-invention Rotation dexmedetomidine) in, contralateral eye IOP is the 90-100% of the IOP of eyes for the treatment of, due to very high systemic Absorption (phase Than with the compositionss of the present invention about 10% systemic Absorption).
In one preferred embodiment, the preparation of the present invention provides 4 hours about 40% in the eyes for the treatment of IOP reduces.Treatment eyes in IOP reduce more than optimized brimonidine preparation (P, 0.1%, PH7.4 or bigger) the middle IOP reduction finding, it is about 20% in the eyes for the treatment of.
The reduction of IOP every 1mm Hg can improve the substantive prevention of visual field losses.During the longer continuous action of the present invention Between produce substantial effect in 24 hours, but the conventional brimonidine preparation of single dose provides IOP to reduce effect only about 12 hours or less.
The common adverse effect of glaucoma medicine especially brimonidine is eyes rubescent (life-time service brimonidine, 20- 25% bounce-back is rubescent), compliance is key issue.For this reason it is believed that with provide compositionss realize rubescent reduction And/or beauty treatment brightens and is possible to significantly increase compliance.Present invention also offers improve wettability and comfortableness, continue to Instillation one hour after.
Additionally, surprisingly, it has been found that new formulation provides the comfortableness more much better than brimonidine, eyes are wet Profit and lubrication, the local side effects substantially reducing, and lead to little (if any) systemic effects.Therefore it provides preparation It is significantly better than brimonidine or the dexmedetomidine preparation of routine.This is more beautiful than dextrorotation with brimonidine for surprising discovery Support miaow pyridine more effectively this prior art more than 20 years is the discovery that contrary.
Therefore, in some embodiments, the beneficial effect of the compositionss being provided includes：
1) onset in a hour；
2) peak effect more than 30%, up to 42% in normotensive eyes；
3) it is reduced beyond the average IOP of the about 15.5 normotensive baseline average of IOP to about 8.66；
4) peak effect of about 3.5 to 4 hours, compared with brimonidine 2 to 2.5 hours；
5) along with the work of great comfortableness and minimum degree to the prolongation not having twinge, ocular pain or eyelid to stimulate With；
6) after instiling, nearly one hour has strong lubrication-wettability effect, only one minute simultaneously instantaneously obscure；
7) pass through reduce rubescent improvement outward appearance and in some cases beauty treatment brighten；
8) compared with the less systemic Absorption of the preparation of invention (reducing about only 16% offside (non-treatment) eyes IOP) With the much higher systemic Absorption of the prior art preparation of dexmedetomidine；
9) the locally and systemically pair relevant with the preparation (such as Aplonidine and brimonidine) of conventional α -2 agonist The minimizing of effect, including but not limited to reduces：MouthfulDry, one's eyes became bloodshot, causalgia and twinge, headache, fuzzy, foreign body sensation, conjunctiva drenches Fawn on, ocular allergies reaction, ocular pruritis, corneal dyeing/erosion, photophobia, eyelid erythema, ocular pain, eyes are dry and astringent, stream Tear, upper airway symptoms, blepharoedema, chemosises, dizziness, blepharitis, eye irritation, gastrointestinal symptom, weakness, vision are different Often, myalgia, eyelid crust, conjunctival hemorrhage, abnormal flavour, insomnia, conjunctiva release, depression, hypertension, anxiety, cardiopalmus/heart rate lose Often, the incidence rate of dryness in the nasal cavity and faintness.
Important some characteristics of compositionss providing are included to α -2 with respect to alpha-1 adrenergic receptor selectivity, Lipophile, tension force and dissolubility
To α -2 with respect to alpha-1 adrenergic receptor selectivity
It is 1000 that selectivity alpha-2 adrenergic receptor agonists have to α -2 comparison α -1 receptor:1 or bigger；More excellent Select 1500:1 or bigger；Even more preferably from 2000:1 or bigger affinity (Ki).Design experiment determines that α -2/ α -1 is functionally selected Property is within the skill of the art.For example, in effect, the active or EC of α -2A receptor50Can be by testing adenyl cyclase The inhibitory action of activity is determining.Further, the inhibitory action of adenyl cyclase activity can stablize table in (but not limited to) Determined in the PC12 cell of the α -2A receptor reaching such as mankind α -2A receptor.Additionally, α -1A receptor effect, activity or EC50Can be determined by measuring intracellular Ca2+.The HEK293 of the α -1A receptor that intracellular Ca2+ stably can be expressed in (but not limited to) Determined in cell such as cattle α -1A receptor.
For the purposes of the present invention it is desirable to avoid or minimize the initiation of α -1 receptor.Even if occurring undesirable α -1 to be subject to The little threshold limit value that body supplements produces sufficient universal vasoconstriction, micro milling change and/or proinflammatory cytokine release, To reduce the effectiveness of the active treatment effect that α -2 receptor causes.Because all known α -2 agonist all have α -2 and compare The relative affinity of α -1, this part affinity is measured by the ratio that α -2 and α -1 receptor senses, the product wherein greatly increasing The storehouse to determine the reality of α -2 and α -1 receptor-inducible for the thing selectivity α -2 affinity i.e. concentration C % degree of-α -2/ α -1 ratio x Total amount.
The scope of the necessary high selectivity, high lipophile and relatively low intensity of discovery of a-1 effect of induction changes completely IOP effect and the side effect distribution of α -2 anti-depressant medications are become.Therefore, when these α -2 agonist are used for treating glaucoma, They substantially reduce IOP, for example rebound hyperemia without being considered the significant side effect related to α -1 receptor.
In some embodiments, the compositions and methods of the invention include the excitement of selectivity alpha-2 adrenergic receptor Agent, it has to α -2 more than 1500 times or bigger K of α -1 receptori, and there is the octanol-water of about LogP2.50 3.0 join Coefficient, but in order to local pH (Log D) is adjusted between 0.75 to 3.08.The physiological pH of tear and ocular fluids is 7.4, It is equal to the pH under LogP, according to the requirement of the present invention, gives the benefit that IOP reduces.Cornea physiological requirements soft and not Same capryl alcohol-water Log value (referred to as Log D is determined by the pH of preparation), so that preparation can not only penetrate on lipophilic cornea Chrotoplast and endotheliocyte, and the hypothalluses of hydrophilic centre can be penetrated.
