CN101094690A - Compositions and methods for treating a posterior segment of an eye - Google Patents
Compositions and methods for treating a posterior segment of an eye Download PDFInfo
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- CN101094690A CN101094690A CN 200480033259 CN200480033259A CN101094690A CN 101094690 A CN101094690 A CN 101094690A CN 200480033259 CN200480033259 CN 200480033259 CN 200480033259 A CN200480033259 A CN 200480033259A CN 101094690 A CN101094690 A CN 101094690A
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Abstract
compositions for injection into the vitreous of human eyes or animal eyes, and methods of using such compositions are provided. Such compositions can include particles containing corticosteroid in a therapeutically effective amount, a viscosity inducing component, and an aqueous carrier component. The compositions have viscosities of at least about 10 cps or about 100 cps at a shear rate of 0.1/second. In a preferred embodiment, the viscosity is in the range of from about 140,000 cps to about 300,000 cps. The compositions advantageously suspend the particles for prolonged periods of time.
Description
The present invention relates to be used for the treatment of the compositions and the method for human or animal's oculi posterior segment.More specifically, the present invention relates to effectively to be injected to the compositions that comprises the corticosteroid composition of described oculi posterior segment, also relate to and use described compositions so that the method for required therapeutic effect to be provided.
One of existing therapy that usually is used for the treatment of the oculi posterior segment disease is at the intravitreal injection corticosteroid, triamcinolone acetonide (TA) for example, and described oculi posterior segment disease is uveitis, degeneration of macula, macular edema etc. for example.Referring to, people's such as Billson U.S. Pat 5,770,589 for example, the disclosure of described patent is this complete including in of mode by quoting.
A kind of medicine that is usually used in above ophthalmology therapy is Kenalog 40.Every milliliter of (ml) Kenalog 40 compositions comprise 40 milligrams of (mg) TA, sodium chloride as tension regulator (tonicity agent), 10mg benzyl alcohol as antiseptic and 7.5mg carboxymethyl cellulose and 0.4mg polysorbate80 as the resuspending auxiliary agent.Although this commercial preparation is extensively adopted by the ophthalmologist, it still has many important limitation.
For example, the existence of benzyl alcohol antiseptic and polysorbate80 surfactant easily causes unnecessary in the ocular tissue of sensitivity and/or over-drastic primary cellular defect or other toxicity.Even some clinician uses saline " cleaning " TA precipitate for several times according to conventional, to reduce the concentration of above-mentioned undesirable substance, this cleaning also is not only inconvenient but also consuming time, the most important thing is, this cleaning can increase the possibility of microorganism or contaminated with endotoxins, thereby causes intraocular infection and inflammation.
In addition, the easy sharp separation and being precipitated out from the composition residues thing also of the TA among the Kenalog 40.For example, if said composition left standstill 1 to 2 hour, can cause the TA precipitate from the composition residues thing, to separate in a large number.Therefore, if said composition is injected to ophthalmic, just it acutely must be rocked and use immediately after rocking, so that suspension uniformly to be provided substantially within the eye.In addition, resuspending is handled and also to be needed to use above-mentioned resuspending auxiliary agent, and at least a described auxiliary agent to be not responsive ocular tissue need fully.
Need be in order to being injected to the new compositions of human or animal's oculi posterior segment, and the method that required therapeutic effect is provided at human or animal's oculi posterior segment.
Summary of the invention
Have now found that the new compositions and the method that are used for the treatment of human or animal's oculi posterior segment.Compositions of the present invention is very suitable for delivering medicine in the vitreous body oculi posterior segment, both need not any " cleaning step ", provides the intraocular damage of reduction in the time of can also using within the eye simultaneously, for example retina injury.Advantageously, compositions of the present invention is not added the antiseptic composition substantially, does not for example contain the benzyl alcohol antiseptic.Further advantageously, compositions of the present invention does not also need the resuspending auxiliary agent.Generally speaking, compositions of the present invention can be injected to human or animal's oculi posterior segment simple and effectively, also can need not resuspending and handle, and for example need not to rock or stir compositions to obtain suspension uniformity substantially, and keep substantially uniform suspended state for a long time, for example keep at least about a week or more of a specified duration.In brief, the compositions and methods of the invention for example with respect to prior art Kenalog 40 compositionss and use for the described existing method for compositions, provide significant improvement and advantage in human or animal's oculi posterior segment.
A more wide in range aspect of the present invention provides in order to be injected to the compositions of human or animal's oculi posterior segment.Described compositions comprises that corticosteroid composition, viscosity brings out composition (viscosityinducing component) and aqueous carrier composition.The corticosteroid composition is the treatment effective dose.The corticosteroid composition exists with a large amount of particulate forms in compositions.
Compositions of the present invention can comprise the most about 25% (w/v) or the more corticosteroid composition of compositions.In an embodiment that is highly profitable, the amount of corticosteroid composition is at least about the 80mg/ml compositions.The amount of preferred corticosteroid composition is about 1% to about 10% or about 20% (w/v) of compositions.
In an embodiment that is highly profitable, the corticosteroid composition comprises triamcinolone acetonide.
Viscosity is brought out the amount of composition for effectively improving the amount of composition viscosity.
Any suitable viscosity is brought out composition, preferably can the eye usefulness viscosity bring out composition, all can use according to the present invention.Most described viscosity bring out composition be proposed be used in that eye is gone up or ophthalmic with in the ophthalmic composition, and/or be used in the above-mentioned ophthalmic composition.Advantageously, viscosity bring out the amount of composition be compositions about 0.5% to about 20% (w/v).In a useful especially embodiment, it is hyaluronic acid polymer composition, for example hyaluronate sodium that viscosity is brought out composition.
In one embodiment, compositions of the present invention cuts at 0.1/ second that viscosity under the speed is at least about 10cps or at least about 100cps, preferably at least about 1, and 000cps, more preferably at least about 10,000cps, further more preferably at least about 70,000cps, for example be up to about 250,000cps, or about 300,000cps.Compositions of the present invention is transformed into certain structure or has a fixed structure (are structured or have make-ups), with effectively for example in manual mode preferably by No. 27 needle tubings, more preferably be injected to human or animal's oculi posterior segment by No. 29 or No. 30 needle tubings.
