CN101137370A - Liquid formulations for treatment of diseases or conditions - Google Patents

Abstract

Diseases and conditions associated with tissues of the body, including tissues in the eye, can be effectively treated by administering therapeutic agents to those tissues. Described herein are self-emulsifying formulations and methods for delivering therapeutic agents to such tissues. A self-emulsifying formulation may be delivered to an aqueous medium of a subject, including but not limited to the vitreous. A method may, for instance, be used to administer rapamycin or related compounds to treat or prevent choroidal neovascularization associated with age-related macular degeneration, or to treat dry AMD. A self-emulsifying formulation may also be administered systernically, such as orally, to treat transplant rejection in a subject. A self-emulsifying formulation may comprise rapamycin, related compounds, or other therapeutic agents.

Description

The liquid preparation that is used for the treatment of disease or disease

Technical field

This paper has described by experimenter's (including but are not limited to people experimenter) delivering therapeutic agents is treated, prevents, suppressed disease or disease, postpones its generation or makes its liquid preparation that disappears, and includes but are not limited to the liquid preparation treatment degeneration of macula (AMD) relevant with the age that comprises therapeutic agent by experimenter's (including but are not limited to people experimenter) eyes are sent.The limiting examples of described liquid preparation comprises solution, suspensoid and in-situ gelling preparation.

With the mutual reference of related application

Submit in the application and on March 21st, 2005 " Liquid Formulations ForTreatment Of Diseases Or Conditions; " by name U.S. Provisional Patent Application serial number 60/664,040, submitted on March 21st, 2005 " In Situ Gelling Formulations AndLiquid Formulations For Treatment of Diseases Or Conditions; " by name U.S. Provisional Patent Application serial number 60/664,306, submitted on February 9th, 2005 " FormulationsFor Ocular Treatment; " by name U.S. Provisional Patent Application serial number 60/651,790 is relevant and require their priority, and each data is used for all purposes as a reference complete the quoting of this paper.

Technical background

The retina of eyes comprises light sensitive cone cell and rod cell.Retinal centre is a macula retinae, and its diameter is about 1/3 to 1/2cm.Macula lutea provides detailed vision (particularly in central authorities' (central fovea)), because cone cell density is higher.Blood vessel, ganglionic cell, inner nuclear layer and cell and plexiform layers all move to a side (rather than being still on the cone cell), thereby make light arrive cone cell with more direct path.

Be choroid under the retina, comprise one group of blood vessel that embeds in the fibrous tissue and the dark plain epithelium that covers choroid layer.Choroidal artery provides nutrition for retina (particularly its visual cell).

There is multiple can't treat at present or present therapy is not best retinal diseases.Normally all are difficult to the retinal diseases with the routine treatment treatment for retinal diseases such as uveitis (uvea: sclera, corpus ciliare and choroidal inflammation), central retinal vein occlusion disease (CRVO), branch retinal vein occlusion (BRVO), degeneration of macula, macular edema, proliferative diabetic retinopathy change and detachment of retina.

Relevant degeneration of macula (AMD) of age is the main cause of U.S.'s age greater than individual severe visual forfeiture in 60 years old.AMD takes place with atrophic or more not general exudative form.The AMD of atrophic form is also referred to as " dry AMD ", and exudative type AMD is also referred to as " moist AMD ".

In exudative type AMD, blood vessel is grown from the defective that choriocapillary layer passes the Bruch's membrane (retinal pigment epithelium below being in some cases).The tissue of serosity of from these vasculars, overflowing or blood exudate cause subsidiary degeneration, the retinal pigment epithelium of macular area fiber blood vessel cicatrization and neuroretina come off and tear, vitreous hemorrhage and central vision permanent loss.This process occupies remarkable more than 80% of visual loss case among the experimenter who suffers from AMD.At present or the treatment that is about to occur comprises laser photocoagulation, photodynamic therapy, with the treatment of VEGF antibody fragment, treat with the aptamer therapeutics of Pegylation and with some micromolecule agent.

Purposes (Macular Photocoagulation Study Groups (1991) inArch.Ophthal.109:1220 of laser photocoagulation in treating the damage of constitutional relevant with AMD or recidivity neovascularity described in some researchs in the recent period; Arch.Ophthal 109:1232; Arch.Ophthal.109:1242).Unfortunately, the AMD patient with damage under the central fovea who carries out laser therapy has experienced visual acuity decline very rapidly (average 3 row) in 3 months tracing study.In addition, treated back 2 years, the eyes through treating only have a small amount of eyesight improving (being respectively average 20/320 and 20/400) compared with their untreated eyes.Another shortcoming of this method is a postoperative vision variation at once.

Photodynamic therapy (PDT) is a kind of optical treatment---comprises making and uses up all treatments that the experimenter produced useful reaction.Best is that PDT destroys unwanted tissue and lets slip normal structure.Generally the experimenter is used the chemical compound that is called photosensitizer.Usually photosensitizer self has a little to the experimenter or does not influence.When light (usually from laser instrument) when directive contains organizing of photosensitizer, photosensitizer is activated and begins to destroy target tissue.Because directive experimenter's light is limited in specific target region, can use optionally targeting abnormal structure of PDT, the health tissues around therefore letting slip.Use PDT treatment retinal diseases such as AMD at present.PDT is the main means (Photodynamic Therapy for SubfovealChoroidal Neovascularization in Age Related Macular Degeneration withVerteporfin (TAP research group) Arch Ophthalmol.1999 117:1329-1345) that are used for the treatment of choroid neovascularization under AMD patient's central fovea at present.

It is that opposing is treated that choroid neovascularization (CNV) is proved to be in most cases.Conventional laser therapy can be excised CNV and be helped to keep vision under the situation of the selection that does not relate to foveal region of retina, but this only limits in about 10% the case.Unfortunately, coagulate art even if carried out successful conventional laser light, also recurrence in the eyes of 50%-70% of neovascularization (3 years is 50%, and 5 years the time 60%).(Macular Photocoagulation Study Group，Arch.Ophthalmol.204：694-701(1986))。In addition, the experimenter of many CNV of suffering from is not the good candidate of laser therapy, because CNV is too big for laser therapy, or can not determine position so the doctor laser that can not take accurate aim.Although photodynamic therapy is applied in nearly under 50% the central fovea among the CNV new case, it only has a small amount of benefit to natural medical history, and postpones the progress of visual loss usually rather than improve the vision that has reduced after the damage under central fovea.PDT is not preventative, neither be deterministic.Each experimenter needs some PDT treatments usually, and in addition, the CNV of some hypotype is good not as other progress ground.

Therefore, still there are the needs that prevent best or significantly suppress the choroid neovascularization and be used to prevent and treat method, compositions and the preparation of moist AMD can be used for for a long time.

Except AMD, the choroid neovascularization is relevant with this class retinal diseases, as ocular tissue's endochylema bacterium syndrome, myopic degeneration, angioid streaks, ICSC, retina and/or the choroid inflammatory disease and the ocular injury of supposition.The angiogenesis damage relevant with neovascularization takes place in multiple disease, comprises diabetic retinopathy, venous occlusion, sickle cell retinopathy, retinopathy of prematurity, detachment of retina, eye ischemia and wound.

Uveitis is to have proved another retinal disorder that uses existing therapy to be difficult to treat.Uveitis is the general term that is used to indicate any assembly inflammation of tunica uvea.The tunica uvea of eyes is made up of sclera, corpus ciliare and choroid.On the inflammation (being called optic neuritis) of the amphiblestroid inflammation (being called retinitis) covered or optic nerve can follow or not follow uveitis and take place.

Before, during and after uveitis is divided into by anatomy the most at large or diversity.Back uveitis is represented in retinitis, choroiditis or the optic neuritis of various ways any.The diversity uveitis is meant and relates to all parts of eyes inflammation of (comprising front portion, middle part and rear structure).

Uveitic symptom and symptom can be slight, and significantly change according to the position of inflammation and seriousness.With regard to the uveitis of back, the most general symptom comprises that the existence of float and vision reduce.Suffer from the back also can exist among the uveitic experimenter cell is arranged in the vitreous humor, white or the damage of Huang-white, exudative detachment of retina, retinal vasculitis and optic nerve edema in retina and/or the following choroid.

Uveitic ophthalmic complications can produce great and irreversible visual loss, particularly when not recognizing or during by inappropriate treatment.The most general complication of back uveitis comprises the neovascularization of detachment of retina, retina, optic nerve or sclera, and cystoid macular edema.

If in background diabetic retinopathy (BDR), in macula lutea (retina of the most key central authorities 5%), record swelling, seepage and hard exudate, macular edema (ME) then take place to vision.Background diabetic retinopathy (BDR) is made up of the retina microaneurysm usually, and this microaneurysm is changed by retinal microcirculation and causes.The visual the earliest variation of the retinopathy that these microaneurysms are seen during normally with ophthalmofundoscopy, it is shown as dispersive red point in the retina, the wherein small blood vessel that weakens expansion.Visual discovery develops into cotton-wool patches, inter-retinal hemorrhage, liquid and oozes out from retinal capillary and retinal exudates in the background diabetic retinopathy process.The vascular permeability that improves also relates to the local growth factor that level improves, as VEGF.Macula lutea is rich in cone cell, and it is to experience color and teleneuron that day mesopic vision relied on.When the retinal capillary permeability that improves influenced macula lutea, avris central or only central vision field occurred fuzzy, saw just as seeing through cellophane.Visual loss can develop in the time of several months, and can make very much people's worry owing to knowing focusing.ME is some VI common reasons.

Once had to make heal with medicine CNV and relevant disease and disease, and the trial of other diseases such as macular edema and chronic inflammatory disease.For example, use rapamycin inhibition CNV and moist AMD to be described in U. S. application No.10/665,203, its integral body is quoted as a reference at this paper.Use rapamycin treatment eyes inflammatory diseases to be described in U.S. Patent number 5,387,589, its title is Method ofTreating Ocular Inflammation, the invention people is Prassad Kulkarni, transfer University of Louisville Research Foundation, its content is quoted in this paper integral body.

Especially for chronic disease (comprising chronic disease as herein described), be starved of and be used for the long-acting method of therapeutic agent delivery to eyes (for example be delivered to back segment with treatment at CNV) as this class disease of AMD, macular edema, proliferative retinopathy and chronic inflammatory disease.The preparation that prolongs delivering therapeutic agents is more comfortable and convenient for the experimenter, because the frequency of ocular injection therapeutic agent reduces.

Can be favourable to eyes delivering therapeutic agents rather than systemic administration directly, because with respect to concentration of treatment agent in experimenter's blood circulation, the concentration of treatment agent of action site improves.In addition, the systemic delivery therapeutic agent can have the side effect of not expecting with the treatment posterior segment disease.Therefore, localized drug delivery can be raised the efficiency, and reduces side effect and general toxicity simultaneously.

Summary of the invention

Methods described herein, compositions and liquid preparation allow the eyes delivering therapeutic agents to experimenter's (including but are not limited to people experimenter) or experimenter.This paper has described and has been used for time expand and sends method, compositions and the liquid preparation of multiple therapeutic agent, described therapeutic agent can be used for treatment, prevention, suppresses various disease conditions or disease, postpones its generation or cause that it disappears, described disease or disease include but not limited to ophthalmic or disease.Liquid preparation include but not limited to solution, suspensoid and in-situ gelling preparation.

This paper has described method, compositions and the liquid preparation that is used for using to people experimenter rapamycin, and the amount of described rapamycin can effectively treat, prevents, suppresses moist AMD, postpones its generation or cause that it disappears.

Describe in further detail as " detailed Description Of The Invention " part, also can use described method, compositions and liquid preparation to be used for being used for the treatment of, preventing, suppressing moist AMD, postpone its generation or cause that it disappears to experimenter's (including but are not limited to people experimenter) or to the rapamycin of people experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation to treat moist AMD.In some modification, use described method, compositions and liquid preparation to be used for pre-moisture resistance AMD.In some modification, use methods described herein and preparation to be used to prevent dryness AMD to change moist AMD into.Described method, compositions and liquid preparation also can be used for being used for the treatment of, preventing, suppressing CNV, postpone its generation or cause that it disappears to experimenter's (including but are not limited to people experimenter) or to the rapamycin of experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation treatment CNV.Described method, compositions and liquid preparation also can be used for to experimenter's (including but are not limited to people experimenter) or are used for the treatment of, prevent, suppress the eye medium vessels to the rapamycin of experimenter's eyes delivery treatments effective dose taking place, postponing its generation or cause that it disappears.In some modification, use described method, compositions and liquid preparation to be used for the treatment of blood vessel and take place.Can use rapamycin treatment, prevention, inhibition, postpone its generation or cause that other diseases and disease that it disappears are described in " disease and the disease " part of " detailed Description Of The Invention ".

Describe in further detail as " detailed Description Of The Invention " part, also can use described method, compositions and liquid preparation to be used for being used for the treatment of, preventing, suppressing moist AMD, postpone its generation or cause that it disappears to experimenter's (including but are not limited to people experimenter) or to the therapeutic agent except that rapamycin of experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation to be used for the treatment of moist AMD.Operable therapeutic agent is described in detail in " therapeutic agent " part.But this class therapeutic agent includes but are not limited in conjunction with exempting from proteic chemical compound.But operable combination is exempted from proteic chemical compound and is included but are not limited to the limus family compound that this paper " therapeutic agent " part further describes, and comprises rapamycin, SDZ-RAD, tacrolimus (tacrolimus), everolimus (everolimus), pimecrolimus (pimecrolimus), CCI-779, AP23841, ABT-578 and derivant, analog, prodrug, salt and ester.Also can use described method, compositions and liquid preparation to be used for being used for the treatment of, preventing, suppressing CNV, postpone its generation or cause that it disappears to experimenter's (including but are not limited to people experimenter) or to the therapeutic agent of experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation to be used for the treatment of CNV.Also can use described method, compositions and liquid preparation to be used for to experimenter's (including but are not limited to people experimenter) or to be used for the treatment of, to prevent, to suppress the eye medium vessels taking place, postponing its generation or cause that it disappears to the therapeutic agent of experimenter's eyes delivery treatments effective dose.In some modification, use described method, compositions and liquid preparation to be used for the treatment of blood vessel and take place.The therapeutic agent of use except that rapamycin can be treated, prevent, suppress, postpone its generation or be caused that other diseases and disease that it disappears are described in " disease and disease " part in " detailed Description Of The Invention ".

A kind of liquid preparation described herein comprises a kind of solution, and described solution contains the therapeutic agent that is dissolved in the solvent.Usually can use any solvent, the eyes that therapeutic agent is dissolved in wherein and it can be administered to experimenter's (including but are not limited to people experimenter) or be administered to the experimenter with required effect.Usually can use the therapeutic agent of any concentration with required effect.In some modification, preparation is undersaturated, saturated or oversaturated solution.Solvent can be that neat solvent maybe can be the liquid flux mixture of ingredients.In some modification, the solution of formation is the in-situ gelling preparation.Operable solvent and solution type are that this type of medicine delivery technique those skilled in the art are known.

When placing lagophthalmos (including but are not limited to the lagophthalmos vitreous body), liquid preparation described herein can form the agglomerate of non-diversity.In some modification, described nondispersive agglomerate comprises gel.In some modification, liquid preparation comprises therapeutic agent and multiple polymers.In some modification, one of polymer is polyacrylate or polymethacrylates.In some modification, one of polymer is a polyvinylpyrrolidone.

In some modification, non-diversity agglomerate comprises depot formulation.In some modification, non-diversity agglomerate is made up of depot formulation.

For the liquid preparation that forms non-diversity agglomerate, non-diversity agglomerate can be any geometry or shape usually.When placing vitreous body, the liquid preparation that forms non-diversity agglomerate can for example be shown as fine and close spherical agglomerate.In some modification, when liquid preparation described herein is placed in the vitreous body, form opal or white semicontinuous or semi-solid non-diversity agglomerate with respect to its medium that is placed.

Liquid preparation can be used with any volume with required effect usually.In one approach, use the liquid preparation of a volume to vitreous body, and liquid preparation is less than the vitreous body volume half.

The route of administration of operable applicating liquid preparation include but not limited to (1) and settles liquid preparation by settling (comprising injection) to advance medium (including but are not limited to intravital aqueous medium), includes but are not limited to ophthalmic or periocular injections; Or (2) oral liquid.Liquid preparation can systemic administration, includes but are not limited to following route of administration: rectum, vagina, inculcate, in the intramuscular, intraperitoneal, intra-arterial, sheath, in the bronchus, in the pond, in the epidermis, subcutaneous, Intradermal, percutaneous, intravenous, cervical canal, in the abdomen, intracranial, lung is interior, intrathoracic, trachea interior, nose, suck, the aerosolization of Sublingual, per os, parenteral or spraying or the agent of use aerosol spray.In some modification, use under the liquid preparation conjunctiva.In some modification, the liquid preparation intravitreal administration.

Liquid preparation described herein can be delivered to any medium (including but are not limited to experimenter's aqueous medium) of experimenter's (including but are not limited to people experimenter).

A kind of liquid preparation described herein comprises the liquid preparation of rapamycin or other treatment agent.Liquid preparation can comprise solution, suspensoid, in-situ gelling preparation or Emulsion.Microdroplet in the Emulsion can be any size generally, include but are not limited to big to about 5,000nm.

In preparations more described herein, liquid preparation can comprise therapeutic agent (including but are not limited to rapamycin) and one or more solubilizing agents or solvent.In some modification, solubilizing agent or solvent are the Polyethylene Glycol (including but are not limited to PEG 300 and PEG 400) of glycerol, DMSO, DMA, N-Methyl pyrrolidone, ethanol, benzyl alcohol, isopropyl alcohol, various molecular weights, or the mixture of propylene glycol or one or more these materials.

In preparations more described herein, liquid preparation comprises hyaluronic acid.

Liquid preparation described herein can be with the time period delivering therapeutic agents that prolongs.This class prolongs the system of limiting examples for the time period that prolongs therapeutic agent being delivered to experimenter's (including but are not limited to people experimenter) or being delivered to experimenter's eyes with the q.s that can keep effective dose of release delivery system, and described effective dose can be treated, prevent, suppresses, postpones disease or disease generation or be caused that it disappears in the experimenter.In some modification, liquid preparation is used for the treatment of experimenter's's (including but are not limited to people experimenter) disease or disease.In some modification, the liquid preparation delivering therapeutic agents continues at least about one month, about two months, about three months, about six months, about nine months or about 12 months.

The time period that liquid preparation described herein can prolong is sent rapamycin or other treatment agent.This class prolongs the eyes of a limiting examples for the time period that prolongs rapamycin being delivered to experimenter's (including but are not limited to people experimenter) or being delivered to the experimenter with the q.s that can keep effective dose of release delivery system, and described effective dose can be treated, prevent, suppresses, postpones the generation of relevant degeneration of macula of moist age or be caused that it disappears in the experimenter.In some modification, liquid preparation is used in relevant degeneration of macula of the moist age of time period internal therapy that prolongs.In some modification, use liquid preparation pre-relevant degeneration of macula of moisture resistance age in the time period that prolongs.In some modification, use liquid preparation prevention dryness AMD in the time period that prolongs to change moist AMD into.In a non-limiting instance, liquid preparation is correlated with rapamycin with enough energy treatments, prevention, inhibition, moist age of delay degeneration of macula takes place or causes that its amount that disappears is delivered in the vitreous body of experimenter's (including but are not limited to people experimenter), sclera, retina, choroid, macula lutea or its hetero-organization at least about three months, about six months, about nine months or about 12 months.In some modification, the level of rapamycin is enough treated AMD.In some modification, the level of rapamycin is the generation of pre-moisture resistance AMD enough.

Other time expands, discharge and are described in " detailed Description Of The Invention ".

Summary of drawings

Figure 1A-1C illustrates the formation of nondispersive agglomerate behind injecting fluid preparation in vitreum, is considered to and can takes place in some modification as it.

Fig. 2 has described the level of rapamycin in vitreous body (ng/ml), retina choroid (ng/ml) and the sclera (ng/ml) of 20,40,67 and 90 days lagophthalmos behind rapamycin water, ethanol and F127 (Lutrol) solution of subconjunctival injection 1.256%.

Fig. 3 has described the level of rapamycin in 14,35,62 and 85 Lepus vitreums (ng/ml) behind the rapamycin PEG 400 of subconjunctival injection 5% and the alcoholic solution, retina choroid (ng/ml) and the sclera (ng/ml).

Fig. 4 has described the level of rapamycin in 14,35,62 and 90 Lepus vitreums (ng/ml) behind the rapamycin PEG 400 of intravitreal injection 5% and the alcoholic solution, retina choroid (ng/ml) and the sclera (ng/ml).Also shown and injected the rapamycin levels (ng/ml) that existed in the vitreous body in back 2 days.

Fig. 5 has described 8 Lepus eye pattern pictures behind the PEG400 suspension of intravitreal injection 10 μ l (Fig. 4 A), 20 μ l (Fig. 4 B) and 40 μ l (Fig. 4 C), 6% rapamycin.

Fig. 6 describes the level of rapamycin in 7,32,45 and 90 Lepus vitreums (ng/ml) behind ethanol, PVP K90, PEG 400 and Eudragit RL 100 solution of subconjunctival injection 4.2% rapamycin, retina tela chorioidea (ng/mg) and the sclera (ng/ml).

Fig. 7 describes the level of rapamycin in 14,42,63 and 91 Lepus vitreums (ng/ml) behind PEG 400 suspensions of subconjunctival injection 3% rapamycin, retina tela chorioidea (ng/mg) and the sclera (ng/mg).

Fig. 8 describe in 14,42,63 and 91 Lepus vitreums (ng/ml) behind PEG 400 suspensions of intravitreal injection 3% rapamycin, retina tela chorioidea (ng/mg) and the sclera (ng/mg) and the 63 and 91 days vitreous body in injection back in the level of horizontal rapamycin.

Fig. 9 describes the level of rapamycin in 14,42,63 and 91 Lepus vitreums (ng/ml) behind subconjunctival injection 2% rapamycin ethanol and PEG 400 solution, retina tela chorioidea (ng/mg) and the sclera (ng/mg).

Figure 10 describes behind intravitreal injection 2% rapamycin ethanol and PEG 400 solution level of rapamycin in 14,42, the 63 and 91 Lepus eyes retina tela chorioideas (ng/mg) and sclera (ng/mg).

Figure 11 describes behind intravitreal injection 2% rapamycin ethanol and PEG 400 solution level (ng/ml) of rapamycin in the 63 and 91 Lepus vitreums.

Figure 12 describes the level of the interior rapamycin of 5,30,60,90 and 120 Lepus vitreums (ng/ml) behind the ethanol of 2% rapamycin of subconjunctival injection 20 μ l, 40 μ l and 60 μ l dosage and PEG 400 solution.

Figure 13 describes the level of the interior rapamycin of 5,30,60,90 and 120 Lepus eyes retina choroid (ng/mg) behind the ethanol of 2% rapamycin of subconjunctival injection 20 μ l, 40 μ l and 60 μ l dosage and PEG 400 solution.

Figure 14 describes the level of the interior rapamycin of 5,30,60,90 and 120 Lepus vitreums (ng/ml) behind the ethanol of 0.4% rapamycin of the ethanol of 2% rapamycin of intravitreal injection 20 μ l and 40 μ l dosage and PEG 400 solution and 100 μ l dosage and PEG 400 solution.

Figure 15 describes the level of the interior rapamycin of 5,30,60,90 and 120 Lepus eyes retina tela chorioideas (ng/mg) behind the ethanol of 0.4% rapamycin of the ethanol of 2% rapamycin of intravitreal injection 20 μ l and 40 μ l dosage and PEG 400 solution and 100 μ l dosage and PEG 400 solution.

Figure 16 describes the level of the interior rapamycin of 5 and 14 Lepus vitreums (ng/ml) behind the ethanol of 2% rapamycin of single part 10 μ l of subconjunctival injection dosage, single part 60 μ l dosage, twice 30 μ l dosage and three times 30 μ l dosage and PEG 400 solution.

Figure 17 describes the level of the interior rapamycin of 5 and 14 Lepus eyes retina tela chorioideas (ng/mg) behind the ethanol of 2% rapamycin of subconjunctival injection single 10 μ l dosage, single 60 μ l dosage, twice 30 μ l dosage and three times 30 μ l dosage and PEG 400 solution.

Figure 18 describes the level of the interior rapamycin of 5,14 and 30 Lepus vitreums (ng/ml) behind PEG 400 suspensions of 3% rapamycin of subconjunctival injection single 10 μ l dosage, single 30 μ, 1 dosage and three times 30 μ l dosage.

Figure 19 describes the level of the interior rapamycin of 5,14 and 30 Lepus eyes retina tela chorioideas (ng/mg) behind PEG 400 suspensions of 3% rapamycin of subconjunctival injection single 10 μ l dosage, single 30 μ l dosage and three times 30 μ l dosage.

Figure 20 describe the ethanol and PEG 400 solution of the ethanol of intravitreal injection 10 μ l 0.2% rapamycin and PEG 400 solution, injection 10 μ l 0.6% rapamycin and inject the ethanol of 10 μ l, 2% rapamycin and PEG 400 solution after the level of the interior rapamycin of 5,30 and 90 Lepus eyes retina tela chorioideas (ng/mg).

Figure 21 describe the ethanol and PEG 400 solution of the ethanol of intravitreal injection 10 μ l 0.2% rapamycin and PEG 400 solution, injection 10 μ l 0.6% rapamycin and inject the ethanol of 10 μ l, 2% rapamycin and PEG 400 solution after the level of the interior rapamycin of 5,30 and 90 Lepus vitreums (ng/ml).

Figure 22 describes behind the ethanol of subconjunctival injection 40 μ l 2% rapamycin and PEG 400 solution after 1,4,7,11,14,21,28,35,54 and 56 day the level of rapamycin in rabbit aqueous humor (ng/ml), cornea (ng/mg) and the retina tela chorioidea (ng/mg).

Detailed Description Of The Invention

This paper describes and relate to composition, liquid preparation and the method for therapeutic agent delivery to experimenter's (including but are not limited to people experimenter) or experimenter's eye. These compositions, liquid preparation and method can be used for treatment, prevention, suppress, postpone eye diseases and illness generation or it is disappeared, described eye diseases and illness include but are not limited to posterior segment disease or illness, include but are not limited to choroid neovascularization, macular degeneration, relevant macular degeneration (comprising moist AMD and dryness AMD), retinal vessel generation, uveitis and other retina hyperplasia illnesss of age. In some modification, described composition, liquid preparation and method are used for the treatment of above-mentioned eye diseases or illness.

This paper describes that (1) can use composition described herein, liquid preparation and method to be delivered to the therapeutic agent of experimenter's (including but are not limited to people experimenter) or experimenter's eye; (2) can treat by delivering therapeutic agents, prevent, suppress, postpone to occur or make its disease that disappears and illness; (3) can be used for the liquid preparation of delivering therapeutic agents; (4) method of administration of delivering liquid preparation; (5) therapeutic agent delivery that extends, described therapeutic agent includes but are not limited to rapamycin; (6) describe the treatment of CNV and moist AMD, described treatment is undertaken by using described composition and liquid preparation to send rapamycin with time period of prolongation to experimenter's (including but are not limited to people experimenter) or experimenter's eye.

The level of accuracy that obtains when term " about " used herein refers to use methods described herein (as the method in embodiment). Yet, determine that the formulation components of amount refers to the 90-110% of described amount by " approximately ".

Therapeutic agent

Generally speaking, known or still to be found so far can be used for treating, prevent, suppress, postpone disease described herein and illness and occur or cause that any compound that it disappears and composition can be the therapeutic agents for composition described herein, liquid preparation and method.

But operable therapeutic agent comprises by exempt from the compound that the protein family member is worked in conjunction with cell protein. This compounds is known as " but in conjunction with the compound of exempting from albumen ". But in conjunction with the compound of exempting from albumen, include but are not limited to " limus " compound family. The example of operable limus compound includes but are not limited to cyclophilin and FKBPL (FKBPs), comprises sirolimus (sirolimus) (rapamycin) and water-soluble analogues SDZ-RAD (Novartis) thereof, TAFA-93 (Isotechnika), tacrolimus, everolimus, RAD-001 (Novartis), Elidel, temsirolimus, CCI-779 (Wyeth), AP23841 (Ariad), AP23573 (Ariad) and ABT-578 (Abbott Laboratories). Operable Limus compound analog and derivative include but not limited to be described in United States Patent (USP) 5,527,907; 6,376,517 and 6,329,386 and the compound of Application No. 09/950,307, each data is quoted as a reference in this paper integral body. Therapeutic agent also comprises analog, prodrug, salt and the ester of limus compound.

This paper term rapamycin, rapa and sirolimus are used interchangeably.

Other spendable rapamycin derivatives include but are not limited to the monoesters of 7-table-rapamycin, 7-sulfidomethyl-rapamycin, 7-table-trimethoxyphenyl-rapamycin, 7-table-sulfidomethyl-rapamycin, 7-demethoxylation-rapamycin, 32-demethoxylation-rapamycin, 2-demethylation-rapamycin, rapamycin and diester deriv, rapamycin 27-oxime; The 42-oxo analog of rapamycin; Two ring rapamycins; The rapamycin dimer; Rapamycin monosilane ether; Rapamycin aromatic yl sulphonate and sulfamate, the monoesters of 31 and 42 and diester, 30-demethoxylation rapamycin, and Vezina etc., " Rapamycin (AY-22; 989), A New Antifungal Antibiotic.I. Taxonomy Of The Producing Streptomycete And Isolation Of The Active Principle " J.Antibiot. (Tokyo) 28:721-726 (1975); Sehgal etc., " Rapamycin (AY-22; 989), A New Antifungal Antibiotic.II.Fermentation, Isolation And Characterization " J.Antibiot. (Tokyo) 28:727-732 (1975); Sehgal etc., " Demethoxyrapamycin (AY-24,668), A New Antifungal Antibiotic " J. Antibiot. (Tokyo) 36:351-354 (1983); With Paiva etc., " Incorporation Of Acetate; Propionate; And Methionine Into Rapamycin By Streptomycetes hygroscopicus " J Nat Prod 54:167-177 (1991), WO 92/05179, and EP 467606, Caufield etc., " Hydrogenated Rapamycin Derivatives " U.S. Patent number No. 5,023,262; Kao etc., " Bicyclic Rapamycins " U.S. Patent number No.5,120,725; Kao etc., " Rapamycin Dimers " U.S. Patent number No.5,120,727; Failli etc., " Silyl Ethers Of Rapamycin " U.S. Patent number No.5,120,842; Failli etc., " Rapamycin 42-Sulfonates And 42-(N-carboalkoxy) Sulfamates Useful As Immunosuppressive Agents " U.S. Patent number 5,177,203; Nicolaou etc., " Total Synthesis Of Rapamycin " J.Am.Chem.Soc.115:4419-4420 (1993); Romo etc., " Total Synthesis Of (-) Rapamycin Using An Evans-Tishchenko Fragment Coupling " J.Am.Chem.Soc.115:7906-7907 (1993); With Hayward etc., " Total Synthesis Of Rapamycin Via A Novel Titanium-Mediated Aldol Macrocyclization Reaction " J.Am.Chem.Soc., described other derivatives of 115:9345-9346 (1993), each data is quoted as a reference in this paper integral body.

Limus family compound can be used for treating, prevent, suppress, postpone mediation occurs blood vessel eye diseases and illness (comprising the choroid neovascularization) and occurs or make in its composition that disappears, liquid preparation and method. Limus compound family can be used for preventing, treats, suppresses, postpones AMD (comprising moist AMD) and occurs or it is disappeared. Rapamycin and rapamycin derivative and analog can be used for preventing, treat, suppress, postpone mediation occurs blood vessel eye diseases and illness (comprising the choroid neovascularization) and occur or it is disappeared. Rapamycin can be used for preventing, treats, suppresses, postpones AMD (comprising moist AMD) and occurs or it is disappeared. In some modification, the member of limus compound family or rapamycin are used for the treatment of moist AMD or the eye diseases and the illness that mediate occur blood vessel, comprises the choroid neovascularization.

Operable other treatment agent is included in disclosed therapeutic agent in following patent and publication, each data is quoted its integral body as a reference at this paper: the open WO 2004/027027 of PCT, on April 1st, 2004 is open, be entitled as Method of inhibiting choroidal neovascularization, transfer Trustees of the University of Pennsylvania; U.S. Patent number 5,387, on February 7th, 589,1995 announced, and was entitled as Method of Treating Ocular Inflammation, and the invention people is Prassad Kulkarni, authorizes University of Louisville Research Foundation; U.S. Patent number 6,376, on April 23rd, 517,2003 announced, and was entitled as Pipecolic acid derivatives for vision and memory disorders, transferred GPI NIL Holdings, Inc; The open WO 2004/028477 of PCT, on April 8th, 2004 is open, is entitled as Method subretinal administration of therapeutics including steroids:method for localizing pharmadynamic action at the choroid and retina; And related methods for treatment and or prevention of retinal diseases, assigned to Innorx, Inc; U.S. Patent number 6,416, on July 9th, 777,2002 submitted to, was entitled as Ophthalmic drug delivery device, transferred Alcon Universal Ltd; U.S. Patent number 6, on March 30th, 713,081,2004 announced, be entitled as Ocular therapeutic agent delivery device and methods for making and using such devices, transfer Department of Health and Human Services; U.S. Patent number 5,100, on March 31st, 899,1992 announced, and was entitled as Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof.