In an also other embodiment, the compositions and methods of the invention include selectivity alpha-2 adrenergic to be subject to Body agonist, it has to α -2 more than 00 times or bigger K of α -1 acceptor 10i, and concentration is about 0.0035% to about 0.035% w/v.
Brimonidine, guanfacine, guanabenz, dexmedetomidine and fado miaow pyridine (fadolmidine) are that some are enough Meet high selectivity α -2 agonist of option demand.However, in these high selectivities α -2 agonist, only dextrorotation Dexmedetomidine meets the preferred formulation characteristic of other extra present invention, such as lipophile.Other α -2 agonist (such as chlorine pressure Fixed) it is probably lipophilic enough, but it is the absence of enough selectivitys.
It is now recognized that the most preferred selectivity alpha-2 adrenergic receptor agonists being suitable for the object of the invention are conducts HCl salt or the dexmedetomidine as citrate.Other salt can similarly substitute HCl.
Therefore, in some embodiments, the compositions and methods of the invention include dexmedetomidine, or other selections Property alpha-2 adrenergic receptor agonists, concentration is about 0.0125% to about 0.125% w/v；Preferably, about 0.025% to about 0.125% w/v；More preferably from about 0.045% to about 0.10% w/v, even more preferably about 0.060% to about 0.087%.
Believe that new α -2 agonist can be synthesized to meet the needs of the present invention.
Lipophile
For any given opthalmological, optimal lipophile exists to maximize the necessary cornea penetrating into lipophilic In superficial epithelial cells and internal layer epithelial cell in lesser degree.If medicine is too hydrophilic, epithelial cell becomes difficult With the obstacle gone beyond.If medicine too lipophilic, medicine can not be by more hydrophilic substrate.
Lipophile can be measured, for example with known evaluation methodology, such as the Log P (log of octanol-water partition coefficient KOW) derivative and/or the coefficient XLogP3-AA being closely related.See, e.g., Tiejun Cheng et al, Computation of Octanol-Water Partition Coefficients by Guiding an Additive Model with Knowledge,J.Chem.Inf.Model.,2007,47(6),pp 2140–2148.These measurements represent for eye drops Topical remedy ophthalmic lipophile value (once i.e., drug osmotic to cup and be in 7.4 pH).The ordinary skill of this area Personnel are very familiar with these measuring methods.Therefore, Log P value is be physiological pH in pH 7.4 under capryl alcohol-water coefficient.
Find in the prior art, increase pH and produce the distribution of more preferable lipophile so that brimonidine when instiling in local Moderate lipophilic, and produce good corneal osmosis.For weak base, α -2 agonist, such as brimonidine and dexmedetomidine, PH gets over meta-alkalescence, stronger in the ionization alkali discharging H+ and the balance migrating to the non-ionized alkali of the left side (non-ionized), Produce the compound of more lipophilic.This is especially true for α -2 agonist of the pKa value having close or larger than 7.0, for bromine not Buddhist nun is fixed and dexmedetomidine it is particularly the case.This is because under more alkaline pH regulator, more compounds with non-from Sub-ization form exists, therefore, on the contrary, under the conditions of more acid pH, more medicines are ionized and lipotropy is deteriorated. Generally, when discuss preparation or will when under the conditions of about 7.4 physiological pH measure Log P and/or XLogP3-AA.
For most medicines, the general trend from 2.0 to 3.0 Log P value be considered as best lipophile scope although The scope that some absorb best medicine is from 1.00 to about 2.50.Because every kind of medicine has the Log P of their own, and warp Often it is examined to stablize the operation of Log D/pH, seldom know how this is further optimized in order to local is administered every kind of medicine. LogP value is that high drug/medicine subclass is specific, although forecasting software algorithm has been developed that do not have entirely accurate Means go to measure preferable LogP value, in order to the pharmaceutical preparation advised is to optimize intraocular penetration.
Scope between+2.0 to+3.0 allows generally for following best compromise therebetween：A) highly lipophilic medicine Penetrate in lipophilic corneal epithelial cell and lesser degree, the need of the very thin internal layer cornea film being referred to as descemet's membrane Want, and b) penetrate the medicine of the highly-hydrophilic of substrate, described substrate is the cornea " three having to penetrate through for effective ocular absorption The middle level of Mingzhi ".
The group of disclosed poloxamer, viscosifier and hypisotonic solution is combined in disclosed concentration range and provides dextrorotation U.S. The delivery vehicles of support miaow pyridine (and thinking the lipophilic drugs to height for other moderates), it does not rely on pH, mainly not Depend on the lipophile of drug alone.
The Optimal pH (that is, physiological equilibrium to before pH 7.4, the local of preparation administration pH) providing preparation is such pH： Log " D " value leading to medicine (initial local lipophile) is between 0.75 to 3.08, between preferably 0.92 to 2.98, is expressed as Best comfort and stability, 4.0 to 8.0 maximum pH scope, 4.5 to 7.0 preferred pH scope.
It is apparent that for some dexmedetomidine preparations it has been observed that the increase of twinge, especially 4.0 to 7.0, Under especially 4.0 to 4.5 pH.Further on, it has been found that, it is added to some of dexmedetomidine in 0.9%NaCl Buffer agent makes medicine less effective：Particularly, its 6.0 to about 6.4pH scope phosphate buffer.
It has been found, however, that the preparation of the present invention (that is, includes those systems of all required composition of all desired concns Agent) local application, insensitive to pH.Further, effect of the preparation of the present invention no longer seems is to be included by buffer agent Phosphate buffer specifically reduces realization.Think in invention formulation, the particular combination of composition is to various active medicines Impart this pH independence and increased solubility range, for glaucoma and other purposes, and the absorption providing increase Property and reduce systemic side effects；Including but not limited to steroid, non-steroidal compounds, anti-infective (antiviral agent and Antimicrobial) and maculopathy Drug therapy such as anti-VEGF.