Be not that hope is limited to the present invention under the prerequisite of any concrete intreractive theory, think and use full-bodied relatively compositions as described in the present application, effective, the uniform steroid composition of preferred general particle suspension liquid are provided, can also be injected to oculi posterior segment by needle tubing commonly used or the needle tubing littler simultaneously than needle tubing commonly used.
In one embodiment of the invention, the corticosteroid composition exists with a large amount of particulate forms, described granule is suspended in the compositions substantially equably, and in compositions, keep substantially uniform suspended state at least about 1 week, preferably at least about 2 weeks or at least about 1 month, and further more preferably at least about 6 months or at least about 1 year or at least about 2 years, need not resuspending simultaneously and handle, promptly need not to rock or stirring so that corticosteroid composition granule is kept substantially suspended state uniformly in compositions.
Have the described corticosteroid composition grains of composition that evenly suspends substantially, the significant advantage of relative prior art is provided.Particularly, compositions of the present invention can be made, transports and store for a long time, and corticosteroid composition granule can not be precipitated out from the residue of compositions yet.In compositions, have the corticosteroid composition granule that evenly suspends substantially, make compositions needn't consider to make described granule resuspending again fast and effeciently in order to the treatment to human or animal's oculi posterior segment to be provided.
The aqueous carrier composition advantageously can eye usefulness, and can comprise that one or more are used for the conventional excipients of ophthalmic composition.
For example, carrier components can comprise at least a in antiseptic composition, tension regulator composition and the buffer agent composition of effective dose.
In an advantageous embodiment, compositions of the present invention is not added the antiseptic composition.This feature has reduced and can have caused or relative ophthalmic untoward reaction by the antiseptic composition, or described untoward reaction is minimized, and perhaps even has substantially eliminated described untoward reaction.
Although the resuspending composition can use according to the present invention, because need not the resuspending processing, compositions of the present invention can keep substantially suspended state uniformly for a long time, therefore in most cases compositions is not advantageously added the resuspending composition.
Also disclose the method for treatment human or animal oculi posterior segment, described method is included in the scope of the present invention.Generally speaking, described method comprises and will contain the compositions of corticosteroid composition that compositions for example of the present invention delivers medicine to, and for example is injected to human or animal's oculi posterior segment.Described administration can provide required therapeutic effect effectively.Dosing step advantageously comprises at least a following mode: inject on (sub-tenon) injection, retrobulbar injection, the choroid under intravitreal injection, subconjunctival injection, the fascia bulbi etc.
Each feature described in the application, and each combinations of two or more described features include within the scope of the invention, are not contradiction each other as long as be included in feature in the described combination.
Above-mentioned and other aspect of the present invention and advantage are apparent in the following specific embodiment, embodiment and claim.
The specific embodiment
The present invention relates in order to be positioned over, preferably be positioned over the compositions of human or animal's oculi posterior segment by the mode of injection.Compositions in the described oculi posterior segment, for example intravitreous compositions for the symptom of one or more oculi posterior segment diseases and/or disease and/or one or more described oculi posterior segment diseases and/or disease, is that treatment is effective.
Generally speaking, compositions of the present invention comprises the corticosteroid composition; Viscosity is brought out composition; And aqueous carrier composition.Described compositions advantageously can eye usefulness.
A considerable advantage of the present composition is, suggestion in order to the compositions of intravitreal injection relatively in the early time to oculi posterior segment, for example trade mark is the commercial composite of Kenalog -40 relatively, the present composition is to the tissue in the oculi posterior segment, as the amphiblestroid compatibility better or more friendly.The spy is in addition, compositions of the present invention is not advantageously added the antiseptic composition substantially, or comprise following effective antiseptic composition, described effective antiseptic composition is included in the benzyl alcohol antiseptic in Kenalog -40 compositions relatively, and the compatibility of its oculi posterior segment (as retina) better or more friendly.
In addition, compositions of the present invention is not preferably added the resuspending composition, or preferably include following resuspending composition, and described resuspending composition is included in the polysorbate80 in Kenalog -40 compositions relatively, and the compatibility of its oculi posterior segment (as retina) is better or more friendly.Of the present invention many other features that the application states in addition also make the relative prior art compositions of compositions of the present invention, relative Kenalog -40 for example, to the compatibility of the oculi posterior segment of placing it better or more friendly.
As mentioned above, compositions of the present invention comprises the corticosteroid composition.Described corticosteroid composition is the treatment effective dose in compositions, the amount of required therapeutic effect promptly effectively is provided at the ophthalmic that is placed with compositions.The corticosteroid composition exists with a large amount of particulate forms in compositions.
Any suitable corticosteroid composition all can use according to the present invention.Described corticosteroid composition advantageously for example has limited dissolubility in the 25EC water.For example, the corticosteroid composition preferably the dissolubility in 25EC water less than 10mg/ml.The corticosteroid composition naturally should eye usefulness, promptly should be substantially ocular structure or ocular tissue not be produced remarkable or over-drastic adverse effect.Useful especially being characterised in that of useful corticosteroid composition of the present invention, described composition can alleviate in being placed with the oculi posterior segment of said composition by one or more oculi posterior segment diseases and/or the caused inflammation of disease.
The example of useful corticosteroid composition includes but not limited to: cortisone, prednisolone, omcilon, triamcinolone acetonide, flurandrenolide, dexamethasone, medrysone, loteprednol, its derivant and composition thereof.Use as the application, term " derivant " is meant with the material that is confirmed to be derivant and compares, structure is enough similar, thus when replacing described material to use function or active similar substantially any material, described function or activity are for example treated effectiveness.
In an embodiment that is highly profitable, the corticosteroid composition comprises triamcinolone acetonide.
The amount of corticosteroid composition advantageously is at least about the every ml compositions of 10mg.A considerable advantage of the present invention is that compositions of the present invention can comprise the corticosteroid of relative more amount or higher concentration effectively.Therefore, the amount of corticosteroid in the present composition can be, compositions about 1% or more be low to moderate about 5% or about 10% or about 20% or about 30% or higher (w/v).The corticosteroid composition of relative higher concentration or more amount is provided in the compositions of the present invention, be of value to and reduce the required amount that is positioned over or is injected to the compositions of oculi posterior segment, thereby include the compositions that is lower than 4% (w/v) corticosteroid composition relatively, for example relative Kenalog -40 can provide same amount or more corticosteroid composition in oculi posterior segment.Therefore, in an embodiment that is highly profitable, compositions of the present invention comprise greater than about 4% (w/v), for example at least about 5% (w/v), to the corticosteroid composition of about 10% (w/v) or about 20% (w/v) or about 30% (w/v).