Spendable other treatment agent comprises pyrrolidines, dithiocar-bamate (NF kB inhibitor); Squalamine; TPN 470 analogs and fumidil; PKC (protein kinase C) inhibitor; Tie-1 and Tie-2 inhibitors of kinases; The vegf receptor kinase inhibitor; The proteosome inhibitor is as being used for the Velcade of injection^TM(bortezomib)；ranibuzumab(Lucentis ^TM) and other antibody for identical target; Pegaptanib (Macugen^TM); Vitronectic receptor antagonist, as the cyclic peptide antagonist of Vitronectic receptor type integrin; α-v/ β-3 integrin antagonists; α-v/ β-1 integrin antagonists; Thiazolidinediones, as Rosiglitazone (rosiglitazone) or troglitazone (troglitazone); Interferon, comprise gamma interferon or by using the interferon of glucan and metal-complexing target CNV; Pigment epidermal derived factors (PEDF); Endostatin; Angiostatin; Tumistatin; Canstatin; NSC 24345 (anecortave acetate); Acetonide; Triamcinolone (triamcinolone); Tetrathiomolybdate; The RNA silence of angiogenesis factor or RNA disturb (RNAi), comprise the ribozyme of target vegf expression; Accutane^TM(Accutane); Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, include but are not limited to quinopril, captopril (captopril) and perindozril; MTOR inhibitors (target of rapamycin in mammal); The amino Thalidomide (3-aminothalidomide) of 3-; PTX (pentoxifylline); Methoxyestradiol (2-methoxyestradiol); Colchicine; AMG-1470; Cyclooxygenase-2 inhibitor, as nepafenac (nepafenac), rofecoxib (rofecoxib), Diclofenac (diclofenac), rofecoxib, NS398, celecoxib (celecoxib), Vioxx (vioxx) and (E)-2-alkyl-2 (4-methyl sulphonyl phenyl)-1-styrene; T-RNA synthase conditioning agent; The MMP-13 inhibitor; Acetylcholinesteraseinhibitors inhibitors; Potassium channel antagonists; Endorepellin; The purine analogue of 6-thioguanine; Cyclic peroxide decomposition ANO-2; (restructuring) arginine deiminase (deiminase); Epigallocatechin-3-gallate (epigallocatechin-3-gallate); Cerivastatin (cerivastatin); Suramin (suramin) analog; The VEGFR1R2-Fc DELTA C1(a) molecule; Apoptosis inhibitor; Visudyne^TM, snET2 and other sensitising agents, it can be used for photodynamic therapy (PDT); HGF inhibitor (growth factor antibodies or its acceptor, the micromolecular inhibitor of c-met EGFR-TK, the clipped form of HGF such as HK4).

Spendable other treatment agent comprises antiinflammatory, includes but are not limited to on-steroidal antiinflammatory and steroids antiinflammatory. In some modification, can use the activating agent in liquid preparation to be ace-inhibitor, the endogenous cell factor, the activating agent that affects basilar memebrane, the activating agent that affects endothelial cell growth, 2-adrenergic agonist components or retarding agent, cholinergic agonist or retarding agent, aldose reductase inhibitor, antalgesic, anesthetic, anti-allergy agent, antibacterium medicine, antihypertensive, supercharging medicine (pressor), antiprotozoan agent, antivirotic, antifungal agent, anti-infective, antitumor agent, antimetabolite and anti-angiogenic agent.

spendable steroid therapy agent includes but are not limited to the 21-acetoxypregnenolone, alclometasone (alclometasone), Algestone (algestone), Amcinonide (amcinonide), beclomethasone (beclomethasone), betamethasone (betamethasone), budesonide (budesonide), Chloroprednisone (chloroprednisone), clobetasol (clobetasol), clobetasone (clobetasone), clocortolone (clocortolone), Cloprednol (cloprednol), cortisone (corticosterone), cortisone (cortisone), cortivazol (cortivazol), deflazacort (deflazacort), desonide (desonide), Desoximetasone (desoximetasone), dexamethasone (dexamethasone), dichloro draws pine (diflorasone), diflucortolone (diflucortolone), Difluprednate (difluprednate), enoxolone (enoxolone), chlorine Zha Kete (fluazacort), flucloronide (flucloronide), aniprime (flumethasone), flunisolide (flunisolide), FA (fluocinolone acetonide), Fluocinonide (fluocinonide), fluocortin butyl (fluocortin butyl), fluocortolone (fluocortolone), fluorometholone (fluorometholone), fluperolone acetate (fluperolone acetate), fluprednylidene acetate (fluprednidene acetate), fluprednisolone (fluprednisolone), Cordran (flurandrenolide), Fluticasone Propionate (fluticasone propionate), fluderma (formocortal), Halcinonide (halcinonide), clobetasol propionate (halobetasol propionate), Halometasone (halometasone), halopredone acetate (halopredone acetate), Hydrocortamate (hydrocortamate), hydrocortisone (hydrocortisone), loteprednol etabonate (loteprednol etabonate), mazipredone (mazipredone), medrysone (medrysone), methyl prednisone (meprednisone), radiosone (methylprednisolone), Mometasone Furoate (mometasone furoate), paramethasone (paramethasone), prednicarbate (prednicarbate), prednisolone (prednisolone), prednisolone-25-lignocaine-acetate (prednisolone 25-diethylamino-acetate), prednisolone phosphate sodium (prednisolone sodium phosphate), metacortandracin (prednisone), prednisolone valerate (prednival), methylene prednisolone (prednylidene), Rimexolone (rimexolone), Tixocortol (tixoeortol), triamcinolone (triamcinolone), Triamcinolone acetonide (triamcinolone acetonide), Triamcinolone Benetonide (triamcinolone benetonide), TATBA (triamcinolone hexacetonide) and any derivative thereof.

In some modification, can use cortisone, dexamethasone, FA, hydrocortisone, methylprednisolone, prednisolone, metacortandracin and triamcinolone and derivative thereof. Liquid preparation can comprise the combination of two or more steroid therapy agent.

In a nonrestrictive example, the steroid therapy agent can form liquid preparation by weight approximately 0.05% to approximately 50%. In another nonrestrictive example, steroids forms liquid preparation by weight approximately 0.05% to approximately 10%, and approximately between 10% to 20%, approximately 30% to approximately between 40%, or approximately 40% to approximately between 50%.

Therapeutic agents may be used other non -limiting examples include , but are not limited to anesthetics , analgesics Agents, cellular transport / migration blockers , such as colchicine , vincristine vincristine, cytochalasin B, and related compounds ; carbonic anhydrase inhibitors such as acetazolamide (acetazolamide), Methazolamide Amine (methazolamide), dichloro- sulfamethoxazole (dichlorphenamide), acetazolamide (diamox) and Neuroprotective agents such as nimodipine and related compounds ; antibiotics such as tetracycline , chlortetracycline , bacitracin , Neomycin , polymyxin , gramicidin , cephalexin , oxytetracycline , chloramphenicol , rifampicin , ring Ciprofloxacin , aminoglycosides , gentamicin, erythromycin and penicillin, quinolones , ceftazidime , Wan Vancomycin carbapenem imine (vancomycine imipeneme); antifungal agents such as amphotericin B, chlorine Itraconazole , ketoconazole , and miconazole (miconazole); antibacterial agents such as sulfa drugs (sulfonamides), Sulfadiazine (sulfadiazine), sulfacetamide (sulfacetamide), sulfamethizole (sulfamethizole) and sulfa exclusive _ azole (sulfisoxazole), nitrofurazone (nitrofurazone) and Sodium propionate ; antivirals such as idoxuridine (idoxuridine), trifluridine (trifluorothymidine), three Fluorouridine (trifluorouridine), acyclovir (aeyclovir), ganciclovir (ganciclovir), Cidofovir (cidofovir), interferon , DDI, AZT, foscarnet (foscamet), Ara gland Glycosides (vidarabine), irbavirin, protease inhibitors and anti- cytomegalovirus agents ; antiallergic agent Such as cromolyn sodium (sodium cromoglycate), Antazoline (antazoline), methapyriline, chlorpheniramine (chlorpheniramine), cetirizine (cetirizine), Xin'an Alternate root (pyrilamine) and non- Nila Min (prophenpyridamine); synthetic glucocorticoid and salt Corticosteroids and cholesterol metabolism comes from the more common forms of hormones (DHEA, progesterone, Estrogen ) ; non-steroidal anti-inflammatory drugs such as salicylates, indomethacin (indomethacin), Advil (ibuprofen), diclofenac, flurbiprofen (flurbiprofen), piroxicam (piroxicam) and COX2 inhibitors ; antitumor agents such as carmustine (carmustine), cisplatin (cisplatin), fluorouracil ; doxorubicin, asparaginase , azacitidine (azacitidine), sulfur azole Purine (azathioprine), bleomycin , busulfan (busulfan), carboplatin (carboplatin), card Secretary Ting Mo , chlorambucil (chlorambucil), cyclophosphamide (cyclophosphamide), cyclosporine Streptozotocin , cytarabine, dacarbazine (dacarbazine), actinomycin D (dactinomycin), Daunorubicin (daunorubicin), doxorubicin (doxorubicin), estramustine (estramustine), etoposide (etoposide), etretinate (etretinate), non- Seoul Division Pavilion (filgrastin), fluorouracil nucleoside (floxuridine), fludarabine (fludarabine), fluorine Uracil , florxymesterone, flutamide (flutamide), goserelin (goserelin), hydroxyl Urea (hydroxyurea), ifosfamide (ifosfamide), leuprolide (leuprolide), levamisole (levamisole), limustine, mechlorethamine (nitrogen mustard), melphalan (melphalan), mercaptopurine (mercaptopurine), methotrexate MTX (methotrexate), mitomycin (mitomycin), mitotane (mitotane), pentostatin (pentostatin), sent parked alkyl bromide (pipobroman), mithramycin (plicamycin), procarbazine (procarbazine),sargramostin(sargramostin), streptozotocin (streptozocin), tamoxifen Raloxifene (tamoxifen), paclitaxel (taxol), teniposide (teniposide), thioguanine , uracil Pyridine nitrogen mustard (uracil mustard), vinblastine (vinblastine), vincristine (vincristine) and Changchun Vindesine (vindesine); immunological drugs such as vaccines and immune stimulant ; insulin , calcitonin, thyroid Next gonadotropin and hypothalamic peptide and vasopressin releasing factor ; β- adrenergic blockers such as timolol (timolol), levobunolol (levobunolol) and betaxolol (betaxolol); cytokine , white Interleukins and growth factor, epidermal growth factor, fibroblast growth factor, platelet -derived growth Factor, transforming growth factor- β, ciliary neurotrophic growth factor, glial cell line -derived neurotrophic due Son , NGF, EPO, PLGF, nerve growth factor (BNGF), vascular endothelial growth factor (vEGF) and growth factors against such monoclonal antibody or fragment thereof ; anti-inflammatory agents such as hydrocortisone Pine , dexamethasone, fluocinolone , prednisone , prednisolone , methylprednisolone , fluorometholone , betamethasone m Pine and triamcinolone ; decongestants such as phenylephrine (phenylephrine), naphazoline rnadhazoline) and tetrahydrazoline; miotics and anti- cholinesterase , such as pilocarpine (pilocarpine), carbachol (carbachoD, diisopropyl fluorophosphate (di-isopropyl fluorophosphates), sulfur iodide diethoxy phosphoryl choline (phospholine iodine) and to the United States bromide (demecarium bromide); mydriatic agents such as atropine sulfate , cyclopentolate (cyclopentolate), Homatropine (homatropine), scopolamine (scopolamine), tropicamide (tropicamide), You Katuo product (eucatropine); sympathomimetic drugs such as epinephrine and vasoconstrictor and vasodilator Tonicity agent , anticoagulant (anticlotting agents) such as heparin , anti fibrinogen, plasmin (fibrinolysin), anticoagulation activating enzyme (anticlotting activase), anti-diabetic agents include acetic acid Hexyl urea (acetohexamide), chlorpropamide (chlorpropamide), glipizide (glipizide), Glibenclamide (glyburide), tolazamide (tolazamide), tolbutamide (tolbutamide), Insulin and aldose reductase inhibitors, hormones, peptides, nucleic acids, carbohydrates, lipids , glycolipids , glycoproteins And other macromolecules , including endocrine hormones such as vasopressin , insulin , insulin -related growth Factor , hormone, growth hormone ; heat shock protein ; immune response modifiers such as muramyl dipeptide , Cyclosporin , interferon ( including Wang α-, p- , and γ- interferon ) , interleukin- 2 , cytokines , FK506 ( An epoxy - pyrido - oxazepine ring tricosene - tetraone , also known as tacrolimus ) , Tumor necrosis factor, pentostatin , thymopentin (thymopentin), transforming growth factor β2, erythrocyte EPO (erythropoetin); Anti nascent proteins ( such as anti- VEGF, interferon ) , antibodies ( single Cloning, polyclonal , humanized , etc. ) or an antibody fragment , aptamer oligomers , aptamers and gene fragments ( oligonucleotides Nucleotides , plasmids , ribozymes , small interfering RNA (SiRNA), nucleic acid fragments , peptides ) , immunomodulators If endoxan (endoxan), thalidomide , tamoxifen ; antithrombotic drugs and vasodilators such as rtPA, Urokinase, plasmin ; nitric oxide donor , nucleic acid , dexamethasone, cyclosporin Yan Su A, azathioprine Methotrexate , cloth quinapril (brequinar), guanidine stand Secretary Mo (gusperimus), 6 - mercaptopurine , Mizoribine (mizoribine), rapamycin , tacrolimus (FK-506), folic acid analogs ( e.g. dimethyl folic acid, Ida song Sand (edatrexate), methotrexate, topiramate song Corzine (piritrexim), butterfly Lo methotrexate (pteropterin), Tomudex_, Acamprosate (trimetrexate)), purine analogs ( eg Cladribine (cladribine), fludarabine (fludarabine), 6 - mercaptopurine , sulfur microphone purine (thiamiprine), thiaguanine), pyrimidine analogs ( eg Anzai gemcitabine (ancitabine), A Tie cytidine 6 - nitrogen uridine , carmofur (carmofur), cytarabine, doxifluridine (doxifluridine), ethyl acetate for fluorine (emitefur), behenic A sugar pyridine (enocitabine), fluorouracil Nucleoside , fluorouracil , gemcitabine , tegafur (tegafur)), fluocinolone , triaminolone, Anecortave acetate , fluorometholone , medroxyprogesterone pine (medrysone) and prednisolone . In some variations , Immunosuppressant dexamethasone . In some variations , the immunosuppressive agent is cyclosporin A.

In some modification, preparation comprises the combination of one or more therapeutic agents.

Described therapeutic agent also can be used in combination with other treatment agent and therapy, includes but are not limited to be used for the treatment of, to prevent, to suppress, to postpone blood vessel generation or neovascularization (particularly CNV) or make its therapeutic agent that disappears and therapy.In some modification, use generation of extra therapeutic agent or therapy for treating blood vessel or neovascularization (particularly CNV) or it is disappeared.The therapeutic agent that this class is extra and the limiting examples of therapy comprise pyrrolidine, dithiocar-bamate (dithiocarbamate) (NF к B inhibitor); Squalamine; TPN 470 analog and Amebacilin; PKC (Protein kinase C) inhibitor; Tie-1 and Tie-2 inhibitors of kinases; The vegf receptor kinase inhibitor; Albuminous body inhibitor such as Velcade ^TM(bortezomib is used for injection; Ranibuzumab (Lucentis ^TM) with other antibody at identical target; Pegaptanib (Macugen ^TM); Vitronectic receptor antagonist is as the cyclic peptide antagonist of Vitronectic receptor type integrin; α-V/ β-3 integrin antagonist; α-V/ β-1 integrin antagonist; Thiazolidinediones such as rosiglitazone or troglitazone; Interferon comprises gamma interferon or by using the interferon of glucosan and metal-complexing targeting CNV; Pigment epidermal derived factors (PEDF); Endostatin; Angiostatin; Tumistatin; Canstatin; NSC 24345; Acetonide; Omcilon; Tetrathiomolybdate (tetrathiomolybdate); The RNA silence of angiogenesis factor or RNA disturb (RNAi), comprise the ribozyme of targeting vegf expression; Accutane ^TM(13-cis-retinoic acid); ACE inhibitor includes but are not limited to quinidine (quinopril), captopril and perindozril; MTOR inhibitor (the mammal target of rapamycin); The amino Thalidomide (3-aminothalidomide) of 3-; Pentoxifylline (pentoxifylline); 2-methoxyestradiol (2-methoxyestradiol); Colchicine; AMG-1470; Cyclooxygenase-2 inhibitor, as nepafenac (nepafenac), rofecoxib (rofecoxib), diclofenac (diclofenac), rofecoxib, NS398, celecoxib (celecoxib), ten thousand networks (vioxx) and (E)-2-alkyl-2 (4-methyl sulphonyl phenyl)-1-styrene; T-RNA synthase regulator; Metalloproteases 13 inhibitor; Acetylcholinesteraseinhibitors inhibitors; Potassium channel antagonists; Endorepellin; The purine analogue of 6-thioguanine; Ring peroxide ANO-2; (reorganization) arginine desimidase; Epigallocatechin-3-epicatechol gallate (epigallocatechin-3-gallate); Cerivastatin (cerivastatin); Suramin (suramin) analog; VEGF trap molecule; Hepatocyte growth factor inhibitor (growth factor antibodies or its receptor, the micromolecular inhibitor of c-met tyrosine kinase, the clipped form of HGF such as HK4); Apoptosis inhibitor; Visudyne ^TM, snET2 and other photodynamic therapies (PDT) photosensitizer; And laser photocoagulation.

Can be treated, be prevented, be suppressed, be postponed its generation or be made its disease that disappears and disease

This paper has described and can use therapeutic agent described herein and preparation, liquid preparation and method to treat, prevent, suppress, postpone its generation or make its disease that disappears and disease.In some modification, use therapeutic agent described herein and preparation, liquid preparation and method to treat described disease and disease.Unless this paper has explanation in addition, the experimenter who is considered as all Therapeutic Method execution includes but are not limited to people experimenter.

Generally speaking, to use the treatment of therapeutic agent described herein and preparation, liquid preparation and method, prevention, suppress, postpone to take place or cause disappear responsive any ophthalmic or disease can be by treatment, prevention, suppress, postpone to take place or cause to disappear.The example of ophthalmic or disease includes but are not limited to and relevant disease or the disease of neovascularization (comprising retina and/or choroid neovascularization).

Use preparation described herein, liquid preparation and method can be treated, prevention, suppress, postpone to take place or cause that disease or the disease relevant with retina and/or choroid neovascularization that disappear comprise (but being not limited only to) diabetic retinopathy, degeneration of macula, moist and dryness AMD, retinopathy of prematurity (Terry's sign disease), cause retinitis or uvaeformis infection, the ocular histoplasmosis of inferring, the myopic degeneration, angioid streaks (angioid streaks) and ocular injury.Use preparation described herein, liquid preparation and method can be treated, prevention, suppress, postpone to take place or cause that the ophthalmic that disappears and other limiting examples of disease comprise (but being not limited only to) pseudoxanthoma elasticum (pseudoxanthoma elasticum), vein obstruction (vein occlusion), obstruction of artery (artery occlusion), carotid artery obstruction disease (carotid obstructive disease), sicklemia (Sickle Cell anemia), eales disease (Eales disease), myopia (myopia), chronic detachment of retina (chronic retinal detachment), hyperviscosity syndrome (hyperviscosity syndromes), toxoplasmosis (toxoplasmosis), wound (trauma), polypoid (the sick polypoidal choroidal of choroidal artery vasculopathy), laser therapy infectious-related complication (post-laser complications), the complication of ICSC (complications of idiopathic central serous chorioretinopathy), choroid inflammation complication (complications of choroidal inflammatory conditions), rubescent (rubeosis), with rubescent relevant disease (canthus neovascularization), neovascular glaucoma (neovascular glaucoma), uveitis and chronic eye uveitis, macular edema, proliferating retinopathy and the disease or the disease that cause by fiber blood vessel or fibrous tissue paraplasm, comprise the proliferative vitreoretinopathy (comprising the postoperative proliferative vitreoretinopathy) of form of ownership, no matter whether relevant with diabetes.

In some modification, preparation described herein and pharmaceutical preparation are used to prevent or postpone the generation of ophthalmic or disease, and wherein experimenter's (including but are not limited to people experimenter) is under the risk of the raising that ophthalmic or disease take place.Experimenter with risk that disease or disease raising take place is the experimenter with one or more signs, and this disease or disease take place in this particular subject probably.In some modification, the experimenter that the raising risk that moist AMD takes place is arranged is the experimenter that at least one eye suffers from dryness AMD.In some modification, branch hole there is the experimenter of the raising risk that moist AMD takes place suffer from the experimenter of moist AMD for another.In some modification, the experimenter CNV that preparation described herein and pharmaceutical preparation are used for preventing or postpone to be under the risk of the raising that CNV takes place takes place, and includes but are not limited to prevention or postpones the generation of experimenter's (including but are not limited to the people experimenter that an eye suffers from AMD) to CNV in the branch hole.In some modification, preparation described herein and pharmaceutical preparation are used for preventing or postpone an eye and suffers from the generation of the patient of moist AMD to branch hole CNV.In some modification, preparation and pharmaceutical preparation comprise the limus chemical compound, include but are not limited to rapamycin.In some modification, preparation and pharmaceutical preparation (include but are not limited under the conjunctiva) to be administered near the eyes has 20/40 or the people experimenter of better vision.In some modification, preparation and pharmaceutical preparation (include but are not limited under the conjunctiva) eye that is administered to people experimenter near the eyes, and the eye of wherein using said preparation has 20/40 or better vision.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of, prevent or postpone AMD and takes place.In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of, prevent or postpone dryness AMD and takes place.In some modification, the experimenter's (including but are not limited to people experimenter) who suffers from non-central geographical atrophy (non-centralgeographic atrophy) is used preparation described herein or the pharmaceutical preparation generation with the geographical atrophy in treatment, prevention or delay center.In some modification, preparation and pharmaceutical preparation contain the limus chemical compound, include but are not limited to rapamycin.In some modification, preparation and pharmaceutical preparation (include but are not limited under the conjunctiva) to be administered near the eyes has 20/40 or the people experimenter of better vision.In some modification, preparation described herein and pharmaceutical preparation are applied, and experimenter's (including but are not limited to people experimenter) also is used for the treatment of the therapy for treating of disease or disease with another.In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of, prevent or postpone generation moist or dryness AMD, and before with preparation described herein and pharmaceutical preparation treatment, in the treatment or after the treatment, experimenter's (including but are not limited to people experimenter) also uses laser therapy (as the photodynamics laser therapy) treatment.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of one or more uveitiss, anaphylaxis conjunctivitis, macular edema, glaucoma or xerophthalmia.

In some modification, preparation or pharmaceutical preparation comprise the thunderous handkerchief mycin of limus chemical compound, and are applied in order to treatment, prevention or the generation of delay xerophthalmia.In some modification, preparation or pharmaceutical preparation comprise the thunderous handkerchief mycin of limus chemical compound, and are applied the generation in order to treatment, prevention or delay anaphylaxis conjunctivitis.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of glaucoma.In some modification, described hereinly be used for the treatment of glaucomatous preparation and pharmaceutical preparation comprises the thunderous handkerchief mycin of limus chemical compound, and as prevention, the surgery adjuvant that alleviates or postpone postoperative complication.In some modification, described hereinly be used for the treatment of glaucomatous preparation and pharmaceutical preparation contains the thunderous handkerchief mycin of limus chemical compound, and in order to improve or to prolong the surgical implant success.In some modification, described hereinly be used for the treatment of glaucomatous preparation and pharmaceutical preparation contains the thunderous handkerchief mycin of limus chemical compound, and the success that is used to promote or prolong argon laser trabecular resection or other glaucoma related surgicals.In some modification, preparation described herein and pharmaceutical preparation have neuroprotective, and in order to the treatment glaucoma.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of retinitis pigmentosa.In some modification, described hereinly be used for the treatment of glaucomatous preparation and pharmaceutical preparation comprises the thunderous handkerchief mycin of limus chemical compound, and be used for the treatment of, prevent or postpone the generation of retinitis pigmentosa.In some modification, preparation described herein and pharmaceutical preparation have neuroprotective, and are used for the treatment of retinitis pigmentosa.

In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of one or more central retinal vein occlusion diseases (CRVO), branch retinal vein occlusion (BRVO), retinal vascular disease and disease, macular edema, diabetic macular edema, sclera neovascularization, diabetic retinopathy or corneal graft rejection.In some modification, preparation and pharmaceutical preparation contain the thunderous handkerchief mycin of limus chemical compound, and are applied to treat, to prevent or postpone the generation of one or more these class diseases or disease.In some modification, preparation described herein and pharmaceutical preparation are administered under the conjunctiva has 20/40 or the eye of better vision.

When being used for the treatment of, preventing, suppressing, postponing the uveitis generation or it is disappeared, preparation described herein and liquid preparation can be used by number of ways known in the art, include but are not limited to by eye or oral administration.Other administration route is known in the art and conventional.In some modification, preparation described herein comprises rapamycin and is used for the treatment of uveitis.

Using preparation described herein, liquid preparation and method can treat, suppress, postpone its generation or make its a kind of disease that disappears is moist AMD.In some modification, use preparation described herein, liquid preparation and method to treat moist AMD.Moist AMD is characterized as blood vessel and grows into the position of not expecting under the retina from their common positions choroid.These neovascularity seepages and the hemorrhage vision that causes reduce, and may lose one's sight.

Preparation described herein, liquid preparation and method also can be used for prevention or delay the conversion of dryness AMD (wherein retinal pigment epithelium or RPE degenerate and cause that the yellow deposit that is called drusen (drusen) under photoreceptor cell death and the retina forms) hygrotropism AMD.

" degeneration of macula " is characterized as excessively generation and retinal pigment epithelium atrophy of fibrous deposit in macula lutea and the retina.Eye by degeneration of macula " torment " used herein is interpreted as at least a detectable physiological feature relevant with macular degeneration disease of this demonstration.Using rapamycin shows restriction angiogenesis (for example without the choroid neovascularization for the treatment of in the age related macular degeneration (AMD) that just can take place) and it is disappeared.Term used herein " angiogenesis " is meant the generation (" neovascularization ") of neovascularity in tissue or the organ.Eye or amphiblestroid " disease or the disease of angiogenesis mediation " are such disease or diseases: neovascularity forms in eye or retina in morbific mode therein, cause vision reduction or forfeiture or other problems, for example relevant choroid neovascularization with AMD.

Preparation described herein also can be used for treating, prevent, suppress, postponing the generation of relevant disease of panimmunity and disease or it is disappeared with liquid preparation (including but are not limited to the preparation and liquid preparation that contain rapamycin), and described disease and disease include but are not limited to organ-graft refection among the host, graft versus host disease, autoimmune disease, inflammatory diseases, super hypertrophy angiopathy, solid tumor and fungal infection.In some modification, preparation described herein is used for the treatment of relevant disease of panimmunity and disease with liquid preparation (including but are not limited to the preparation and liquid preparation that contain rapamycin), and described disease and disease include but are not limited to organ-graft refection among the host, graft versus host disease, autoimmune disease, inflammatory diseases, super hypertrophy angiopathy, solid tumor and fungal infection.Preparation described herein and liquid preparation (including but are not limited to the preparation and the liquid preparation that contain rapamycin) useful as immunosuppressants.Preparation described herein and liquid preparation (including but are not limited to the preparation and the liquid preparation that contain rapamycin) can be used for treating, prevent, suppressing or postpone the generation of transplanted organ or tissue rejection or it is disappeared, and described transplanted organ or tissue include but are not limited to heart, liver,kidney,spleen, lung, small intestinal, pancreas and the bone marrow of transplanting.In some modification, preparation described herein and liquid preparation are used for the treatment of the generation of transplanted organ or tissue rejection, and described transplanted organ or tissue include but are not limited to heart, liver,kidney,spleen, lung, small intestinal, pancreas and the bone marrow of transplanting.Immune correlated disease (including but are not limited to transplant rejection) takes place or when it is disappeared when being used for the treatment of, preventing, suppressing, postponing, preparation described herein and liquid preparation can be used by number of ways known in the art, include but are not limited to by Orally administered.

General is used and can be finished by oral liquid.The approach that other generals are used is this area routine techniques.The some of them example is listed in the detailed Description Of The Invention part.

Used hereinly be meant after the administering therapeutic agent by administering therapeutic agent " inhibition " disease or disease, compare with the progress of the disease of not using this therapeutic agent or disease, at least one the detected physiological feature of this disease or disease or the development of symptom are delayed or are stopped.

Used herein by administering therapeutic agent " prevention " disease or disease be after the administering therapeutic agent development refer to the detected physiological feature or the symptom of this disease or disease.

" generation " by administering therapeutic agent " delay " disease or disease used herein is meant after the administering therapeutic agent, compare the later development of at least one detected physiological feature of this disease or disease or symptom with the progress of the disease of not using this therapeutic agent or disease.

This paper uses and is meant after the administering therapeutic agent by administering therapeutic agent " treatment " disease or disease, compare with the progress of the disease of not using this therapeutic agent or disease, at least one the detected physiological feature of this disease or disease or the progress of symptom are delayed, are stopped or being reversed.

Used hereinly " cause " by the administering therapeutic agent that disease or disease " disappear " and be meant that after the administering therapeutic agent this disease or at least one detected physiological feature of disease or the progress of symptom are reversed to a certain extent.

Having procatarxis maybe needs the experimenter's (including but are not limited to people experimenter) who prevents to be determined according to the instruction of this paper by method and standard that skilled doctor determines by this area.Skilled doctor also can be used to identify that blood vessel takes place and/or the standard of determining of neovascularization easily diagnoses needs to suppress according to the instruction of this paper or the individuality of treatment according to this area.

" experimenter " used herein can benefit from any animal of using therapeutic agent described herein.In some modification, therapeutic agent is administered to mammalian subject.In some modification, therapeutic agent is administered to people experimenter.In some modification, therapeutic agent can be administered to the veterinary animal experimenter.In some modification, therapeutic agent can be administered to the model experiment animal subjects.

Use methods described herein can treat, prevent, suppress, postpone its generation or make its other diseases that disappears and disease comprise disclosed disease and disease in following patent and the publication, the content of each data is quoted its integral body as a reference at this paper: the open WO 2004/027027 of PCT, on April 1st, 2004 is open, be entitled as Method of inhibiting choroidal neovascularization, transfer Trustees of the University of Pennsylvania; U.S. Patent number 5,387,589 announces that be entitled as Method of Treating Ocular Inflammation, the invention people is Prassad Kulkarni, transfers University of Louisville Research Foundation February 7 nineteen ninety-five; U.S. Patent number 6,376 was announced on April 23rd, 517,2003, was entitled as Pipecolic acidderivatives for vision and memory disorders, transferred GPI NIL Holdings, Inc; The open WO 2004/028477 of PCT, on April 8th, 2004 is open, is entitled as Methodsubretinal administration of therapeutics including steroids:method forlocalizing pharmadynamic action at the choroid and retina; And relatedmethods for treatment and or prevention of retinal diseases transfers Innorx, Inc; U.S. Patent number 6,416 was announced on July 9th, 777,2002, was entitled as Ophthalmic drugdelivery device, transferred Alcon Universal Ltd; U.S. Patent number 6, announced on March 30th, 713,081,2004, be entitled as Ocular therapeutic agent delivery device andmethods for making and using such devices, transfer Department of Healthand Human Services; With U.S. Patent number 5,536,729, on July 16th, 1996 submitted to, was entitled as Rapamycin Formulations for Oral Administration, transferred AmericanHome Products Corp., with Application No. 60/503,840 and 10/945,682.

Liquid preparation

Liquid preparation described herein contains therapeutic agent and can be any liquid preparation usually, includes but are not limited to solution, suspensoid and Emulsion.In some modification, liquid preparation forms the nondispersive agglomerate with respect to surrounding medium when placing in the lagophthalmos vitreous body.

When using the liquid preparation of certain volume, there is certain inaccuracy in the accuracy that should understand the plurality of devices that can be used for the applicating liquid preparation.When being appointed as certain volume, should understand that it is the purpose volume.Yet some equipment such as insulin syringe inaccuracy be greater than 10%, and sometimes inaccuracy greater than 20% or more.Hamilton HPLC type syringe be it is generally acknowledged degree of accuracy in 10%, and recommendation is used for the volume to be injected less than 10 μ l.

In some modification, the volume that is administered to the Vitrea liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is less than about 500 μ l, less than about 400 μ l, less than about 300 μ l, less than about 200 μ l, less than about 100 μ l, less than about 90 μ l, less than about 80 μ l, less than about 70 μ l, less than about 60 μ l, less than about 50 μ l, less than about 40 μ l, less than about 30 μ l, less than about 20 μ l, less than about 10 μ l, less than about 5 μ l, less than about 3 μ l or less than about 1 μ l.In some modification, the volume that is administered to the Vitrea liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is less than about 20 μ l.In some modification, the volume that is administered to the Vitrea liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is less than about 10 μ l.In some modification, the volume that is administered to the Vitrea liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is between about 0.1 μ l and about 200 μ l, between about 50 μ l and about 200 μ l, between about 50 μ l and about 150 μ l, between about 0.1 μ l and about 100 μ l, between about 0.1 μ l and about 50 μ l, between about 1 μ l and about 40 μ l, between about 1 μ l and about 30 μ l, between about 1 μ l and about 20 μ l, at about 1 μ l and about 10 μ l or between about 1 μ l and about 5 μ l.In some modification, the volume that is administered to the intravitreous liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is between about 1 μ l and about 10 μ l.In some modification, the volume that is administered to the intravitreous liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is between about 1 μ l and about 5 μ l.In some modification, the volume that is administered to the intravitreous liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) is between about 1 μ l and about 5 μ l.In some modification, the volume that is administered to the liquid preparation described herein in lagophthalmos or the experimenter's vitreum is between about 0.1 μ l and about 200 μ l.

In some modification, the cumulative volume that is administered to the liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under the conjunctiva is less than about 1000 μ l, less than about 900 μ l, less than about 800 μ l, less than about 700 μ l, less than about 600 μ l, less than about 500 μ l, less than about 400 μ l, less than about 300 μ l, less than about 200 μ l, less than about 100 μ l, less than about 90 μ l, less than about 80 μ l, less than about 70 μ l, less than about 60 μ l, less than about 50 μ l, less than about 40 μ l, less than about 30 μ l, less than about 20 μ l, less than about 10 μ l, less than about 5 μ l, less than about 3 μ l or less than about 1 μ l.In some modification, the volume of liquid preparation described herein that is administered to lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under the conjunctiva is less than about 20 μ l.In some modification, the volume of liquid preparation described herein that is administered to lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under the conjunctiva is less than about 10 μ l.In some modification, the volume that is administered to the liquid preparation described herein of lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under the conjunctiva arrives between about 200 μ l at about 0.1 μ l, between about 50 μ l and about 200 μ l, between about 200 μ l and about 300 μ l, between about 300 μ l and about 400 μ l, between about 400 μ l and about 500 μ l, between about 600 μ l and about 700 μ l, between about 700 μ l and about 800 μ l, between about 800 μ l and about 900 μ l, between about 900 μ l and about 1000 μ l, between about 50 μ l and about 150 μ l, between about 0.1 μ l and about 100 μ l, between about 0.1 μ l and about 50 μ l, between about 1 μ l and about 40 μ l, between about 1 μ l and about 30 μ l, between about 1 μ l and about 20 μ l, between about 1 μ l and about 10 μ l or between about 1 μ l and about 5 μ l.In some modification, the volume of liquid preparation described herein that is administered to lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under the conjunctiva is between about 1 μ l and about 10 μ l.In some modification, the volume of liquid preparation described herein that is administered to lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under the conjunctiva is between about 1 μ l and about 5 μ l.In some modification, the volume of liquid preparation described herein that is administered to lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under the conjunctiva is between about 1 μ l and about 5 μ l.In some modification, the volume of liquid preparation described herein that is administered to lagophthalmos or experimenter's eye (including but are not limited to people experimenter's eye) under the conjunctiva is between about 0.1 μ l and about 200 μ l.