According to currently preferred LogP (and XLogP3-AA) value limit ophthalmic performance those for the mesh of the present invention Be suitable between about 1.00 to 4.50；It is highly preferred that between about 2.0 to 3.50.If the selection of specific α -2 agonist Property is substantially greater than 1000:1 (for example, 1500:1), then extra advantage think be endowed affine by more preferable α -2 agonist Property and reduce α -1 agonist induction ischemia.For example, as it is known that optic nerve injury is in progress to circulation change and ischemia Extremely sensitive.Because when medicine used within a very long time, even if lacking in the local of unconscious α -1 agonist-induction The little reduction of blood aspect can also be beneficial.Therefore, the discovery α -2 agonist ophthalmic lipophile of the present invention is by Log P table Show, by α -2:The selectivity that α -1 receptor recruitment rate represents, seems the higher effect for α -2 agonist glaucoma drug Extremely important.If selectivity is more than such as 2000:1 it is likely that this agonist can be under the lipophile of less reduction The purpose of the present invention is effective, and vice versa.
Table 1 provides known XLogP3-AA value (more accurately Log P) and affine to α 2/ α 1 of several α -2 agonist Power.
Table 1
Table 1 shows in listed α -2 agonist, only dexmedetomidine have high lipophile (XLogP3-AA) and High selectivity α 2:The optimum combination of α 1 coefficient.However, obtain meeting what the present invention limited in selectivity and lipophile classification Require, preparation including other α -2 agonist is possible.
In some embodiments, dexmedetomidine or other selectivity alpha-2 adrenergic receptor agonists, About 3.10 are had under the conditions of ophthalmic pH7.4；Preferably, about 2.0 to 5.00；More preferably from about 2.75 to 3.50 Log P.
Because LogD refers to the lipophile value under the conditions of given pH, this measurement especially to measure local lipophile and The level of the corneal permeability of the corneal epithelial cell by highly lipophilic property for the topical composition producing therewith is useful.
Normally, higher LogP value, such as 3.0 or bigger, it is limited by highly lipophilic property substrate, therefore for most eyes For topical remedy of section, the lipophile of compromise is 1.0 to 3.0, more preferably 1.5 to 2.5.Corneal permeability is complicated item, It can be subject to polar surfaces, H+The impact of donor activity, key rotation and active delivery phenomenon.
The present invention is the discovery that, about 0.75 to about 2.20, the LogD value of more particularly about 1.00 to about 1.50 is for carrying The corneal permeability of α -2 agonist similar with other of the dexmedetomidine in high normal saline is preferred, preferably shorter than 6.4 To 6.5 pH, " carrier " of the present invention includes poloxamer, viscosifier and hypotonic saline or sterilized water, greatly reduces and possible Such pH is completely eliminated limit.
When selectivity α -2 agonist is dexmedetomidine, under conditions of local pH is about 4.7 to 6.0, most preferably Log D value is 0.75 to 2.2, more preferably from about 1.00 to 2.00.
Tension force
In order to local conveys comfortable purpose, opthalmological typically requires about 275 to 320mOsm/kg tension force.Various tension force Reinforcing agent, including but not limited to electrolyte, especially 0.9%NaCl, and polyhydric alcohol, such as Mannitol, can be used for realizing institute Desired scope.
The present invention surprising discovery is that, poloxamer, alkyl Polyethylene Glycol or the ring being about 3% or more when concentration When dextrin is combined with viscosifier, such comfort level is enhanced, and does not have tension force to strengthen or tension force strengthens reduction about 25- 150mOsm/kg, single poloxamer local height under 3% or bigger concentration stimulates.
Dissolubility
The dissolubility of α -2 agonist exponentially reduces under conditions of pH increase.Table 2 shows dexmedetomidine The relation of pH and dissolubility in water.Its display declines with higher pH, the solvable CI formula of dexmedetomidine.For The dissolubility of 4.0 6.0 pH, very high level exists.
Table 2
PH solution Dissolubility (mg/ml) Maximum solvable concentration
6.0 1.953 0.195%
6.4 ～0.60 0.060%
7.0 0.224 0.023%
7.4 ～0.150 0.015%
8.0 0.134 0.013%
In order to realize maximum dissolubility while retentive activity, the compositionss of the present invention should include salt；Concentration is 12% w/v or less poloxamer；And viscosifier.For example, using the compositionss providing, dexmedetomidine Exhibit up to or the solubility more than 0.15%.
The dissolubility of other similar medication in dexmedetomidine and its subclass generally increases and exponential form fall with pH Low.For example under the conditions of high alkalinity pH, dexmedetomidine is only about 0.025% solvable in normal saline.It is believed that the system of invention Agent leads to the raising of the dissolubility of dexmedetomidine, by the extension of other members of subclass, under ph basic conditions can be very It is higher than well 0.125%.
Think the activity of α -2 agonist and dexmedetomidine, may be by some hydrophilic especially in normal saline Or the excipient of polarity negatively affects, described excipient include citrate, various viscosity intensifier (such as polyvinyl alcohol), Various buffer agents (such as phosphate buffer) and various gellant (such as xanthan gum).
Therefore, innovation rather than inappreciable be that the concrete combination of the only little composition of quantity leads to preferably Activity and stability, thus unexpectedly outstanding than other similar formulations.This result is completely unexpected, and It is unlikely to be and strengthened by simple gelation or viscosity：For example, xanthan gum,954 and carboxy methylcellulose Element is individually or combination all can not give the effect equal with brimonidine.
Therefore, very unexpected and it is surprising that compared with the dexmedetomidine preparation in normal saline, carry For the composition of preparation provide not only effect of improvement, and be prepared for the preparation than brimonidine preparation higher level.This is Wonderful, because the comparison of prior art dexmedetomidine and brimonidine under condition of similarity confirms brimonidine being Preferably α -2 agonist.It is more less than brimonidine that the prior art test confirms that dexmedetomidine (and clonidine) leads to The reduction of IOP and more preferable systemic Absorption.Therefore, unexpectedly and it is surprising that specific and very limited Under conditions of, dexmedetomidine is more more effective than the dexmedetomidine preparation of prior art, and effective sex ratio brimonidine High by about 200% (IOP of relative time reduces, and it is the criterion of the key of effectiveness that IOP reduces).