Viscosity is brought out the amount of composition for effectively improving the amount of composition viscosity, advantageously for significantly improving the amount of composition viscosity effectively.Be not that hope is limited to the present invention under the prerequisite of any concrete intreractive theory, think when composition viscosity is increased to the viscosity that is higher than water, when for example cutting speed down at least about 100cps in 0.1/ second, the compositions that obtains can be positioned over very effectively, for example is injected in human or animal's oculi posterior segment.The relative viscosity higher of the present composition, except compositions of the present invention advantageously being positioned over or being injected to the deutomerite, think that also it can improve the following ability of the present composition, promptly need not the resuspending processing and make corticosteroid composition granule in compositions, keep substantially the evenly ability of suspended state for a long time, for example keep at least about a week.Another benefit of the relative viscosity higher of the present composition is, have at least the compositions of helping to exist, when for example making described corticosteroid composition keep substantially evenly suspended state for a long time, can also have the corticosteroid composition of volume more or higher concentration, state in addition as the application.
Advantageously, the present composition cuts at 0.1/ second that viscosity under the speed is at least about 10cps or at least about 100cps or at least about 1000cps, more preferably at least about 10,000cps, and further more preferably at least about 70,000cps or higher, for example be up to about 200,000cps or about 250,000cps, or about 300,000cps or higher.Compositions of the present invention not only has above-mentioned higher relatively viscosity, can also be positioned over effectively, be positioned over effectively after perhaps being transformed into certain structure or structure, for example be injected in human or animal's oculi posterior segment, preferably by No. 27 needle tubings or even No. 30 needle tubings.
Useful viscosity of the present invention is brought out composition and is preferably shear thinning composition (shear thinningcomponent), this be because, bring out the compositions of the present invention of composition by narrow space when containing described shear thinning viscosity, for example be passed to or when being injected to oculi posterior segment, the viscosity of compositions significantly reduces under shear conditions in described transmittance process by No. 27 needle tubings.Through after the above-mentioned transmission, compositions returns to the viscosity before its injection substantially, so that corticosteroid composition granule is kept suspended state within the eye.
Any suitable viscosity is brought out composition, for example can the eye usefulness viscosity bring out composition, all can use according to the present invention.Most described viscosity bring out composition be proposed be used in that eye is gone up or ophthalmic with in the ophthalmic composition, and/or be used in the above-mentioned ophthalmic composition.Viscosity is brought out the amount of composition for the amount of required viscosity effectively is provided to compositions.Advantageously, to bring out the amount of composition be about 0.5% or about 1.0% to about 5% or about 10% or about 20% (w/v) of compositions to viscosity.The accurate consumption that viscosity is brought out composition depends on all multifactor, comprise, such as but not limited to, employed concrete viscosity bring out composition, employed viscosity bring out the molecular weight of composition, required viscosity prepared and/or the employed present composition, or the like.Viscosity is brought out composition to be selected, so that compositions of the present invention has at least one advantage in the following areas, preferred a plurality of advantage, for example: injectable is to oculi posterior segment, viscosity, need not resuspending and handle and make the corticosteroid granule keep suspended state for a long time, for example keep substantially suspended state uniformly, to compatibility of the oculi posterior segment tissue that is placed with compositions or the like.Selected viscosity is brought out composition more preferably can effectively provide above-mentioned two or more benefits, and above-mentioned benefiting further more preferably is provided.
Viscosity is brought out composition and is preferably included component of polymer and/or at least a viscoelastic agent (viscoelastic agent), for example is used for the material of external coat method.
The example that useful viscosity is brought out composition includes but not limited to: hyaluronic acid, carbomer, polyacrylic acid, cellulose derivative, polyacrylic resin, polyvinylpyrrolidone, gelatin, dextrin, polysaccharide, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, its derivant and composition thereof.
The molecular weight that useful viscosity of the present invention is brought out composition can be, about 10,000 dalton or more be low to moderate about 2,000,000 dalton or higher.In a useful especially embodiment, the molecular weight that viscosity is brought out composition is that about 100,000 dalton or about 200,000 dalton are to about 1,000,000 dalton or about 1,500,000 dalton.In addition, the viscosity used of the present invention molecular weight that brings out composition can change in quite wide scope according to following factor: employed viscosity is brought out required final viscosity and one or more other possible factors of the kind of composition, the described present composition.
In an embodiment that is highly profitable, it is polymerization hyaluronic acid salt component that viscosity is brought out composition, for example hyaluronic acid slaine composition is preferably selected from hyaluronic acid alkali metal salt, hyaluronic acid alkali salt and composition thereof, and further more preferably is selected from hyaluronate sodium and composition thereof.The molecular weight of described hyaluronic acid salt component is preferably, and about 50,000 dalton or about 100,000 dalton are to about 1,300,000 dalton or about 2,000,000 dalton.In one embodiment, compositions of the present invention comprises about 0.05% to about 0.5% (w/v) polymerization hyaluronic acid salt component.In another useful embodiment, the amount of hyaluronic acid salt component be compositions about 1% to about 4% (w/v).Under a kind of situation in back, high polymer viscosity can form and make particles settling speed be reduced to the gel of following degree, promptly in the compositions storage life of expection, for example needn't carry out resuspending and handle at least about 2 years.Because not easy-to-use needle tubing of gel and syringe shift from bulk container (bulk container), therefore described compositions can be contained in advance in the syringe and sell.
The aqueous carrier composition advantageously can eye usefulness, and can comprise that one or more are used for the conventional excipients of ophthalmic composition.
Compositions of the present invention preferably includes a large amount of aqueous waters.Compositions of the present invention for example can be aseptic before being used for ophthalmic, and preferably aseptic.