In some modification, liquid preparation described herein (includes but are not limited to each other in one hour) in a period of time and is applied in a plurality of conjunctiva upper/lower positions.Not bound by theory, think that this class repeatedly uses (for example multiple injection) and allow to compare with single dose and use bigger accumulated dose under the conjunctiva, possible limited because topical ophthalmic tissue absorbs the ability of larger volume.

A kind of liquid preparation described herein is the in-situ gelling preparation.In-situ gelling preparation as described herein comprises therapeutic agent and multiple polymers, and it provides the preparation that forms gel or gel-like substance when placing aqueous medium (including but are not limited to the aqueous medium of eye).

In some modification of liquid preparation described herein, therapeutic agent is solution or the suspension of rapamycin in liquid medium.Liquid medium includes but are not limited to solvent, and described solvent includes but are not limited to the solvent of " therapeutic agent solubilising " part.

Liquid preparation described herein can comprise the solubilizing agent composition.In some modification, the solubilizing agent composition is a surfactant.Attention exists overlapping between the composition that can be solvent and solubilizing agent, and therefore identical composition can be used as solvent or solubilizing agent in some systems.Liquid preparation contains therapeutic agent and composition, and described composition can be considered to solvent or solubilizing agent or surfactant, thinks solvent if this composition plays solvent action; If this composition does not play solvent action, then this composition can be considered to solubilizing agent or surfactant.

Liquid preparation also can randomly comprise stabilizing agent, excipient, gellant, adjuvant, antioxidant and/or other compositions described herein.

In some modification, all the components in the liquid preparation except that therapeutic agent at room temperature is a liquid.

In some modification, liquid preparation comprises the release dressing agent.In some modification, discharging dressing agent is the film forming polymer composition.The film forming polymer composition can comprise one or more film forming polymers.Any film forming polymer can be used in the excipient composition.In some modification, the film forming polymer composition contains the polymer that forms water-fast film.In some modification, discharge the dressing agent composition and comprise acrylate polymer, include but are not limited to polymethacrylates, include but are not limited to Eudragit RL.

This paper has described and has been used to send " therapeutic agent " partly compositions and liquid preparation of the therapeutic agent of description.Use compositions described herein and liquid preparation delivering therapeutic agents to can be used for treatment, prevention, suppress, postpone the generation of described disease of " disease and disease " part and disease or it is disappeared.Compositions described herein and liquid preparation can contain any therapeutic agent that " therapeutic agent " part is described, and include but are not limited to rapamycin.Compositions as herein described and liquid preparation can comprise a kind of or more than a kind of therapeutic agent.Can use compositions and compositions the liquid preparation and the liquid preparation clearly described except that this paper.

When therapeutic agent was rapamycin, compositions and liquid preparation were used in and keep a certain amount of rapamycin in the vitreous body, and described amount can effectively be treated moist AMD.In a limiting examples, believe that the following liquid preparation of sending rapamycin can be used for treating moist AMD, described preparation can be kept the rapamycin concentrations to about 2 μ g/ml of about 10pg/ml in the vitreous body in a period of time.When rapamycin was contained in the liquid preparation that forms nondispersive agglomerate, the rapamycin concentrations of being stated had been represented the amount of effective treatment ophthalmic or disease, but not only exists only in the nondispersive agglomerate form.In another limiting examples, believe that the following delivery system of sending rapamycin can be used for treating moist AMD, described delivery system can be kept the rapamycin concentrations to about 10ng/mg of about 0.01pg/mg in the retina tela chorioidea in a period of time.The therapeutic agent of other treatment effective dose also is possible, and can easily be determined according to the instruction of this paper by those skilled in the art.

When therapeutic agent was rapamycin, compositions described herein and liquid preparation can be used for sending to experimenter's (including but are not limited to people experimenter) or experimenter's eye the rapamycin of doses.In a limiting examples, believe that containing the 20 μ g that have an appointment can be used for treating moist AMD to the liquid preparation of about 4mg dosage.

In some modification, the therapeutic agent in the liquid preparation account for composition total weight about 0.01% and about 30% between; Between about 0.05% and about 15%; Between about 0.1% and about 10%; Between about 1% and about 5%; Or between about 5% and about 15%; Between about 8% and about 10%; Between about 0.01% and about 1%; Between about 0.05% and about 5%; Between about 0.1% and about 0.2%; Between about 0.2% and about 0.3%; Between about 0.3% and about 0.4%; Between about 0.4% and about 0.5%; Between about 0.5% and about 0.6%; Between about 0.6% and about 0.7%; Between about 0.7% and about 1%; Between about 1% and about 5%; Between about 5% and about 10%; About 15% and about 30%, about 20% and about 30%; Or between about 25% and about 30%.

Those skilled in the art can determine that based on this paper instruction the given therapeutic agent of which kind of amount or concentration is equal to the rapamycin of a certain amount of or concentration, for example by be applied to therapeutic agent in the disease model system (for example in the body or external model system) with not commensurability or concentration and the result in the comparison model system with respect to the result of the rapamycin of multiple amount or concentration.Those skilled in the art also can determine that the given therapeutic agent of which kind of amount or concentration is equal to the rapamycin of a certain amount of or concentration by looking back the comparison rapamycin that carries out in the scientific literature and the experiment of other treatment agent based on this paper instruction.Should understand when for example assessing different diseases or disease, or when using various types of agents, even if identical therapeutic agent also can have different same levels such as rapamycin.Limiting examples at the scientific literature of ophthalmic comparative study rapamycin and other treatment agent is Ohia etc., Effects of steroids andimmunosuppressive drugs on endotoxin-uveitis in rabbits, J.Ocul.Pharmacol.8 (4): 295-307 (1992); Kulkarni, Steroidal and nonsteroidal drugsin endotoxin-induced uveitis, J.Ocul.Pharmacol.10 (1): 329-34 (1994); Hafizi etc., Differential effects of rapamycin, cyclosporine A, and FK506 onhuman coronary artery smooth muscle cell proliferation and signaling, Vascul Pharmacol.41 (4-5): 167-76 (2004); With US 2005/0187241.

For example in moist AMD model, if find that therapeutic agent is renderd a service than rapamycin or effect is hanged down 10 times when the moist AMD of treatment, then the concentration of treatment agent of 10ng/ml should be equal to the rapamycin concentrations of 1ng/ml.If find that perhaps therapeutic agent renders a service than rapamycin or effect is hanged down 10 times, then should use the therapeutic agent with respect to 10 times of amounts of amount of rapamycin when the moist AMD of treatment.

Solvent composition for example can form composition total weight about 0.01% and about 99.9% between; Between about 0.1% and about 99%; Between about 25% and about 55%; Between about 30% and about 50%; Or between about 35% and about 45%; Between about 0.1% and about 10%; Between about 10% and about 20%; Between about 20% and about 30%; Between about 30% and about 40%; Between about 40% and about 45%; Between about 40% and about 45%; Between about 45% and about 50%; Between about 50% and about 60%; Between about 50% and about 70%; Between about 70% and about 80%; Between about 80% and about 90%; Or between about 90% and about 100%.

The solubilizing agent composition for example can form composition total weight about 0.01% and about 30% between; Between about 0.1% and about 20%; Between about 2.5% and about 15%; Between about 10% and about 15%; Or between about 5% and about 10%; Between about 8% and about 12%; Between about 10% and about 20%; Between about 20% and about 30%.

In some modification, liquid preparation described herein has the viscosity between 40% and 120% centipoise.In some modification, liquid preparation described herein has the viscosity between 60% and 80% centipoise.

In some modification, liquid preparation described herein contains therapeutic agent and solvent composition.Solvent composition can contain the combination of single solvent or solvent.Therapeutic agent component can contain the combination of single therapy agent or therapeutic agent.In some modification; solvent is a glycerol; dimethyl sulfoxide; N-Methyl pyrrolidone; dimethyl acetylamide (DMA); dimethyl formamide; glyceryl formal; ethoxydiglycol; the triethylene glycol dimethyl ether; glyceryl triacetate; Glycerine 1,3-diacetate; Semen Maydis oil; CitroflexA-2 (ATC); ethyl lactate; the caprylin of Pegylation; gamma butyrolactone; dimethyl isosorbide; benzyl alcohol; ethanol; isopropyl alcohol; Polyethylene Glycol of various molecular weights (including but are not limited to PEG 300 and PEG 400) or propylene glycol, or one of them or more mixture.

In some modification, liquid preparation described herein is a solution, and comprises therapeutic agent and solvent composition.In some modification, solvent composition comprises ethanol.In some modification, solvent composition comprises ethanol and Polyethylene Glycol, includes but are not limited to liquid macrogol (include but are not limited among PEG 300 or the PEG 400 one or more).

In some modification, liquid preparation described herein contains the Polyethylene Glycol of no more than about 250 μ l.In some modification, liquid preparation described herein contains the Polyethylene Glycol of no more than about 250 μ l, no more than about 200 μ l, no more than about 150 μ l, no more than about 125 μ l, no more than about 100 μ l, no more than about 75 μ l, no more than about 50 μ l, no more than about 25 μ l, no more than about 20 μ l, no more than about 15 μ l, no more than about 10 μ l, no more than about 7.5 μ l, no more than about 5 μ l, no more than about 2.5 μ l, no more than about 1.0 μ l or no more than about 0.5 μ l.The preparation that contains Polyethylene Glycol can contain for example PEG 300 or PEG 400.

In some modification, liquid preparation described herein is suspensoid and comprises therapeutic agent and diluent components.In some modification, diluent components contains the composition that one or more this paper list as solvent or solubilizing agent, and the mixture that wherein obtains is a suspension.

In some modification, liquid preparation partly is that solution and part are suspension.

In some modification, liquid preparation is the in-situ gelling preparation, and comprises therapeutic agent and component of polymer, and wherein component of polymer can contain multiple polymers.In some modification, liquid preparation contains polymethacrylate polymer.In some modification, liquid preparation contains polyvinyl pyrrolidone polymers.

Some modification of liquid preparation contain the therapeutic agent that accounts between gross weight about 0.01% and about 20% (for example but be not limited only to rapamycin), account for solvent between gross weight about 5% and about 15%, account between gross weight about 5% and about 15% solubilizing agent (including but are not limited to surfactant) and as the main water that keeps composition.In some modification, preparation also comprises stabilizing agent, excipient, adjuvant or the antioxidant that accounts between gross weight about 0 and about 40%.

In some modification, liquid preparation contains the therapeutic agent (including but are not limited to rapamycin) that accounts for gross weight about at the most 5%; With the solvent composition that accounts for gross weight about at the most 99.9%.In some modification, liquid preparation contains the therapeutic agent (including but are not limited to rapamycin) that accounts for gross weight about at the most 5%; About at the most 99.9% diluent components.

In some modification, liquid preparation contains the therapeutic agent (including but are not limited to rapamycin) that accounts for gross weight about at the most 5%; Account for the solvent composition of gross weight about at the most 10%; With the solubilising composition that accounts for gross weight about at the most 85%.In some modification, the solubilising composition is the aqueous solution of surfactant.

The multiple polymers composition for example can form composition total weight about 0.01% and about 30% between; Between about 0.1% and about 20%; Between about 2.5% and about 15%; Between about 10% and about 15%; Between about 3% and about 5%; Between about 5% and about 10%; Between about 8% and about 12%; Between about 10% and about 20%; Or between about 20% and about 30%.

Some modification of liquid preparation contain the therapeutic agent (including but are not limited to rapamycin) that accounts between gross weight about 0.01% and about 20%, account for the solvent composition between gross weight about 60% and about 98%, and multiple polymers, the percentage ratio of its combination account for gross weight about 0.1% and about 15% between.In some modification, preparation also comprises stabilizing agent, excipient, adjuvant or the antioxidant that accounts between gross weight about 0 and about 40%.

In some modification, liquid preparation can contain the therapeutic agent (including but are not limited to rapamycin) that accounts for gross weight about 4%; Account for the solvent of gross weight about 91%; With the component of polymer that accounts for gross weight about 5%.

Some examples of liquid preparation described herein and modification are produced and are listed in the table 1.Type according to them is called one or more solutions (" S "), suspensoid (" SP "), Emulsion (" E ") or situ-gel (" ISG ") with the preparation of listing.Some suspensoids are listed the granular size intermediate value.As described herein, some liquid preparations for example are being injected into the nondispersive agglomerate of aqueous environments (as the vitreous body of eye) back formation.For being injected into Vitrea these preparations of lagophthalmos, the right-hand column of table 1 indicates whether form nondispersive agglomerate (NDM) after designated volume is injected into the lagophthalmos vitreous body.

Show one or more preparations (including but are not limited to the rapamycin preparation) below with reference to data, it has been incorporated herein and has described the rapamycin of various dose and the purposes that the other treatment agent is used for the treatment of multiple disease or disease with its integral body: US 60/651,790,2/9/2005 submits to, be entitled as FORMULATIONS FOR OCULAR TREATMENT, application attorney docket (attorneydocket number) 57796-30002.00; US 60/664,040, and 2/9/2005 submits to, and application attorney docket 57796-30004.00 is entitled as LIQUID FORMULATIONS FOR TREATMENTOF DISEASES OR CONDITIONS; US 60/664,119, and 3/21/2005 submits to, and application attorney docket 57796-30005.00 is entitled as DRUG DELIVERY SYSTEMS FORTREATMENT OFDISEASES OR CONDITIONS; US 60/664,306, and 3/21/2005 submits to, and application attorney docket 57796-30006.00 is entitled as IN SITU GELLINGFORMULATIONS AND LIQUID FORMULATIONS FOR TREATMENTOF DISEASES OR CONDITIONS; US__/_ _, 2/9/2006 submits to, is entitled as FORMULATIONS FOR OCULAR TREATMENT, application attorney docket 57796-20002.00; _ _/_ _, 2/9/2006 submits to, and application attorney docket 57796-20004.00 is entitled as LIQUID FORMULATIONS FOR TREATMENT OF DISEASES ORCONDITIONS; US 2005/0187241 and US 2005/0064010.

Form the liquid preparation of nondispersive agglomerate

A class I liquid I preparation described herein forms nondispersive agglomerate when placing aqueous medium.This paper uses " nondispersive agglomerate " to be meant when liquid preparation places environment, with respect to the structure of its environment that is placed into formation or the shape that presents.Generally speaking, the nondispersive agglomerate of liquid preparation is any situation except that liquid preparation is evenly distributed in the surrounding medium.The liquid preparation that nondispersive agglomerate can be for example be applied by observation also characterizes its outward appearance with respect to surrounding and points out.

In some modification, aqueous medium is a water.In some modification, aqueous medium is de-ionized water, distilled water, sterilized water or tap water (including but are not limited to the City at MacuSight in Union, obtainable tap water in the scope of offical duty of California).

In some modification, aqueous medium is experimenter's a aqueous medium.In some modification, aqueous medium is the aqueous medium of experimenter's eye, includes but are not limited to the vitreous body of experimenter's eye.In some modification, the experimenter experimenter that behaves.In some modification, the experimenter is a rabbit.

In some modification, liquid preparation in being exposed to certain temperature or temperature range (include but are not limited to be about room temperature, be about ambient temperature, be about 30 ℃, be about 37 ℃ or be about the temperature of experimenter's aqueous medium) time form nondispersive agglomerate.

In some modification, liquid preparation forms nondispersive agglomerate when (including but are not limited to the pH between about 6 and about 8) in being exposed to certain pH or pH scope.

In some modification, nondispersive agglomerate comprises gel or gel-like substance.

In some modification, nondispersive agglomerate comprises polymeric matrix.In some modification, nondispersive agglomerate comprises that therapeutic agent is dispersed in polymeric matrix wherein.

Liquid preparation described herein generally can be any geometry or shape after being administered to experimenter or experimenter's eye (including but are not limited to people experimenter).In some modification, nondispersive agglomerate is between about 0.1mm and about 5mm.In some modification, nondispersive agglomerate is between about 1mm and about 3mm.The liquid preparation that forms nondispersive agglomerate can be shown as for example fine and close spherical agglomerate when being administered to vitreous body.In some cases, liquid preparation can be rendered as nondispersive agglomerate with respect to surrounding medium, and wherein said nondispersive agglomerate definition is more indeterminate, and compare its geometry with sphere more unsetting.

The liquid preparation of the nondispersive agglomerate of formation described herein can form nondispersive agglomerate at once when placing medium, or nondispersive agglomerate can a period of time formation after placing liquid preparation.In some modification, nondispersive agglomerate formed in about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days or about 7 days.In some modification, nondispersive agglomerate formed in about 1 week, about 2 weeks or about 3 weeks.

In some modification, the liquid preparation of the nondispersive agglomerate of formation described herein is shown as milky or the albescent semicontinuous or nondispersive agglomerate of semisolid with respect to its medium that is placed.

A kind of liquid preparation as herein described forms following nondispersive agglomerate, and described nondispersive agglomerate forms solid storage storehouse when preparation is injected in any or all water (between lagophthalmos vitreous body or the lagophthalmos CSC).A kind of liquid preparation as herein described forms following nondispersive agglomerate, and described nondispersive agglomerate forms semisolid when preparation is injected in any or all water (between lagophthalmos vitreous body or the lagophthalmos CSC).A kind of liquid preparation as herein described forms following nondispersive agglomerate, and described nondispersive agglomerate forms polymeric matrix when preparation is injected in any or all water (between lagophthalmos vitreous body or the lagophthalmos CSC).A kind of liquid preparation as herein described forms following nondispersive agglomerate, and described nondispersive agglomerate has the form of gel, hydrogel or gel-like substance when preparation is injected in any or all water (between lagophthalmos vitreous body or the lagophthalmos CSC).

In modification more as herein described, when surrounding medium was aqueous, liquid preparation formed nondispersive agglomerate with respect to surrounding medium." aqueous medium " or " aqueous environments " is medium or the environment that contains at least about 50% water.The example of aqueous medium includes but are not limited between water, vitreous body, extracellular fluid, conjunctiva, sclera, the CSC, aqueous humor, gastric juice and comprise any tissue or body fluid at least about 50% water.Aqueous medium includes but are not limited to gel structure, includes but are not limited to the gel structure of conjunctivae and selerae.

In some modification, liquid preparation described herein forms nondispersive agglomerate when the liquid preparation of test volume is placed in the lagophthalmos vitreous body.In some modification, test volume is applied to lagophthalmos, and test volume equals to be administered to the volume of experimenter's's (including but are not limited to people experimenter's eye) liquid preparation.

In some modification, the volume that the test volume that is administered to lagophthalmos equals to be administered to experimenter's eye multiply by scale factor, and scale factor equals the average external volume of lagophthalmos average external volume divided by experimenter's eye." average external volume " of eye used herein generally is meant the similar age member's of the species of being considered average eye volume, and the average external volume of any concrete individual eye is relative.

In some modification, the test volume that is administered to lagophthalmos is between about 10 μ l and the about 50 μ l.In some modification, the test volume that is administered to lagophthalmos is between about 1 μ l and the about 30 μ l.In some modification, the test volume that is administered to lagophthalmos is between about 50 μ l and the about 100 μ l.In some modification, the test volume that is administered to lagophthalmos is between about 25 μ l and the about 75 μ l.In some modification, the test volume that is administered to lagophthalmos is about 30 μ l.

In some modification, the liquid preparation that forms nondispersive agglomerate when placing medium comprises one or more therapeutic agents that account for concentration between gross weight about 0.01% and about 10%, and accounts for the solvent between gross weight about 10% and about 99%.In some modification, liquid preparation also comprises solubilizing agent, includes but are not limited to surfactant.In some modification, liquid preparation also contains stabilizing agent, excipient, adjuvant or the antioxidant etc. that account between gross weight about 0 and about 40%.In some modification, therapeutic agent accounts for the about 5% of gross weight, and solvent composition accounts for gross weight about 95%.

Whether liquid preparation shows nondispersive agglomerate with respect to surrounding medium in the time of can determining to be present in experimenter's (including but are not limited to people experimenter) or the experimenter's eye by following method: with therapeutic agent and solvent, be administered to vitreous body and the comparative liquid preparation and the surrounding medium of experimenter's (including but are not limited to people experimenter) eye.

Can be used for treatment, prevention, suppressing, postpone the generation of experimenter's (including but are not limited to people experimenter) disease and disease or make its a kind of liquid preparation that disappears is the liquid preparation that forms nondispersive agglomerate when placing in the lagophthalmos vitreous body.When being used for the treatment of, preventing, suppressing, postponing the generation of experimenter's disease or disease or it is disappeared, liquid preparation is administered to the experimenter.Liquid preparation can form or not form nondispersive agglomerate in the experimenter.A kind of liquid preparation described herein forms nondispersive agglomerate when being applied to the experimenter, and forms nondispersive agglomerate when being applied to lagophthalmos.

Not bound by theory, believe that rapamycin helps the rapamycin liquid preparation that contains more as herein described to form nondispersive agglomerate at intravitreous low solubility.Vitreous body is the classifying gel of being made up of water (up to 99%) fully basically.Not bound by theory, believe that rapamycin precipitates when the rapamycin in the preparation of injection contacts with vitreous body.

Not bound by theory, believe that the nondispersive agglomerate of influence forms and the factor of shape comprises the concentration of rapamycin in the preparation, the viscosity of preparation, the ethanol content and the volume injected of preparation.Believe that the rapamycin of keeping higher concentration behind ejection preparation facilitates the formation of nondispersive agglomerate, low opposite with rapamycin local concentration behind the ejection preparation.When the volume of given dose increases, more do not help forming nondispersive agglomerate.When improving rapamycin concentrations and/or improving viscosity, can more help forming nondispersive agglomerate.Ethanol content influences the viscosity of the dissolubility and the preparation of rapamycin in the preparation.

In a comparison, the solution of 0.4% rapamycin of 100 μ l, 4.0% ethanol and 95.6%PEG 400 (400 μ g dosage) does not form nondispersive agglomerate after being injected into lagophthalmos.On the contrary, the solution of 2.00% rapamycin of 20 μ l, 4.0% ethanol and 94%PEG 400 (also being 400 μ g dosage) forms fine and close spherical nondispersive agglomerate after being injected into lagophthalmos.

Not bound by theory, in one example of back, suppose formation such as Figure 1A-1C and the generation hereinafter described of nondispersive agglomerate.During injection, liquid preparation is because its viscosity has formed spheroid 100 in vitreous body 110.Ethanol spreads from this bead then, forms the localized precipitation 120 of rapamycin in the bead.At last, Polyethylene Glycol also spreads from bead, obtains solid-state, the fine and close nondispersive agglomerate 130 of rapamycin.

In some modification, nondispersive agglomerate described herein by by volume at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or therapeutic agent at least about in 95% the injection lagophthalmos vitreous body time form.

In some modification, when forming the nondispersive agglomerate contain rapamycin, in the time period that prolongs, continue to send with roughly constant speed.Be not bound by any theory, believe that sending rapamycin from nondispersive agglomerate in vitreous body depends on rapamycin in intravitreous dissolving, this depends on the clearance rate of medicine from vitreous body to its hetero-organization again.Be not bound by any theory, believe that this dispose procedure keeps the Css of rapamycin in the vitreous body.

In some modification, to compare with the dosage that is equal to that does not form nondispersive agglomerate, the formation of nondispersive agglomerate has reduced the toxicity of injection liquid preparations.In being injected into the modification that intravitreous liquid preparation do not form nondispersive agglomerate, medicine (for example rapamycin) shows and is dispersed in the vitreous body.

In some modification, this can disturb vision.

In some modification, for the liquid preparation of suspension forms nondispersive agglomerate after being injected into vitreous body.When the suspension particle size increased, forming nondispersive agglomerate from the suspension of injecting can be more favourable.

In some modification, believe be injected into experimenter's (including but are not limited to people experimenter) at the moment liquid preparation can form the visible nondispersive agglomerate of vision.

In some modification, liquid preparation can form nondispersive agglomerate when believing subconjunctival injection.In some modification, believe that the applicating liquid preparation can form the storage storehouse under the conjunctiva in scleral tissue.Believing promptly that therapeutic agent is absorbed into forms the medicine local concentration near the sclera of injection site and in sclera.

The in-situ gelling preparation

This paper has described the liquid preparation of the nondispersive agglomerate of following formation, forms gel or gel-like substance when described preparation places aqueous medium.In some modification, nondispersive agglomerate comprises gel; Gel is a hydrogel in some modification.

This paper uses " in-situ gelling preparation " to be meant the liquid preparation that forms the nondispersive agglomerate of gel sample when liquid preparation places aqueous medium (include but are not limited to and be the aqueous medium between water, lagophthalmos vitreous body and the lagophthalmos CSC).In some modification, the in-situ gelling preparation forms the nondispersive agglomerate of gel sample when placing tap water.

In some modification, the in-situ gelling preparation was suspension before placing aqueous medium, and formed gel when placing aqueous medium.In some modification, the in-situ gelling preparation is solution before placing aqueous medium, and original position forms gel when placing aqueous medium.In some modification, the in-situ gelling preparation is Emulsion before placing aqueous medium, and forms gel when placing aqueous medium.In some modification, place aqueous medium (include but are not limited between water, vitreous body or eye sclera and the conjunctiva any or whole) back to form the nondispersive agglomerate of gel sample in the in-situ gelling preparation.In some modification, situ-gel is formed by polymeric matrix.Therapeutic agent is dispersed in the polymeric matrix in some modification.

This paper has described and can be used for treatment, prevention, inhibition, delay experimenter's (including but are not limited to people experimenter) disease and the generation of disease or the in-situ gelling preparation that it is disappeared.When the generation that is used for the treatment of, prevents, suppresses, postpones experimenter's disease or disease or when it is disappeared, use the in-situ gelling preparation to the experimenter.A kind of liquid preparation described herein comprises the in-situ gelling preparation, and described in-situ gelling preparation forms nondispersive agglomerate when being applied to the experimenter, and forms nondispersive agglomerate when being applied to lagophthalmos.

In some modification, the in-situ gelling preparation comprises one or more polymer.This paper has described polytype polymer, is included as the polymer of solvent, is the polymer of solubilizing agent, be to discharge the polymer of dressing agent, for the polymer of stabilizing agent etc.In some modification, use any combination of polymer, wherein when placing aqueous medium (include but are not limited between water, vitreous body or the CSC any or all), form any or whole of nondispersive agglomerate, gel, hydrogel or polymeric matrix when polymer and therapeutic agent combination.

In some modification, when being applied to the experimenter, the in-situ gelling preparation sends the therapeutic agent that prolongs release to the experimenter.

In some modification, liquid preparation comprises therapeutic agent and multiple polymers, and wherein one of polymer is a polymethacrylates.Polymethacrylates is known as multiple title and can derives from several formulations, includes but are not limited to polymethacrylates, methacrylic acid-ethyl propylene acid ester copolymer (1: 1), the methacrylic acid of dispersion 30%-ethyl propylene acid ester copolymer (1: 1), methacrylic acid-methyl methacrylate ester copolymer (1: 2), methacrylic acid-methyl methacrylate ester copolymer (1: 1), acidum methacrylicum et ethylis acrylas polymerisatum 1: 1,1: 1 dispersio 30 percentum of acidummethacrylicum et ethylis acrylas polymerisatum, acidum methacrylicum et methylis methacrylas polymerisatum1: 1, acidum methacrylicum et methylis methacrylas polymerisatum 1: 2, USPNF: ammonio methacrylate copolymer, methacrylic acid copolymer, the methacrylic acid copolymer dispersion.

In some modification, one of polymer is a polyvinylpyrrolidone.Polyvinylpyrrolidone is known as multiple title and can obtains in several formulations, includes but are not limited to polyvidone, povidonum, kollidon; Plasdone; Poly-[1-(2-oxygen-1-pyrrolidinyl) ethylene]; Polyvidone; PVP; 1-vinyl-2-pyrrolidinyl polymer and 1 vinyl 2 pyrrolidone homopolymer.

A kind of liquid preparation as herein described comprises therapeutic agent and solvent composition.Described solvent composition can comprise the combination of single solvent or solvent.

In some modification, solvent is the Polyethylene Glycol (including but are not limited to PEG 300 and PEG 400) or the propylene glycol of glycerol, dimethyl sulfoxide, N-Methyl pyrrolidone, ethanol, isopropyl alcohol, various molecular weights, or one of them or multiple mixture.

In some modification, solvent is a Polyethylene Glycol.Polyethylene Glycol is known as multiple title and can obtains in several formulations, includes but are not limited to Polyethylene Glycol, PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, Macrogol 2000 0, macrogola, breox PEG; Carbowax; Carbowax sentry:Hodag PEG; Lipo; Lipoxol; Lutrol E; PEG; Pluriol E; Polyethylene Glycol and alpha-hydro-omega-hydroxy-poly (Oxy-1,2-second two bases).

The compositions and the liquid preparation that are used for delivering therapeutic agents

Compositions described herein and liquid preparation can be used for sending a certain amount of therapeutic agent, and described amount can effectively treat, prevent, suppresses, postpones the generation of described disease of " disease and disease " part and disease or it is disappeared.Compositions described herein and liquid preparation are sent one or more therapeutic agents in the time period that prolongs in some modification.

" effective dose " (it is also referred to as " treatment effective dose " in this article) that is used for the therapeutic agent of using described herein be meant when being administered to experimenter's (including but are not limited to people experimenter), seeks to provide the amount of the therapeutic agent of therapeutic effect.The realization of different treatment effects can need the different effective dose of therapeutic agent.For example be used for prevent disease or treatment of conditions agent the treatment effective dose can be used for the treatment of, suppress, postpone disease or disease and take place or make its treatment effective dose that disappears different.In addition, the treatment effective dose can be depending on the described disease of age, body weight and processing or known other health status of disease those skilled in the art of experimenter.Therefore, the treatment effective dose therapeutic agent be applied to each experimenter in can be different.

Be used for the treatment of, prevent, suppress, postpone the generation of specified disease or disease or make the therapeutic agent of its effective dose that disappears refer to also that in this article the amount of its therapeutic agent that disappears takes place or makes for effective treatment, prevention, inhibition, delay disease or disease.

For whether the level of determining therapeutic agent is treatment, prevention, suppresses, postpones " treatment effective dose " that the described disease of " disease and disease " part and disease take place or it is disappeared, can be to the animal model applicating liquid preparation of purpose disease or disease, and observing effect.In addition, can carry out the interior dosage of people's clinical trial scope to determine the treatment effective dose of therapeutic agent.

Usually, therapeutic agent can following any compositions or the liquid preparation preparation, and described compositions or liquid preparation can be to experimenter or the experimenter's eye therapeutic agents with required Delivery time delivery treatments effective dose.Compositions comprises liquid preparation.

The solubilising of therapeutic agent

Operable a kind of compositions or liquid preparation are that therapeutic agent is dissolved in compositions or the liquid preparation in the solvent composition.Usually, any solvent with required effect can be used, and therapeutic agent is dissolved in wherein.Solvent is an aqueous in some modification.Solvent is nonaqueous in some modification." aqueous solvent " is for containing the solvent at least about 50% water.

Usually, can use the dissolved therapeutic agent of any concentration with required effect.Solvent composition can be the mixture of single solvent or solvent.The type of solvent and solution is that the technical staff is known in the medicine delivery technique.Consult for example Remington:The Science and Practice ofPharmacy, the 20th edition, Lippincott Williams ﹠amp; Wilkins; The 20th edition (on December 15th, 2000); Ansel ' s Pharmaceutical Dosage Forms and Drug DeliverySystems, the 8th edition, Lippincott Williams ﹠amp; Wilkins (in August, 2004); HandbookOf Pharmaceutical Excipients 2003, American Pharmaceutical Association, Washington, DC, USA and Pharmaceutical Press, London, UK; And Strickley, solubilizing Excipients in Oral and Injectable Formulations, Pharmaceutical Research, the 21st volume, No.2, in February, 2004.

As discussed previously, some solvents also can be used as solubilizing agent.

Spendable solvent includes but are not limited to DMSO, ethanol, methanol, isopropyl alcohol; Oleum Ricini; propylene glycol; glycerol; polyoxyethylene sorbitan monoleate; benzyl alcohol; dimethyl acetylamide (DMA); dimethyl formamide (DMF); glyceryl triacetate; Glycerine 1,3-diacetate; Semen Maydis oil; CitroflexA-2 (ATC); ethyl lactate; glyceryl formal; ethoxydiglycol (Transcutol; Gattefosse); triethylene glycol dimethyl ether. (Triglyme); dimethyl isosorbide (DMI); gamma-butyrolacton; N-N-methyl-2-2-pyrrolidone N-(NMP); caprylin (the Labrasol of Polyethylene Glycol of various molecular weights (including but are not limited to PEG 300 and PEG 400) and Pegylation; Gattefosse); aforementioned any one or a plurality of combinations, or aforementioned any one or a plurality of analog or derivants.

In some modification, solvent is a Polyethylene Glycol.Polyethylene Glycol is known as multiple title and can obtains in several formulations, includes but are not limited to Polyethylene Glycol, PEG400, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000, Macrogol 2000 0, macrogola, breox PEG; Carbowax; Carbowax sentry; Hodag PEG; Lipo; Lipoxol; Lutrol E; PEG; Pluriol E; Polyethylene Glycol and alpha-hydro-omega-hydroxy-poly (Oxy-1,2-second two bases).

In some modification, Polyethylene Glycol is liquid PEG, and is PEG 300 or PEG 400 one or more.

Other solvents comprise a certain amount of C ₆-C ₂₄Fatty acid, the enough solubilising therapeutic agents of described amount.

Also can use the phospholipid solvent, for example the mixture of lecithin, phosphatidylcholine or the multiple diglyceride (stearic acid, Palmic acid and oleic diglyceride) that links to each other with the phosphocholine ester; Hydrogenant S-PC (HSPC), distearyl phosphatidyl glycerol (DSPG), L-α-dimyristoyl phosphatidyl choline (DMPC), L-α-GLYCEROL,DIMYRISTOYL PHOSPHATIDYL (DMPG).