Can be used for the purpose of the present invention raising dissolubility other medicaments (if salt, poloxamer, alkyl Polyethylene Glycol Or cyclodextrin and viscosifier are included in the composition) include, but not limited to polyanion (with multiple negative charges) compound, Such as methylcellulose and derivant, especially carboxymethyl cellulose or other cellulose derivatives；Hypotonic saline；Sodium acetate, Calcium salt, metilsulfate (mesylate), hydrobromate/bromide, acetate, fumarate, sulfate/disulfate, Succinate, citrate, phosphate, maleate, nitrate, tartrate, benzoate, carbonate, embonate, Borate, carboxylic acetate, pivalate, sodium citrate monohydrate, sodium citrate trihydrate, sodium carbonate, ethylenediamine Tetraacethyl sodium (" EDTA "), phosphoric acid, pentetic acid five sodium, etidronic acid four sodium, tetrasodium pyrophosphate, ethylenediamine triacetic acid diammonium, hydroxyl Ethyl-3-acetic acid ethylenediamine, diethylenetriamine pentaacetic acid, nitrilotriacetic acid and various other alkaline buffer salt and/or interpolation cyclodextrin And/or their derivant, especially (2- hydroxypropyl)-beta-schardinger dextrin-；Some solvents are for example20 (Tween is The registered trade mark of Uniqema Americas company limited),80th, polyvinyl alcohol, propylene glycol and its analog or derivative Thing；Some penetrating agent, such as Mannitol or sucrose, hydroxypropyl methyl cellulose (" HPMC ") or its analog and/or derivant, Or some chelating agen.
Some preferred embodiment in, described compositionss include anhydrous citric acid sodium about 0.17% and/or sodium acetate About 0.39%；And/or calcium salt about 0.048%.
The compositions and methods of the invention
The compositions and methods of the invention include all isomery bodily forms of described alpha-2 adrenergic receptor agonists Formula, their racemic mixture, Enol forms, solvation and nonsolvated forms, analog, prodrug, derivant, including but It is not limited to ester and ether, and pharmaceutically acceptable salt, including sour salt adding.Suitably form the acid of salt example be hydrochloric acid, sulphuric acid, Phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, first sulphur Acid, tartaric acid and other mineral carboxylic acids well known in the art.In conventional manner, described salt can by free alkali form with required The acid contact of q.s produces salt to prepare.Free alkali form can be by for example dilute hydroxide of the aqueous slkali of the dilution with being suitable for Potassium, ammonium carbonate and sodium bicarbonate aqueous solution process described salt regeneration.In terms of some physical propertys, free alkali form is to a certain degree Above different from its respective salt form, such as the dissolubility in polar solvent, but for the purpose of the present invention, acid salt etc. It is same as its respective free alkali form.(see, e.g. S.M.Berge, et al., " Pharmaceutical Salts, " J.Pharm.Sci.,66:1-19 (1977), it is incorporated herein).
As long as be suitable for the specific isomer of selectivity alpha-2 adrenergic receptor agonists, salt, analog, prodrug or Other derivants are so that it may for the purpose of the present invention.
In some embodiments, the compositions and methods of the invention include the excitement of selectivity alpha-2 adrenergic receptor Agent, it has affinity (K α -2 being exceeded to 00 times of α -1 acceptor 10 or biggeri), and be highly lipophilic, have about 2.00 or bigger octanol-water partition coefficient.By comparing, brimonidine has and α -2 is exceeded to about 976 times of α -1 receptor Affinity, its lipophile scope, even if optimized by pH, also it is less than about 300 times of dexmedetomidine, preferred embodiment party Formula.
In another embodiment, the compositions and methods of the invention include selectivity alpha-2 adrenergic receptor swash Dynamic agent, it has and α -2 is exceeded to 00 times or bigger K of α -1 acceptor 10i, concentration is about 0.001% to about 0.035% weight Volume ratio.
In some embodiments, the compositions and methods of the invention include the excitement of selectivity alpha-2 adrenergic receptor Agent, it has and α -2 is exceeded to 1500 times or bigger K of α -1i, dense with about 0.010% to about 0.040% w/v Degree exists, and has about 6.2 or less pH.
In some embodiments, the compositionss of the present invention may also include other therapeutic agents；However, the mesh of described compositionss Be in the case of not needing any other therapeutic agent (specifically include, but be not limited to, α -1 antagonist) effectively.
Present invention also offers with provide composition treatment and/or preventing glaucoma method.The method providing reduces IOP in glaucoma patient, reduce rubescent and provide eyes to brighten.The neuroprotective of the compositionss due to providing, carries For method also can treat the neuropathy of ischemic optic neuropathy and other various causes of disease.
The compositionss of the present invention are preferably mammal and are more preferably mankind's preparation.In an embodiment of the invention In, described compositionss are transported to eyes as ophthalmic solution.Present invention further contemplates that topical composition, it includes, but not limited to Gel and emulsifiable paste.They may also include extra non-treatment component, and it includes, but not limited to preservative, delivery vehicles, tension force Regulator, buffer agent, pH adjusting agent, antioxidant, toughness regulator, mucoadhesive, viscosity modifier and water.
In order to prepare the topical composition of the present invention, can simply dilute selectivity α -2 Agonist solutions of more concentration, make With the diluent of method well known in the art specific gellant in the solution, it is Polyethylene Glycol in a preferred embodiment 40 stearates.Additionally, the preparation of the present invention optionally includes one or more electrolyte or tension-elevating agent, preferably a kind of Or multiple weak acid and/or its salt, to realize 4.0-8.0, more preferably the preparation pH of 5.5-6.5.
A kind of method for optimizing being diluted is related to frozen overnight, dissolving active medicine and other excipient.This is dissolving Known technology with medicine associated with poloxamer.It is also possible, however, to use additive method.The compositionss of the present invention may include logical It is usually used in the various non-active ingredients prepared topical composition and preparation stability can be improved.For example, the compositionss of the present invention May include alcohol and/or surfactant, including but not limited to polyglycol ether, Polyethylene Glycol-nonyl 2, 2-Oxydiphenol, Polyethylene Glycol loses Water sorbitan monolaurate, Polyethylene Glycol sorbitan monooleate, polyethylene glycol monooleate, Polyethylene Glycol stearic acid Ester, Polyethylene Glycol glycol polypropylene ether, polyvinyl alcohol, polyvinylpyrrolidine, PEG and its derivant (including but not limited to PEG 4000 or PEG 6000), its total content is the 0.05% to 5% of composition quality.