Compositions of the present invention preferably includes the buffer agent composition of the amount of at least a effective control combination thing pH, and/or comprises the tension regulator composition of the amount of at least a effective control combination thing tension force or osmotic pressure.Preferred, compositions of the present invention had both comprised that the buffer agent composition also comprised the tension regulator composition.
Buffer agent composition and tension regulator composition can be chosen from field of ophthalmology routine and known corresponding composition.
The example of described buffer agent composition includes but not limited to: acetate buffer, citrate buffer agent, phosphate buffer, borate buffer etc. and composition thereof.Useful especially is phosphate buffer.Useful tension regulator composition includes but not limited to: salt, particularly sodium chloride, potassium chloride, any suitable other can eye with tension regulator composition and composition thereof.
The pH that the consumption of buffer agent composition preferably is enough to make compositions is about 6 to about 8 scopes, and more preferably from about 7 to about 7.5 scopes.The osmotic pressure that the consumption of tension regulator composition preferably is enough to make the present composition is respectively about 200 to about 400mOsmol/kg scope, and more preferably from about 250 to about 350mOsmol/kg scope.Advantageously, compositions of the present invention is isoosmotic substantially.
Compositions of the present invention can comprise one or more other compositions, and the amount of described other compositions is for effectively providing the amount of one or more useful performances and/or benefit to the present composition.For example, although compositions of the present invention can not added the antiseptic composition substantially, but in other embodiments, compositions of the present invention has still comprised the antiseptic composition of effective dose, described antiseptic composition is for the tissue in the oculi posterior segment that is placed with compositions, and is preferably perhaps more friendly mutually than benzyl alcohol.The example of described antiseptic composition includes but not limited to: benzalkonium chloride, chlorhexidine, PHMB (poly hexamethylene biguanide), methyl hydroxybenzoate and ethyl hydroxybenzoate, hexedine, the chlorite composition, for example stable chlorine dioxide disinfectant, chlorous acid slaine etc., antiseptic that other can eye usefulness etc. and composition thereof.The concentration of antiseptic composition in the present composition if any, for making the effective antiseptical concentration of compositions, is generally about 0.00001% to about 0.05% or about 0.1% (w/v) of compositions.
In addition, compositions of the present invention also can comprise the resuspending composition of effective dose, and described resuspending composition can effectively promote corticosteroid composition particle suspending or resuspending in compositions of the present invention.As mentioned above, in certain embodiments, compositions of the present invention is not added the resuspending composition.Other embodiments of the present composition have then been used the resuspending composition of effective dose, for example to guarantee that more corticosteroid composition granule is in suspended state as required, and/or relatively easily resuspending is in compositions of the present invention to guarantee corticosteroid composition granule more, and wherein said resuspending state is needed.Advantageously, resuspending composition used in the present invention if any, is selected it, and is so that it is for the tissue in the oculi posterior segment that is placed with compositions, perhaps more friendly mutually than polysorbate80.
Any suitable resuspending composition all can use according to the present invention.The example of described resuspending composition includes but not limited to: surfactant, for example poloxamer (poloxane), for example commercially available poloxamer of trade mark Pluronic by name; Alevaire; Sarcosinate; Polyoxyethylenated castor oil, other surfactants etc. and composition thereof.
The resuspending composition that one class is highly profitable is selected from vitamin derivative.Although above-mentioned substance has been proposed in the early time and has been used as surfactant in the ophthalmic composition, have been found that it can effectively be used as the resuspending composition in the present composition.The example of useful vitamin derivative includes but not limited to: vitamin E tocopherol polyethyleneglycol succinate, for example vitamin E tocopherol polyethyleneglycol 1000 succinates (vitamin E TPGS).Other useful vitamin derivatives include but not limited to: vitamin E tocopherol polyethyleneglycol succinamide (polyethylene glycolsuccinamide), vitamin E tocopherol polyethyleneglycol 1000 succinamides (vitamin E TPGSA) for example, wherein the ester bond between Polyethylene Glycol and the succinic acid is replaced by amide groups.
The amount of useful resuspending composition of the present invention in the present composition, if any, for for example in the preparation of compositions process or effectively promote the amount of particle suspending in the present composition thereafter.The accurate consumption of resuspending composition can foundation, and for example following factor changes in the scope of broad: employed concrete resuspending composition, wherein use the resuspending composition concrete compositions, or the like.The suitable concentration of resuspending composition in the present composition, if any, be generally compositions about 0.01% to about 5%, for example about 0.02% or about 0.05% to about 1.0% (w/v).
For the corticosteroid composition that is slightly soluble in eye inner tissue, triamcinolone acetonide for example, its rate of dissolution may limit the availability of this material.Dissolving is both favourable also harmful to the patient more slowly.On the one hand, separately after the intravitreal injection compositions of the present invention, do not excise at vitreous body among the patient of (nonvitrectonize) advantageously, the average elimination half-life of triamcinolone acetonide is quite long, for example about 19 days, and can survey levels of drugs and all can detect being about most in 3 months.On the other hand, because the particulate rate of dissolution of corticosteroid composition is slow, so camera vitrea bulbi may can't reach therapeutic drug levels about 1 in about 3 days.
In one embodiment of the invention, the solubilization composition (solubilizing component) of effective dose is provided in compositions, so that a spot of corticosteroid composition dissolving promptly is lower than 50%, for example 1% or about 5% to about 10% or about 20% corticosteroid composition dissolving.For example, comprise about 0.5 cyclodextrin component to about 5.0% (w/v), for example beta-schardinger dextrin-, sulfobutyl ether beta-schardinger dextrin-(SBE), other cyclodextrin etc. and composition thereof can make the about 1 triamcinolone acetonide dissolving to about 10% predose.Dissolved in advance this part provides the loading dose that is easy to biological utilisation (loading dose), thereby has avoided the extension of treatment effectiveness to take place.
The use of described solubilization composition helps corticosteroid composition rapid release to ophthalmic and treats effectiveness with acquisition.Described solubilization composition naturally should eye usefulness, or at least the oculi posterior segment that is placed with compositions is had enough compatibilitys, to avoid that described oculi posterior segment tissue is caused over-drastic damage.