Other examples of solvent comprise for example following composition: the propylene glycol of esterifications such as alcohol, propylene glycol, different molecular weight polyethylene glycol, propylene glycol ester, usefulness fatty acid such as oleic acid, stearic acid, Palmic acid, capric acid, linoleic acid; Single, double or three acid esters of medium-chain glycerol, long-chain fatty acid, naturally occurring oil and composition thereof.The oil component of dicyandiamide solution comprises oil and the naturally occurring oil that commerce can be buied.Described oil can also be vegetable oil or mineral oil.Described oil can be characterized by on-surface-active oil, and it does not have hydrophilic lipophilic balance value usually.The commerce that comprises the heavy chain triglyceride can be buied material and be included but are not limited to Captex 100, Captex 300, Captex 355, Miglyol 810, Miglyol 812, Miglyol 818, Miglyol 829 and Dynacerin 660.The commercial propylene glycol ester compositions that can buy comprises Captex 200 and Miglyol 840 etc.Commercially available prod Capmul MCM comprises one of many possible medium chain mixture that contains monoglyceride and diglyceride.

Other solvents comprise naturally occurring oil, as Oleum menthae and seed oil.Exemplary natural oil comprises oleic acid, Oleum Ricini, Semen Carthami oil, soybean oil, olive oil, Oleum Helianthi, Oleum sesami and Oleum Arachidis hypogaeae semen.Also can use soya bean fatty acid.The example of fully saturated non-aqueous solvent comprises that (C for example has an appointment to the ester of long-chain fatty acid during load is not limited only to ₆To about C ₂₄The fatty acid triglycercide of chain length).Also can use oil with hydrogenated soybean and other plant oil.The mixture of fatty acid can separate from natural oil (for example Oleum Cocois, palm-kernel oil, babassu wet goods) and refine.In some embodiments, can use medium chain (about C from Oleum Cocois or Petiolus Trachycarpi seed oil ₈To about C ₁₂) triglyceride such as caprylic/capric triglyceride.Also can use medium chain monoglyceride or diglyceride.Other fully saturated non-aqueous solvents comprise that load is not limited only to saturated Oleum Cocois (it generally includes the mixture of lauric acid, myristic acid, Palmic acid, capric acid and caproic acid), comprise from Huls with trade mark Miglyol ^TMSell and have those of trade name 810,812,829 and 840.NeoBee by Drew Chemicals sale ^TMProduct also is mentioned.Non-aqueous solvent comprises isopropyl myristate.The example of artificial oil comprises the triglyceride and the propylene glycol ester of the saturated or unsaturated fatty acid with 6 to 24 carbon atoms, and described fatty acid is for example caproic acid, sad (caprylic acid), n-nonanoic acid (n-nonanoic acid), capric acid (capric acid), hendecanoic acid, dodecylic acid, tridecanoic acid, tetradecanoic acid (myristic acid), pentadecanoic acid, hexadecanoic acid (Palmic acid), heptadecanoic acid, octadecanoid acid (stearic acid), nonadecylic acid, heptadecanoic acid, arachic acid, heneicosanoic acid, behenic acid and tetracosanoic acid etc.The example of unsaturated carboxylic acid comprises oleic acid, linoleic acid plus linolenic acid etc.Non-aqueous solvent can comprise monoglyceride, diglyceride and triglyceride or blended glyceride and/or the propylene glycol monoester or the diester of fatty acid, and wherein at least one glycerol molecule is had the fatty acid esterification of different carbon atom length.A limiting examples that is used as " the non-oil " of solvent is a Polyethylene Glycol.

Exemplary vegetable oil comprises Oleum Gossypii semen, Semen Maydis oil, Oleum sesami, soybean oil, olive oil, fractionated coconut oil, Oleum Arachidis hypogaeae semen, Oleum Helianthi, safflower oil, almond oil, American Avocado Tree oil, Petiolus Trachycarpi oil, palm-kernel oil, babassu oil, beech nut oil, Semen Lini oil, Semen Allii Tuberosi wet goods.Also can use monoglyceride, diglyceride and the triglyceride of plant (including but are not limited to corn) oil.

Also can use crosslinked or uncrosslinked polyvinylpyrrolidone (PVP) as solvent.Other solvent includes but are not limited to C ₆-C ₂₄Fatty acid, oleic acid, Imwitor 742, Capmul, F68, F68 (Lutrol), PLURONICS (include but are not limited to PLURONICS F108, F127 and F68, poloxamer, Jeffamines), Tetronics, F127; Cyclodextrin such as alpha-cyclodextrin, beta-schardinger dextrin-, HP-, sulfo group butyl ether-beta-schardinger dextrin-(Captisol); The Polyethylene Glycol of CMC, polysorbitan 20, Cavitron, various molecular weights includes but are not limited to PEG300 and PEG 400.

Also can use Cera Flava and d-alpha-tocopherol (vitamin E) as solvent.

The solvent that is used for liquid preparation can determine that described method includes but are not limited to (1) and uses this area standard equation to estimate their solubility parameter value and the solvent of selection and therapeutic agent coupling in theory by several different methods known in the art; (2) determine the saturation solubility of therapeutic agent in solvent to test, and select to show the solvent of required dissolubility.

The solubilising of rapamycin

When therapeutic agent was rapamycin, the solvent that can be used for preparing rapamycin solution or suspensoid included but are not limited to any solvent described herein, includes but are not limited to DMSO, glycerol, ethanol, methanol, isopropyl alcohol; Oleum Ricini, propylene glycol, polyethylene propylene, glycerol, polyoxyethylene sorbitan monoleate, benzyl alcohol, dimethyl acetylamide (DMA), dimethyl formamide (DMF), glyceryl formal, ethoxydiglycol (Transcutol, Gattefosse), caprylin (Labrasol, Gattefosse) any one or more of Polyethylene Glycol of triethylene glycol dimethyl ether. (Triglyme), dimethyl isosorbide (DMI), gamma-butyrolacton, N-N-methyl-2-2-pyrrolidone N-(NMP), various molecular weights (including but are not limited to PEG 300 and PEG 400) and Pegylation.

Other solvents include but are not limited to C ₆-C ₂₄Fatty acid, oleic acid, Imwitor 742, Capmul, F68, F68 (Lutrol), PLURONICS (include but are not limited to PLURONICS F108, F127 and F68, poloxamer, Jeffamines), Tetronics, F127, beta-schardinger dextrin-, CMC, polysorbitan 20, Cavitron, softigen 767, captisol and Oleum sesami.

The additive method that can be used for dissolving rapamycin is described in Solubilization ofRapamycin, Int ' l J.Pharma 213 (2001) 25-29 such as P.Simamora, and its whole content is quoted as a reference at this paper.

As non-limiting instance, rapamycin dissolves in the saline solution that balance crosses in 5%DMSO or the methanol.Rapamycin solution can be undersaturated, saturated or oversaturated rapamycin solution.Rapamycin solution can contact with the solid rapamycin.In a non-limiting instance, rapamycin can be dissolved as the concentration up to about 400mg/ml.Rapamycin also can for example be dissolved in in the fatty acid-esterified propylene glycol, and described fatty acid is for example oleic acid, stearic acid, Palmic acid, capric acid, linoleic acid etc.

Many other solvents are possible.This area routine techniques personnel can find that the solvent of instructing evaluation to be used for rapamycin according to this paper is conventional.

Solubilizing agent

Usually, the combination of any solubilizing agent or solubilizing agent can be used for liquid preparation described herein.

In some modification, solubilizing agent is the combination of surfactant or surfactant.Many surfactants are possible.Also can use the combination of surfactant, comprise the combination of polytype surfactant.For example, can use non-ionic, anion (as soap, sulfonate), cation (as CTAB), zwitterionic, polymeric or amphoteric surfactant.

Can be by therapeutic interest agent and the solvent of inferring and the surfactant of inferring be mixed, and observation is exposed to behind the medium character of said preparation and determines spendable surfactant.

The example of surfactant includes but are not limited to fatty acid ester or amide or ether analogs thing, or its hydrophilic derivant; Monoesters or diester, or its hydrophilic derivant; Or its mixture; Monoglyceride or diglyceride, or its hydrophilic derivant; Or its mixture; Monoglyceride with enrichment is or/and the mixture of diglyceride, or its hydrophilic derivant; The part deutero-surfactant of hydrophilic segment; The monoesters of other alcohol, polyhydric alcohol, sugar or oligosaccharide or polysaccharide or diester or polyester, its oxyalkylene oligomer or polymer or block polymer, or its hydrophilic derivant, or its amide analogue; The derivative of fatty acid of amine, polyamines, many imines, amino alcohol, amino sugar, hydroxyalkyl amine, hydroxy polyamine, peptide, polypeptide or its ether analogs thing.

Hydrophilic-lipophilic balance (" HLB ") the presentation surface activating agent attracts simultaneously to water and the relative of oil (or to described Emulsion system biphase).

Surfactant characterizes according to the balance between the hydrophilic and lipophilic portion of their molecules.Hydrophil lipophil balance (HLB) number is pointed out the molecular polarities in any range of 1-40, and the emulsifying agent of normal use has the value between the 1-20.HLB increases with hydrophilic.

Operable surfactant comprises but is not limited only to have greater than 10,11,12,13 or the surfactant of 14HLB.The example of surfactant comprises castor oil hydrogenated, polyoxyethylene-sorbitan fatty acid esters, castor oil derivatives of the Oleum Ricini of polyoxyethylene product, polyethoxylated of hydrogenated vegetable oil or polyethoxylated etc., for example Nikkol HCO-50, NikkolHCO-35, Nikkol HCO-40, Nikkol HCO-60 (from Nikko Chemicals Co.Ltd.); Cremophor (from BASF) is as Cremophor RH40, Cremophor RH60, Cremophor EL, TWEENs (from ICI Chemicals), for example polysorbas20, tween 21, polysorbate40, polysorbate60, Tween 80, sorbimacrogol oleate100, Cremophor RH 410, Cremophor RH455 etc.

Surfactant component can be selected to have at least one and has at least about 12 chemical compounds to the aliphatic alcohol chain of about 22 carbon atoms from the ether that forms at least about 1 to 100 ethylene oxide unit(s) and at least one; Have at least one and have chemical compound at least about the fatty acid chain of 12 to 22 carbon atoms from the ester that forms at least about 1 to 100 ethylene oxide unit(s) and at least one; Has at least one from the ether, ester or the amide that form at least about 1 to 100 ethylene oxide unit(s) and the chemical compound of at least one vitamin or vitamin derivative; With its by no more than two kinds of combinations that surfactant is formed.

Other examples of surfactant comprise Lumulse GRH-40, TGPS, Tween-80 (tween 80), Tween-20 (tween 20), polyoxyethylene (20) sorbitan monooleate, glyceryl glycol ester, macrogol ester, polyglycolyzed glyceride (polyglycolyzedglycerides) etc. or its mixture; Polyethylene sorbitan fatty acid ester, polyoxyethylene glyceride such as Tagat TO, Tagat L, Tagat I, tagat I2 and Tagat O (can be commercial available from Goldschmidt Chemical Co., Essen, Germany); Glycol ester is as glycol stearate and diglycol stearate; Propylene glycol ester is as the tetradecylic acid propylene glycol ester; Fatty glyceride is as tristerin and glyceryl monostearate; Sorbitan ester is as spans and Tweens; Polyglycerin ester is as polyglyceryl 4. oleates; Alcohol ethoxylate is as the Brij emulsifying agent; The propenoxylated block copolymer of ethoxylation is as poloxamer; The macrogol ester of fatty acid is as PEG 300 glyceryl linoleates or Labrafil 2125 CS, PEG 300 oleins or Labrafil M 1944 CS, PEG 400 caprylic/capric glyceride or Labrasol and PEG 300 caprylic/capric glyceride or Softigen 767; Cremophors is as Cremophor E, CREMOPHORE EL or Cremophor EL, Cremophor EL-P, Cremophor RH 40P, polyoxyl 40 hydrogenated castor oil, Cremophor RH40; Polyoxyethylene 60 castor oil hydrogenated or cremophor RH 60, single caprylic/capric glyceride are as campmul cM 10; Polyoxyethylene fatty acid (PEG-stearate, PED-laurate, Brij_), the ethylating fatty glyceride of polyoxy, the ethylating fatty acid glyceride of polyoxy are as Solutol HS-15; PEG-ether (Mirj_, dehydrated sorbitol derivative (tween), dehydrated sorbitol mono-fatty acid ester or Span 20, aromatic (Tritons_), PEG-glyceride (PECEOL ^TM, PEG-PPG (polypropylene glycol) copolymer (PLURONICS includes but are not limited to PLURONICS F108, F127 and F68, poloxamer, Jeffamines), Tetronics, polyglycereol, PEG-tocopherol, PEG-LICoL 6-oleate; The alkyl of propanediol derivative, sugar and polysaccharide and acyl derivative (octyl group sucrose, sucrose stearate, lauroyl glucosan etc.) and/or its mixture; Based on the oleic acid of polyhydric alcohol and oxirane copolymerization or the surfactant of laurate; Labrasol Gelucire 44/14; Myrj 45; Saturated polyglycolyzed glyceride; Or poloxamer; Its all can commerce buy.Polyoxyethylene dehydration sorbitol fatty acid ester can comprise Polysorbate, for example polysorbate 20, polysorbate 40, polysorbate 60 and polyoxyethylene sorbitan monoleate.Myrj 45 can comprise polyoxyethylene 6 stearates, Myrj 45, polyoxyethylene 12 stearates and polyoxyethylene 20 stearates.Saturated polyglycolyzed glyceride is for example GELUCIRE 44/14 or GELUCIRE ^TM50/13 (Gattefosse, Westwood, N.J., U.S.A.).Poloxamer used herein comprises poloxamer 124 and poloxamer 188.

Surfactant comprises d-alpha-tocopherol base cetomacrogol 1000 succinate (TPGS), Myrj 45 (PEG 400 monostearates), Myrj 52 (PEG 1750 monostearates) and Oleum menthae.

In some modification, use to have the surfactant that is lower than 10 HLB.This class surfactant can randomly with as other combinations-of surfactants of cosurfactant use.Some have the surfactant that is less than or equal to 10 HLB, mixture and other, and to be equal to compositions be propylene glycol, glyceryl fatty acid, glycerin fatty acid ester, macrogol ester, glyceryl glycol ester, polyglycolyzed glyceride and polyoxyethylene sterol base ether.Propylene glycol ester or part ester form the component of commercial product such as Lauroglycol FCC (it contains lauric acid propylene glycol ester).The commercial excipient Maisine 35-1 that can buy comprises long-chain fatty acid, for example glyceryl linoleate.Also can use the product that comprises polyoxyethylene 8 stearate ether, as Acconon E.Labrafil M 1944 CS are examples of surfactant, and wherein said composition contains the mixture of glyceryl glycol ester and macrogol ester.

The solubilizing agent of rapamycin

Many solubilizing agents can be used for rapamycin, include but are not limited to above the described solubilizing agent of " solubilizing agent " part.

In some modification, solubilizing agent is a surfactant.The limiting examples that can be used for the surfactant of rapamycin includes but are not limited to the surfactant that has greater than 10,11,12,13 or 14 HLB.A non-limiting instance is Cremophor EL.In some modification, surfactant can be polymeric surfactant, includes but are not limited to PLURONICS F108, F127 and F68 and Tetronics.Solvents more used herein are useful as surfactants also.This area routine techniques personnel can find that it is conventional instructing which kind of solubilizing agent of evaluation and surfactant to can be used for rapamycin according to this paper.

The viscosity dressing agent

Liquid preparation described herein can be used or also contains the viscosity dressing agent with the viscosity dressing agent.

Spendable a kind of exemplary viscosity dressing agent is a hyaluronic acid.Hyaluronic acid is a glycosaminoglycans.Its repetitive sequence by glucuronic acid and glycosamine is formed.Hyaluronic acid is present in the many tissues and organ of health, and helps the viscosity and the denseness of this class tissue and organ.Hyaluronic acid is present in the eye (vitreous body that comprises eye) and with collagen and helps its viscosity.Liquid preparation described herein can also comprise hyaluronic acid or therewith use.

Other limiting examples of viscosity dressing agent comprise polyalkylene oxide, glycerol, carboxymethyl cellulose, sodium alginate, chitosan, glucosan, dextran sulfate and collagen.These viscosity dressing agents can be by chemical modification.

Operable other viscosity dressing agents include but are not limited to carrageenan, cellulose gel, silicon dioxide colloid, gelatin, propylene carbonate, carbonic acid, alginic acid, agar, CVP Carbopol ETD2050 or carbomer and polyacrylamide, arabic gum, ester gum, guar gum, arabic gum, ghatti, karaya gum, the tragakanta, terra, pectin, tamarind, the larch arabinogalactan, alginate, Semen sophorae, xanthan gum, starch, aluminium-magnesium silicate, the tragakanta, polyvinyl alcohol, gellan gum, hydrocolloid admixture and polyvidone.Also can use other viscosity dressing agents known in the art, include but are not limited to sodium carboxymethyl cellulose, sodium alginate, antler glue, galactomannan, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, Polyethylene Glycol, polyvinylpyrrolidone, carboxymethyl chitosan sodium, Sensor Chip CM 5 sodium, carboxymethyl starch sodium, xanthan gum and zein.

Other compositions of liquid preparation

Preparation described herein also can comprise multiple other compositions, for example stabilizing agent.The stabilizing agent that can be used for preparation described herein comprises but the compatibility of the meeting of being not limited only to (1) raising excipient and cover material such as gelatin, (2) stability (for example crystal growth of the thunderous handkerchief mycin of prophylactic treatment agent) of raising thunderous handkerchief mycin of therapeutic agent and/or rapamycin derivative, and/or (3) improve the reagent of preparation stability.Note being the composition of stabilizing agent and overlapping, and identical composition can be brought into play more than a kind of effect for existing between the composition of solvent, solubilizing agent or surfactant.

Stabilizing agent can be selected from hydrophilic derivant, polyvinylpyrrolidone, polyvinylether, polyvinyl alcohol, hydrocarbon, hydrophobic polymer, absorbent polymer and the combination thereof of fatty acid, aliphatic alcohol, alcohol, long-chain fatty acid ester, long chain ether, fatty acid.Also can use the amide analogue of aforementioned stable agent.Selected stabilizing agent can change the hydrophobicity (for example oleic acid, wax) of preparation or promote the level of wetness (for example PVP) of the mixing (as ethanol) of multiple composition in the preparation, control preparation, mobility (material with the fusing point that is higher than room temperature, for example long-chain fatty acid, alcohol, ester, ether, amide etc. or its mixture of control phase; Wax) and/or promote the compatibility (for example oleic acid or wax) of preparation and cover material.Some of these stabilizing agents can be used as solvent/co-solvent may (for example ethanol).Can there be crystallization with suppression therapy agent (for example rapamycin) in stabilizing agent with q.s.

That the example of stabilizing agent includes but are not limited to is saturated, monoene, polyenoid, ramose, contain fatty acid ring, alkynes, dicarboxyl and that contain functional group such as oleic acid, sad, capric acid, caproic acid, lauric acid, myristic acid, Palmic acid, stearic acid, behenic acid, linoleic acid, linolenic acid, eicosapentaenoic acid (EPA), DHA; Aliphatic alcohol such as hard ester alcohol, hexadecanol, ceteryl alcohol; Other alcohol are as ethanol, isopropyl alcohol, butanols; Long-chain fatty acid ester, ether or amide are as tristerin, stearic acid hexadecyl ester, oleyl ether, hard ester acyl ether, cetyl ether, oil base amide, hard esteramides; The hydrophilic derivant of fatty acid is as polyglyceryl fatty acid, cithrol; Polyvinylpyrrolidone, polyvinyl alcohol (PVA), wax, docosahexenoic acid and dehydroabietic acid etc.

Described preparation also can contain by gellant, and it is by forming the quality that gel changes final preparation.

Therapeutic agent as described herein (thunderous handkerchief mycin) can carry out conventional pharmaceutical operation (for example sterilization), and the compositions that contains therapeutic agent also can contain conventional adjuvant, as antiseptic, stabilizing agent, wetting agent, emulsifying agent, buffer agent etc.Therapeutic agent also can be prepared with the pharmaceutical acceptable excipient of clinical use, is used to make pharmaceutical composition.Be used for a preparation of using and exist for the explant of solution, suspension, solid material particle, solid material, the form of mixing polymeric matrix, liquid preparation or other any ocular administrations.The medicine that therapeutic agent can be used for preparing and is used for the treatment of, prevents, suppresses, postpones the generation of arbitrary disease described herein or it is disappeared.In some modification, therapeutic agent can be used for preparing the medicine for the treatment of arbitrary disease described herein.

The compositions that contains therapeutic agent (thunderous handkerchief mycin) can contain the adjuvant that one or more are applicable to specified route of administration.Therapeutic agent can include but are not limited to lactose, glucose, starch powder, alkanoic acid cellulose esters, stearic acid, Talcum, magnesium stearate, magnesium oxide, phosphoric acid and vitriolic sodium salt and calcium salt, arabic gum, gelatin, sodium alginate, polyvinylpyrrolidine and/or polyvinyl alcohol by blended with it adjuvant.When needing the preparation of solubilising, therapeutic agent can be in following solvents, and described solvent includes but are not limited to different molecular weight polyethylene glycol, propylene glycol, carboxymethyl cellulose gum liquid solution, methanol, ethanol, DMSO, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum sesami, Tragacanth and/or multiple buffer.Other adjuvants and method of application are that pharmaceutical field is known, and can be used in the practice of methods described herein, compositions and liquid preparation.Carrier or diluent can comprise time-delay material (as separately or with the glyceryl monostearate or the distearin of wax) or other materials well known in the art.The preparation that is used for purposes described herein also can comprise gel preparation, polymer, microsphere and liposome that easily lose and that be difficult for erosion.

Spendable other adjuvants and excipient include but are not limited to C ₈-C ₁₀Fatty acid ester such as softigen 767, polyoxyethylene sorbitan monoleate, PLURONICS, Tetronics, Miglyol and Transcutol.

Can randomly be added in pharmaceutical composition and the liquid preparation at normally used additive of pharmaceutical field and diluent.These additives and diluent comprise thickening agent, granulating agent, dispersant, flavoring agent, sweeting agent, coloring agent and stabilizing agent (comprising the pH stabilizing agent), other excipient, antioxidant (for example tocopherol, BHA, BHT, TBHQ, tocopherol acetate, ascorbic palmitate, ascorbic acid propyl gallate etc.), antiseptic (as p-Hydroxybenzoate) etc.Exemplary antiseptic include but not limited to benzyl alcohol, ethanol, benzalkonium chloride, phenol, chlorobutanol etc.Some useful antioxidants provide oxygen or peroxide inhibitor for preparation, and include but are not limited to butylated hydroxytoluene, butylated hydroxyanisole (BHA), propyl gallate, ascorbic palmitate, alpha-tocopherol etc.Thickening agent such as lecithin, hydroxypropyl cellulose, aluminium stearate etc. can improve the quality of preparation.

In some modification, therapeutic agent is a rapamycin, and rapamycin is formulated as the rapamycin of solid or liquid form.In some modification, rapamycin is formulated as oral dose.

In addition, can in suspension, add heavy-gravity polymer, assist location and placement and processing easily.In some purposes of liquid preparation, can in sclera, form bag by surgical operation, so that the injection of acceptable solution body preparation.The hydrogel structure of sclera can be used as the film of control speed.The therapeutic agent material grains that is used to form suspension can be by the known method manufacturing, and described method includes but are not limited to for example uses ceramic bead by the ball milling manufacturing.For example, Cole Parmer ball mill such as Labmill 8000 can use with the 0.8mm YTZ ceramic bead from Tosoh or Norstone Inc.

Preparation can be present in the unit dosage forms expediently and can prepare by the conventional pharmaceutical technology.This class technology comprises therapeutic agent and pharmaceutical carrier or the bonded step of excipient.Can when needed the product molding be prepared preparation then by with solid carrier or the two the evenly also nearly combination of active component with liquid-carrier or segmentation.

In some modification, preparation described herein provides with one or more unit dosage forms, and wherein said unit dosage forms comprises a certain amount of liquid preparation described herein, and its disease that is applied or disease can effectively be treated or prevent to described amount.In some modification, preparation described herein provides with one or more unit dosage forms, and wherein said unit dosage forms comprises a certain amount of liquid rapamycin preparation described herein, and its disease that is applied or disease can effectively be treated or prevent to described amount.

In some embodiments, unit dosage forms is prepared the concentration that is applied with it.In some modification, unit dosage forms is diluted before being administered to the experimenter.In some modification, liquid preparation described herein was diluted in the aqueous medium before being administered to the experimenter.Aqueous medium oozes medium for waiting in some modification.In some modification, liquid preparation described herein was diluted in the non-aqueous media before being administered to the experimenter.

This paper provides the medicine box that comprises one or more unit dosage forms described herein on the other hand.In some embodiments, described medicine box comprises one or more packings and the description that is used for the treatment of one or more diseases or disease.In some embodiments, described medicine box comprises the diluent that does not physically contact with preparation or pharmaceutical formulations.In some embodiments, described medicine box comprises the described herein any or multiple unit dosage forms in one or more sealed tubes.In some embodiments, described medicine box comprises any or multiple sterile unit dosage form.

In some modification, unit dosage forms is a container, includes but are not limited to the container of sterile sealing.In some modification, container is bottle, ampoule or small size applicator (applicator), includes but are not limited to syringe.In some modification, the small size applicator is filled with the rapamycin that is used for the treatment of ophthalmic diseases or disease in advance, includes but are not limited to the limus chemical compound that is used for the treatment of relevant degeneration of macula of age.This paper has described the prepackage small size applicator that the preparation that contains therapeutic agent (including but are not limited to rapamycin) is housed in advance.In some modification, the small size applicator is equipped with the solution that contains therapeutic agent (including but are not limited to rapamycin) and Polyethylene Glycol in advance, and randomly also comprises one or more extra compositions, includes but are not limited to ethanol.In some modification, the small size applicator of prepackage is equipped with in advance and contains about 2% rapamycin, about 94%PEG-400, about 4% alcoholic acid solution.

This paper has described the medicine box that comprises one or more containers.In some modification, the medicine box that comprises one or more small size applicators is equipped with the preparation that contains therapeutic agent as herein described in advance, includes but are not limited to the preparation that comprises rapamycin, comprises rapamycin and Polyethylene Glycol and randomly also comprise the preparation (described extra composition includes but are not limited to ethanol) of one or more extra compositions and comprise about 2% rapamycin, about 94%PEG-400, about 4% alcoholic acid liquid absorption member.In some modification, medicine box comprises one or more containers (including but are not limited to prepackage small size applicator) and operation instruction thereof.In another modification, medicine box comprises one or more small size applicators that rapamycin is housed in advance, and is used for the treatment of the operation instruction of ophthalmic or disease.In some modification, container described herein is in secondary package.

Route of administration

Compositions described herein, method and liquid preparation with one or more therapeutic agent delivery to experimenter (including but are not limited to people experimenter).

In some modification, in compositions described herein, method and liquid preparation the aqueous medium with one or more therapeutic agent delivery the pure man experimenters.

In some modification, compositions described herein, method and liquid preparation with one or more therapeutic agent delivery to treating, prevent, suppress, postpone its generation or making in its disease that disappears or the disease zone or near the aqueous medium it.

In some modification, compositions described herein, method and liquid preparation are delivered to one or more therapeutic agents experimenter's eye with a certain amount of and persistent period, comprise macula lutea and retina tela chorioidea, described amount and persistent period can effectively treat, prevent, suppress, postpone the generation of described disease of " disease and disease " part and disease or it is disappeared.

It is synonym that this paper uses " retina choroid " and " retina tela chorioidea ", and is meant the bonded retina and the tela chorioidea of eye.

As limiting examples, compositions described herein, liquid preparation and method can take place or make its amount that disappears and persistent period to treat, prevent, to postpone CNV and moist AMD effectively, directly or by approach near the eyes are applied to following tissue: between vitreous body, aqueous humor, sclera, conjunctiva, CSC, retina tela chorioidea, macula lutea or in experimenter's eye or near other zones the eye.Effective dose and persistent period for each treatment, prevention, to suppress that CNV and moist AMD take place or it is disappeared can be different, and can be different for variant site of delivery.

Intravitreal administration has more invasive than the eye operation of some other types.Because the risk of possible ill effect, intravitreal administration is not the best to the healthy relatively eye of treatment.Compare, use near the eyes (using) as under the conjunctiva more much smaller than intravitreal administration invasive.When therapeutic agent when approach is sent near the eyes, can treat patient, rather than can use the patient of intravitreal administration treatment than healthy eyes.In some modification, use the subconjunctival injection prevention or postpone the disease of eye or the generation of disease, wherein experimenter's eye has 20/40 or better visual acuity.

" under the conjunctiva " used herein places or injection is meant placement or injection between CSC.Being sometimes referred to as " sub-conj " at this paper under the conjunctiva uses.

The route of administration that can be used for the applicating liquid preparation includes but are not limited to (for example by injection) liquid preparation is placed experimenter's aqueous medium, includes but are not limited to place (including but are not limited to by injection) experimenter's (including but are not limited to people experimenter) eye.But the liquid preparation general is used, and includes but are not limited to following route of delivery: rectum, vagina, inculcate, in the intramuscular, intraperitoneal, intra-arterial, sheath, in the bronchus, in the pond, in the epidermis, subcutaneous, Intradermal, percutaneous, intravenous, neck, in the abdomen, in interior, intrathoracic, the trachea of intracranial, ophthalmic, lung, per nasal, cheek, Sublingual, mouth, parenteral or the use aerosol propellant is sprayed or atomize.

The compositions and the liquid preparation that comprise therapeutic agent can use multiple program to be applied directly to eye, include but are not limited to following program, (1) therapeutic agent is used by using the injection of syringe and hypodermic needle in the described program, (2) use the agent of specially designed equipment injection for curing, (3) before the injection for curing agent, operation forms bag in sclera, as the container of therapeutic agent or therapeutic agent compositions.For example, use in the program at one, the surgeon forms bag in the sclera of eye, and the solution or the liquid preparation that will contain therapeutic agent then are injected in the bag.

Other are used program and include but are not limited to following program, (1) therapeutic drug formulation is injected by specially designed bend cannula in the described program, therapeutic agent is directly placed the part of eye, (2) therapeutic agent of compressed format is directly placed the part of eye, (3) by specially designed syringe or inserter therapeutic agent is inserted in the sclera, (4) liquid preparation that comprises therapeutic agent mixes in the polymer, (5) surgeon produces little conjunctival incision, stitching thread and any therapeutic agent delivery structure are passed this otch, thereby with this structure and sclera adjacent fixed, (6) are used pin to be used for direct injection and are entered the vitreous body of eye or enter described any other position.

Liquid preparation described herein can (for example by injection) directly use, be used for local application (include but are not limited to and pass through eye drop) as elixir, or be used in soft or glutoid or starch capsule in.Capsule can be tied with anti-leak.

Pass through injected delivery

Can be used for sending a kind of method of compositions described herein and liquid preparation for passing through injected delivery.In the method, compositions and liquid preparation injectable advance experimenter's (including but are not limited to people experimenter), or are injected in experimenter's eye or near the position the eye, for delivery to experimenter or experimenter's eye.Injection includes but are not limited to ophthalmic and periocular injections.The limiting examples of position is as follows in experimenter's eye or near the eye.

Injection of therapeutic agent advances the high local concentrations that therapeutic agent can be provided in the vitreous body in vitreous body and retina.In addition, found to increase with molecular weight in the removing half-life of glass drug disposition.

Also can use intracameral injection or be injected into the anterior chamber.In an example, but intracameral injection 100 μ l at the most.

The approach of sending near the eyes can not have therapeutic agent delivery some risks of sending in the vitreous body to retina.Near the eyes approach include but are not limited under the conjunctiva, behind the subtenon, eyeball, send behind eyeball week and the juxtascleral." near the eyes " route of delivery be meant place the eye near or on every side.Periocular routesfor retinal drugdelivery is consulted in the exemplary description of the approach near the eyes that the retina medicine is sent, Raghava etc. (2004), Expert Opin.Drug Deliv.1 (1): 99-114, its integral body is quoted as a reference at this paper.

In some modification, liquid preparation ophthalmic described herein is used.Ophthalmic use comprise place or be injected into the eye (including but are not limited to vitreous body).

Subconjunctival injection can be by advancing injection of therapeutic agent under the conjunctiva, or between the CSC.In an example, but the about at the most 500 μ l of subconjunctival injection.As a non-limiting instance, can use about 25 to 30 specifications and the long syringe needle of about 30mm.The local pressure in site can improve therapeutic agent sending to back segment by reducing local choroid blood flow under the conjunctiva that therapeutic agent is used.

The Subtenon injection can be by advancing injection of therapeutic agent in tenon ' the s capsule on every side of a top and being injected in the superior rectus " abdomen ".In an example, but subtenon is injected to many about 4ml.As a limiting examples, can use the long blunt intubation of about 2.5cm.

Retrobulbar injection is meant that the conical area that is injected into behind the eyeball four rectus and intermuscular septum film thereof is indoor.In an example, but the about at the most 5ml of retrobulbar injection.As a limiting examples, can use about 25 or the blunt nosed pin of about 27 specifications.

Eyeball week injection can be the position of four rectus and intermuscular septum diaphragm area thereof outer (being that muscle cone is outer).But eyeball week injection is for example up to about the volume of 10ml.As a limiting examples, can use the blunt intubation of about 1.25 inches long and about 25 specifications.

Send behind the Juxtascleral and be meant and place therapeutic agent near the macula lutea or on the macula lutea, directly contact with the outer surface of sclera, and the eyeball that do not puncture.In an example, but injection as many as about 500ml behind the juxtascleral.As a non-limiting instance, use blunt nosed bend cannula (particularly being designed to 56 °) that therapeutic agent is placed scleral incision.

In some modification, liquid preparation intraocular injection described herein.Intraocular injection comprises and is injected into ophthalmic.

The site that compositions and liquid preparation can be used includes but are not limited between vitreous body, aqueous humor, sclera, conjunctiva, the CSC, near in retina tela chorioidea, macula lutea or the experimenter's eye or other zones.The method that can be used for placing compositions and liquid preparation includes but are not limited to injection.

In a spendable method, therapeutic agent is dissolved in solvent or the solvent mixture, then according to above-mentioned arbitrary program injection enter between experimenter's vitreous body, aqueous humor, sclera, conjunctiva, the CSC, in retina tela chorioidea, macula lutea or the eye or in other media of near other zones or experimenter or injection in its vicinity.In spendable these class methods, therapeutic agent is the rapamycin in the liquid preparation.

When therapeutic agent was rapamycin, compositions and liquid preparation can be used for sending or keep a certain amount of rapamycin in the ocular tissue, and described ocular tissue includes but are not limited to retina, choroid or vitreous body, and described amount can effectively be treated AMD.In a non-limiting instance, believe with the liquid preparation of sending a certain amount of rapamycin to can be used for treating moist AMD that described amount can provide the interior about 0.1pg/ml of vitreous body rapamycin concentrations to about 2 μ g/ml.In some non-limiting instance, believe that sending about 0.1pg/mg in the retina tela chorioidea can be used for treating moist AMD to the liquid preparation of about 1 μ g/mg rapamycin concentrations.Other valid density can easily be determined based on instruction described herein by those skilled in the art.