In some embodiments, the compositionss of the present invention may include acid or have the fatty acid of 8 to 12 carbon atoms Monoglyceride, when its 0.5 1.5M, preferably with Alpha's 2 agonist equimolar concentration when can be formed by ion pair；Or antioxidant Such as ion exchange/photooxidation stabilizer (including but not limited to citric acid, sorbic acid, boric acid, octanoic acid, Capmul MCM C8, list Caproin, glyceryl monolaurate, sodium pyrosulfite) improving corneal osmosis.
In some embodiments, the compositions and methods of the invention may include the chelating agen improving stability further, It includes but is not limited to related acid in ethylenediaminetetraacetic acid (" EDTA ") and structure, even more preferably citric acid or its salt. In some embodiments, described chelating agen is existed with the concentration of 0.005% to 0.2% weight/volume.
Preservative includes, but not limited to benzalkonium chloride (" BAK "), methyl parahydroxybenzoate, poly benzene Ester, methaform, thimerosal, phenylmercuric acetate, perborate or phenylmercuric nitrate.Especially have been found that BAK with preferably Embodiment effective.
Delivery vehicles include, but not limited to polyvinyl alcohol, Polyethylene Glycol (" PEG ") and the like, polyvidone, hydroxypropyl Ylmethyl cellulose, poloxamer, carboxymethyl cellulose (" CMC "), hydroxyethyl cellulose and purified water.Also physiology salt can be used Aqueous solution is as main carrier.
Tension regulator includes, but not limited to salt such as sodium chloride, potassium chloride, glucosan, cyclodextrin, Mannitol, dextrorotation Sugar, glycerol, or other acceptable tension regulators pharmaceutically or on ophthalmology.In some embodiments, this tension modifier Existed with the concentration of 0.1% to 1% w/v.
The compositionss of the present invention may include corneal osmosis reinforcing agent, and it includes, but not limited to preservative, cyclodextrin, thickening Agent and ion channel agent.In some embodiments, corneal osmosis reinforcing agent includes citrate, citrate and/or increase Other salt of dissolubility, chelating agen such as EDTA, preservative, ion channel agent, cyclodextrin, or increase other of corneal permeability Additive.
In certain embodiments of the present invention, corneal osmosis reinforcing agent is selected from 0.007%-0.02% w/v BAK, the EDTA of 0.015% w/v, octanoic acid, citric acid, boric acid, sorbic acid and/or its salt, derivant with similar Thing, wherein citric acid or its salt are preferred embodiment.
In some embodiments, the compositions and methods of the invention may include other viscosifier and/or improve dissolving Degree and/or the medicament of stability, including but not limited to Polyvinylpyrrolidone, Polyethylene Glycol (" PEG "), the fibre of various molecular weight Dimension element or cellulose derivative (including methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose, CMC and its salt), gelatin, Sorbitol, Alpha-cyclodextrin and/or other cyclodextrin derivative, nicotiamide, the Carbomer of various molecular weight (include card ripple Nurse 934P and 974P), xanthan gum, alginic acid, guar gum, tracasol, shitosan, propylene glycol, polyvinyl alcohol, poly- sorbic acid Ester (inclusion polysorbate 80), glycerol, Mannitol, benzylalcohol, phenethanol, polyvidone, boron ester, acetate, phosphate and other Similar buffer agent salt or medicament, BAK, essence of Niobe, sodium sulfite or peroxide protective system, surfactant, etc. Deng.In some embodiments, these medicaments are existed with the total content of 0.05%-5%w/v..
Listed many additives (such as BAK, EDTA etc.) can be used for multiple purposes：For example, they be used as anti-corrosion Agent and corneal osmosis reinforcing agent (such as BAK), or solubilising, antiseptical and corneal osmosis enhanced medicament (such as citric acid Salt).
Buffer agent and pH adjusting agent include, but not limited to acetate buffer, carbonate buffer agent, Citrate buffer Agent, phosphate buffer and borate buffer.It should be appreciated that multiple acid or alkali can be used for adjusting described group as needed The pH of compound.PH adjusting agent includes, but not limited to sodium hydroxide and hydrochloric acid.Antioxidant includes, but are not limited to, sodium pyrosulfite, Sodium thiosulfate, acetylcysteine, butylhydroxy anisole and ditertbutylparacresol.
Embodiment 1 intraocular pressure (IOP), rubescent and causalgia/twinge
Experimental design
By the preparation of multiple α -2 agonist be individually applied to normotensive (<21mm Hg) human experimenter.Tested Person experiences the baseline IOP test using standard applanation tonometry by slit lamp first.After fluorescein instils, in the morning greatly About 7:00 to 9:Between 00, medicine is slowly instilled according to morning dose.In the preliminary surveying card of 2,3,3.5,4 and 4.5 hours Substantive peak effect between about 3.45 to 4.15 hours for the preferred preparation of the real present invention.Follow-up IOP checks and sets It is calculated as about 4 hours after initial instillation, wherein instiling to be dripped by 1-2 forms.
Experimental result
Comparison human research be：A) the preferred embodiment contrast of the present invention；B) dextrorotation not containing poloxamer is beautiful Support miaow pyridine preparation；And c) brimonidine confirms compared to existing technology, the significant treatment advantages of compositionss of the present invention.
Especially, dexmedetomidine (in phosphate buffer 6.4) and brimonidine (P) existing The test of technology preparation is consistent with disclosed data, is shown in normotensive rabbit 30-35%IOP and reduces (equal in blood pressure The decline of about 20% in normal human eye, human eye has thicker cornea and less intraocular penetration).Compare it Under, the present invention shows wonderful improvement, peak value about 4 hours (comparing not fixed 2 hours of Buddhist nun) in terms of IOP reduction, compares Brimonidine reduces close to the big IOP of twice, more preferable local comfort, preferably rubescent minimizing, the local side effects of minimizing And the systemic side effects reducing.
Table 3 shows the result of this experiment.
Table 3
Table 4-8 summarizes containing the various preparations of dexmedetomidine and the research of excipient.Especially, table 4 display is worked as Dexmedetomidine concentration is equal to or greater than about when 0.02% notable side effect, for example calm, compares table 4 and prior art is ground Study carefully, table 5 shows the substantial amounts of and wonderful improvement preferred embodiment using dexmedetomidine.