The pharmacokinetics of glass vivo medicine-feeding corticosteroid composition (for example triamcinolone acetonide) both can relate to the rate of dissolution of medicine, also can relate to medicine through the effusive speed of anterior ocular segment approach (anterior route).For example, intravitreal injection contains after the compositions of 4% (w/v) triamcinolone acetonide separately, and TA concentration reaches peak (monitoring in the aqueous humor) after a couple of days, the thousands of milligammas of promptly every mL.This peak (C
Max) afterwards, be to continue about 200 hours quick decline, be half-life in about 19 days slower elimination stage at last.The patient needs repetitively administered usually, and for example about every three months once.
In one embodiment of the invention, compositions also comprises the slow release composition of the amount of effective reduction local diffusion speed and/or corticosteroid granule rate of dissolution, and for example polymer for example gathers (D, the L-lactide) or poly-(D, L-lactide-glycolide copolymer).Consequently obtain C
MaxThe elimination rate curve of lower more straight (flatter) and longer treatment curtain heading tape prolong the interval that most of patients need be injected with this.
Any suitable slow release composition, the slow release composition of optimum condition acceptance (conditionallyacceptable) all can adopt.Useful example as mentioned above.Slow release composition preferably ophthalmic is biodegradable, but or the ophthalmic bio-absorbable, with realize long-time in no residue residual.The amount of included slow release composition can change in the scope of broad relatively according to following factor for example: employed concrete slow release composition, required concrete release profiles, or the like.Be included in the common consumption of the slow release composition in the present composition, if any, be about 0.05% to 0.1% to about 0.5% or about 1% (w/v) or higher of compositions.
Compositions of the present invention can be by mixing/process technology or the technology preparation that is fit to, for example by one or more conventional hybrid technologies.The reply preparation for processing is selected so that the present composition becomes the form that can be positioned over or be injected to human or animal's oculi posterior segment.In a useful embodiment, the corticosteroid composition is combined with water, prepared dense corticosteroid composition dispersion liquid, wherein excipient (replace viscosity and bring out composition) is included in the final composition.Said components is mixed, and the corticosteroid composition is disperseed, then autoclaving.Perhaps, the steroid powder also can be by γ-excite before adding to sterile carrier.Viscosity is brought out composition both can buy commercially available sterile product, also can sterilize by conventional method, and weak solution is filtered, and the low pressure sublimation drying obtains sterilized powder then.Make aseptic viscosity bring out composition and combine, make the aqueous dope with water.Under the aseptic condition, mix dense corticosteroid composition dispersion liquid, and add to viscosity with the form of serosity and bring out in the composition dope.Add capacity (in right amount) water,, compositions is mixed to evenly so that desired composition to be provided.
The method of using the present composition also is provided, and described method is included in the scope of the present invention.Generally speaking, described method comprises compositions of the present invention is delivered medicine to human or animal's oculi posterior segment, obtains required therapeutic effect with this.Dosing step advantageously comprises at least a following mode: inject on injection under intravitreal injection, subconjunctival injection, the fascia bulbi, retrobulbar injection, the choroid etc.The injecting apparatus that comprises appropriate size needle tubing (for example No. 27 needle tubings or No. 30 needle tubings) can be effectively in order to be injected to compositions human or animal's oculi posterior segment.
Can include but not limited to according to the present invention's treatment or disease/disease of handling:
Maculopathy/retinal degeneration: non-exudative age-related macular degeneration (ARMD), exudative age-related macular degeneration (ARMD), choroidal neovascularization formation, diabetic retinopathy, acute macula lutea neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, diabetic macular edema;
Uveitis/retinitis/choroiditis: acute many kitchen ranges property squamous pigment epithelium pathological changes, Behcet (Behcet ' s Disease), birdshot sample retina choroidopathy, infectious disease (syphilis, Lyme disease (Lyme), tuberculosis, toxoplasmosis), intermediate uveitis ((orbiculus ciliaris inflammation), many kitchen ranges property choroiditis, multiple one property crossed white point syndrome (MultipleEvanescent White Dot Syndrome, MEWDS), ocular tubercle disease (OcularSarcoidosis), posterior scleritis, crawl row choroiditis (serpiginouschoroiditis), fibrosis and uveitis syndrome under the retina, Vogt-Koyanagi-harada's syndrome;
Angiopathy/exudative disease: retinal artery occlusion disease, central retinal vein occlusion, DIC, branch retinal vein occlusion, the hypertensive cerebral optical fundus changes, ocular ischemia syndrome, the arteria retina microaneurysm, chronic Coats disease (Coat ' sDisease), parafovea telangiectasis, the half side vein obstruction of retina (Hemi-RetinalVein Occlusion), look nipple phlebitis (Papiilophlebitis), central retinal artery occlusion, branch retinal artery occlusion, carotid disease (CAD), frost sample dendroid vasculitis (Frosted Branch Angitis), meniscocyte's property retinopathy and other hemoglobinopathies become (Hemoglobinopathy), angioid streaks, familial exudative vitreoretinopathy, eales's disease (Eales Disease);
Traumatic/operation property: hypoperfusion, radiation retinopathy, bone marrow transplantation retinopathy in sympathetic ophthalmia, uveitis retinopathy, detachment of retina, wound, laser, PDT, photocoagulation, the operation;
Proliferative disorders: proliferative vitreoretinopathy and preretinal membrane (EpiretinalMembrane), proliferative diabetic retinopathy become;
Infectiousness disease: ocular histoplasmosis, ocular toxocariasis, intend ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, infect relevant retinal diseases with HIV, infect relevant choroidal diseases with HIV, infect relevant uveal disease with HIV, viral retinitis, acute retinal necrosis, the ectoretina necrosis (Progressive OuterRetinal Necrosis) of carrying out property, the fungoid retinal diseases, ocular syphilis, the tuberculosis of eye disease, the subacute neuroretinitis of the one-sided property of diffusivity, myiasis;
Heritability disease: retinitis pigmentosa, the systemic disorders relevant with the retina malnutrition, congenital stationary night blindness, cone dystrophy, Si Tajiateshi disease (Stargardt ' sDisease) and fundus flavimaculatus, best's disease (Best ' s Disease), the figure malnutrition of retinal pigment epithelium (pattern dystrophy), X sex-linkage (X-linked) retinoschisis, Suo Si Bi Shi fundus dystrophy (Sorsby ' s Fundus Dystrophy), optimum proper alignment maculopathy (Benign Concentric Maculopathy), than Ai Teshi crystalline malnutrition (Bietti ' s Crystalline Dystrophy), pseudoxanthoma elasticum;
Retinal hole/fissure cavity: detachment of retina, macular hole, huge retinal hole;
Tumor: the retinal diseases relevant, the congenital hypertrophy of RPE, back tunica uvea melanoma (Posterior Uveal Melanoma), choroidal hemangioma, choroidal osteoma, choroid transfer, retina and retinal pigment epithelium Combination hamartoma, retinoblastoma, optical fundus blood vessel hypertrophy tumor, retina astrocytoma, Intraocular lymphoma with tumor;
Other: choroidopathy, acute utmost point portion afterwards many kitchen ranges property squamous pigment epithelium pathological changes, myopic degeneration of retina, acute retinal pigment epithelitis etc. in the point-like.