The method for preparing liquid preparation

The non-limiting method that can be used for preparing liquid preparation described herein (including but are not limited to the liquid preparation that contains rapamycin) is cooled off preparation then for by with solvent and therapeutic agent at room temperature or mix (can randomly use ultrasonoscope) under the temperature that improves slightly together up to acquisition solution or suspension.Other compositions (including but are not limited to mentioned component) can be mixed with preparation then.Spendable other preparation methoies at this paper, comprise among the embodiment and describing that and those skilled in the art can select other preparation methoies according to the instruction of this paper.

Prolong delivering therapeutic agents

This paper has described and has shown compositions and the liquid preparation of sending or remove spectrum in the body with following one or more features.Send or remove spectrum for compositions or liquid preparation subconjunctival injection or be injected in the lagophthalmos vitreous body removing spectrum of back therapeutic agent.In some modification, send or remove spectrum and be or after being injected into the lagophthalmos vitreous body removing of rapamycin spectrum in the body with compositions or liquid preparation subconjunctival injection.About 30-40% of the Vitrea volume behaviour of rabbit vitreous body volume.The amount of therapeutic agent is used as commercial measurement as described in the embodiment 2, but is not subjected to the restriction of preparation described in the embodiment 2 and therapeutic agent.

In some modification, have the therapeutic agent of sending or remove spectrum in the body described herein include but are not limited to be described in " therapeutic agent " part in those.Therapeutic agent is a rapamycin in some modification.In some modification, liquid preparation described herein is used for the concentration delivering therapeutic agents to be equal to rapamycin.Liquid preparation described herein can comprise (including but are not limited to the concentration described herein that comprises among the embodiment) the arbitrary therapeutic agent that is equal to rapamycin, includes but are not limited to the described therapeutic agent of " therapeutic agent " part.

" body in average percent " level is meant at select preset time from the mean concentration of the therapeutic agent of a plurality of lagophthalmos acquisitions, and with the therapeutic agent mean concentration of the time point therapeutic agent mean concentration divided by another time point.In some modification of average percent level, therapeutic agent is a rapamycin in vivo.

When using preset time behind the preparation that contains therapeutic agent in the lagophthalmos tissue mean concentration of therapeutic agent can measure according to following method.When injection during, use the Hamilton syringe less than the volume of 10 μ l.

Liquid preparation is stored under the 2-8 ℃ of temperature before using.

Laboratory animal is the New Zealand white rabbit (New Zealand Whiterabbits) of SFF (SPF).Use about 50% male, about 50% female population mixture.Rabbit is at least 12 ages in week, at least 14 ages in week usually during administration.The heavy 2.2kg at least of each rabbit during administration, 2.5kg at least usually.Preceding quarantine at least one week of animal of research is also checked the general health parameter.Do not use any unsound animal in the research.For one preset time point, measure 6 eyes and average at least.

Settle and sanitized according to the standardization program of using in the industry.Offer the high fiber rabbit grain (Teklad Certified Hi-Fiber Rabbit Diet) of the about 150 gram Teklad checks of animal every day, and tap water unrestrictedly is provided.Do not have pollution in the known water, not except that local water community provided additional analysis.The monitoring environment condition.

Ophthalmologic examination before the treatment that veterinary's ophthalmologists that each animal stands to be authenticated by committee carries out (slit lamp and ophthalmoscopy).According to Dermatoxicology, F. N.Marzulli and H.I.Maibach, McDonald described in 1977 " Eye Irritation, " T.O.McDonald and the J.A.Shadduck (579-582 page or leaf) and Shadduck scoring system are marked to the eye examination result.Use standardized data collection table record observed result.Be used to study to accept standard as follows: conjunctival congestion and swelling score value≤1; Every other observation variable score value is 0.

Medication the previous day, the medication same day (the 1st day) and medication one day after (the 2nd day) in two eyes of each animal every day the administered twice eyedrops of garamycin.Medication was carried out with two stages, and the phase I comprises a treated animal, and second stage comprises other animals.Before each medication stage, animal is randomized in the treatment group of sheltering according to the Latin square of revising.Animal fasting 8 hours at least before the injection.The zero-time and the inject time of record fasting.

The animal of weighing is also used ketamine/xylazine mixture (87mg/mL ketamine, 13mg/mL xylazine) anesthetized animal of intravenous injection 0.1-0.2mL/kg volume.The following preparation of the eyes of each animal is used for injection: injection precontract 5 minutes, and with the eye moistening eye of povidone-iodine (Betadine).With Sterile Saline povidone-iodine is washed out from eye after five minutes.Each is sent the proparacaine hydrochloride (Proparacaine hydrochloride) of 0.5% (1-2 drips).For eye, send 1% tropicamide (Tropicamide) (1) to each with intravitreal injection.

The 1st day, eyes ejection testing product or the reference substance of each animal.Animal in selected group was administration for the second time in the 90th ± 1 day.Following or the glass vivo medicine-feeding of conjunctiva.Actual therapeutic, injection site and dose volume are sheltered, and disclose when research finishes.

Use insulin syringe and 30 specification x1/2 inch syringe needles to carry out subconjunctival injection.Use the bulbar conjunctiva in the tweezers rising dorsotemporal quadrant.Test article is injected into space under the conjunctiva.

Use insulin syringe and 30 specification x1/2 inch pins to carry out intravitreal injection.For each injection, pin is passed the abdomen-nose quadrant, limbus of corneae of eye after 2-3mm introduce, the inclined-plane of pin is pointed to down and the rear to, to avoid crystalline lens.To detect product in the single bolus infusion mode is injected near the retina in the vitreous body.

Mortality rate/sickness rate of twice observation every day animal.Be defined as dying animal and use the commercially available euthanasia solution of intravenous injection euthanasia.Win eyes and freezing being stored in-70 and ℃ be used in the future possible assessment.If before postmortem rigidity, find animal dead, win eyes and freezing being stored in-70 and ℃ be used in the future possible assessment.Take place to find that dead animal does not carry out necropsy behind the postmortem rigidity.

The animal of weighing at random before medication in the 1st day and before the euthanasia.

(in some modification on the more late date) are carried out ophthalmology to all animals and are observed (slit lamp and an eye microscopy indirect review method) in the time of the 5th ± 1,30 ± 1,60 ± 1,90 ± 1 day.Observation is undertaken by the veterinary's ophthalmologists that authenticates through committee.For will before medication, carrying out ophthalmology and observe the animal of medication in the 90th ± 1 day.According to Dermatoxicology, E. N.Marzulli and H.I.Maibach, 1977 " Eye Irritation; " McDonald described in the T.O.McDonald and J.A.Shadduck (579-582 page or leaf) and Shadduck scoring system are marked to the ophthalmologic examination result, and use standardized data collection table record observed result.

From each animal, whole blood sample (each sample 1-3mL) is collected in the vacutainer pipe that contains EDTA before the necropsy.Each pipe is full of at least 2/3, and thoroughly mixes at least 30 seconds.The pipe freezing is until transporting on dry ice.

Make animal euthanasia with the commercially available euthanasia solution of intravenous injection.Carry out euthanasia according to the standardization program of using in the industry.

For the treatment group of using placebo in the vitreous body or under the conjunctiva, placed Davidsons solution about 24 hours from these all eyes of organizing each group.After 24 hours eye is transferred in 70% ethanol; The pathology assessment that the veterinary pathologist that these eyeballs are authenticated by committee is sheltered.The record eye places the time of Davidsons and the time of taking-up.

To with in the test article vitreous body or the treatment group of medication under the conjunctiva, freezing and carry out the pharmacokinetics analysis at-70 ℃ from some eyes of each group.Residue eye from each group placed Davidsons solution about 24 hours.After 24 hours, eye is transferred in 70% ethanol; The histopathological evaluation that the veterinary pathologist that these eyeballs are authenticated by committee is sheltered.The record eye places the time of Davidsons and the time of taking-up.

Carrying out the freezing sample of pharmacokinetics analysis dissects with disposable instrument.Every is used one group of instrument, abandons then.Sample thaws 1 to 2 minute to guarantee that the frost around the tissue is removed in room temperature.It is 4 quadrants that sclera is dissected, and takes out vitreous body.If high-visible nondispersive agglomerate (NDM) in the vitreous body then is separated to vitreous body in two sections.The section that has NDM is about Vitrea 2/3rds.The section with NDM is not apart from NDM Vitrea part farthest.Separate aqueous humor, crystalline lens, iris and cornea.Use tweezers to take out retina tela chorioidea and collect and be used for analyzing.Conjunctiva is separated with sclera.

Multiple types of organization is collected in the isolating bottle of into weighing in advance, cover then the pipe and weigh.Organize bottle to be stored in-80 ℃ until analysis.

Use 32-O-de-methoxy rapamycin as interior mark, determine the sirolimus content of retina choroid, sclera, vitreous humor and anticoagulated whole blood by high pressure liquid chromatography/tandem mass spectrum (HPLC/MS/MS).When observing NDM in the vitreous body, the vitreous body section that contains NDM is analyzed respectively with the vitreous body section that does not contain NDM.

The mean treatment agent concentration of a period of time is for the representative time point that refers to this time period, the mean concentration of each time point.For example, if the time cycle is 30 days, mean concentration can be with 5 days interval measurement: for the 5th day mean concentration, should calculate the 5th day repeatedly average of measurement of concetration; For the 10th day mean concentration, should calculate the 10th day repeatedly average of measurement of concetration, or the like.

In some modification, liquid preparation described herein can have feature hereinafter described arranged in Vitrea body, send spectrum, wherein send spectrum and be used for after liquid preparation being injected between the lagophthalmos CSC, delivering therapeutic agents in the body.A non-limiting modification of sending spectrum in the Vitrea body is shown in Fig. 2.

Injection back is in the time of the 40th day, and level can be between about 70% and about 100% in the time of the 20th day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 80% and about 90%.Injection back is in the time of the 40th day, and level can be greater than about 70% in the time of the 20th day with respect to the injection back for average percent vitreous body level in the body, and more frequent greater than about 80%.

Injection back is in the time of the 67th day, and average percent vitreous body level can be between about 75% and about 115% with respect to the level of injection back in the time of the 20th day in the body, and more through being everlasting between about 85% and about 105%.Injection back is in the time of the 67th day, and average percent vitreous body level can be greater than about 75% with respect to the level of injection back in the time of the 20th day in the body, and more frequent greater than about 85%.

Injection back is in the time of the 90th day, and average percent vitreous body level can be between about 20% and about 50% with respect to the level of injection back in the time of the 20th day in the body, and more through being everlasting between about 30% and about 40%.Injection back is in the time of the 90th day, and average percent vitreous body level can be greater than about 20% with respect to the level of injection back in the time of the 20th day in the body, and more frequent greater than about 30%.

In some modification, average percent vitreous body level has following feature with respect to the 20th day performance level in injection back in the body: after injection the 40th day, it was less than about 100%; It was less than about 115% in the 67th day after injection; It was less than about 50% in the 90th day with the injection back.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, cause after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 1ng/mL.

In some modification, liquid preparation described herein can have following characteristics arranged in retinochoroid body, send spectrum, after liquid preparation being injected between the lagophthalmos CSC, delivering therapeutic agents sends spectrum in the body when wherein sending spectrum.

Injection back is in the time of the 40th day, and performance level can be between about 350% and about 410% in the time of the 20th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 360% and about 400%.Injection back is in the time of the 40th day, and performance level can be greater than about 350% in the time of the 20th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 360%.

Injection back is in the time of the 67th day, and performance level can be between about 125% and about 165% in the time of the 20th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 135% and about 155%.Injection back is in the time of the 67th day, and performance level can be greater than about 125% in the time of the 20th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 135%.

Injection back is in the time of the 90th day, and performance level can be between about 10% and about 50% in the time of the 20th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 20% and about 40%.Injection back is in the time of the 90th day, and performance level can be greater than about 10% in the time of the 20th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 20%.

In some modification, average percent retina choroid level has following feature with respect to the 20th day performance level in injection back in the body: after injection the 40th day, it was less than about 410%; It was less than about 165% in the 67th day after injection; It was less than about 50% in the 90th day with the injection back.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos retina tela chorioidea in 90 days at least about the therapeutic agent mean concentration of 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos glass retina tela chorioidea in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mL.

In some modification, the level of treatment agent that exists in the retina tela chorioidea at first rises, and reaches peak value and reduction then.Peak value can for example generation in about the 40th day after injection.

In some modification, liquid preparation described herein can have sclera removing spectrum in the body that following characteristics is arranged, and wherein removing spectrum is liquid preparation to be injected into the removing of removing in the body of back therapeutic agent between the lagophthalmos CSC compose.When being injected between the CSC, think that the sclera level comprises institute's injection liquid preparations.

Injection back is in the time of the 40th day, and performance level can be between about 150% and about 230% in the time of the 20th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 170% and about 210%.Injection back is in the time of the 40th day, and performance level can be greater than about 150% in the time of the 20th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 170%.

Injection back is in the time of the 67th day, and performance level can be between about 30% and about 70% in the time of the 20th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 40% and about 60%.Injection back is in the time of the 67th day, and performance level can be greater than about 30% in the time of the 20th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 40%.

Injection back is in the time of the 90th day, and performance level can be between about 110% and about 160% in the time of the 20th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 125% and about 145%.Injection back is in the time of the 90th day, and performance level can be greater than about 110% in the time of the 20th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 125%.

In some modification, average percent sclera level has following feature with respect to the 20th day performance level in injection back in the body: after injection the 40th day, it was less than about 230%; It was less than about 70% in the 67th day after injection; It was less than about 160% in the 90th day with the injection back.

In some modification, the level of treatment agent that exists in the sclera at first rises, and reaches peak value and reduction then.Peak value can for example generation in about the 40th day after injection.

In some modification, liquid preparation described herein can have following characteristics arranged in Vitrea body, send spectrum, wherein sending spectrum is after liquid preparation being injected between the lagophthalmos CSC, delivering therapeutic agents sends spectrum in the body.

Injection back is in the time of the 14th day, and performance level can be between about 1350% and about 1650% in the time of the 2nd day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 1450% and about 1550%.Injection back is in the time of the 14th day, and performance level can be greater than about 1350% in the time of the 2nd day with respect to the injection back for average percent vitreous body level in the body, and more frequent greater than about 1450%.

Injection back is in the time of the 35th day, and performance level can be between about 200% and about 300% in the time of the 2nd day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 225% and about 275%.Injection back is in the time of the 35th day, and performance level can be greater than about 200% in the time of the 2nd day with respect to the injection back for average percent vitreous body level in the body, and more frequent greater than about 225%.

Injection back is in the time of the 62nd day, and performance level can be between about 100% and about 160% in the time of the 2nd day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 115% and about 145%.Injection back is in the time of the 62nd day, and performance level can be greater than about 100% in the time of the 2nd day with respect to the injection back for average percent vitreous body level in the body, and more frequent greater than about 115%.

Injection back is in the time of the 85th day, and performance level can be between about 5% and about 30% in the time of the 2nd day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 10% and about 25%.Injection back is in the time of the 85th day, and performance level can be greater than about 5% in the time of the 2nd day with respect to the injection back for average percent vitreous body level in the body, and more frequent greater than about 10%.

In some modification, average percent vitreous body level has following feature with respect to the 2nd day performance level in injection back in the body: after injection the 14th day, it was less than about 1600%; It was less than about 300% in the 35th day after injection; It was less than about 160% with it was less than about 30% in the 85th day injection back in the 62nd day after injection.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 85 days at least about the therapeutic agent mean concentration of 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 85 days at least about the therapeutic agent mean concentration of 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about in the lagophthalmos vitreous body in 60 days at least about the therapeutic agent mean concentration of 1ng/mL.

In some modification, the level of treatment agent that exists in the vitreous body at first rises, and reaches peak value and reduction then.Peak value can for example generation in about the 14th day after injection.

In some modification, liquid preparation described herein can have following characteristics arranged in retinochoroid body, send spectrum, wherein sending spectrum is after liquid preparation being injected between the lagophthalmos CSC, delivering therapeutic agents sends spectrum in the body.

Injection back is in the time of the 35th day, and performance level can be between about 320% and about 400% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 340% and about 380%.Injection back is in the time of the 35th day, and performance level can be greater than about 320% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 340%.

Injection back is in the time of the 62nd day, and performance level can be between about 3% and about 25% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 6% and about 20%.Injection back is in the time of the 62nd day, and performance level can be greater than about 3% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 6%.

Injection back is in the time of the 85th day, and performance level can be between about 0.1% and about 6% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 0.5% and about 4%.Injection back is in the time of the 85th day, and performance level can be greater than about 0.1% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 0.5%.

In some modification, average percent retina choroid level has following feature with respect to the 14th day performance level in injection back in the body: after injection the 35th day, it was less than about 400%; It was less than about 25% in the 62nd day after injection; It was less than about 6% in the 85th day with the injection back.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos retina tela chorioidea in 85 days at least about the therapeutic agent mean concentration of 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos retina tela chorioidea in 85 days at least about the therapeutic agent mean concentration of 0.01ng/mL.

In some modification, liquid preparation described herein can have sclera removing spectrum in the body that following characteristics is arranged, and wherein removing spectrum is liquid preparation to be injected into the removing of removing in the body of back therapeutic agent between the lagophthalmos CSC compose.When being injected between the CSC, think that the sclera level comprises institute's injection liquid preparations.

Injection back is in the time of the 35th day, and performance level can be between about 0.1% and about 0.7% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 0.2% and about 0.6%.Injection back is in the time of the 35th day, and performance level can be greater than about 0.1% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 0.2%.

Injection back is in the time of the 62nd day, and performance level can be between about 0.05% and about 0.35% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 0.07% and about 0.3%.Injection back is in the time of the 62nd day, and performance level can be greater than about 0.05% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 0.07%.

Injection back is in the time of the 85th day, and performance level can be between about 0.1% and about 0.9% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 0.3% and about 0.7%.Injection back is in the time of the 85th day, and performance level can be greater than about 0.1% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 0.3%.

In some modification, in the body average percent sclera level with respect to the injection back in the time of the 14th day performance level have following feature: after injection the 35th day, it was less than about 0.7%; It was less than about 0.35% in the 62nd day after injection; It was less than about 0.9% in back 85 days with injection.

In some modification, liquid preparation described herein can have vitreous body removing spectrum in the body that following characteristics is arranged, and wherein removes the removing spectrum of removing in the body of spectrum for therapeutic agent after being injected into liquid preparation in the lagophthalmos vitreous body.When being injected in the vitreous body, think that measured vitreous body level comprises the preparation of being injected.

Injection back is in the time of the 35th day, and performance level can be between about 1% and about 40% in the time of the 14th day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 1% and about 10%.The injection back is in the time of the 35th day, and performance level can be greater than about 1% in the time of the 14th day with respect to the injection back for average percent vitreous body level in the body.

Injection back is in the time of the 62nd day, and performance level can be between about 1% and about 40% in the time of the 14th day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 5% and about 25%.Injection back is in the time of the 62nd day, and performance level can be greater than about 1% in the time of the 14th day with respect to the injection back for average percent vitreous body level in the body, and more frequent with respect to the injection back in the time of the 14th day performance level greater than about 5%.

Injection back is in the time of the 90th day, and performance level can be between about 1% and about 40% in the time of the 14th day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 10% and about 30%.Injection back is in the time of the 90th day, and performance level can be greater than about 1% in the time of the 14th day with respect to the injection back for average percent vitreous body level in the body, and more frequent with respect to the injection back in the time of the 14th day performance level greater than about 10%.

In some modification, the level of treatment agent that exists in the vitreous body at first rises, and reaches peak value and reduction then.Peak value can for example generation in about the 14th day after injection.

In some modification, liquid preparation described herein can have following characteristics arranged in retinochoroid body, send spectrum, wherein sending spectrum is after liquid preparation is injected into the lagophthalmos vitreous body, delivering therapeutic agents sends spectrum in the body.

Injection back is in the time of the 35th day, and performance level can be between about 3400% and about 5100% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 3750% and about 4750%.Injection back is in the time of the 35th day, and performance level can be greater than about 3400% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 3750%.

When injecting back 62 days, performance level can be between about 0.1% and about 5% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 1% and about 3%.Injection back is in the time of the 62nd day, and performance level can be greater than about 0.1% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 1%.

When injecting back 90 days, performance level can be between about 10% and about 50% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more through being everlasting between about 20% and about 40%.Injection back is in the time of the 90th day, and performance level can be greater than about 10% in the time of the 14th day with respect to the injection back for average percent retina choroid level in the body, and more frequent greater than about 20%.

In some modification, average percent retina choroid level has following feature with respect to the 14th day performance level in injection back in the body: after injection the 35th day, it was less than about 5100%; It was less than about 5% in the 62nd day after injection; It was less than about 50% in the 90th day with the injection back.

In some modification, liquid preparation described herein can have following characteristics arranged in the body of sclera, send spectrum, wherein send spectrum for after liquid preparation being injected in the lagophthalmos vitreous body, delivering therapeutic agents sends spectrum in the body.

Injection back is in the time of the 35th day, and performance level can be between about 1700% and about 2600% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 1900% and about 2400%.Injection back is in the time of the 35th day, and performance level can be greater than about 1700% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 1900%.

Injection back is in the time of the 62nd day, and performance level can be between about 120% and about 180% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 140% and about 160%.Injection back is in the time of the 62nd day, and performance level can be greater than about 120% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 140%.

Injection back is in the time of the 90th day, and performance level can be between about 95% and about 155% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more through being everlasting between about 115% and about 135%.Injection back is in the time of the 90th day, and performance level can be greater than about 95% in the time of the 14th day with respect to the injection back for average percent sclera level in the body, and more frequent greater than about 115%.

In some modification, in the body average percent sclera level with respect to the injection back in the time of the 14th day performance level have following feature: after injection the 35th day, it was less than about 2600%; It was less than about 180% in the 62nd day after injection; It was less than about 155% in back 90 days with injection.

In some modification, delivering therapeutic agents when liquid preparation is injected into the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos sclera in 90 days at least about the therapeutic agent mean concentration of 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected into the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos sclera in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected into the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos sclera in 90 days at least about the therapeutic agent mean concentration of 0.1ng/mL.

In some modification, the level of treatment agent that exists in the vitreous body at first rises, and reaches peak value and reduction then.Peak value can for example generation in about the 35th day after injection.

In some modification, in-situ gelling preparation described herein can have following characteristics arranged in Vitrea body, send spectrum, wherein send spectrum for after liquid preparation being injected between the lagophthalmos CSC, delivering therapeutic agents sends spectrum in the body.

Injection back is in the time of the 32nd day, and performance level can be between about 25% and about 85% in the time of the 7th day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 45% and about 65%.Injection back is in the time of the 40th day, and performance level can be greater than about 25% in the time of the 7th day with respect to the injection back for average percent vitreous body level in the body, and more frequent greater than about 45%.

Injection back is in the time of the 45th day, and performance level can be between about 2% and about 50% in the time of the 7th day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 8% and about 20%.Injection back is in the time of the 67th day, and performance level can be greater than about 2% in the time of the 7th day with respect to the injection back for average percent vitreous body level in the body, and more frequent greater than about 5%.

Injection back is in the time of the 90th day, and performance level can be between about 40% and about 100% in the time of the 7th day with respect to the injection back for average percent vitreous body level in the body, and more through being everlasting between about 60% and about 80%.Injection back is in the time of the 90th day, and performance level can be greater than about 40% in the time of the 7th day with respect to the injection back for average percent vitreous body level in the body, and more frequent greater than about 60%.

In some modification, average percent vitreous body level has following feature with respect to the 7th day performance level in injection back in the body: after injection the 32nd day, it was less than about 80%; It was less than about 30% in the 45th day after injection; It was less than about 100% in the 90th day with the injection back.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.1pg/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 10ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC obtains after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days in the lagophthalmos vitreous body therapeutic agent mean concentration of 0.001ng/mL at least at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days, at least about 90 days or at least about the therapeutic agent mean concentration of 0.01ng/mL at least in the lagophthalmos vitreous body in 120 days.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC obtains after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days in the lagophthalmos vitreous body therapeutic agent mean concentration of 0.1ng/mL at least at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC obtains after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days in the lagophthalmos vitreous body therapeutic agent mean concentration of 0.5ng/mL at least at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC obtains after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration between the 0.001ng/mL and 10.0ng/mL in the lagophthalmos vitreous body at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC obtains after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration between the 0.01ng/mL and 10.0ng/mL in the lagophthalmos vitreous body at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC obtains after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration between the 0.1ng/mL and 10ng/mL in the lagophthalmos vitreous body at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC obtains after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration between the 0.5ng/mL and 10.0ng/mL in the lagophthalmos vitreous body at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 100.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 50.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 10.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 5.

" roughly constant " used herein is to say that the change greater than a magnitude does not take place in the time period that prolongs average level, and promptly mean concentration maximum and the difference between the minima that different time is measured in the correlation time section is less than 10 times.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after solution is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place greater than 0.001ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place greater than 0.01ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after solution is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place greater than 0.1ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place of 1.0ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 0.001ng/mg at least in the lagophthalmos retina tela chorioidea at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 0.005ng/mg at least in the lagophthalmos retina tela chorioidea at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 0.01ng/mg at least in the lagophthalmos retina tela chorioidea at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.001ng/mg and the 1.0ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.001ng/mg and the 0.50ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.001ng/mg and the 0.15ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.001ng/mg and the 0.1ng/mg at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.005ng/mg and the 1.0ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.005ng/mg and the 0.50ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.005ng/mg and the 0.15ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.005ng/mg and the 0.1ng/mg at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.01ng/mg and the 1.0ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.01ng/mg and the 0.50ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.01ng/mg and the 0.15ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.01ng/mg and the 0.1ng/mg at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos retina tela chorioidea internal therapy agent and lagophthalmos retina tela chorioidea internal therapy agent minimum average B configuration concentration is less than 100.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos retina tela chorioidea internal therapy agent and lagophthalmos retina tela chorioidea internal therapy agent minimum average B configuration concentration is less than 50.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos retina tela chorioidea internal therapy agent and lagophthalmos retina tela chorioidea internal therapy agent minimum average B configuration concentration is less than 10.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos retina tela chorioidea internal therapy agent and lagophthalmos retina tela chorioidea internal therapy agent minimum average B configuration concentration is less than 5.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is roughly constant at the numerical value place greater than 0.001ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is roughly constant at the numerical value place greater than 0.005ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is roughly constant at the numerical value place greater than 0.01ng/mg.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 100ng/mL at least in the lagophthalmos vitreous body at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 1000ng/mL at least in the lagophthalmos vitreous body at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos at least 30 days, at least 60 days, at least 90 days or at least 120 days, in the lagophthalmos vitreous body at least 10, the therapeutic agent mean concentration of 000ng/mL.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, 90 days or 120 days 100ng/mL and 100 in the lagophthalmos vitreous body, the therapeutic agent mean concentration between the 000ng/mL at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, 90 days or 120 days 100ng/mL and 50 in the lagophthalmos vitreous body, the therapeutic agent mean concentration between the 000ng/mL at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, 90 days or 120 days 1000ng/mL and 100 in the lagophthalmos vitreous body, the therapeutic agent mean concentration between the 000g/mL at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, 90 days or 120 days 1000ng/mL and 50 in the lagophthalmos vitreous body, the therapeutic agent mean concentration between the 000ng/mL at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 100.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 50.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos vitreous body internal therapy agent and lagophthalmos vitreous body internal therapy agent minimum average B configuration concentration is less than 10.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place greater than 100ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is roughly constant at the numerical value place greater than 1000ng/mL.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the mean concentration of lagophthalmos vitreous body internal therapy agent is greater than 10, and the numerical value place of 000ng/mL is roughly constant.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 0.001ng/mg at least in the lagophthalmos retina tela chorioidea at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 0.01ng/mg at least in the lagophthalmos retina tela chorioidea at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 0.05ng/mg at least in the lagophthalmos retina tela chorioidea at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration of 0.10ng/mg at least in the lagophthalmos retina tela chorioidea at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.001ng/mg and the 10.00ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.001ng/mg and the 5.00ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.001ng/mg and the 1.00ng/mg at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.01ng/mg and the 10.00ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.01ng/mg and the 5.00ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.01ng/mg and the 1.00ng/mg at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.05ng/mg and the 10.00ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.05ng/mg and the 5.00ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.05ng/mg and the 1.00ng/mg at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.10ng/mg and the 10.00ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.10ng/mg and the 5.00ng/mg at least at least at least at least.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days, 60 days, 90 days or 120 days the therapeutic agent mean concentration in the lagophthalmos retina tela chorioidea between 0.10ng/mg and the 1.00ng/mg at least at least at least at least.

In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos retina tela chorioidea internal therapy agent and lagophthalmos retina tela chorioidea internal therapy agent minimum average B configuration concentration is less than 100.In some modification, delivering therapeutic agents when liquid preparation is injected in the lagophthalmos vitreous body, obtain after liquid preparation is applied to lagophthalmos in 30 days at least 60 days, at least 90 days or at least 120 days, the ratio of maximum mean concentration of lagophthalmos retina tela chorioidea internal therapy agent and lagophthalmos retina tela chorioidea internal therapy agent minimum average B configuration concentration is less than 50.

In some modification, in-situ gelling preparation described herein can have following characteristics arranged in the body of retina tela chorioidea, send spectrum, wherein send spectrum for after liquid preparation being injected between the lagophthalmos CSC, delivering therapeutic agents sends spectrum in the body.

Injection back is in the time of the 32nd day, and performance level can be between about 20% and about 80% in the time of the 7th day with respect to the injection back for percentage ratio vitreous body level in the body, and more through being everlasting between about 40% and about 60%.Injection back is in the time of the 40th day, and performance level can be greater than about 20% in the time of the 7th day with respect to the injection back for percentage ratio vitreous body level in the body, and more frequent greater than about 40%.

Injection back is in the time of the 45th day, and performance level can be between about 15% and about 55% in the time of the 7th day with respect to the injection back for percentage ratio vitreous body level in the body, and more through being everlasting between about 25% and about 45%.Injection back is in the time of the 67th day, and performance level can be greater than about 15% in the time of the 7th day with respect to the injection back for percentage ratio vitreous body level in the body, and more frequent greater than about 25%.

Injection back is in the time of the 90th day, and performance level can be between about 60% and about 100% in the time of the 7th day with respect to the injection back for percentage ratio vitreous body level in the body, and more through being everlasting between about 70% and about 90%.Injection back is in the time of the 90th day, and performance level can be greater than about 60% in the time of the 7th day with respect to the injection back for percentage ratio vitreous body level in the body, and more frequent greater than about 70%.

In some modification, percentage ratio vitreous body level has following feature with respect to the 7th day performance level in injection back in the body: after injection the 32nd day, it was less than about 80%; It was less than about 60% in the 45th day after injection; It was less than about 100% in the 90th day with the injection back.

In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos retina tela chorioidea in 90 days at least about the therapeutic agent mean concentration of 0.1pg/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.01ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 0.1ng/mg.In some modification, delivering therapeutic agents when liquid preparation is injected between the lagophthalmos CSC, obtain after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or at least about in the lagophthalmos vitreous body in 90 days at least about the therapeutic agent mean concentration of 1ng/mg.

In some modification, place the in-situ gelling preparation near eye or the eye after, retina tela chorioidea, sclera and Vitrea two or more in the average level of therapeutic agents be that the logarithmic ratio in the end is roughly constant in the time period of prolongation with ten.In some modification, the in-situ gelling preparation is placed between the CSC of eye after, be the logarithmic ratio in the end with ten roughly constant in the time period of prolongation for the average level of therapeutic agent in two or more retina tela chorioideas, sclera and the vitreous body.In some modification, place the in-situ gelling preparation between eye sclera and the conjunctiva after, to be the logarithmic ratio in the end with ten roughly constant in the time period that prolongs for the average level of therapeutic agent in vitreous body and the sclera.

In some modification, the average level of therapeutic agent is that the logarithmic ratio in the end is roughly constant in the time period that prolongs with ten in vitreous body and the retina tela chorioidea.In other words, when considering with logarithmic scale, when vitreous body internal therapy agent level rose, the level of therapeutic agent rose to similar degree in the retina tela chorioidea, and vice versa.

In some modification, to be the logarithmic ratio in the end with ten roughly constant in the time period of about 7 days, about 30 days, about 60 days or about 90 days prolongation for the average level of therapeutic agent in the vitreous body contrast retina tela chorioidea.In some modification, after placing the in-situ gelling preparation between eye sclera and the conjunctiva, vitreous body internal therapy agent average level is constant at the 7th day with respect to the ratio of therapeutic agent average level in the retina tela chorioidea to be about 37: 1, the 32nd day about 40: 1, the 45th day about 10: 1 and the 90th day about 34: 1.

In some modification, vitreous body internal therapy agent average level is constant when about 7 days, about 32 days, about 45 days or about 90 days with respect to the ratio of therapeutic agent average level in the retina tela chorioidea to be about 40: 1.

In some modification, place the in-situ gelling preparation near ophthalmic or the eye after, in retina tela chorioidea, sclera and the vitreous body any or all of in the therapeutic agent average level roughly constant in the time period that prolongs.

In some modification, place the in-situ gelling preparation between the CSC after, the average level of vitreous body internal therapy agent is roughly constant at about 8.1ng/ml.In some modification, place the in-situ gelling preparation between the CSC after, the average level of retina tela chorioidea internal therapy agent is roughly constant at about 0.25ng/mg.In some modification, place the in-situ gelling preparation between the CSC after, the mean concentration of sclera internal therapy agent is roughly constant at about 1930ng/mg.

In some modification, when being injected between the lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1pg/mL place at least about the average level of keeping the agent of lagophthalmos vitreous body internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.001ng/mL place at least about the average level of keeping the agent of lagophthalmos vitreous body internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.01g/mL place at least about the average level of keeping the agent of lagophthalmos vitreous body internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1ng/mL place at least about the average level of keeping the agent of lagophthalmos vitreous body internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 1ng/mL place at least about the average level of keeping the agent of lagophthalmos vitreous body internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 10ng/mL place at least about the average level of keeping the agent of lagophthalmos vitreous body internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 100ng/mL place at least about the average level of keeping the agent of lagophthalmos vitreous body internal therapy in 90 days.

In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1pg/mg place at least about the average level of keeping the internal therapy agent of retina tela chorioidea in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.001ng/mg place at least about the average level of keeping the internal therapy agent of retina tela chorioidea in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.01ng/mg place at least about the average level of keeping the internal therapy agent of retina tela chorioidea in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1ng/mg place at least about the average level of keeping the internal therapy agent of retina tela chorioidea in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 1ng/mg place at least about the average level of keeping the internal therapy agent of retina tela chorioidea in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 10ng/mg place at least about the average level of keeping the internal therapy agent of retina tela chorioidea in 90 days.