Table 4
Poloxamer, normal saline
* separate sources
Table 5
CMC, poloxamer, normal saline
* phosphate-buffered
Table 6
Poloxamer, CMC, hypotonic NaCl, pH
* alternative source
* * 0 is lacrimal ductule blocking in 30 seconds
Table 7
Other viscosifier, xanthan gum, poloxamer, pH
* phosphate-buffered
Table 8
Xanthan gum, NaCl, polysorbate80
As shown in table 4-8, have minimum side-effect profile maximally effective compositionss be comprise about 5-6% poloxamer, Those of CMC, sodium chloride and BAK.For the preferred embodiment of the present invention, the peak dose responding IOP reduction occurs in about 0.070%-0.10%.
Embodiment 2 utilizes the intraocular pressure (IOP) of Polyethylene Glycol 40 stearate
Experimental design
0.08% dexmedetomidine, 5.5% Polyethylene Glycol 40 stearate, 0.80% carboxymethyl cellulose will be included (1%=2500 centipoise), 0.015% sodium ethylene diamine tetracetate, 0.037% sodium chloride, 0.02% benzalkonium chloride and 5mM pH are The preparation of 6.0 phosphate buffer be separately administered to normotensive (<21mmHg) human experimenter.Experimenter experiences first Using the baseline IOP test by slit lamp for the standard applanation tonometry, the baseline IOP of its display 15.After fluorescein instils, In about morning 7:00 to 9:Between 00, medicine is slowly instilled according to morning dose.At the beginning of 2,3,3.5,4 and 4.5 hours Pacing amount confirms the preferred preparation of the present invention substantive peak effect between about 3.45 to 4.15 hours.Follow-up IOP checks and is designed as about 4 hours after initial instillation, wherein instiling to be dripped by 1-2 forms.
Experimental result
Especially, dexmedetomidine (in phosphate buffer 6.4) and brimonidine (P) existing The test of technology preparation is consistent with disclosed data, is shown in normotensive rabbit 30-35%IOP and reduces (equal in blood pressure The decline of about 20% in normal human eye, human eye has thicker cornea and less intraocular penetration).Compare it Under, present invention show in human experimenter wonderful be improved to 8.66 IOP reduce (42% baseline is comparedIt is less than 15%-20% in normotensive eyes), peak value is in about 3.5 hours (comparing not fixed 2 hours of Buddhist nun), phase Ratio brimonidine, reduces close to the big IOP of twice and 1/2nd times, more preferable local comfort, preferably rubescent minimizing, subtracts Few local side effects and the systemic side effects of minimizing.
The effect to intraocular pressure (IOP) and side effect for the embodiment 3
Experimental design
First, after fluorescein instils, using flattening slit lamp tonometry, experimenter is carried out with baseline IOP test.So Afterwards, apply the topical agent of two tests at a distance of the several seconds to left eye, lacrimal point blocks 30 seconds.After about 4 hours, carry out IOP again Test.Obtain three initial readings and given up to guarantee patient's blepharospasm of minimum degree, afterwards by rear three readings Record is simultaneously average.Several days removing phases to 1 week are had during test.The time instiled is morning 8:00-9:00 point, Suo Youji Line IOP measurement is all between 15.0-15.5mm Hg.
For the test of two dexmedetomidine preparations, side effect is qualitatively classified as 0-4, and (0- has no side effect；4- Height side effect (twinge during instillation, eyes are dry, pharyngeal dryness, fatigue, calm).
Experimental result
Comparison human research be：A) the preferred embodiment contrast of the present invention；B) pH not containing poloxamer exists 0.10% dexmedetomidine preparation in the phosphate buffer of 6.4-6.5；And c) brimonidine it was demonstrated that comparing bromine not Buddhist nun The prior art preparation of fixed or dexmedetomidine, the significant treatment advantages of compositionss of the present invention.
Present invention show the improvement of wonderful IOP reduction aspect, compare brimonidine, close to the big IOP of twice Reduce, more preferable comfortableness, preferably rubescent minimizing, the local side effects of minimizing and the systemic side effects of minimizing.
Table 9 shows the result of this experiment.
Table 9
* public data
* dexmedetomidine 0.10%, poloxamer gel 5-6%.The high mixed thing 0.75% of CMC.BAK 0.02%, pH 6.0
This experiment confirms the prior art preparation comparing brimonidine or dexmedetomidine, the combination of the invention providing The treatment benefit being greatly improved and the whole body of improvement and local side effects distribution that thing produces.
Embodiment 4 954 and the impact to dexmedetomidine for the Poloxamer 407, strengthen with and without viscosity Agent, with and without NaCl
Experimental design
The target of this experiment is that research is added954 (C) and Poloxamer 407 (P) (independent and combination) opposite The impact of the effectiveness of local dexmedetomidine of 0.025% w/v in reason saline.954P and pool Lip river The concentration of husky nurse 407 is in the range of 1% to 8%.
Experimental result
Table 10 shows the result of this experiment.
Table 10
C：Carbomer 934P
P：Poloxamer 407
As shown in table 10, the mankind are applied, single Poloxamer 407 or single Carbomer 934P are It is not provided that satisfied local comfort.However, the combination of the Poloxamer 407 of certain concentration and viscosity agent (such as CMC) carries The comfortableness improved and IOP has been supplied to reduce.Extra comfortableness and higher IOP is had to reduce under conditions of more hypotonic solution Effect.
Especially, the combination of the salinity of poloxamer 1-10%, viscosity agent and reduction provides splendid comfortableness.Best Preparation comprise the high mixed thing CMC 0.62-0.75%+NaCl 0.025% of poloxamer 5-6%+.It provides best comfortable Property, IOP impact treatment eyes and minimum local-systemic effects (pharyngeal dryness).
Embodiment 5 compares the right side using the brimonidine 0.20% in phosphate buffered saline (PBS), dexmedetomidine 0.010% The comparison of the eyes intraocular pressure for the treatment of and non-treatment of rotation dexmedetomidine preferred implementation
Experimental design
Following preparation is compared：
A) brimonidine (P) (compositionss B)
B) 0.01% dexmedetomidine, phosphate-buffered to pH 6.4 (compositionss C)；With
C) 0.1% dexmedetomidine and 5% Poloxamer 407 (F127), the high mixed thing of 0.25%NaCl, CMC 0.75% and BAK 0.02%pH 6.1 (compositionss A) (preferred embodiment).