Method of the present invention can comprise and is injected to oculi posterior segment separately, also can comprise the injection repeatedly in the certain hour, injects repeatedly in for example about week or about 1 month or about 3 months to about 6 months or about 1 year or longer time.
Following non-limiting example has been set forth some aspect of the present invention.
Embodiment 1 to 4
Four kinds of compositionss are as follows:
| Component | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
| Triamcinolone acetonide | 2％(w/v) | 2％(w/v) | 4％(w/v) | ?4％(w/v) |
| Hyaluronate sodium (0.6 * 10 6Dalton) | 0.05％(w/v) | 0.5％(w/v) | 0.05％(w/v) | ?0.5％(w/v) |
| Sodium phosphate | 0.4％(w/v) | 0.4％(w/v) | 0.4％(w/v) | ?0.4％(w/v) |
| Vitamin E-TPGS | 0.5％(w/v) | 0.5％(w/v) | 0.0 | ?0.0 |
| The 8-cyclodextrin | 0.5％(w/v) | 0.5％(w/v) | 0.0 | ?0.0 |
| Water for injection | In right amount | In right amount | In right amount | In right amount |
| 0.1/ cut speed viscosity down second | 20cps | 500cps | ?20cps | ?500cps |
Above-mentioned each preparation of compositions is as follows.
Triamcinolone acetonide is combined with water, also combine if any, to prepare dense triamcinolone acetonide dispersion liquid with vitamin E-TPGS and 8-cyclodextrin.Said components is mixed, and triamcinolone acetonide is disperseed, then autoclaving.Hyaluronate sodium both can be bought commercially available sterilized powder, also can sterilize by the following method: weak solution is filtered, and the low pressure sublimation drying obtains sterilized powder then.Make aseptic hyaluronate sodium soluble in water, make the aqueous dope.Dense triamcinolone acetonide dispersion liquid is mixed, and add in the hyaluronate sodium dope with the form of serosity.Add suitable quantity of water, mixture is mixed to evenly.
Above-mentioned each compositions makes that the reunion (floctuation) of triamcinolone acetonide is loose, thereby is easy to get final product resuspending by the appropriateness inversion.Above-mentioned composition can be packed into and be sold in the low capacity pharmaceutical grade vial, has found above-mentioned composition when intravitreal injection the pure man ophthalmic, to the macular edema treatment effectively.
Embodiment 5 to 7
Three kinds of compositionss are as follows:
| Component | Embodiment 5 | Embodiment 6 | Embodiment 7 |
| Triamcinolone acetonide | 2.0％(w/v) | 4.0％(w/v) | 8.0％(w/v) |
| Hyaluronate sodium | 3.0％(w/v) | 2.5％(w/v) | 2.0％(w/v) |
| Sodium phosphate | 0.4％(w/v) | 0.4％(w/v) | 0.4％(w/v) |
| Water for injection | In right amount | In right amount | In right amount |
| 0.1/ cut speed viscosity down second | 180,000cps | 120,000cps | 80,000cps |
Above-mentioned composition is to prepare to embodiment 1 described similar substantially mode.
The viscosity higher of compositions makes the particulate rate of settling significantly be reduced to following degree, promptly in the compositions storage life of expection, needn't or not need to carry out resuspending in for example about 2 years and handles.Because not easy-to-use needle tubing of described compositions and syringe shift from container, therefore can be contained in advance in the syringe and sell.Yet, be contained in the compositions in the syringe in advance, still can effectively be injected to people's oculi posterior segment, so that required therapeutic effect to be provided in human eye by No. 27 or No. 30 needle tubings.
The compositions of embodiment 5 to 7 adopts or has comprised the sufficiently high high molecular weight sodium hyaluronate of concentration, at the moment to form gluey bolt (gelatinous plug) or drug depot (drug depot) at the intravitreal injection the pure man.With for example use compositions like its viscosity and the water, compare as Kenalog 40, the triamcinolone acetonide granule capture effectively in or be stored in the above-mentioned heavy-gravity bolt, thereby avoided the generation of deleterious " plume (pluming) ", also significantly reduced drug particles and directly be deposited on risk on the retinal tissue unfriendly.Because sodium hyaluronate solution is subjected to extremely strong shear thinning effect, therefore above-mentioned preparation is easy to by No. 27 needle tubings or even No. 30 needle tubings injections.
Embodiment 8 and 9
Two kinds of compositionss are as follows:
| Component | Embodiment 8 | Embodiment 9 |
| Triamcinolone acetonide | 2.0％(w/v) | 8.0％(w/v) |
| Hyaluronate sodium | 2.5％(w/v) | 2.3％(w/v) |
| Sodium chloride | 0.63％(w/v) | 0.6％(w/v) |
| Sodium hydrogen phosphate, heptahydrate | 0.30％(w/v) | 0.30％(w/v) |
| Sodium dihydrogen phosphate, monohydrate | 0.04％(w/v) | 0.04％(w/v) |
| Water for injection | In right amount | In right amount |
| 0.1/ cut speed viscosity down second | 170,000±25％cps | 200,000±25％cps |
Above-mentioned composition is to prepare to embodiment 1 described similar substantially mode.