In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1pg/mg place at least about the average level of keeping the agent of sclera internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.001ng/mg place at least about the average level of keeping the agent of sclera internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.01ng/mg place at least about the average level of keeping the agent of sclera internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 0.1ng/mg place at least about the average level of keeping the agent of sclera internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 1ng/mg place at least about the average level of keeping the agent of sclera internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 10ng/mg place at least about the average level of keeping the agent of sclera internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 100ng/mg place at least about the average level of keeping the agent of sclera internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 1 μ g/mg place at least about the average level of keeping the agent of sclera internal therapy in 90 days.In some modification, when being injected between the lagophthalmos CSC, the in-situ gelling preparation after liquid preparation is applied to lagophthalmos at least about 30 days, at least about 60 days or roughly constant at about 10 μ g/mg places at least about the average level of keeping the agent of sclera internal therapy in 90 days.

For the generation for the treatment of, prevent, suppress, postpone some disease or disease or it is disappeared, can be desirably in the therapeutic agent of keeping the delivery treatments effective dose in time period of prolongation.Based on treating, prevent, suppress, postpone its generation or make its disease that disappears or disease, the time period of this prolongation can be at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months or at least about 1 year.Yet the Delivery time of common any prolongation can be possible.The therapeutic agent of treatment effective dose can be sent the time of prolongation by liquid preparation or compositions, described liquid preparation or compositions are kept the concentration of therapeutic agent in experimenter or the experimenter's eye in the time that prolongs, described concentration is the therapeutic agent of delivery treatments effective dose in the time that prolongs enough.

The therapeutic agent of delivery treatments effective dose can pass through to place a kind of compositions or liquid preparation in the time that prolongs, or finishes by compositions or the liquid preparation of using two or more dosage.The limiting examples of repeatedly using as this class, the therapeutic dose of rapamycin being kept the generation that was used for the treatment of, prevents, suppresses, postpones moist AMD in three months or it is disappeared can be by using delivery treatments amount 3 months a kind of liquid preparation or compositions, or uses multiple liquid preparation or compositions is finished by order.The optimal dose strategy will depend on therapeutic dose and its time that need be sent of the therapeutic agent that need be sent.The technical staff that the administration field is sent in the extended treatment agent can understand how to instruct definite spendable administration strategy based on this paper.

When using some therapeutic agent or being used for the treatment of, preventing, suppressing, postponing the generation of some disease or it is disappeared, sending of therapeutic agent do not get started in the time of can expecting to place liquid preparation or compositions in the eye zone, but begins after some delay to send.For example (but not limiting), when therapeutic agent suppresses or postpones wound healing, and the release that need be delayed is when making any wound healing that produces when placing liquid preparation or compositions, the release that this class is delayed can be useful.Treated, prevent, suppress, postpone its generation or make its disease that disappears and disease according to therapeutic agent of being sent and/or quilt, can be about 1 hour, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 21 days, about 28 days, about 35 days or about 42 days period of delay before therapeutic agent delivery began.Also can be possible other period of delay.Spendable delayed release preparation is that to be proficient in the personnel of this technology known.

Sending rapamycin in the vitreous body and under the conjunctiva is used for the treatment of, prevents, suppresses, postpones the AMD generation or it is disappeared

In a kind of method described herein, to comprise and send or send in the vitreum with treatment, prevention under the liquid preparation conjunctiva of rapamycin, suppress, postpone the eye medium vessels and take place or it is disappeared, include but are not limited to treatment as observed CNV in AMD.In some modification, use liquid preparation treatment eye medium vessels to take place, include but are not limited to treatment as observed CNV in AMD.Rapamycin has been presented in rabbit and the mouse model and has suppressed CNV, and is of U. S. application number 10/665,203, quotes its integral body as a reference at this paper.Observe rapamycin and when using under systemic administration and the retina, suppressed Matrigel ^TMCNV with induced with laser.In addition, the periocular injections rapamycin suppresses the CNV of induced with laser.

Can be delivered to eye (particularly vitreum) and be used for the treatment of, prevent, suppress, postpone the generation of eye angiogenesis (as CNV) or make its other therapeutic agent that disappears, include but are not limited to everolimus and tacrolimus (FK-506) for the limus family compound except that rapamycin.

As described herein, the dosage of therapeutic agent depends on handled disease (no matter this disease will be treated, prevent, suppress, postpone its generation or it be disappeared), concrete therapeutic agent and other clinical factor, as experimenter's the body weight and the approach of situation and administering therapeutic agent.Should understand methods described herein, liquid preparation and compositions can be used for people and veterinary purpose and is used for other possible animal.As described herein, the tissue concentration of the therapeutic agent of expressing with the unit of mass/volume typically refers to the tissue that is essentially aqueous, as vitreous body.The tissue concentration of the therapeutic agent of expressing with mass/mass unit typically refers to other tissue, for example sclera or retina tela chorioidea.

A kind of rapamycin concentrations that can be used for methods described herein is organized the concentration of level for about 0.01pg/ml or pg/mg or more rapamycins are provided.Operable another concentration is for providing about 0.1pg/ml or ng/mg or more concentration organizing on the level.Operable another concentration is for organizing the concentration that about 1pg/ml or ng/mg or more rapamycins are provided on the level.Operable another concentration is for providing about 0.01ng/ml or ng/mg or more concentration organizing on the level.Operable another concentration is for providing about 0.1ng/ml or ng/mg or more concentration organizing on the level.Operable another concentration is for providing about 0.5ng/ml or ng/mg or more concentration organizing on the level.Operable another concentration is for providing about 1ng/ml or more concentration organizing on the level.Operable another concentration is for providing about 2ng/ml or more concentration organizing on the level.Operable another concentration is for providing about 3ng/ml or more concentration organizing on the level.Operable another concentration is for providing about 5ng/ml or more concentration organizing on the level.Operable another concentration is for providing about 10ng/ml or more concentration organizing on the level.Operable another concentration is for providing about 15ng/ml or more concentration organizing on the level.Operable another concentration is for providing about 20ng/ml or more concentration organizing on the level.Operable another concentration is for providing about 30ng/ml or more concentration organizing on the level.Operable another concentration is for providing about 50ng/ml or more concentration organizing on the level.Those skilled in the art can know how to reach suitable concentration according to employed route of administration and persistent period according to the instruction of this paper.

Usually, the amount of the rapamycin of using in the liquid preparation is enough to treat, prevent, suppress, postpone the amount that ophthalmic or disease take place or it is disappeared in required time quantum.In some modification, the amount of the rapamycin of using in the liquid preparation is the amount of enough treating ophthalmic or disease in required time quantum.

In some modification, use the rapamycin that is less than about 5mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 5.0mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 4.5mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 4.0mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 3.5mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 3.0mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 2.5mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 2mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 1.2mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 1.0mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 0.8mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 0.6mg total amount under the conjunctiva.In some modification, use the rapamycin that is less than about 0.4mg total amount under the conjunctiva.In some modification, use the volumes of formulation that comprises rapamycin amount described herein.

In some modification, liquid preparation described herein contains the liquid preparation that accounts for rapamycin concentrations between gross weight about 0.5% and about 6% by weight to using under people experimenter's conjunctiva between about 0.1 μ l and the about 200 μ l by using.In some modification, liquid preparation described herein contains the liquid preparation that accounts for rapamycin concentrations between gross weight about 0.5% and about 4% by weight to using under people experimenter's conjunctiva between about 1 μ l and the about 50 μ l by using.In some modification, liquid preparation described herein contains the liquid preparation that accounts for rapamycin concentrations between gross weight about 1.5% and about 3.5% by weight to using under people experimenter's conjunctiva between about 1 μ l and the about 15 μ l by using.In some modification, under people experimenter's conjunctiva, use and contain the liquid preparation that accounts for about 2% rapamycin concentrations of gross weight by weight by using between about 1 μ l and the about 15 μ l liquid preparation described herein.

In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 0.2 μ g and the about 4mg to using under people experimenter's conjunctiva between about 0.1 μ l and the about 200 μ l by using.In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 20 μ g and the about 2mg to using under people experimenter's conjunctiva between about 0.1 μ l and the about 100 μ l by using.In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 20 μ g and the about 1mg to using under people experimenter's conjunctiva between about 1 μ l and the about 50 μ l by using.In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 20 μ g and the about 500 μ g to using under people experimenter's conjunctiva between about 1 μ l and the about 25 μ l by using.In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 20 μ g and the about 300 μ g to using under people experimenter's conjunctiva between about 1 μ l and the about 15 μ l by using.

In some modification, intravitreal administration is less than the rapamycin of about 200 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of about 200 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of about 300 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of about 400 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of about 500 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of about 600 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of about 800 μ g total amounts.In some modification, intravitreal administration is less than the rapamycin of about 1mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 2mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 2.5mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 3 mg total amounts.In some modification, intravitreal administration is less than the rapamycin of about 3.5mg total amount.In some modification, intravitreal administration is less than the rapamycin of about 4mg total amount.In some modification, use the volumes of formulation that contains amount rapamycin described herein.

In some modification, liquid preparation described herein contains the liquid preparation that accounts for rapamycin concentrations between gross weight about 0.5% and about 6% by weight between about 0.1 μ l and the about 200 μ l to people experimenter's intravitreal administration by using.In some modification, liquid preparation described herein contains the liquid preparation that accounts for rapamycin concentrations between gross weight about 0.5% and about 4% by weight between about 1 μ l and the about 50 μ l to people experimenter's intravitreal administration by using.In some modification, liquid preparation described herein contains the liquid preparation that accounts for rapamycin concentrations between gross weight about 1.5% and about 3.5% by weight between about 1 μ l and the about 15 μ l to people experimenter's intravitreal administration by using.In some modification, liquid preparation described herein contains the liquid preparation that accounts for about 2% rapamycin concentrations of gross weight by weight between about 1 μ l and the about 15 μ l to people experimenter's intravitreal administration by using.

In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 0.2 μ g and the about 4mg between about 0.1 μ l and the about 200 μ l to people experimenter's intravitreal administration by using.In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 20 μ g and the about 2mg between about 1 μ l and the about 100 μ l to people experimenter's intravitreal administration by using.In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 20 μ g and the about 1mg between about 1 μ l and the about 50 μ l to people experimenter's intravitreal administration by using.In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 20 μ g and the about 500 μ g between about 1 μ l and the about 25 μ l to people experimenter's intravitreal administration by using.In some modification, liquid preparation described herein contains the liquid preparation of measuring rapamycin between about 20 μ g and the about 300 μ g between about 1 μ l and the about 15 μ l to people experimenter's intravitreal administration by using.

In some modification, use the liquid preparation described herein that contains amount rapamycin between about 1 μ g and the about 5mg to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 20 μ g and the about 4mg to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 20 μ g and the about 1.2mg to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 10 μ g and the about 0.5mg to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 10 μ g and the about 90 μ g to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 60 μ g and the about 120 μ g to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 100 μ g and the about 400 μ g to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 400 μ g and the about 1mg to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 1mg and the about 5mg to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 3mg and the about 7mg to people experimenter, be used for the treatment of moist AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 5mg and the about 10mg to people experimenter, be used for the treatment of moist AMD.

In some modification, use the liquid preparation described herein that contains amount rapamycin between about 1 μ g and the about 5mg to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 20 μ g and the about 4mg to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 20 μ g and the about 1.2mg to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 10 μ g and the about 0.5mg to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 10 μ g and the about 90 μ g to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 60 μ g and the about 120 μ g to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 100 μ g and the about 400 μ g to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 400 μ g and the about 1mg to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 1mg and the about 5mg to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 3mg and the about 7mg to people experimenter, be used for pre-moisture resistance AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 5mg and the about 10mg to people experimenter, be used for pre-moisture resistance AMD.

In some modification, use the liquid preparation described herein that contains amount rapamycin between about 1 μ g and the about 5mg to people experimenter, be used for the treatment of dryness AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 20 μ g and the about 4mg to people experimenter, be used for the treatment of dryness AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 20 μ g and the about 1.2mg to people experimenter, be used for the treatment of dryness AMD.In some modification, use the liquid preparation described herein that contains amount rapamycin between about 10 μ g and the about 0.5mg to people experimenter, be used for the treatment of dryness AMD.In some modification, use to contain between about 10 μ g and the about 90 μ g to people experimenter and measure rapamycin, be used for the treatment of dryness AMD.In some modification, use to contain between about 60 μ g and the about 120 μ g to people experimenter and measure rapamycin, be used for the treatment of dryness AMD.In some modification, use to contain between about 100 μ g and the about 400 μ g to people experimenter and measure rapamycin, be used for the treatment of dryness AMD.In some modification, use to contain between about 400 μ g and the about 1mg to people experimenter and measure rapamycin, be used for the treatment of dryness AMD.In some modification, use to contain between about 1mg and the about 5mg to people experimenter and measure rapamycin, be used for the treatment of dryness AMD.In some modification, use to contain between about 3mg and the about 7mg to people experimenter and measure rapamycin, be used for the treatment of dryness AMD.In some modification, use to contain between about 5mg and the about 10mg to people experimenter and measure rapamycin, be used for the treatment of dryness AMD.

In some modification, use the liquid preparation described herein that contains amount rapamycin between about 1 μ g and the about 5mg to people experimenter, be used for the treatment of blood vessel and take place, include but are not limited to the choroid neovascularization.In some modification, use the rapamycin of measuring between about 20 μ g and the about 4mg to people experimenter; Between about 20 μ g and the about 1.2mg; Use the rapamycin of measuring between about 10 μ g and the about 0.5mg to people experimenter and be used for the treatment of moist AMD, to people experimenter use between about 10 μ g and the 90 μ g, between about 60 μ g and the 120 μ g; To people experimenter use between about 100 μ g and the 400 μ g, between about 400 μ g and the 1mg; In some modification, use the rapamycin of measuring between about 1mg and the 5mg to people experimenter; In some modification, use the rapamycin of measuring between about 3mg and the 7mg to people experimenter; In some modification, use the rapamycin of measuring between about 5mg and the 10mg to people experimenter and be used for the treatment of the blood vessel generation, include but are not limited to the choroid neovascularization.

In one approach, liquid preparation described herein contains a certain amount of therapeutic agent that is equal to a certain amount of rapamycin.

In one approach, to people experimenter use contain and about 1 μ g and about 5mg between the liquid preparation described herein of amount of the therapeutic agent that is equal to of amount rapamycin, be used for the treatment of moist AMD.In some modification, to people experimenter use and about 1 μ g and about 5mg between the amount of the therapeutic agent that is equal to of rapamycin; Between about 20 μ g and the about 1.2mg; Use between about 10 μ g and the about 0.5mg to people experimenter and to be used for the treatment of moist AMD, to people experimenter use between about 10 μ g and the 90 μ g, between about 60 μ g and the 120 μ g; To people experimenter use between about 100 μ g and the 400 μ g, between about 400 μ g and the 1mg; In some modification, to people experimenter use and about 1mg and 5mg between the amount of the therapeutic agent that is equal to of amount rapamycin; In some modification, to people experimenter use and about 3mg and 7mg between the amount of the therapeutic agent that is equal to of amount rapamycin; In some modification, to people experimenter use and about 5mg and 10mg between the amount of the therapeutic agent that is equal to of amount rapamycin.

In some modification, to people experimenter use contain and about 1 μ g and about 5mg between the liquid preparation described herein of amount of the therapeutic agent that is equal to of amount rapamycin, be used for the treatment of dryness AMD.In some modification, to people experimenter use and about 20 μ g and about 4mg between the amount of the therapeutic agent that is equal to of rapamycin; Between about 20 μ g and the about 1.2mg; Use between about 10 μ g and the about 0.5mg to people experimenter and to be used for the treatment of moist AMD, to people experimenter use between about 10 μ g and the 90 μ g, between about 60 μ g and the 120 μ g; To people experimenter use between about 100 μ g and the 400 μ g, between about 400 μ g and the 1mg; In some modification, to people experimenter use and about 400 μ g and 1mg between the amount of the therapeutic agent that is equal to of amount rapamycin; In some modification, to people experimenter use and about 1mg and 5mg between the amount of the therapeutic agent that is equal to of amount rapamycin; In some modification, to people experimenter use and about 3mg and 7mg between the amount of the therapeutic agent that is equal to of amount rapamycin; In some modification, to people experimenter use and about 5mg and 10mg between the amount of the therapeutic agent that is equal to of amount rapamycin treat dryness AMD.

In some modification, to people experimenter use contain and about 1 μ g and about 5mg between the liquid preparation described herein of amount of the therapeutic agent that is equal to of amount rapamycin, be used for pre-moisture resistance AMD.In some modification, to people experimenter use and about 20 μ g and about 4 μ g between the amount of the therapeutic agent that is equal to of rapamycin; Between about 20 μ g and the about 1.2mg; Use between about 10 μ g and the about 0.5mg to people experimenter and to be used for pre-moisture resistance AMD, to people experimenter use between about 10 μ g and the 90 μ g, between about 60 μ g and the 120 μ g; To people experimenter use between about 100 μ g and the 400 μ g, between about 400 μ g and the 1mg; In some modification, to people experimenter use and about 400 μ g and 1mg between the amount of the therapeutic agent that is equal to of amount rapamycin; In some modification, to people experimenter use and about 1mg and 5mg between the amount of the therapeutic agent that is equal to of amount rapamycin; In some modification, to people experimenter use and about 3mg and 7mg between the amount of the therapeutic agent that is equal to of amount rapamycin; In some modification, to people experimenter use and about 5mg and 10mg between the amount of the therapeutic agent that is equal to of amount rapamycin be used for pre-moisture resistance AMD.

In some modification, per 3 or more months, per 6 or more months, per 9 or more months or per 12 or more months or longer time intravitreal administration any one or more preparation described herein, in order among treatment choroid neovascularization, moist AMD, the dryness AMD one or more, in order to pre-moisture resistance AMD or be used to prevent the development of dryness AMD hygrotropism AMD.In some modification, use any one or more preparation described herein under per 3 or more months, per 6 or more months, per 9 or more months or per 12 or more months or the longer time conjunctiva, in order among treatment choroid neovascularization, moist AMD, the dryness AMD one or more, or be used for pre-moisture resistance AMD.

In some modification, per 3 or more months, per 6 or more months, per 9 or more months or per 12 or more months or longer time intravitreal administration any one or more rapamycin preparation described herein, in order among treatment choroid neovascularization, moist AMD, the dryness AMD one or more, in order to pre-moisture resistance AMD or be used to prevent the development of dryness AMD hygrotropism AMD.In some modification, use any one or more rapamycin preparation described herein under per 3 or more months, per 6 or more months, per 9 or more months or per 12 or more months or the longer time conjunctiva, in order among treatment choroid neovascularization, moist AMD, the dryness AMD one or more, or be used for pre-moisture resistance AMD.In some modification, the effect of rapamycin continue to its be present in ocular tissue during beyond.

Therapeutic agent described herein send can be for example with the dosage range between about 1ng/ days and about 100 μ g/ days, or be higher or lower than this scope dosage send, depend on the approach and the persistent period of using.In some modification of liquid preparation that uses in methods described herein or compositions, therapeutic agent can be sent with the dosage range between about 0.1 μ g/ days and about 10 μ g/ days.In some modification of liquid preparation that uses in methods described herein or compositions, therapeutic agent can be sent with the dosage range between about 1 μ g/ days and about 5 μ g/ days.Be used for the treatment of, prevent, suppress, postpone the generation of multiple disease described herein and disease or make the dosage of its multiple therapeutic agent that disappears to pass through to use clinical trial optimization.

The liquid preparation and the compositions as herein described that include but are not limited to solution, suspensoid, Emulsion and in-situ gelling preparation can be used for the rapamycin of treatment effective dose is delivered to eye (as a kind of limiting examples in the time period that prolongs, use or use near the eyes by eye), therefore be used for the treatment of, prevent, suppress, postpone the generation of CNV or it is disappeared, and can be used for the treatment of, prevent, suppress, postpone the generation of moist AMD or it be disappeared or the conversion of dryness AMD hygrotropism AMD.Believe that some feature by changing liquid preparation described herein (includes but are not limited to the composition of liquid preparation, described liquid preparation and sent position in the eye into, include but are not limited under the conjunctiva or the interior storing of vitreous body), described liquid preparation can be used for will the treatment effective dose rapamycin in the time period of multiple prolongation, be delivered to eye, comprise with the treatment effective dose send more than about 1 week, more than about 2 weeks, more than about 3 weeks, more than about 1 month, more than about 3 months, more than about 6 months, more than about 9 months, more than about 1 year.

When the rapamycin of treatment effective dose was administered to the experimenter who suffers from moist AMD, rapamycin can treat, suppress moist AMD or it is disappeared.Treat, suppress or it is disappeared to need different treatment effective doses.The experimenter who suffers from moist AMD can have the CNV damage, and believes that the rapamycin of administering therapeutic effective dose can have multiple effect, includes but are not limited to the development that causes CNV damage disappearing, stablize CNV damage and prophylactic activity CNV damage.

When to the rapamycin of experimenter's administering therapeutic effective dose of suffering from dryness AMD, believe that rapamycin can prevent or delay the development of dryness AMD to moist AMD.

Embodiment

Unless context has explanation in addition, the error line in the chart shows a standard deviation.When using ethanol, it is from Gold Shield Distributors, Hayward, the 200 proof ethanol of CA.When using rapamycin, it is from LC laboratories, Woburn, MA or Chunghwa ChemicalSynthesis ﹠amp; Biotech Co., LTD (CCSB), Taipei Hsien, Taiwan, ROC.When using PEG 400, it is from The Dow Chemical Company, New Milford, CT.Some figure refer to μ L or μ L respectively with the expression of " uL " or " ug ".When using 10 μ L or more during small size, using Hamilton HPLC syringe.

Embodiment 1-preparation and sign contain the solution of rapamycin

1.256% rapamycin (percentage ratio of gross weight) is dissolved in 9.676% ethanol (percentage ratio of gross weight).At the sterilized water aqueous solution that continues slowly to add under the stirring 15%F127 (Lutrol).Final concentration is about 78.57% sterilized water (percentage ratio of gross weight) and about 10.50%F127 (Lutrol) (percentage ratio of gross weight).This solution is listed as preparation #32 in table 1.This solution places 2 ℃ until use.

Embodiment 2-subconjunctival injection contains the solution of rapamycin

The injection of solution that 50 μ l embodiment 1 describe is advanced between the New Zealand white rabbit CSC.

Fig. 2 has described to be present in 20,40,67 and 90 days after the injection mean concentration of the rapamycin logarithmic scale in vitreous body (ng/ml), retina choroid (ng/mg) and the sclera (ng/mg).

Mark is analyzed by liquid chromatography-mass spectrometry (LCMS) in using.

At each time point,, and use the eye number of being analyzed to calculate the mean concentration of rapamycin divided by total amount by the rapamycin concentrations addition of every eye of each rabbit that will obtain.In this experiment, each time point is represented two rabbits meansigma methods (two eyes of described time point) of the meansigma methods of eyes (four eyes of described time point) or rabbit eyes separately.

The whole vitreous body of homogenate is also analyzed.By with measured rapamycin quality divided by the Vitrea mean concentration of being analyzed of vitreous body volume calculation.Sample does not comprise site of administration; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels by solution.

After the subconjunctival injection in 20,40,67 and 90 days vitreous body the average level of rapamycin be respectively about 4.425,3.800,4.100 and 1.500ng/ml.

The whole retina choroid of homogenate and to its analysis.By with measured rapamycin quality divided by the retina choroid quality of being analyzed, calculate retinochoroid mean concentration.Sample does not comprise uses the site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels by solution.

After the subconjunctival injection in 20,40,67 and 90 days retina choroid the average level of rapamycin be respectively about 0.055,0.209,0.080 and 0.017ng/mg.

Analyze sclera in the mode identical with the retina choroid.The sclera sample comprises injection site; Therefore, the clearance rate of rapamycin from sclera pointed out in this measurement.

After the subconjunctival injection in 20,40,67 and 90 days scleras the average level of rapamycin be respectively about 0.141,0.271,0.067 and 0.192ng/ml.

Embodiment 3-preparation and sign contain the solution of rapamycin

5.233% rapamycin (accounting for the percentage ratio of total formulation weight amount behind the adding all the components) is dissolved among the 0.4177g EtOH; The amount of EtOH by forced evaporation (heating) reduce to 0.1296g (6.344%, w/w).Continuing to add PEG 400 under the stirring.Final concentration as total weight percent is approximately: rapamycin 5.233%, ethanol 6.344% and PEG 400 88.424%.When contacting with vitreous body, preparation forms the nondispersive agglomerate with respect to surrounding medium.This solution is listed as preparation #34 in table 1.

Embodiment 4-subconjunctival injection contains the solution of rapamycin

The injection of solution that 25 μ l embodiment 3 describe is advanced between the New Zealand white rabbit CSC.

Fig. 3 has described to be present in 14,35,62 and 85 days after the injection rapamycin levels of logarithmic scale in vitreous body (ng/ml), retina choroid (ng/mg) and the sclera (ng/mg).

With vitreous body homogenate and analyze as described in example 2 above, just analyzed in three rabbits every single eye at the 2nd day; Every eyes in two rabbits of analysis in the 14th day; Analyzed the eyes of a rabbit at the 35th day; Analyzed the eyes of a rabbit at the 62nd day; And analyzed at the 85th day from the simple eye of a rabbit with from the eyes of another rabbit.

The vitreous body sample does not comprise uses the site; Therefore, this measurement is pointed out to send into Vitrea rapamycin levels by solution.After the subconjunctival injection in 2,14,35 and 85 days vitreous body the average level of rapamycin be respectively about 3.57,53.65,9.00,4.700 and 0.600ng/ml.

With homogenate and the analysis as described in example 2 above of retina choroid, as above taking a sample about the described date of vitreous body.Do not carry out analyzing in the 2nd day.Retina choroid sample does not comprise uses the site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels by solution.After the subconjunctival injection in 14,35,62 and 85 days retina choroid the average level of rapamycin be respectively about 0.4815,1.725,0.057 and 0.009ng/mg.

The sclera sample is analyzed as described in example 2 above, as about the sampling of described date of retina choroid.The sclera sample comprises uses the site; Therefore, the clearance rate of rapamycin from sclera pointed out in this measurement.After the subconjunctival injection in 14,35,62 and 85 days scleras the average level of rapamycin be respectively about 34.5815,0.135,0.042 and 0.163666667ng/mg.

Embodiment 5-intravitreal injection contains the solution of rapamycin

The injection of solution that 25 μ l embodiment 3 describe is advanced in the vitreous body of New Zealand white rabbit eye.Fig. 4 has described to be present in 14,35,62 and 90 days after the injection level of the rapamycin logarithmic scale in vitreous body (ng/ml), retina choroid (ng/mg) and the sclera (ng/mg).Also show the rapamycin levels that injection was present in the vitreous body (ng/ml) in back 2 days.

With vitreous body homogenate and analyze as described in example 2 above, just analyzed in three rabbits of about 1 μ l every simple eye at the 2nd day; Analyzed each eyes only of two rabbits at the 14th day; Analyzed the eyes of a rabbit at the 35th day; Analyzed the eyes of a rabbit at the 62nd day; And in the 90th day analyzes from two rabbits every eyes.

Except the 2nd day sample, the vitreous body sample comprises uses the site.Avoid the solution used when possible as far as possible.Yet the accuracy of measured rapamycin levels may be owing to having comprised the influence that the solution of being used is subjected to sampling error because of carelessness.

Behind the intravitreal injection in 2,14,35,62 and 90 days vitreous body the average level of rapamycin be respectively about 11.4,136538,2850.3,21820.35 and 27142.75ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, as above-mentionedly be used for Vitrea date sampling.Do not carry out analyzing in the 2nd day.Retina choroid sample does not comprise uses the site; Therefore, this measurement is pointed out to send into retinochoroid rapamycin levels by solution.Behind the intravitreal injection in 14,35,62 and 90 days retina choroid the average level of rapamycin be respectively about 5.78975,244.485,0.105 and 1.782ng/mg.

The sclera sample is analyzed as described in example 2 above, as above-mentionedly be used for the sampling of retinochoroid date.The sclera sample does not comprise the injection site; Therefore, the clearance rate of rapamycin from sclera pointed out in this measurement.Behind the intravitreal injection in 14,35,62 and 90 days scleras the average level of rapamycin be respectively about 0.5695,12.34,0.8505 and 0.71175ng/mg.

Embodiment 6-preparation and sign contain the suspension of rapamycin

6% rapamycin (percentage ratio of gross weight) is scattered among the 94%PEG400 (percentage ratio of gross weight).This suspension is classified preparation #55 as in table 1.

Embodiment 7-intravitreal injection contains the suspension of rapamycin

The solution intravitreal injection of preparation among the embodiment 6 is advanced the New Zealand white rabbit ophthalmic.Fig. 5 has described the image that intravitreal injection 10 μ l (Fig. 5 A), 20 μ l (Fig. 5 B) and 40 μ l (Fig. 5 C) are suspended in the 6% rapamycin lagophthalmos of PEG400.This causes about 0.6, about 1.2 and the injected dose of about 2.4mg.Image focusing is on the suspension of being used.These pictorial display suspensions form nondispersive agglomerate with respect to vitreous body medium on every side.

Embodiment 8-preparation and sign contain the in-situ gelling preparation of rapamycin

4.2% rapamycin (derives from LC laboratories in Woburn, MA and ChunghwaChemical Synthesis ﹠amp; BioTech.Co, Ltd in Taiwan), 4.3% ethanol (derives from GoldShield Chemical in Hayward, CA), the liquid preparation of 2.2%PVP K90 (deriving from BASF), 87.1%PEG 400 (deriving from DOW Chemical) and 2.2%Eudragit RL 100 (deriving from RohmPharma Polymers), wherein all percentage ratios are the percentage ratio that accounts for gross weight.

Eudragit RL 100 is dissolved in ethanol.This step can need sonication and heating.Ethanol-Eudragit is added among the PEG 400.In Eudragit-ethanol-PEG solution, slowly add PVP, obtain the blended solution of homogeneous.This step can need abundant mixing.

Add rapamycin and it is dissolved in Eudragit-ethanol-PEG-PVP mixture.Can use heating and sonication.Preparation thoroughly mixes (using vortice or blender) and reaches homogeneous.Said preparation is classified #37 as in table 1.

When placing deionized water or tap water, liquid preparation forms nondispersive agglomerate.This nondispersive agglomerate is shown as gel-like substance.

Embodiment 9-subconjunctival injection contains the preparation of the nondispersive agglomerate of one-tenth of rapamycin

The injection of solution that 50 μ l embodiment 8 describe is advanced between the New Zealand white rabbit CSC.

Fig. 6 has described to be present in 7,32,45 and 90 days behind the injection in-situ gelling preparation mean concentration of rapamycin in vitreous body (ng/ml), retina choroid (ng/mg) and the sclera (ng/mg).

Analyze by LCMS (liquid chromatography (LC)-mass spectrography).

When analyzing when simple eye, by will deriving from the rapamycin concentrations addition of each each eye of rabbit, and with the mean concentration of total amount divided by the eye number calculating rapamycin of being analyzed.In this experiment, with respect to average level, the time point representative in the 7th, 32 and 45 days of vitreous body the 7th day and sclera is simple eye.Remaining the 7th, 32 and 45 day time point represented the meansigma methods of rabbit eyes, and the 90th day time point represented the meansigma methods (totally four eyes) of the eyes of each in two rabbits.

The whole vitreous body of homogenate is also analyzed.By with measured rapamycin quality divided by the Vitrea mean concentration of being analyzed of vitreous body volume calculation.Sample does not comprise uses the site; Therefore, this measurement is pointed out to advance Vitrea rapamycin levels by the in-situ gelling formulation delivered.

After the subconjunctival injection 7,32,45 and 90 days, the average level of rapamycin was respectively about 13.9, about 7.4, about 1.35 and about 9.9ng/ml in the vitreous body.

The whole retina choroid of homogenate and to its analysis.By with measured rapamycin quality divided by the retinochoroid mean concentration of being analyzed of retina tela chorioidea Mass Calculation.Sample does not comprise uses the site; Therefore, this measurement points out to advance by the in-situ gelling formulation delivered rapamycin levels of retina tela chorioidea.

After the subconjunctival injection in 7,32,45 and 90 days retina tela chorioideas the average level of rapamycin be respectively about 0.376, about 0.1875, about 0.136 and about 0.29ng/mg.

Analyze sclera in the mode identical with retina tela chorioidea.The sclera sample can comprise injection liquid preparations; Therefore, the clearance rate of rapamycin from sclera pointed out in this measurement.

After the subconjunctival injection in 7,32,45 and 90 days scleras the average level of rapamycin be respectively about 2033, about 1653, about 3626 and about 420.5ng/mg.

Embodiment 10-preparation and sign contain the suspension of rapamycin

By 150.5ng rapamycin (by weight 3.004%) being scattered in the suspension that preparation among the 4860.3mg PEG400 (by weight 96.996%) contains rapamycin.Said preparation is classified #49 as in table 1.150.5mg rapamycin (by weight 3.004%) and 4860.3mg PEG 400 (by weight 96.996%) are placed the succinum colour tube.The high abrasion zirconium oxide that adds the 3mm diameter culture medium (High Wear Resistant Zirconia Grinding Media) (pearl) of milling is at most 3/4ths of cumulative volume.Sealed tube also placed the Cole-Parmer milling device 48 hours.Rapamycin granular size intermediate value is 2.8386mm, and average is 3.1275mm.Said preparation is kept at 4 ℃ until use.When placing in the lagophthalmos vitreous body, the volume of 20 μ l and 40 μ l respectively forms nondispersive agglomerate.

Embodiment 11-subconjunctival injection contains the suspension of rapamycin

The suspension that 40 μ l embodiment 10 are described is injected between the New Zealand white rabbit CSC.Fig. 7 has described to inject the level of back 14,42, the 63 and 91 days rapamycin logarithmic scales in vitreous body (ng/ml), retina choroid (ng/mg) and the sclera (ng/mg).

With vitreous body homogenate and analysis as described in example 2 above.Remove the 91st beyond the highest heavens, each time point is analyzed from each eyes of two rabbits, at the eyes of analysis in the 91st day from a rabbit.The vitreous body sample does not comprise uses the site; Therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 14,42,63 and 91 days vitreous body the average level of rapamycin be respectively about 4.031,23.11,53.27 and 13.94ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, as above-mentionedly be used for Vitrea date sampling.The retina choroid does not comprise uses the site; Therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 14,42,63 and 91 days retina choroid the average level of rapamycin be respectively about 0.1577,4.965,0.385 and 0.05ng/mg.