Two every kind of test formulation are put into the left eye of experimenter, be not used for accurately on the single date between administration Obturation and remove (weakening) (between several days to one week).After 2.5 and 3.75 hours, treatment and enter in the eyes of non-treatment Row intraocular pressure measures.
Experimental result
Table 11 shows the result of this experiment.
As shown in table 11, this experiment confirms herein below：
1) compare brimonidine (compositionss B), produce twice in the eyes for the treatment of with the preparation (compositionss A) of the present invention Big IOP peak value % reduces；
2) compare brimonidine (compositionss B), produce twice with the preparation (compositionss A) of the present invention in the eyes of non-treatment Few IOP% reduces；
3) compare the dexmedetomidine preparation (compositionss C) of replacement, after 4 hours, with the preparation (compositionss A) of the present invention Produce the big IOP peak value % of twice to reduce in the eyes for the treatment of；
4) brimonidine (compositionss B), the longer work of the peak I OP reduction of the preparation (compositionss A) of the present invention are compared Increase to 4 hours with the persistent period from 2.5 hours.
These results show compared with similar dexmedetomidine compositionss and traditional brimonidine compositions, this The raising of effect of compositionss of invention and the minimizing of systemic Absorption.
Represented relatively using the larger difference that the composition treatment IOP and the eyes of non-treatment between of the present invention reduces Low low systemic side effects distribution, such as it is understood to have with the systemic Absorption of medicine of eyes of non-treatment of leveling off to reducing Close.
Embodiment 6 compares baseline, the impact to IOP for compositionss A during 24 hours
Experimental design
In the morning 8:30, treat normal with two compositionss A (as described in example 5 above) list instillation each eyes Power baseline IOP (<Three experimenters 21mmHg), then inaccessible 30 seconds on time, applied at the 1st, 3,5 days.
In one or more 4 hours, 8 hours, 12 hours, 24 hours, measurement in 32 hours, comfortableness and side effect divided IOP Cloth is qualitatively assessed.
Experimental result
Table 12 shows the result of this experiment.
Table 12
Table 12 (Continued)
Table 12 (Continued)
As shown in Table 12, the preparation of the invention tested is realized peak I OP for about 4 to 8 hours after instillation and is reduced effect. Further, in two patients in three, 24 hours IOP after instillation are maintained at below baseline.Generally, conventional bromine is not Buddhist nun's customization agent about 2-3 hour after instillation occurs peak I OP of about 15-18% in only normotensive eyes to reduce effect.This It is higher that the IOP of the preparation of invention reduces effect：Instil latter 8 hours from 41.7% to 58.8%.
Therefore, brimonidine and glaucoma medicine known to other, under similar test condition, the system of the present invention are compared Agent shows the raising (use of 1-2 days, normotensive eyes) of performance.
Significant locally or systemically side effect is not observed.
Embodiment 7 is used Replace the effect of poloxamer or alkyl polyglycol surfactants
Table 13 is usedReplace the effect of poloxamer or alkyl polyglycol surfactants
By the formula of table 13 be used alone in normotensive (<21mm Hg) human experimenter.Experimenter experiences first Using the baseline IOP test by slit lamp for the standard applanation tonometry, (day becomes the baseline IOP of its display about 15.0-16.5 Change curve, depending on the daily time).After fluorescein instils, in about morning 7:00 to 9:Between 00, by medicine according to morning Dosage slowly instills.Preliminary surveying at 2,3,3.5,4 and 4.5 hours confirm the preferred formulation of the present invention about 3.45 to Substantive peak effect between 4.15 hours.Follow-up IOP checks and is designed as, about 4 hours after initial instillation, wherein instiling Dripped by 1-2 and form.
Experimental result
Especially, dexmedetomidine (in phosphate buffer 6.4) and brimonidine (P) existing The test of technology preparation is consistent with disclosed data, and described disclosed data display is in the IOP of normotensive rabbit 30-35% Reduce that (equal to the decline of about 20% in normotensive human eye, human eye has thicker cornea and less Intraocular penetration).By contrast, the present invention shows wonderful improvement in terms of IOP reduction, and peak value (was compared at about 4 hours Mo Niding 2 hours), compare brimonidine and reduce close to the big IOP of twice, more preferable local comfort, preferably rubescent minimizing, The local side effects reducing and the systemic side effects of minimizing.In the normotensive eyes of human experimenter, (as above-mentioned reality Applying and see in example 2) formula #33 shows that wonderful about 5.0 improvement in terms of IOP reduction (are compared baseline to reduce 30%), peak value is about 3.5 hours (comparing brimonidine 2 hours), compare brimonidine close to two and 1/2nd times big IOP reduces.Adding sodium lauryl sulfate (" SLS ") in formula #34 leads to IOP reduction to be further increased to about from baseline 33.5% reduces (comparing formula #33,3.5% improvement).Be converted to from Polyethylene Glycol 40 stearateLead to IOP Reduction is further increased to about 43.5% reduction from baseline and (compares formula #3,33.5% improvement.Be converted toSimultaneously Add the additional effect that SLS leads to make IOP reduction increase to about 47% (comparing formula #33,13.5% improvement) from baseline.So And,In SLS be totally different from Polyethylene Glycol 40 stearate, lead to significant twinge.The interpolation of CAPB mitigates ?The twinge that middle SLS finds, creates the preparation (formula #37) of highest ranking.In addition, with Polyethylene Glycol 40 Hard Fat Acid esters is compared, due toMobility relative increase, the concentration of CMC increases from 0.80%w/v (formula #33 and #34) It is added to the scope of 0.90% to 1.1%w/v (formula #35-37), preferably 1.05%.

Claims (20)

1. a kind of pharmaceutical composition, it includes
I concentration is the alpha-2 adrenergic receptor agonists of about 0.0125% to about 0.125% w/v, wherein said Alpha-2 adrenergic receptor has 2.0 or bigger LogP value, and has alpha-2 adrenergic receptor is exceeded to α -1 kidney 50 times of upper parathyrine energy receptor 9 or bigger affinity；
The hypotonic salt of ii or sterilized water；
Iii concentration is cyclodextrin, poloxamer or the alkyl Polyethylene Glycol of about 2% to about 12% w/v；And
Viscosifier,
Wherein said pharmaceutical composition has the viscosity between 25 to 500cps,
Wherein said pharmaceutical composition is effective to treating glaucoma in patient in need.