The viscosity higher of compositions makes the particulate rate of settling significantly be reduced to following degree, promptly in the compositions storage life of expection, needn't or not need to carry out resuspending in for example about 2 years and handles.Because not easy-to-use needle tubing of described compositions and syringe shift from container, therefore can be contained in advance in the syringe and sell.Yet, be contained in the compositions in the syringe in advance, still can effectively be injected to people's oculi posterior segment, so that required therapeutic effect to be provided in human eye by No. 27 or No. 30 needle tubings.
In the above-mentioned composition water content of (and in other compositionss of determining of the embodiment of the present application) employed hyaluronate sodium powder be about 4 weight % to about 20 weight %, preferred about 4 weight % are to about 8 weight %.Water content is different between the water content of powder, particularly powder and powder, can cause two or more " nominally " the present composition that chemical composition is identical has different viscosity.Therefore, the viscosity of the application's indication is interpreted as target viscosities, and compositions is higher or lower than about 25% or about 30% or all can use of (±) target viscosities at about 35% o'clock at its practical viscosity.
Because the density of described each compositions of embodiment is about 1mg/ml, so also can be considered to based on the percentage ratio of weight to weight (w/w) based on the percentage ratio of weight to volume (w/v) described in the application.
Embodiment 8 and 9 compositions adopt or have comprised the sufficiently high high molecular weight sodium hyaluronate of concentration, at the moment to form gluey bolt or drug depot at the intravitreal injection the pure man.With for example use compositions like its viscosity and the water, compare as Kenalog 40, the triamcinolone acetonide granule capture effectively in or be stored in the above-mentioned heavy-gravity bolt, thereby avoided the generation of deleterious " plume ", also significantly reduced drug particles and directly be deposited on risk on the retinal tissue unfriendly.Because sodium hyaluronate solution is subjected to extremely strong shear thinning effect, therefore above-mentioned preparation is easy to by No. 27 needle tubings or even No. 30 needle tubings injections.
Although with regard to different specific embodiments and embodiment the present invention is narrated, still being interpreted as the present invention is not to be limited to this, and the present invention can implement in the scope of following claim by different way.
Claims (62)
1. in order to be injected to the compositions of human or animal's oculi posterior segment, described compositions comprises:
The corticosteroid composition of treatment effective dose, described corticosteroid composition exists with a large amount of particulate forms;
Effectively the viscosity that improves the amount of described composition viscosity is brought out composition; And
The aqueous carrier composition, the viscosity that described compositions was cut under the speed at 0.1/ second is at least about 10cps, and described compositions can effectively be injected to human or animal's oculi posterior segment.
2. the viscosity that the compositions of claim 1, described compositions were cut at 0.1/ second under the speed is 100cps at least.
3. the compositions of claim 1, the viscosity that described compositions was cut under the speed at 0.1/ second is at least 10,000cps.
4. the compositions of claim 1, described compositions were cut viscosity under the speed at 0.1/ second be about 140, and 000cps-is about 300,000cps.
5. the compositions of claim 1, described compositions can effectively be injected to human or animal's oculi posterior segment by No. 27 needle tubings.
6. the compositions of claim 1, described compositions can effectively be injected to human or animal's oculi posterior segment by No. 30 needle tubings.
7. the compositions of claim 1, wherein said granule is suspended in the described compositions substantially equably.
8. the compositions of claim 7, wherein said granule need not resuspending and handle and be suspended in equably in the compositions at least about 1 week substantially.
9. the compositions of claim 7, wherein said granule need not resuspending and handle and be suspended in equably in the compositions at least about 1 month substantially.
10. the compositions of claim 7, wherein said granule need not resuspending and handle and be suspended in equably in the compositions at least about 6 months substantially.
Handle and be suspended in equably in the compositions at least about 1 year substantially 11. the compositions of claim 7, wherein said granule need not resuspending.
Handle and be suspended in equably in the compositions at least about 2 years substantially 12. the compositions of claim 7, wherein said granule need not resuspending.
13. the compositions of claim 1, the amount of wherein said corticosteroid composition are up to about 25% (w/v) of compositions.
14. the compositions of claim 1, the amount of wherein said corticosteroid composition is at least about the 10mg/ml compositions.
15. the compositions of claim 1, the amount of wherein said corticosteroid composition be compositions about 1% to about 20% (w/v).
16. the compositions of claim 1, the amount of wherein said corticosteroid composition be compositions about 1% to about 10% (w/v).
17. the compositions of claim 1, the dissolubility of wherein said corticosteroid composition in 25EC water is lower than 10mg/ml.
18. the compositions of claim 1, wherein said corticosteroid composition is selected from cortisone, prednisolone, omcilon, flurandrenolide, dexamethasone, medrysone, loteprednol, its derivant and composition thereof.
19. the compositions of claim 1, wherein said corticosteroid composition is a triamcinolone acetonide.
20. the compositions of claim 1, wherein said carrier components comprise at least a in antiseptic composition, tension regulator composition and the buffer agent composition of effective dose.
21. the compositions of claim 1, described compositions is not added the antiseptic composition.
22. the compositions of claim 1, described compositions is not added the resuspending composition.
23. the compositions of claim 1, wherein said viscosity bring out the amount of composition be compositions about 0.05% to about 20% (w/v).
24. the compositions of claim 1, wherein said viscosity are brought out composition and are comprised component of polymer.
25. the compositions of claim 1, wherein said viscosity are brought out composition and are comprised at least a viscoelastic agent.
26. the compositions of claim 1, wherein said viscosity are brought out composition and are selected from polymerization hyaluronic acid, carbomer, polyacrylic acid, cellulose derivative, polyacrylic resin, polyvinylpyrrolidone, gelatin, dextrin, polysaccharide, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, its derivant and composition thereof.
27. the compositions of claim 1, wherein said viscosity are brought out composition and are comprised the hyaluronic acid salt component.
28. the compositions of claim 27, wherein said hyaluronic acid salt component comprises hyaluronate sodium.
29. Therapeutic Method, described method comprise that the compositions with claim 1 delivers medicine to human or animal's oculi posterior segment, obtains required therapeutic effect with this.
30. the method for claim 29, wherein said dosing step comprises intravitreal injection.
31. the method for claim 29, wherein said dosing step comprises subconjunctival injection.
32. the method for claim 29, wherein said dosing step comprise injection under the fascia bulbi.
33. the method for claim 29, wherein said dosing step comprises retrobulbar injection.