With the homogenate and analyze as described in example 2 above of sclera sample, be used for Vitrea mode and take a sample as above-mentioned.The sclera sample comprises injection site.After the subconjunctival injection in 14,42,63 and 91 days scleras the average level of rapamycin be respectively about 1283,476.3,854.2 and 168.5ng/mg.

Embodiment 12-intravitreal injection contains the suspension of rapamycin

The suspension that 20 μ l embodiment 10 are described is injected in the vitreous body of New Zealand white rabbit eye.Injected suspension forms nondispersive agglomerate with respect to surrounding medium.Fig. 8 has described to inject the rapamycin levels of 63 and 91 days middle logarithmic scales of vitreous body (ng/ml) of 14,42, the 63 and 91 days retina choroid (ng/mg) and sclera (ng/mg) neutralization injection backs in back.

With vitreous body homogenate and analysis as described in example 2 above.Analyze from each eyes of two rabbits at each time point.The vitreous body sample can comprise uses the site.The average level of 63 and 91 days interior rapamycins of vitreous body is respectively about 381,600 and 150,400ng/ml behind the intravitreal injection.

With homogenate and the analysis as described in example 2 above of retina choroid.Analyze from each eyes of two rabbits at each time point.The retina choroid does not comprise uses the site, so this measurement points out to send into retinochoroid rapamycin levels.Behind the intravitreal injection in 14,42,63 and 91 days retina choroid the average level of rapamycin be respectively about 2.588,4.249,21.42 and 0.922ng/mg.

With the homogenate and analyze as described in example 2 above of sclera sample, be used for retinochoroid mode and take a sample as above-mentioned.The sclera sample does not comprise injection site; Therefore, this measurement points out to be delivered to the level of the rapamycin of sclera.Behind the intravitreal injection in 14,42,63 and 91 days scleras the average level of rapamycin be respectively about 0.7327,6.053,1.373 and 17.49ng/mg.

Embodiment 13-preparation and sign contain the solution of rapamycin

Form the solution that contains rapamycin by the 116.6mg rapamycin being placed ethanol and mixture being stored 6 hours at 4 ℃.Then this solution is mixed obtaining following solution with 4647.5mg PEG 400, described solution has the final concentration of 2.29% rapamycin, 6.05% ethanol and 91.66%PEG400 by weight.This solution is classified preparation #51 as in table 1.The volume of 30 μ l forms nondispersive agglomerate when placing in the lagophthalmos vitreous body.

Embodiment 14-subconjunctival injection contains the solution of rapamycin

The injection of solution that 40 μ l embodiment 13 describe is advanced between the CSC of New Zealand white rabbit eye.Fig. 9 has described to inject the rapamycin levels of back 14,42, the 63 and 91 days linear-scale in vitreous body (ng/ml), retina choroid (ng/mg) and the sclera (ng/mg).

With vitreous body homogenate and analysis as described in example 2 above.Remove the 91st beyond the highest heavens, each time point is analyzed from each eyes of two rabbits, at the eyes of analysis in the 91st day from a rabbit.The vitreous body sample does not comprise uses the site; Therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 14,42,63 and 91 days vitreous body the average level of rapamycin be respectively about 1.804,1.854,1.785 and 1.255ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site; Therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 14,42,63 and 91 days retina choroid the average level of rapamycin be respectively about 1.221,4.697,0.1075 and 0.02ng/mg.

With the homogenate and analyze as described in example 2 above of sclera sample, be used for Vitrea mode and take a sample as above-mentioned.The sclera sample comprises injection site.After the subconjunctival injection in 14,42,63 and 91 days scleras the average level of rapamycin be respectively about 1.987,1.884,0.56 and 10.84ng/mg.

Embodiment 15-intravitreal injection contains the solution of rapamycin

The injection of solution that 30 μ l embodiment 13 describe is advanced in the vitreous body of New Zealand white rabbit eye.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Figure 10 has described the rapamycin levels of 14,42,63 and 91 days retina choroid (ng/mg) in injection back and sclera (ng/mg) neutral line yardstick.

With homogenate and the analysis as described in example 2 above of retina choroid.Analyze from each eyes of two rabbits at each time point.The retina choroid does not comprise uses the site, so this measurement points out to send into retinochoroid rapamycin levels.Behind the intravitreal injection in 14,42,63 and 91 days retina choroid the average level of rapamycin be respectively about 5.515,5.388,0.3833 and 11.52ng/mg.

With the homogenate and analyze as described in example 2 above of sclera sample, be used for retinochoroid mode and take a sample as above-mentioned.The sclera sample does not comprise injection site, so this measurement points out to send the into rapamycin levels of sclera.Behind the intravitreal injection in 14,42,63 and 91 days scleras the average level of rapamycin be respectively about 1.077,0.9239,0.0975 and 2.0825ng/mg.

Figure 11 has described the rapamycin levels of 63 and 91 days vitreous body (ng/ml) the neutral line yardsticks in injection back.With vitreous body homogenate and analysis as described in example 2 above.Analyze from each eyes of two rabbits at each time point.The vitreous body sample can comprise uses the site.The average level of 63 and 91 days interior rapamycins of vitreous body is respectively about 299,900 and 196,600ng/ml behind the intravitreal injection.

Embodiment 16-preparation and sign contain the solution of rapamycin

About 320g ethanol N ₂Washed about 10 minutes, and in ethanol, added about 40g sirolimus then.About 20 minutes of mixture sonication, sirolimuss all during end have entered solution, form the sirolimus storage liquid.By with about 60 minutes of about 1880g PEG 400 sonications preparation retarder thinner, about 10 minutes then with this solvent of nitrogen wash.

In rotary evaporator, sirolimus storage solutions and PEG 400 were rotated under about room temperature about 10 minutes then, so that storage solutions and retarder thinner are mixed.With solution about 10 minutes, and covered about 5 minutes after the mixing with nitrogen with nitrogen wash.When solution with nitrogen wash and after being full of, by improving solution temperature, in the time period that prolongs, keep being no more than 40 ℃ temperature and continuing rotation solution about 2.5 hours, the unnecessary alcohol of about 240g is evaporated from solution.

The solution that obtains comprises about 40g sirolimus (about by weight 2%), about 80g ethanol (about by weight 4%) and about 1880g PEG 400 (about by weight 94%).This solution was covered about 5 minutes with about 10 minutes of nitrogen wash and with nitrogen.Then solution is filtered by 0.2 micron filter.Each is crossed filtered solution and packs in the HPLC bottle with 2ml, stays the headroom of about 400 μ l in each container.This headroom is full of with nitrogen and closes the lid.

Embodiment 17-preparation and sign contain the solution of rapamycin

Place container to obtain the final concentration of about by weight 2.00% rapamycin, about 4.00% ethanol and about 94.00%PEG 400 rapamycin, ethanol and PEG 400.This mixture cover lid and sonication 1-2 hour.Sonication produces heat, and temperature is up to about 40 or 50 ℃.This solution is classified preparation #100 as in table 1.1 μ l, 3 μ l, 20 μ l and 40 μ l volumes form nondispersive agglomerate in the lagophthalmos vitreous body.

Embodiment 18-subconjunctival injection contains the solution of rapamycin

The injection of solution that 20 μ l embodiment 17 describe is advanced between New Zealand white rabbit eye sclera and the conjunctiva.Figure 12 has described to be present in 5,30,60,90 and 120 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 13 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.For relatively, Figure 12 and Figure 13 have also described the result of the similar research carried out with 40 μ l and 60 μ l injection, description among embodiment 19 and the embodiment 20 hereinafter.

In the Figure 12-15 that is discussed in present embodiment and following examples, some exceptional values are omitted.Compare mutually from the number of individuals strong point of identical research at identical time point.When the arithmetic mean of instantaneous value of data point was lower than their standard deviation, the data point that is higher or lower than an order of magnitude was considered to exceptional value.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.The vitreous body sample does not comprise uses the site; Therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5,30,60,90 and 120 days vitreous body the average level of rapamycin be respectively about 1.81,0.45,0.39,1.85 and 1.49ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site; Therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5,30,60,90 and 120 days retina choroid the average level of rapamycin be respectively about 0.14,0.03,0.02,0.02 and 0.01ng/mg.

Embodiment 19-subconjunctival injection contains the solution of rapamycin

The injection of solution that 40 μ l embodiment 17 describe is advanced between New Zealand white rabbit eye sclera and the conjunctiva.Figure 12 has described to be present in 5,30,60,90 and 120 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 13 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.The vitreous body sample does not comprise uses the site; Therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5,30,60,90 and 120 days vitreous body the average level of rapamycin be respectively about 2.39,0.65,0.54,2.07 and 1.92ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site; Therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5,30,60,90 and 120 days retina choroid the average level of rapamycin be respectively about 0.47,0.04,0.01,0.05 and 0.0ng/mg.

Embodiment 20-subconjunctival injection contains the solution of rapamycin

The injection of solution that 60 μ l embodiment 17 describe is advanced between New Zealand white rabbit eye sclera and the conjunctiva.Figure 12 has described to be present in 5,30,60,90 and 120 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 13 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.The vitreous body sample does not comprise uses the site; Therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5,30,60,90 and 120 days vitreous body the average level of rapamycin be respectively about 8.65,0.29,0.18,2.00,1.41ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site; Therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5,30,60,90 and 120 days retina choroid the average level of rapamycin be respectively about 0.63,0.02,0.02,0.06 and 0.01ng/mg.

Embodiment 21-intravitreal injection contains the solution of rapamycin

The injection of solution that 20 μ l embodiment 17 describe is advanced in the vitreous body of New Zealand white rabbit eye.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Figure 14 has described the rapamycin levels of 5,30,60, the 90 and 120 days interior logarithmic scales of vitreous body in injection back.Figure 15 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.For relatively, Figure 14 and Figure 15 have also described the hereinafter result of other research described in the embodiment 22 and embodiment 24.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.The vitreous body sample can comprise uses the site.The average level of 5,30,60,90 and 120 days interior rapamycins of vitreous body is respectively about 162,100 behind the intravitreal injection; 18,780; 57,830; 94,040 and 13,150ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.Retina choroid sample does not comprise uses the site; Therefore, this measurement points out to send into retinochoroid rapamycin levels.Behind the intravitreal injection in 5,30,60,90 and 120 days retina choroid the average level of rapamycin be respectively about 2.84,2.26,0.17,0.22 and 0.05ng/mg.

Embodiment 22-intravitreal injection contains the solution of rapamycin

The injection of solution that 40 μ l embodiment 17 describe is advanced in the vitreous body of New Zealand white rabbit eye.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Figure 14 has described the rapamycin levels of 5,30,60, the 90 and 120 days interior logarithmic scales of vitreous body in injection back.Figure 15 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.The vitreous body sample can comprise uses the site.The average level of 5,30,60,90 and 120 days interior rapamycins of vitreous body is respectively about 415,600 behind the intravitreal injection; 4,830; 74,510; 301,300 and 7,854ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.Retina choroid sample does not comprise uses the site; Therefore, this measurement points out to send into retinochoroid rapamycin levels.Behind the intravitreal injection in 5,30,60,90 and 120 days retina choroid the average level of rapamycin be respectively about 5.36,0.23,1.27,1.08 and 0.08ng/mg.

Embodiment 23-preparation and sign contain the solution of rapamycin.

Place container to obtain the final concentration of about by weight 0.4% rapamycin, about 4.0% ethanol and about 95.6%PEG 400 rapamycin, ethanol and PEG 400.This mixture sonication 1-2 hour.Sonication causes that temperature raises paramount about 40 to 50 ℃.This solution is classified preparation #99 as in table 1.

Embodiment 24-intravitreal injection contains the solution of rapamycin

The injection of solution that 100 μ l embodiment 23 describe is advanced in the vitreous body of New Zealand white rabbit eye.Injected solution does not form nondispersive agglomerate with respect to surrounding medium.Figure 14 has described the rapamycin levels of 5,30,60, the 90 and 120 days interior logarithmic scales of vitreous body in injection back.Figure 15 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed two to five lagophthalmos.The vitreous body sample can comprise uses the site.The average level of 5,30,60,90 and 120 days interior rapamycins of vitreous body is respectively about 151,000 behind the intravitreal injection; 14,890; 4,743 and 1620ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.Retina choroid sample does not comprise uses the site; Therefore, this measurement points out to send into retinochoroid rapamycin levels.Behind the intravitreal injection in 5,30,60,90 and 120 days retina choroid the average level of rapamycin be respectively about 1.21,1.84,0.04,0.71 and 0.0ng/mg.

Embodiment 25 preparations and sign contain the solution of rapamycin.

By the 102.4mg rapamycin is placed ethanol, add 4719.3mg PEG 400 and vortex, form the solution that contains rapamycin.The solution that produces has the final concentration of 2.036% rapamycin, 4.154% ethanol and 93.81%PEG 400 by weight.This solution is classified preparation #139 as in table 1.

Embodiment 26 subconjunctival injections contain the solution of rapamycin

The solution that 10 μ l embodiment 25 are described is injected between New Zealand white rabbit eye sclera and the conjunctiva as single dose.Figure 16 has described to be present in 5 and 14 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 17 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.In order to compare, Figure 16 and Figure 17 have also described the hereinafter result of other research described in the embodiment 27-29.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.The vitreous body sample does not comprise uses the site, and therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5 and 14 days vitreous body the average level of rapamycin be respectively about 2.45 and 20.13ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5 and 14 days retina choroid the average level of rapamycin be respectively about 0.13 and 0.19ng/mg.

Embodiment 27-subconjunctival injection contains the solution of rapamycin

The solution that 60 μ l embodiment 25 are described is injected between New Zealand white rabbit eye sclera and the conjunctiva as single dose.Figure 16 has described to be present in 5 and 14 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 17 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.The vitreous body sample does not comprise uses the site, and therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5 and 14 days vitreous body the average level of rapamycin be respectively about 17.98 and 87.03ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5 and 14 days retina choroid the average level of rapamycin be respectively about 0.27 and 0.21ng/mg.

Embodiment 28-subconjunctival injection contains the solution of rapamycin

The solution that 60 μ l embodiment 25 are described is injected into two sites between New Zealand white rabbit eye sclera and the conjunctiva as two 30 μ l dosage.Figure 16 has described to be present in 5 and 14 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 17 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.The vitreous body sample does not comprise uses the site, and therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5 and 14 days vitreous body the average level of rapamycin be respectively about 502.2 and 31.80ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5 and 14 days retina choroid the average level of rapamycin be respectively about 0.80 and 0.15ng/mg.

Embodiment 29-subconjunctival injection contains the solution of rapamycin

The solution that 90 μ l embodiment 25 are described is injected into three sites between New Zealand white rabbit eye sclera and the conjunctiva as three 30 μ l dosage.Figure 16 has described to be present in 5 and 14 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 17 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.The vitreous body sample does not comprise uses the site, and therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5 and 14 days vitreous body the average level of rapamycin be respectively about 39.05 and 13.63ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5 and 14 days retina choroid the average level of rapamycin be respectively about 0.83 and 0.10ng/mg.

Embodiment 30-preparation and sign contain the suspension of rapamycin

By 1201.6mg rapamycin (by weight 3.000%) being placed 6518.8mg PEG400 (by weight 97.000%) and vortex preparation contain the suspension of rapamycin.The granular size that obtains is not quantitative, but very big, estimates to have an appointment 10 μ m.This suspension is classified preparation #147 as in table 1.

Embodiment 31-subconjunctival injection contains the suspension of rapamycin

The suspension that 10 μ l embodiment 30 are described is injected between New Zealand white rabbit eye sclera and the conjunctiva as single dose.Figure 18 has described to be present in 5,14 and 30 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 19 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.For relatively, Figure 18 and Figure 19 have also described the hereinafter result of other research described in the embodiment 32 and embodiment 33.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed the eye of four rabbit.The vitreous body sample does not comprise uses the site, and therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5,14 and 30 days vitreous body the average level of rapamycin be respectively about 2.68,0.90 and 5.43ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.Retina choroid sample does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5,14 and 30 days retina choroid the average level of rapamycin be respectively about 0.20,0.06 and 1.23ng/mg.

Embodiment 32-subconjunctival injection contains the suspension of rapamycin

The solution that 30 μ l embodiment 30 are described is injected between New Zealand white rabbit eye sclera and the conjunctiva as single dose.Figure 18 has described to be present in 5,14 and 30 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 19 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed the eye of four rabbit.The vitreous body sample does not comprise uses the site, and therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5,14 and 30 days vitreous body the average level of rapamycin be respectively about 84.55,11.23 and 66.35ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.Retina choroid sample does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5,14 and 30 days retina choroid the average level of rapamycin be respectively about 1.09,0.19 and 1.02ng/mg.

Embodiment 33-subconjunctival injection contains the suspension of rapamycin

The solution that 90 μ l embodiment 30 are described is injected into three sites between New Zealand white rabbit eye sclera and the conjunctiva as three times 30 μ l dosage.Figure 18 has described to be present in 5,14 and 30 days after the injection rapamycin levels of logarithmic scale in the vitreous body.Figure 19 has described the rapamycin levels of logarithmic scale in the identical time point retina choroid.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed the eye of four rabbit.The vitreous body sample does not comprise uses the site, and therefore, this measurement points out to send into Vitrea rapamycin levels.After the subconjunctival injection in 5,14 and 30 days vitreous body the average level of rapamycin be respectively about 29.95,15.30 and 49.20ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.Retina choroid sample does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.After the subconjunctival injection in 5,14 and 30 days retina choroid the average level of rapamycin be respectively about 0.55,1.31 and 5.74ng/mg.

Embodiment 34 preparations and sign contain the solution of rapamycin.

The 10.3mg rapamycin is placed ethanol, add 4995.8mg PEG 400, and the mixture vortex is obtained having the solution of 0.205% rapamycin, 0.544% ethanol and 99.251%PEG400 final concentration by weight.This solution is classified preparation #140 as in table 1.This solution of 10 μ l volumes forms nondispersive agglomerate when placing in the lagophthalmos vitreous body.

Embodiment 35-intravitreal injection contains the solution of rapamycin

The injection of solution that 10 μ l embodiment 34 describe is advanced in the vitreous body of New Zealand white rabbit eye.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Figure 20 has described the rapamycin levels of logarithmic scale in the 5 and 30 days retina choroid in injection back.Figure 21 has described the rapamycin levels of logarithmic scale in the identical time point vitreous body.For relatively, Figure 20 and Figure 21 have also described the hereinafter result of other research described in the embodiment 37 and embodiment 39.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed five lagophthalmos.The vitreous body sample can comprise uses the site.Behind the intravitreal injection in 5 and 30 days vitreous body the average level of rapamycin be respectively about 12.02 and 0.92ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.Behind the intravitreal injection in 5 and 30 days retina choroid the average level of rapamycin be respectively about 0.08 and 0.02ng/mg.

Embodiment 36 preparations and sign contain the solution of rapamycin

The 31.5mg rapamycin is placed ethanol, add 4918.9mg PEG 400, and with the solution vortex.Final concentration by weight is 0.6238% rapamycin, 1.337% ethanol and 98.035%PEG 400.Said preparation is standby 4 ℃ of preservations.This solution is classified preparation #142 as in table 1.This solution of 10 μ l volumes forms nondispersive agglomerate when placing in the lagophthalmos vitreous body.

Embodiment 37-intravitreal injection contains the solution of rapamycin

The injection of solution that 10 μ l embodiment 36 describe is advanced in the vitreous body of New Zealand white rabbit eye.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Figure 20 has described the rapamycin levels of logarithmic scale in the 5 and 30 days retina choroid in injection back.Figure 21 has described the rapamycin levels of logarithmic scale in the identical time point vitreous body.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed five lagophthalmos.The vitreous body sample can comprise uses the site.Behind the intravitreal injection in 5 and 30 days vitreous body the average level of rapamycin be respectively about 87.46 and 44.34ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.Behind the intravitreal injection in 5 and 30 days retina choroid the average level of rapamycin be respectively about 1.40 and 0.01ng/mg.

Embodiment 38 preparations and sign contain the solution of rapamycin

The 103.5mg rapamycin is placed ethanol, add 4720.8mg PEG 400, and the mixture vortex is obtained having the solution of 2.057% rapamycin, 4.116% ethanol and 93.827%PEG 400 final concentrations by weight.This solution is classified preparation #144 as in table 1.This solution of 10 μ l volumes forms nondispersive agglomerate in the lagophthalmos vitreous body.

Embodiment 39-intravitreal injection contains the solution of rapamycin

The injection of solution that 10 μ l embodiment 38 describe is advanced in the vitreous body of New Zealand white rabbit eye.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Figure 20 has described the rapamycin levels of logarithmic scale in 5, the 30 and 90 days retina choroid in injection back.Figure 21 has described the rapamycin levels of logarithmic scale in the identical time point vitreous body.

With vitreous body homogenate and analysis as described in example 2 above.Each time point is analyzed four lagophthalmos.The vitreous body sample can comprise uses the site.The average level of 5,30 and 90 days interior rapamycins of vitreous body is respectively about 120,500 behind the intravitreal injection; 55,160 and 0.55ng/ml.

With the homogenate and analyze as described in example 2 above of retina choroid, be used for Vitrea mode and take a sample as above-mentioned, be that described five lagophthalmos were 5 days and time point analysis in 30 days.Retina choroid sample does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.Behind the intravitreal injection in 5,30 and 90 days retina choroid the average level of rapamycin be respectively about 4.75,0.17 and 0.01ng/mg.

Embodiment 40-subconjunctival injection contains the solution of rapamycin

The injection of solution that 40 μ l embodiment 17 describe is advanced between New Zealand white rabbit eye sclera and the conjunctiva.Figure 22 has described the level of 4,14,21 and 35 days corneas (ng/mg) in the rapamycin levels (ng/ml) of logarithmic scale in 1,4,7,11,14,21,28,35, the 54 and 56 day aqueous humor in injection back and injection back and the middle rapamycin of retina choroid (ng/mg).Retina choroid level is labeled as " R/ choroid " in Figure 22.

With aqueous humor homogenate then by liquid chromatography (LC) and analytical reagent composition.Each time point is analyzed four lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the into rapamycin levels of aqueous humor.The rapamycin average level is respectively about 0.875,1.0,7.0,0.725,0.5,0.525,0.0,0.125,0.014 and 0.0485ng/ml in 1,4,7,11,14,21,28,35, the 54 and 56 day aqueous humor in injection back.

With cornea homogenate then by liquid chromatography (LC) and analytical reagent composition.Cornea does not comprise injection site, so this measurement points out to send the into rapamycin levels of cornea.Each time point is analyzed four lagophthalmos.The rapamycin average level is respectively about 0.3225,0.1,0.0275 and 0.0125ng/mg in 4,14, the 21 and 35 days corneas in injection back.

With the homogenate of retina choroid and as analysis as described in the embodiment 2, be used for Vitrea mode and take a sample as above-mentioned.The retina choroid does not comprise uses the site, and therefore, this measurement points out to send into retinochoroid rapamycin levels.The average level of rapamycin is respectively about 11.61,0.2,0.0275 and 2.655ng/mg in 4,14, the 21 and 35 days retina choroid in injection back.

Embodiment 41-intravitreal injection contains the solution of rapamycin

The injection of solution that 1.0 μ l embodiment 17 describe is advanced in the New Zealand white rabbit vitreum.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Table 2 has been reported the average level of injecting rapamycin in the aqueous humor one day after.In order to compare, table 2 has also been reported the hereinafter result of the research of embodiment 42-45 description.

With aqueous humor homogenate and analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the into rapamycin levels of aqueous humor.Inject one day after that the rapamycin average level is about 0.438ng/ml in the aqueous humor, standard deviation is about 0.141ng/ml.

Embodiment 42-intravitreal injection contains the solution of rapamycin

The injection of solution that 3.0 μ l embodiment 17 describe is advanced in the New Zealand white rabbit vitreum.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Table 2 has been reported the average level of injecting rapamycin in the aqueous humor one day after.

With aqueous humor homogenate and analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the into rapamycin levels of aqueous humor.Inject one day after that the rapamycin average level is about 0.355ng/ml in the aqueous humor, standard deviation is about 0.234mg/ml.

Embodiment 43-subconjunctival injection contains the solution of rapamycin

The injection of solution that 3.0 μ l embodiment 17 describe is advanced between New Zealand white rabbit eye sclera and the conjunctiva.Injected solution forms nondispersive agglomerate with respect to surrounding medium.Table 2 has been reported the average level of injecting rapamycin in the aqueous humor one day after.

With aqueous humor homogenate and analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the into rapamycin levels of aqueous humor.Inject one day after that the rapamycin average level is about 0.338ng/ml in the aqueous humor, standard deviation is about 0.122ng/ml.

Embodiment 44-anterior chamber uses the solution that contains rapamycin

The solution that 5.0 μ l embodiment 17 are described is injected in the New Zealand white rabbit camera oculi anterior by the front end that is expelled to eye.Use syringe to extract aqueous humor.Table 2 has been reported the average level of injecting rapamycin in back 14 days aqueous humors.

With aqueous humor homogenate and analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the into rapamycin levels of aqueous humor.Inject that the rapamycin average level is about 0.166ng/ml in back 14 days aqueous humors, standard deviation is about 0.183ng/ml.

Embodiment 45-anterior chamber uses the solution that contains rapamycin

The injection of solution that 10 μ l embodiment 17 describe is advanced in the New Zealand white rabbit camera oculi anterior.Table 2 has been reported the average level of injecting rapamycin in back 14 days aqueous humors.

With aqueous humor homogenate and analysis as described in example 40 above.Analyze two lagophthalmos.Aqueous humor does not comprise injection site, so this measurement points out to send the into rapamycin levels of aqueous humor.Inject that the rapamycin average level is about 0.004ng/ml in back 14 days aqueous humors, standard deviation is about 0.006ng/ml.

The list of references that all this paper quote (comprising patent, patent application and publication) is quoted as a reference with its integral body at this paper, no matter before specific reference whether.

Table 1 liquid preparation

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					1	DMSO=2000mg (20%) water=8000mg (80%)	S
2	F68=1000mg (10%) water=9000mg (90%)	S
					3	F68=3000mg (30%) water=7000mg (70%)	S
4	F127=1000mg (10%) water=9000mg (90%)	S
					5	F127=1500mg (15%) water=8500mg (85%)	S
6	Beta-schardinger dextrin-=250mg (2.5%) water=9750mg (97.5%)	S
					7	Rapamycin=10.2mg (0.101%) Pluronic, F68=1010mg (9.99%) water=9090mg (89.909%)	S		Not, 50 μ L

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					8	Rapamycin=10.2mg (0.102%) Pluronic, F68=3000mg (29.969%) water=7000mg (69.929%)	S		Not, 50 μ L
9	Rapamycin=10.5mg (0.104%) Pluronic, F127=1010mg (9.99%) water=9090mg (89.907%)	S		Not, 50 μ L
					10	Rapamycin=10.5mg (0.105%) Pluronic, F127=1500mg (14.984%) water=8925mg (84.9%)	S		Not, 50 μ L
11	Rapamycin=10.7mg (0.105%) beta-schardinger dextrin-=255mg (2.497%) water=9945mg (97.398%)	S		Not, 50 μ L
					12	Rapamycin=6.4mg (0.0999%) CMC=48mg (0.7493%) Polysorbitan 20=2.56mg (0.04%) water=6349.44mg (99.111%)	SP
13	Rapamycin=6.5mg (0.0999%) DMSO=325mg (4.995%) water=6175mg (94.905%)	S
					14	Rapamycin=13.5mg (0.0999%) CMC=101.25mg (0.7493%) Polysorbitan 20=5.4mg (0.04%) water=13393.35mg (99.112%)	SP
15	Rapamycin=11.0mg (0.2%) EtOH=5500mg (99.8%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					16	Rapamycin=6.6mg (0.1%) EtOH=1054.6mg (1 5.933%) F127=833.64mg (12.595%) water=4723.96mg (71.372%)	S
17	Rapamycin=5mg (0.1%) Cavitron=0.25g (5%) 95% ethanol=57mg (1.1%) sterilized water=4.753g (93.8%)	S
					18	Rapamycin=5mg (0.1%) 95% ethanol=150mg (2.9%) PEG400=1.0g (19.4%) sterilized water=4.01g (77.6%)	S
19	Rapamycin=5mg (0.1%) 95% ethanol=152mg (3.2%) PEG400=1.5227g (30.2%) sterilized water=3.3592g (66.67%)	S		Be 50 μ L
					20	Rapamycin=6.6mg (0.1%) EtOH=505.1mg (7.618%) F127=917.8mg (13.843%) water=5200.6mg (78.44%)	S
21	Rapamycin=6.6mg (0.1%) EtOH=536mg (7.5%) Pluronic, F127=983.75mg (14.0%) water=5574.56mg (78.4%)	S		Not, 50 μ L

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					22	Rapamycin=5.2mg (0.1023%) EtOH=56.6mg (1.1 27%) Captisol=2008.9mg (39.5%) water=3013.3mg (59.3%)	S
23	Rapamycin=6.9mg (0.201%) EtOH=3418.0mg (99.799%)	S
					24	Rapamycin=9.1mg (0.491%) EtOH=90.9mg (4.908%) F127=262.8mg (14.191%) water=1489.1mg (80.409%)	S
25	Rapamycin=0mg (0%) EtOH=310.2mg (5.144%) F127=858.1mg (14.228%) water=4862.6mg (80.628%)	S
					26	Rapamycin=0mg (0%) EtOH=613.1mg (10.19%) F127=810.6mg (13.471%) water=4593.6mg (76.339%)	S
27	Rapamycin=53.5mg (1.095%) EtOH=414.8mg (8.488%) F127=662.8mg (13.563%) water=3755.7mg (76.854%)	S		Be 50 μ L
					28	Rapamycin=0.3g (10%) PVP K90=0.35g (12%) Eudragit RS30D=2.35g (78%)	ISG， SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					29	Rapamycin=0.2154g (7.31%) PVP K90=0.25g (8.5%) Eudragit RS30D=2.48g (84.19%)	ISG， SP
30	Rapamycin=53.9mg (1.103%) EtOH=413.6mg (8.463%) sterilized water=3843.5mg (78.647%) F127 (Lutrol)=576.0mg (11.786%)	S		Not, 50 μ L
					31	Rapamycin=0mg (0%) EtOH=411.9mg (8.513%) sterilized water=3849.3mg (79.554%) F127 (Lutrol)=577.4mg (11.933%)	S
32	Rapamycin=54.1mg (1.256%) EtOH=416.8mg (9.676%) sterilized water=3836.3mg (78.569%) F127 (Lutrol)=577.5mg (10.499%)	S
					33	Rapamycin=80.7g (1.964%) EtOH=65.0mg (0.158%) PEG400=4021.8mg (97.878%)	S
34	Rapamycin=106.9g (5.233%) EtOH=129.6mg (6.344%) PEG400=1806.5mg (88.424%)	S		Be 25 μ L
					35	Rapamycin=0mg (0%) PVP K90=0.204g (2.3%) 100% ethanol=0.4g (4.5%) Eudragit RL100=0.201g (2.3%) PEG 400=8.00g (90.9%)	ISG， SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					36	Rapamycin=0mg (0%) PVP K90=0.2g (2.2%) 100% ethanol=0.4g (4.4%) PVAP=0.4g (4.4%) PEG 400=8.00g (88.9%)	ISG， SP
37	Rapamycin=106.1mg (4.2%) PVP K90=55.2mg (2.2%) 100% ethanol=108mg (4.3%) Eudragit RL100=55mg (2.2%) PEG 400=2.2g (87.1%)	ISG， SP
					38	Rapamycin=399.6mg (9.965%) F68 (Lutrol)=40.6mg (1.012%) sterilized water=3569.7mg (89.022%)	S		Be 20 μ L
39	Rapamycin=53.8mg (1.1%) EtOH=415.2mg (8.489%) sterilized water=3844.2mg (78.594%) F127=578.0mg (11.817%)	S
					40	Rapamycin=208.1mg (3.148%) PEG400=6403.4mg (96.852%)	S		Be 20 μ L
41	Rapamycin=200.4mg (5.148%) F68 (Lutrol)=20.8mg (0.534%) PEG400=3569.3mg (91.697%) EtOH (95%)=102mg (2.62%)	SP
					42	Rapamycin=200.4g (5.259%) PEG400=3561.4mg (93.46%) Tween 80=48.8mg (1.281%)	SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					43	Rapamycin=30.9mg (1.03%) PEG 400=2.9624g (98.97%)	S		Not, 50 μ L
44	Rapamycin=61mg (1.96%) 100% ethanol=0.1860g (6%) PEG 400=2.8588g (92.04%)	S		Be 50 μ L
					45	Rapamycin=90.7mg (3.02%) 100% ethanol=0.2722g (9.06%) PEG 400=2.6423g (87.94%)	S		Be 50 μ L
46	Rapamycin=101.6mg (4.997%) EtOH=331.6mg (16.308%) PEG400=1600.1mg (78.695%)	S
					47	Rapamycin=120.9g (3.189%) F68 (Lutrol)=42.4mg (1.118%) sterilized water=3627.7mg (95.692%)	SP
48	Rapamycin=100.1g (1.999%) EtOH=305.1mg (6.092%) PEG400=4602.9mg (91.909%)	S
					49	Rapamycin=150.5mg (3.004%) PEG400=4860.3mg (96.996%)	SP		Be 20 μ L, 40 μ L
50	Rapamycin=153.4mg (3.055%) F68 (Pluronic)=50.6mg (1.008%) sterilized water=4816.6mg (95.937%)	SP		Not, 20 μ L
					51	Rapamycin=116.6mg (2.29%) EtOH=306.6mg (6.05%) PEG400=4647.5mg (91.66%)	S		Be 30 μ L