2. pharmaceutical composition according to claim 1, wherein said alpha-2 adrenergic receptor agonists are concentration is about The dexmedetomidine of 0.035% to about 0.10% w/v.
3. pharmaceutical composition according to claim 1, wherein said salt be selected from sodium chloride, citrate, mesylate, Hydrobromate/bromide, acetate, fumarate, sulfate/disulfate, succinate, phosphate, maleate, nitre The group that hydrochlorate, tartrate, benzoate, carbonate and embonate are constituted.
4. pharmaceutical composition according to claim 1, wherein said salt is sodium chloride.
5. pharmaceutical composition according to claim 1, wherein said viscosifier are selected from carboxymethyl cellulose, Methyl cellulose Element, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, Polyethylene Glycol, glucosan, polyvidone, alginic acid, Guar gum, Radix Acaciae senegalis,Gelatin, shitosan,Tracasol, acid polycarbophil, Portugal gather The group that sugar, pectin, polyvidone, povidone, polyvinyl alcohol and hyaluronic acid are constituted.
6. pharmaceutical composition according to claim 4, wherein said viscosifier are carboxymethyl celluloses.
7. compositionss according to claim 6, wherein said carboxymethyl cellulose is concentration is 0.1% to 1.25% weight The height of volume ratio mixes thing.
8. pharmaceutical composition according to claim 1, wherein said cyclodextrin, poloxamer or alkyl Polyethylene Glycol with The concentration of 5% to 6% w/v exists.
9. pharmaceutical composition according to claim 1, it further includes buffer agent.
10. pharmaceutical composition according to claim 9, wherein said buffer agent is selected from citrate buffer agent, borate Buffer agent, maleate buffer, succinate buffers, phosphate buffer, acetate buffer, sorbate buffer agent The group constituting with carbonate buffer agent.
11. pharmaceutical compositions according to claim 9, the concentration of wherein said buffer agent is at 4 mMs to 10 mMs Between.
12. pharmaceutical compositions according to claim 1, it further includes mucoadhesive, described mucoadhesive choosing FromXanthan gum and the group of cellulose derivative composition.
A kind of 13. pharmaceutical compositions, it includes：
I. concentration is about 0.0125% to about 0.125%w/v dexmedetomidine；
Ii. concentration is about 1% to about 15%w/v surfactant, and it is selected from Polyethylene Glycol 40 stearate, cyclodextrin, γ ring Dextrin andThe group constituting；
Iii. concentration is about 0.10% to about 1.25%w/v carboxymethyl cellulose (1%=2500 centipoise)；
Iv. concentration is about 0.025% to about 0.90%w/v sodium chloride；
V. concentration is about 0.007% to about 0.02%w/v benzalkonium chloride；
Vi. optionally, concentration is about 0.005% to about 0.05%w/v antioxidant；
Vii. optionally, concentration is about 1 mM to about 100 mMs of buffer agent；
Wherein w/v represents w/v, and the pH of wherein said compositionss is about 4.0 to about 8.0, wherein said pharmaceutical composition Treatment to glaucoma in patient in need is effective.
14. pharmaceutical compositions according to claim 13, wherein,
I. the concentration of dexmedetomidine is about 0.060% to about 0.087%w/v；
Ii. described surfactant is Polyethylene Glycol 40 stearate that concentration is about 5.5%w/v；
Iii. the concentration of carboxymethyl cellulose (1%=2500 centipoise) is about 0.80%w/v；
Iv. the concentration of sodium chloride is about 0.037%w/v；
V. the concentration of benzalkonium chloride is about 0.02%w/v；And
Vi. the concentration of optional antioxidant is about 0.015%w/v；
Vii. optional buffer agent is the phosphate buffer that concentration is about 1 to about 5 mM,
The pH of wherein said compositionss is about 6.0 to about 7.0.
15. compositionss according to claim 14, it further includes the moon that concentration is about 0.01% to about 5.0%w/v Osmanthus base sodium sulfate.
16. compositionss according to claim 13, wherein
I. the concentration of dexmedetomidine is about 0.06% to 0.087%w/v；
Ii. surfactant be concentration be about 5.5%w/v
Iii. the concentration of carboxymethyl cellulose (1%=2500 centipoise) is about 0.90% to about 1.2%w/v；
Iv. the concentration of sodium chloride is about 0.037%w/v；
V. the concentration of benzalkonium chloride is about 0.02%w/v；
Vi. the concentration of optional antioxidant is about 0.015%w/v；And
Vii. optional buffer agent is phosphate buffer, and concentration is about 1 to about 5 mM；
The pH of wherein said compositionss is about 6.0 to about 7.0.
17. compositionss according to claim 16, it further includes the Laurel that concentration is about 0.1% to about 1.0%w/v Base sodium sulfate.
A kind of 18. pharmaceutical compositions, it includes：
I. dexmedetomidine, concentration is about 0.080%w/v；
ii.Concentration is about 5.5%w/v；
Ii. sodium lauryl sulfate, concentration is about 0.5%w/v；
Iii. cocamido propyl betaine, concentration is about 0.05% to about 0.5%w/v；
Iii. carboxymethyl cellulose (1%=2500 centipoise), concentration is about 0.90% to about 1.2%w/v；
Iv. sodium chloride, concentration is about 0.037%w/v；
V. sodium ethylene diamine tetracetate, concentration is about 0.015%w/v；
Vi. benzalkonium chloride, concentration is about 0.02%w/v；And
Vii. optionally phosphate buffer or borate buffer, concentration is about 1 mM to about 5 mMs,
Wherein w/v represents w/v, and wherein said compositionss pH are about 6.0 to 7.0, and wherein said pharmaceutical composition is to having The treatment of the glaucoma of patient needing is effective.
A kind of 19. methods treating glaucoma in patient in need, apply according to claim 1 including to described patient Pharmaceutical composition.
A kind of 20. methods of the eyes Posterior pole neurodegenerative diseases treated in patient in need, including to described patient Apply pharmaceutical composition according to claim 1.
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