34. the method for claim 29, wherein said dosing step comprises on the choroid injects.
35. in order to be injected to the compositions of human or animal's oculi posterior segment, described compositions comprises:
The corticosteroid composition of treatment effective dose, described corticosteroid composition exists with a large amount of particulate forms;
Effectively the viscosity that improves the amount of described composition viscosity is brought out composition; And
The aqueous carrier composition, described granule is suspended in the described compositions substantially equably, and need not resuspending and handle and be suspended in equably in the described compositions at least about 1 week substantially.
Handle and be suspended in equably in the described compositions at least about 2 weeks substantially 36. the compositions of claim 35, wherein said granule need not resuspending.
Handle and be suspended in equably in the described compositions at least about 1 month substantially 37. the compositions of claim 35, wherein said granule need not resuspending.
Handle and be suspended in equably in the described compositions at least about 6 months substantially 38. the compositions of claim 35, wherein said granule need not resuspending.
Handle and be suspended in equably in the described compositions at least about 1 year substantially 39. the compositions of claim 35, wherein said granule need not resuspending.
Handle and be suspended in equably in the described compositions at least about 2 years substantially 40. the compositions of claim 35, wherein said granule need not resuspending.
41. the compositions of claim 35, the amount of wherein said corticosteroid composition are up to about 25% (w/v) of compositions.
42. the compositions of claim 35, the amount of wherein said corticosteroid composition is at least about the 10mg/ml compositions.
43. the compositions of claim 35, the amount of wherein said corticosteroid composition be compositions about 1% to about 20% (w/v).
44. the compositions of claim 35, the amount of wherein said corticosteroid composition be compositions about 1% to about 10% (w/v).
45. the compositions of claim 35, the dissolubility of wherein said corticosteroid composition in 25EC water is lower than 10mg/ml.
46. the compositions of claim 35, wherein said corticosteroid composition is selected from cortisone, prednisolone, omcilon, flurandrenolide, dexamethasone, medrysone, loteprednol, its derivant and composition thereof.
47. the compositions of claim 35, wherein said corticosteroid composition is a triamcinolone acetonide.
48. the compositions of claim 35, wherein said carrier components comprise at least a in antiseptic composition, tension regulator composition and the buffer agent composition of effective dose.
49. the compositions of claim 35, described compositions is not added the antiseptic composition.
50. the compositions of claim 35, described compositions is not added the resuspending composition.
51. the compositions of claim 35, wherein said viscosity bring out the amount of composition be compositions about 0.05% to about 20% (w/v).
52. the compositions of claim 35, wherein said viscosity are brought out composition and are comprised component of polymer.
53. the compositions of claim 35, wherein said viscosity are brought out composition and are comprised at least a viscoelastic agent.
54. the compositions of claim 35, wherein said viscosity are brought out composition and are selected from polymerization hyaluronic acid, carbomer, polyacrylic acid, cellulose derivative, polyacrylic resin, polyvinylpyrrolidone, gelatin, dextrin, polysaccharide, polyacrylamide, polyvinyl alcohol, polyvinyl acetate, its derivant and composition thereof.
55. the compositions of claim 35, wherein said viscosity are brought out composition and are comprised the hyaluronic acid salt component.
56. the compositions of claim 55, wherein said hyaluronic acid salt component comprises hyaluronate sodium.
57. Therapeutic Method, described method comprise that the compositions with claim 35 delivers medicine to human or animal's oculi posterior segment, obtains required therapeutic effect with this.
58. the method for claim 57, wherein said dosing step comprises intravitreal injection.
59. the method for claim 57, wherein said dosing step comprises subconjunctival injection.
60. the method for claim 57, wherein said dosing step comprise injection under the fascia bulbi.
61. the method for claim 57, wherein said dosing step comprises retrobulbar injection.
62. the method for claim 57, wherein said dosing step comprises on the choroid injects.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US51923703P | 2003-11-12 | 2003-11-12 | |
| US60/519,237 | 2003-11-12 | ||
| US60/530,062 | 2003-12-16 | ||
| US10/966,764 | 2004-10-14 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610121191.6A Division CN105748407A (en) | 2003-11-12 | 2004-11-08 | Compositions and methods for treating a posterior segment of an eye |
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| Publication Number | Publication Date |
|---|---|
| CN101094690A true CN101094690A (en) | 2007-12-26 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480033259 Pending CN101094690A (en) | 2003-11-12 | 2004-11-08 | Compositions and methods for treating a posterior segment of an eye |
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| Country | Link |
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| CN (1) | CN101094690A (en) |
| ZA (1) | ZA200603549B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104667287A (en) * | 2013-11-27 | 2015-06-03 | 山东博士伦福瑞达制药有限公司 | Eye-use composition for treating posterior chamber new vessel hyperplasia and application of eye-use composition |
| CN104971039A (en) * | 2015-07-07 | 2015-10-14 | 上海通用药业股份有限公司 | Medical product containing solution-type triamcinolone acetonide acetate |
| CN107205926A (en) * | 2015-01-21 | 2017-09-26 | 塞姆努尔药物公司 | Pharmaceutical preparation |
-
2004
- 2004-11-08 CN CN 200480033259 patent/CN101094690A/en active Pending
-
2006
- 2006-05-04 ZA ZA200603549A patent/ZA200603549B/en unknown
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104667287A (en) * | 2013-11-27 | 2015-06-03 | 山东博士伦福瑞达制药有限公司 | Eye-use composition for treating posterior chamber new vessel hyperplasia and application of eye-use composition |
| CN104667287B (en) * | 2013-11-27 | 2018-02-06 | 山东博士伦福瑞达制药有限公司 | Ophthalmic composition for treating camera oculi posterior neovascularization resulting and application thereof |
| CN107205926A (en) * | 2015-01-21 | 2017-09-26 | 塞姆努尔药物公司 | Pharmaceutical preparation |
| CN104971039A (en) * | 2015-07-07 | 2015-10-14 | 上海通用药业股份有限公司 | Medical product containing solution-type triamcinolone acetonide acetate |
| CN104971039B (en) * | 2015-07-07 | 2018-04-17 | 上海通用药业股份有限公司 | A kind of curable product of the triamcinolone acetonide acetate containing solution-type |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200603549B (en) | 2007-09-26 |
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