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					52	Rapamycin=150.4mg (2.994%) F68 Lutrol=15.4mg (0.306%) sterilized water=4859.1mg (96.7%)	SP
53	Rapamycin=306.5mg (6.088%) PEG 400=4727.7mg (93.912%)	SP
					54	Rapamycin=309.3mg (6.146%) PEG 400=4723.3mg (93.854%)	SP
55	Rapamycin=303.3mg (6.061%) PEG 400=4700.6mg (93.939%)	SP
					56	Rapamycin=305.4mg (6.088%) PEG 400=4711.0mg (93.912%)	SP
57	Rapamycin=306.9mg (6.098%) PEG 400=4725.5mg (93.902%)	SP
					58	Rapamycin=302.5mg (6.021%) PEG 400=4721.6mg (93.979%)	SP
59	Rapamycin=304.5mg (6.053%) PEG 400=4726.4mg (93.947%)	SP
					60	Dexamethasone=251.4mg (5.011%) PEG 400=4765.2mg (94.989%)	SP
61	Dexamethasone=252.4mg (5%) PEG 400=4600mg (92%) EtOH=150mg (3%)	SP
					62	Rapa＝32.2mg(0.641％) PEG 400＝4677.9mg(93.096％) EtOH＝314.7mg(6.263％)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					63	Rapa＝32.3mg(0.6％) PEG 400＝5516.3mg(93.1％) EtOH＝314.7mg(6.263％)	S
64	Rapa＝54.4mg(1.007％) PEG 400＝4638.9mg(92.702％) EtOH＝314.8mg(6.291％)	S
					65	Rapa＝50.8mg(1.013％) PEG 400＝4963.2mg(98.987％)	S
66	Rapa＝52.1mg(1.035％) PEG 400＝4868.6mg(96.718％) EtOH＝113.1mg(2.247％)	S
					67	Rapa＝50.5mg(1.009％) PEG 400＝4752.8mg(94.953％) EtOH＝202.1mg(4.038％)	S		Be that 20 μ L deny 40 μ L, 100 μ L
68	Rapa＝101.8mg(2.030％) PEG 400＝4712.4mg(93.970％) EtOH＝200.6mg(4.000％)	S
					69	Rapa＝102.1mg(2.036％) PEG 400＝4605.5mg(91.847％) EtOH＝306.7mg(6.117％)	S
70	Rapa＝101.6mg(2.025％) PEG 400＝4510.6mg(89.892％) EtOH＝405.6mg(8.083％)	S
					71	Rapa＝75.9mg(3.019％) PEG 400＝2438.4mg(96.981％)	SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					72	Rapa＝50.9mg(2.034％) PEG 400＝2350.1mg(93.914％) EtOH＝101.4mg(4.052％)	S
73	Rapa＝12.5mg(0.620％) PEG 400＝2004.8mg(99.380％)	SP
					74	Rapamycin=1.20949g (2.0152%) EtOH=2.401g (4.000%) PEG 400=56.407g (93.9848%)	S
75	Rapamycin=16.0mg g (0.795%) EtOH=80.0mg (3.976%) PEG 400=1916.0mg (95.2298%)	S		Not, 50 μ L
					76	Rapa＝8.1mg(0.400％) PEG 400＝2014.5mg(99.600％)	SP
77	Rapa＝8.6mg(0.428％) PEG 400＝2002.5mg(99.572％)	S
					78	Rapa＝8.2mg(0.410％) PEG 400＝1992.0mg(99.590％)	S
79	Rapa＝8.7mg(0.433％) PEG 400＝1998.8mg(99.567％)	S
					80	Rapa＝8.6mg(0.427％) PEG 400＝2003.2mg(99.573％)	S
81	Rapa＝8.6mg(0.428％) PEG 400＝1999.3mg(99.572％)	S
					82	Rapa＝9.0mg(0.448％) PEG 400＝2000.8mg(99.552％)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					83	Rapa＝8.0mg(0.397％) PEG 400＝2008.8mg(99.603％)	S
84	Rapa＝8.5mg(0.422％) PEG 400＝2006.8mg(99.578％)	S
					85	Rapa＝8.0mg(0.399％) PEG 400＝1998.2mg(99.601％)	S
86	Rapa＝8.5mg(0.422％) PEG 400＝2004.3mg(99.578％)	S
					87	Rapa＝8.6mg(0.428％) PEG 400＝2002.5mg(99.572％)	S
88	Rapamycin=0.7g (1.983%) EtOH=1.4g (3.966%) PEG 400=33.2g (94.051%)	S
					89	Rapamycin=0g (0%) EtOH=0.574g (1.995%) PEG 400=28.2g (98.005%)	S
90	Rapamycin=1.95g (1.950%) EtOH=4.05g (4.050%) PEG 400=94.00g (94000.%)	S
					91	Rapamycin=0.0107g (0.534%) EtOH=0.0805g (4.0 19%) PEG 400=1.912g (95.447%)	S		Not, 80 μ L
92	Rapamycin=0.0081g (0.403%) EtOH=0.0804g (4.003%) PEG 400=1.920g (95.594%)	S		Not, 100 μ L

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					93	Rapamycin=1.992g (2%) EtOH=3.9419 (4%) PEG 400=93.95g (94%)	S
94	Rapamycin=0.405g (0.4%) EtOH=4.24g (4%) PEG 400=95.6 (95.6%)	S
					95	PEG 400＝96g(96％) EtOH＝3.9027(4％)	S
96	Rapamycin=0.4020g (0.402%) EtOH=3.970g (3.971%) PEG 400=95.600g (95.627%)	S
					97	Rapamycin=2.000g (1.990%) EtOH=4.000g (3.980%) PEG 400=94.500g (94.030%)	S
98	PEG 400＝96g(96％) EtOH＝3.92g(4％)	S
					99	Rapamycin=0.4036g (0.4%) EtOH=3.9054g (4%) PEG 400=95.6 (95.6%)	S		Not, 100 μ L
100	Rapamycin=2.0025g (2%) EtOH=3.98g (4%) PEG 400=94.00g (94%)	S		Be 1 μ L, 3 μ L, 20 μ L, 40 μ L
					101	Rapamycin=9.5mg (0.472%) EtOH=90.3mg (4.485%) PEG 600=1913.5mg (95.043%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					102	Rapamycin=44.6mg (2.21%) EtOH=86.1.0mg (4.26%) PEG 600=1891.1mg (93.53%)	S
103	Rapamycin=1.97g (2%) EtOH=4.10g (4%) PEG 400=94.15g (94%)	S
					104	Rapamycin=1.95g (2%) EtOH=4.00g (4%) PEG 400=94.0g (94%)	S
105	Rapamycin=8.00g (2%) PEG 400=376.0g EtOH=16.0g (4%)	S
					106	Rapamycin=6.00g (2%) PEG 400=282.0g (94%) EtOH=12.0g (4%)	S
107	Rapamycin=8.9mg (0.4434%) EtOH=80.3mg (4.0006%) PEG 300=1918.0mg (95.556%)	S
					108	Rapamycin=40.8mg (2.00886%) EtOH=110.0mg (5.41605%) PEG 300=1880.2mg (92.57509%)	S
109	Rapamycin=9.9mg (0.488%) EtOH=86.7mg (4.277%) PEG 400/300 (50/50)=1930.3mg (95.235%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					110	Dexamethasone=142.5mg (4.994%) PEG 400=2710.7mg (95.006%)	SP	0.3305 μm	Be 30 μ L
111	Dexamethasone=134.3mg (4.891%) PEG 400=2611.4mg (95.109%)	SP	>10μm
					112	Omcilon=139.2mg (5.087%) PEG 400=2597.4mg (94.9 13%)	SP	3.98 μm	Be 30 μ L
113	Omcilon=135.3mg (5.089%) PEG 400=2523.5mg (94.911%)	SP	>10μm
					114	EtOH＝206.4mg(4.121％) PEG 400＝4801.6mg(95.879％)	S		Not, 30 μ L
115	Rapamycin=43.0mg (2.144%) PEG 400=1962.3mg (97.8567%)	SP	61.4390 μm
					116	Rapamycin=40.0mg (2.001%) PEG 400=1959.1mg (97.999%)	SP	3.7128 μm
117	Rapamycin=42.9mg (2.142%) PEG 400=1959.7mg (97.858%)	SP	2.7313 μm
					118	Rapamycin=100.8mg (2.013%) PEG 400=4906.0mg (97.987%)	SP	4.1063 μm
119	Rapamycin=20.9mg (0.42%) EtOH=209.1mg (4.17%) PEG 400=4784.9mg (95.41%)	S
					120	Rapamycin=20.6mg (0.41%) EtOH=211.5mg (4.22%) Benz.Chl=19.1mg (0.38%) PEG 400=4762.0mg (94.99%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					121	Rapamycin=20.1mg (0.40%) EtOH=211.5mg (4.22%) Benz.Chl=2.3mg (0.05%) PEG 400=4782.3mg (95.34%)	S
122	Rapamycin=8.0g (2%) EtOH=16.0g (4%) PEG 400=376.0g (94%)	S
					123	Rapamycin=351.3mg (2.006%) EtOH=2353.1mg (4.093%) PEG 400=16448.2mg (93.901%)	S
124	Rapamycin=2.2035g (2%) EtOH=4.45g (4%) PEG 400=103.7g (94% (	S
					125	Rapamycin=515.5mg (2.021%) PEG 400=24,993.8mg (97.979%)	SP	18.1453 μm
126	Rapamycin=0.3g (2%) EtOH=0.6g (4%) PEG 400=14.1g (94%) BHT=0.0002 (0.002%)	S
					127	Rapamycin=0.3g (2%) EtOH=0.6g (4%) PEG 400=14.1g (94%) BHT=0.00037 (0.004%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					128	Rapamycin=0.3g (2%) EtOH=0.6g (4%) PEG 400=14.1g (94%) BHT=0.0081 (0.05%)	S
129	Rapamycin=243.2mg (1.869%) EtOH=4.88.4mg (3.753%) PEG 400=12283.3mg (94.378%)	S
					130	Rapamycin=0.404g (2%) EtOH=0.8g (4%) PEG 400=18.8g (94%) BHT=0.00051 (0.002%)	S
131	Rapamycin=0.6024g (2%) EtOH=1.2g (4%) PEG 400=28.25g (94%)	S
					132	Rapamycin=2.001g (2%) EtOH=4.05g (4%) PEG 400=94.45g (94%)	S
133	Rapamycin=0.5155g (2.057%) EtOH=1.0198g (4.070%) PEG 400=23.5225g (93.873%)	S
					134	PEG 400＝9.6g(96％) EtOH＝0.4g(4％)	S
135	Rapamycin=0.610g (2%) EtOH=1.2g (4%) PEG 400=28.2g (94%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					136	Rapamycin=24.6mg (1.193%) EtOH=91.1mg (4.418%) tyloxapol=219.6mg (10.649%) BSS=1726.8mg (83.740%)	S
137	Rapamycin=100.0mg (1.993%) PEG 400=4916.9mg (98.007%)	SP
					138	Rapamycin=201.6mg (4.005%) PEG 400=4831.5mg (95.995%)	SP
139	Rapamycin=102.4mg (2.036%) EtOH=209.0mg (4.154%) PEG 400=4719.3mg (93.810%)	S
					140	Rapamycin=10.3mg (0.205%) EtOH=27.4mg (0.544%) PEG 400=4995.8mg (99.251%)	S		Be 10 μ L
141	Rapamycin=10.6mg (0.211%) EtOH=208.4mg (4.150%) PEG 400=4802.3mg (95.639%)	S		Not, 10 μ L
					142	Rapamycin=31.5mg (0.628%) EtOH=67.1mg (1.337%) PEG 400=4918.9mg (98.035%)	S		Be 10 μ L
143	Rapamycin=30.8mg (0.613%) EtOH=204.5mg (4.073%) PEG 400=4786.1mg (95.314%)	S		Not, 10 μ L, 100 μ L
					144	Rapamycin=103.5mg (2.057%) EtOH=207.1mg (4.116%) PEG 400=4720.8mg (93.827%)	S		Be 10 μ L

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					145	Rapamycin=283.0 g (2.020%) EtOH=566.1mg (4.041%) PEG 400=13,160.8mg (93.939%)	S
146	Rapamycin=280.1mg (1.998%) EtOH=565.2mg (4.033%) PEG 400=13,171.7mg (93.969%)	S
					147	Rapamycin=201.6mg (3.000%) PEG 400=6518.8mg (97.000%)	SP
148	Rapamycin=31.9mg (1.019%) benzyl alcohol=1021.9mg (20.070%) Oleum sesami=4017.9mg (78.911%)	S
					149	Rapamycin=51.5mg (1.03%) benzyl alcohol=259.9mg (5.19%) Oleum sesami=4694.3mg (93.78%)	S
150	Rapamycin=5.96g (2%) EtOH=12.0g (4%) PEG 400=282.0g (94%)	S
					151	Rapamycin=54.5mg (1.07%) benzyl alcohol=1014.3mg (19.95%) olive oil=4014.8mg (78.98%)	S
152	Rapa=0mg (0.00%) benzyl alcohol=269.4mg (5.421%) tyloxapol=608.2mg (12.238%) Oleum sesami=4092.2mg (82.341%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					153	Rapamycin=76.3mg (1.75%) benzyl alcohol=307.0mg (7.06%) tyloxapol=607.8mg (13.97%) Oleum sesami=3000.5mg (68.97%) Span 80=63.1mg (1.45%) EtOH=295.5mg (6.79%)	S
154	Preparation #150=200g (99.998) BHT=0.004g (0.002%)	S
					155	Rapamycin=51.0mg (0.87%) EtOH=642.3mg (10.93%) benzyl alcohol=431.8mg (7.34%) Oleum sesami=4753.7mg (80.86%)	S
156	Rapamycin=51.4mg (1.03%) benzyl alcohol=518.4mg (10.34%) olive oil=4444.7mg (88.64%)	S
					157	Rapamycin=8.1g (2%) EtOH=16.0g (4%) PEG 400=376.0g (94%)	S
158	Preparation #157=225.00g (99.998%) BHT=0.0045g (0.002%)	S
					159	Rapamycin=8.1g (2%) EtOH=16.0g (4%) PEG 400=376g (94%)	S
160	Preparation #159=112.0g (99.998%) BHT=0.00224g (0.002%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					161	Preparation #159=112.0g (99.998%) BHT=0.0019g (0.002%)	S
162	Rapamycin=55.4mg (1.10%) EtOH=112.7mg (2.25%) benzyl alcohol=157.8mg (3.15%) Oleum Gossypii semen=4688.0mg (93.50%)	S
					163	Rapamycin=5.005g (1%) EtOH=10.0g (2%) PEG 400=485.5g (97%)	S
164	PEG 400＝9.82g(98％) EtOH＝0.235g(2％)	S
					165	Preparation #163=100.25g (99.998%) BHT=0.0026g (0.002%)	S
166	Rapamycin=203.1mg (2.025%) F68=30.3mg (0.303%) sterilized water=9792.6mg (97.672%)	SP	2.8651 μm
					167	Rapamycin=201.4mg (2.0005%) polysorbas20=43.9mg (0.436%) sterilized water=9822.8mg (97.564%)	SP	1.0984 μm
168	EtOH＝0.8301g(4.144％) PEG 400＝19.2014g(95.856％)	S
					169	Preparation #168=300 μ l	S
170	Preparation #168=250 μ l preparation #154=50 μ l	S
					171	Preparation #168=200 μ l preparation #154=100 μ l	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					172	Preparation #168=150 μ l preparation #154=150 μ l	S
173	Preparation #154=300 μ l	S
					174	Rapamycin=102.2mg (2.041%) F68=16.0mg (0.32%) sterilized water=4889.0mg (97.639%)	SP	0.4165 μm
175	Rapamycin=101.1mg (2.010%) polysorbas20=27.7mg (0.551%) sterilized water=4901.0mg (97.439%)	SP	0.5294 μm
					176	BSS+=0 μ l sterilized water=0 μ l preparation #154=1000 μ l	S
177	BSS+=200 μ l sterilized water=0 μ l preparation #154=800 μ l	SP
					178	BSS+=400 μ l preparation #154=600 μ l	SP
179	BSS+=500 μ l preparation #154=500 μ l	SP
					180	BSS+=600 μ l preparation #154=400 μ l	SP
181	BSS+=800 μ l preparation #154=200 μ l	SP
					182	Sterilized water=200 μ l preparation #154=800 μ l	SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					183	Sterilized water=400 μ l preparation #154=600 μ l	SP
184	Sterilized water=500 μ l preparation #154=500 μ l	SP
					185	Sterilized water=600 μ l preparation #154=400 μ l	SP
186	Sterilized water=800 μ l preparation #154=200 μ l	SP
					187	BSS+=2536.9mg (49.98%) preparation #154=2538.7mg (50.02%)	SP	60.2075 μm
188	Sterilized water=2515.6mg (49.84%) preparation #154=2532.2mg (50.16%)	SP	617.515 7μm
					189	F68=12.6mg (0.25%) sterilized water=2524.7mg (49.79%) preparation #154=2533.1mg (49.96%)	SP	70.6089 μm
190	Rapamycin=2.0225g (2%) EtOH=3.65g (4%) PEG 400=94.0g (94%) BHT=0.002g (0.002%)	S
					191	F68=12.1mg sterilized water=2558.9mg preparation #154=2556.4mg	SP
192	F68=19.8mg sterilized water=2564.1mg preparation #154=25557.5mg	SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					193	F68=25.3mg sterilized water=2575.1mg preparation #154=2572.9mg	SP
194	F68=32.4mg sterilized water=2572.1mg preparation #154=2562.1mg	SP
					195	F68=38.3mg sterilized water=2563.2mg preparation #154=2573.5mg	SP
196	F68=43.6mg sterilized water=2541.1mg preparation #154=2556.0mg	SP
					197	F68=51.2mg sterilized water=2594.5mg preparation #154=2594.1mg	SP
198	PEG 400＝1920g(96％) EtOH＝80g(4％)	S
					199	Preparation #168=1000 μ l	S
200	Preparation #168=200 μ l preparation #154=800 μ l	S
					201	Preparation #168=400 μ l preparation #154=600 μ l	S
202	Preparation #168=500 μ l preparation #154=500 μ l	S
					203	Preparation #168=600 μ l preparation #154=400 μ l	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					204	Preparation #168=800 μ l preparation #154=200 μ l	S
205	PEG 400=200 μ l preparation #154=800 μ l	S
					206	PEG 400=400 μ l preparation #154=600 μ l	S
207	PEG 400=500 μ l preparation #154=500 μ l	S
					208	PEG 400=600 μ l preparation #154=400 μ l	S
209	PEG 400=800 μ l preparation #154=200 μ l	S
					210	Phosal 50PG=6735.0mg (99.002%) Tween 80=67.9mg (0.998%)	S
211	Rapamycin=2.0047g (2%) EtOH=4.00g (4%) PEG 400=94.05g (94%)	S
					212	Phosal 50PG=20.0662g (98.999%) Tween 80=0.2029g (1.001%)	S
213	Preparation #154=100 μ l preparation #168=900 μ l	S
					214	Preparation #154=100 μ l preparation #168=900 μ l	S
215	Preparation #154=100 μ l preparation #168=900 μ l	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					216	Preparation #154=100 μ l PEG 400=900 μ l	S
217	Preparation #154=100 μ l PEG 400=900 μ l	S
					218	Preparation #154=100 μ l PEG 400=900 μ l	S
219	Preparation #154=100 μ l BSS+=900 μ l	SP
					220	Preparation #154=100 μ l BSS+=900 μ l	SP
221	Preparation #154=100 μ l BSS+=900 μ l	SP
					222	Preparation #154=1000 μ l	S
223	Preparation #154=1000 μ l	S
					224	Preparation #154=100 μ l preparation #168=900 μ l	S
225	Preparation #154=100 μ l preparation #168=900 μ l	S
					226	Preparation #154=100 μ l preparation #168=900 μ l	S
227	Preparation #154=100 μ l PEG 400=900 μ l	S
					228	Preparation #154=100 μ l PEG 400=900 μ l	S
229	Preparation #154=100 μ l PEG 400=900 μ l	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					230	Preparation #154=100 μ l BSS+=900 μ l	SP
231	Preparation #154=100 μ l BSS+=900 μ l	SP
					232	Preparation #154=100 μ l BSS+=900 μ l	SP
233	Preparation #154=200 μ l preparation #168=800 μ l	S
					234	Preparation #154=200 μ l preparation #168=800 μ l	S
235	Preparation #154=200 μ l preparation #168=800 μ l	S
					236	Preparation #154=200 μ l preparation #168=800 μ l	S
237	Preparation #154=200 μ l PEG 400=800 μ l	S
					238	Preparation #154=200 μ l PEG 400=800 μ l	S
239	Preparation #154=200 μ l BSS+=800 μ l	SP
					240	Preparation #154=200 μ l BSS+=800 μ l	SP
241	Preparation #154=200 μ l BSS+=800 μ l	SP
					242	Preparation #154=100 μ l preparation #168=900 μ l	S		Not, 10 μ L

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					243	Preparation #154=100 μ l PEG 400=900 μ l	S		Be 10 μ L
244	Preparation #154=100 μ l BSS+=900 μ l	SP		Be 10 μ l
					245	Preparation #154=100 μ l BSS+/CMC (0.5%)=900 μ l	SP
246	Preparation #154=400 μ l preparation #168=900 μ l	S		Not, 10 μ L
					247	Preparation #154=400 μ l PEG 400=900 μ l	S		Be 10 μ L
248	Preparation #154=400 μ l BSS+=900 μ l	SP		Be 10 μ L
					249	Preparation #154=400 μ l BSS+/CMC (0.5%)=900 μ l	SP
250	Preparation #154=100 μ l BSS+/CMC (0.5%)=900 μ l	SP
					251	Preparation #154=100 μ l BSS+/CMC (0.5%)=900 μ l	SP
252	Preparation #154=100 μ l BSS+/CMC (0.5%)=900 μ l	SP
					253	Preparation #154=200 μ l BSS+/CMC (0.5%)=800 μ l	SP
254	Preparation #154=200 μ l BSS+/CMC (0.5%)=800 μ l	SP
					255	Preparation #154=200 μ l BSS+/CMC (0.5%)=800 μ l	SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					256	Preparation #154=400 μ l BSS+/CMC (0.5%)=900 μ l	SP
257	Preparation #154=400 μ l BSS+/CMC (0.5%)=900 μ l	SP
					258	Preparation #154=400 μ l BSS+/CMC (0.5%)=900 μ l	SP
259	EtOH＝17.1mg(0.57％) PEG 400＝2997.3mg(99.43％)	S
					260	EtOH＝40.8mg(1.35％) PEG 400＝2980.2mg(98.65％)	S
261	EtOH＝47.1mg(1.57％) PEG 400＝2950.1mg(98.43％)	S
					262	Rapamycin=2.0032g (2%) EtOH=3.92g (4%) PEG 400=94.00g (94%)	S
263	Triamcinolone acetonide=80.8mg (4.04%) PEG 400=1920.8mg (95.96%)	SP
					264	Be filled in the NFF-0007 in the glove box	S
265	PEG 400＝9.598g(96％) EtOH＝0.4052(4％)	S
					266	Triamcinolone acetonide=42.2mg (4.123%) PEG 400=981.3mg (95.877%)	SP
267	Phosal 50PG=20.0783g (99.00835%) Tween 80=0.2011g (0.99165%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					277	The CMC=112.4mg (0.75%) of sterilized water=14934.0g (99.25%) medium viscosity	S
278	Propylene glycol=1893.7mg (93.85%) EtOH=83.8mg (4.16%) rapamycin=40.2mg (1.99%)	S		Be 10 μ L
					279	Propylene glycol=1946.2mg (95.68%) benzyl alcohol=47.1mg (2.31%) rapamycin=40.8mg (2.01%)	S		Be 10 μ L
280	PEG 300=1894.1mg (93.74%) EtOH=40.1mg (1.98%) rapamycin=86.4mg (4.28%)	S		Be 10 μ L
					281	PEG 300=1925.5mg (95.88%) EtOH=39.8mg (1.98%) rapamycin=43.0mg (2.14%)	S		Be 10 μ L, 30 μ L
282	Rapamycin=100.6mg (2.01%) MSF-03-176-02=4910.8mg (97.99%)	SP		Be 10 μ L, 30 μ L
					283	Rapamycin=11.5mg (0.57%) PEG 300=2012.5mg (99.43%)	S
284	Rapamycin=10.3mg (0.51%) PEG 400=2017.2mg (99.49%)	S
					285	Rapamycin=9.8mg (0.486%) PEG 600=2005.9mg (99.51%)	S
286	Tacrolimus=42.7mg (2.11%) EtOH=46.0mg (2.27%) PG=1938.7mg (95.62%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					287	Tacrolimus=40.7mg (2.01%) EtOH=43.0mg (2.12%) PEG 300=1942.1mg (95.87%)	S
288	Tacrolimus=40.3mg (1.99%) EtOH=43.8mg (2.16%) PEG 400=1942.3mg (95.85%)	S
					289	Tacrolimus=40.8mg (2.03%) EtOH=44.5mg (2.21%) PEG 600=1924.0mg (95.76%)	S
290	Rapamycin=61.0mg (3.17%) NMP=1226.54mg (63.80%) PLGA 75/25=634.96mg (33.03%)	S
					291	Rapamycin=100.2mg (5.13%) NMP=1492.95mg mg (76.37%) PLGA 75/25=361.65mg (18.50%)	S
292	Rapamycin=62.9mg (3.04%) NMP=1103.8g mg (53.40%) PLGA 75/25=900.2mg (43.56%)	S
					293	Rapamycin=62.4mg (3.00%) NMP=1205.1mg mg (58.11%) PLGA 75/25=806.4mg (38.89%)	S
294	Sterilized water+1%CMC Med.=4909.1mg (97.99%) rapamycin=100.5mg (2.01%)	SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					295	Sterilized water+1%CMC high.=4903.8mg (97.96%) rapamycin=101.9mg (2.04%)	SP
296	Rapamycin=40.5mg (2.03%) NMP=1958.7mg (97.97%)	S
					297	Rapamycin=20.5mg (2.0%) DMA=41.4mg (4.0%) PVP=35.0mg (3.4%) H2O=934.7mg (90.6%)	SP
298	Rapamycin=10.6mg (2.0%) DMA=10.6mg (2.0%) PEG 400=506.1mg (96%)	S
					299	1%DMA=257.4mg (98%) among rapamycin=5.2mg (2.0%) PEG 400	SP
300	Rapamycin=20.0mg (2.0%) DMA=7.8mg (0.8%) PEG 400=974mg (97.2%)	S
					301	Rapamycin=20.1mg (1.3%) DMA=19.5mg (1.3%) PEG 400=1449.6mg (97.3%)	S
302	Rapamycin=20.0mg (2.0%) PVP=10.8mg (1.1%) PEG 400=994.5mg (97.0%)	SP

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					303	Rapamycin=20.4mg (2.0%) PVP=24.5mg (2.4%) PEG 400=990.7mg (95.7%)	SP
304	Rapamycin=25.5mg (2.4%) PVP=51.9mg (4.8%) PEG 400=1000.6mg (92.8%)	SP
					305	Rapamycin=22.5mg (2.3%) BA=27.5mg (2.7%) PEG 400=950.7mg (95.0%)	S
306	Rapamycin=30.2mg (2.3%) PVP=240.9mg (18.6%) PEG 400=1021.2mg (79.0%)	SP
					307	Rapamycin=8.7mg (3.1%) 1%PVP in H2O=273mg (96.9%)	SP
308	Rapamycin=12.6mg (2.53%) 5%PVP in H2O=501.6mg (97.5%)	SP
					309	Rapamycin=20.3mg (3.8%) 10%PVP in H2O=513.9mg (96.2%)	SP
310	Rapamycin=100.5mg (2.0%) DMA=67.8mg (1.4%) PEG 400=4838.3mg (96.6%)	S		Be 10 μ L
					311	Rapamycin=96.8mg (1.9%) BA=157.5mg (3.2%) PEG 400=4748.7mg (94.9%)	S		Be 10 μ L

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					312	Rapamycin=105.8mg (2.1%) DMA=5.63mg (0.1%) PEG 400=4888.9mg (97.8%)	S
313	Rapamycin=20.2mg (2.0%) PVP=99.2mg (9.9%) H2O=882.3mg (88.1%)	SP
					314	Rapamycin=100.3mg (2.0%) PVP=251.4mg (5.0%) H2O=4662.8mg (93.0%)	SP
315	Rapamycin=20.3mg (2.0%) DMA=983.9mg (98%)	S
					316	Omcilon=22.8mg (2.0%) DMA=12.0mg (1.1%) PEG 400=1104.5mg (96.9%)	S		Be 10 μ L
317	Omcilon=1.0mg (0.1%) EtOH=49.30mg (4.0%) PEG 400=1191.9mg (96.0%)	S
					318	Omcilon=18.7mg (0.9%) PEG 400=959.8mg (99.1%)	S
319	Omcilon=25.5mg (1.3%) EtOH=83.0mg (4.1%) PEG 400=1905.6mg (94.6%)	S
					320	Dexamethasone=20.4mg (1.2%) EtOH=71.7mg (4.1%) PEG 400=1737.6mg (98.8%)	S

Preparation #	Component (mg), % (w/w)	Preparation type	The granular size intermediate value	The NDM preparation, volume injected
					321	Dexamethasone=27.5mg (2.0%) DMA=5.6mg (0.4%) PEG 400=1347.3mg (97.6%)	S		Be 10 μ L
322	Rapamycin=9.1mg (0.152%) EtOH=90.9mg (1.514%) F127=262.8mg (4.378%) water=1489.1mg (24.804%) Oleum sesami=4151.5mg (69.152%)	E
					323	Rapamycin=24.4mg (0.625%) Phosal 50PG=203.1mg (5.201%) EtOH=166.8mg (4.272%) Labrafac CC=1502.8mg (38.486%) Oleum sesami=2007.7mg (51.416%)	E
324	Preparation #174 and 2mm pearl	SP	0.4929 μm
					325	Preparation #175 and 2mm pearl	SP	0.4804 μm

Table 2 aqueous humor rapamycin concentrations

Inject 2% rapamycin-PEG-EtOH solution	Average rapamycin concentrations (ng/mL)	Standard deviation (ng/mL)
			1.0 in the μ L vitreous body	(0.438 injecting back 1 day)	0.141

3.0 in the μ L vitreous body	(0.355 injecting back 1 day)	0.234
			3.0 under the μ L conjunctiva	(0.338 injecting back 1 day)	0.122
5.0 in the μ L anterior chamber	(0.167 injecting back 14 days)	0.183
			10.0 in the μ L anterior chamber	(0.004 injecting back 14 days)	0.006

Claims (27)

1. the liquid preparation that contains therapeutic agent, send the therapeutic agent of q.s when wherein this liquid preparation is injected into the vitreous body of lagophthalmos, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of the retina tela chorioidea internal therapy agent of lagophthalmos is equal to the rapamycin concentrations of 0.01ng/mg at least.

2. the liquid preparation that contains therapeutic agent, send the therapeutic agent of q.s when wherein this liquid preparation is injected into the vitreous body of lagophthalmos, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of the vitreous body internal therapy agent of lagophthalmos is equal to the rapamycin concentrations of 1000ng/ml at least.

3. the liquid preparation that contains therapeutic agent, send the therapeutic agent of q.s when wherein this liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos vitreous body internal therapy agent is equal to the rapamycin concentrations of 0.01ng/ml at least.

4. the liquid preparation that contains therapeutic agent, send the therapeutic agent of q.s when wherein this liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.001ng/mg at least.

5. the liquid preparation that contains therapeutic agent forms nondispersive agglomerate when wherein this liquid preparation is injected in the lagophthalmos vitreous body.

6. the liquid preparation of claim 1, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilin, FK506 conjugated protein (FKBP), TAFA-93, RAD-001, temsirolimus, AP23573,7-table-rapamycin, 7-sulfidomethyl-rapamycin, 7-table-trimethoxyphenyl-rapamycin, 7-table-sulfidomethyl-rapamycin, 7-demethoxylation-rapamycin, 32-demethoxylation-rapamycin, 2-demethylation-rapamycin, the monoester derivates of rapamycin, the diester deriv of rapamycin, rapamycin 27-oxime; The 42-oxo analog of rapamycin; The bicyclo-rapamycin; The rapamycin dimer; Rapamycin monosilane ether; Rapamycin aromatic yl sulphonate, rapamycin sulfamate, 31 and 42 monoesters, 31 and 42 diester, 30-demethoxylation rapamycin and pharmaceutically acceptable prodrug, analog, salt and ester.

7. the liquid preparation of claim 6, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester.

8. the liquid preparation of claim 2, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilin, FK506 conjugated protein (FKBP), TAFA-93, RAD-001, temsirolimus, AP23573,7-table-rapamycin, 7-sulfidomethyl-rapamycin, 7-table-trimethoxyphenyl-rapamycin, 7-table-sulfidomethyl-rapamycin, 7-demethoxylation-rapamycin, 32-demethoxylation-rapamycin, 2-demethylation-rapamycin, the monoester derivates of rapamycin, the diester deriv of rapamycin, rapamycin 27-oxime; The 42-oxo analog of rapamycin; The bicyclo-rapamycin; The rapamycin dimer; Rapamycin monosilane ether; Rapamycin aromatic yl sulphonate, rapamycin sulfamate, 31 and 42 monoesters, 31 and 42 diester, 30-demethoxylation rapamycin and pharmaceutically acceptable prodrug, analog, salt and ester.

9. the liquid preparation of claim 8, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester.

10. the liquid preparation of claim 3, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilin, FK506 conjugated protein (FKBP), TAFA-93, RAD-001, temsirolimus, AP23573,7-table-rapamycin, 7-sulfidomethyl-rapamycin, 7-table-trimethoxyphenyl-rapamycin, 7-table-sulfidomethyl-rapamycin, 7-demethoxylation-rapamycin, 32-demethoxylation-rapamycin, 2-demethylation-rapamycin, the monoester derivates of rapamycin, the diester deriv of rapamycin, rapamycin 27-oxime; The 42-oxo analog of rapamycin; The bicyclo-rapamycin; The rapamycin dimer; Rapamycin monosilane ether; Rapamycin aromatic yl sulphonate, rapamycin sulfamate, 31 and 42 monoesters, 31 and 42 diester, 30-demethoxylation rapamycin and pharmaceutically acceptable prodrug, analog, salt and ester.

11. the liquid preparation of claim 10, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester.

12. the liquid preparation of claim 4, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilin, FK506 conjugated protein (FKBP), TAFA-93, RAD-001, temsirolimus, AP23573,7-table-rapamycin, 7-sulfidomethyl-rapamycin, 7-table-trimethoxyphenyl-rapamycin, 7-table-sulfidomethyl-rapamycin, 7-demethoxylation-rapamycin, 32-demethoxylation-rapamycin, 2-demethylation-rapamycin, the monoester derivates of rapamycin, the diester deriv of rapamycin, rapamycin 27-oxime; The 42-oxo analog of rapamycin; The bicyclo-rapamycin; The rapamycin dimer; Rapamycin monosilane ether; Rapamycin aromatic yl sulphonate, rapamycin sulfamate, 31 and 42 monoesters, 31 and 42 diester, 30-demethoxylation rapamycin and pharmaceutically acceptable prodrug, analog, salt and ester.

13. the liquid preparation of claim 12, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester.

14. the liquid preparation of claim 5, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578, cyclophilin, FK506 conjugated protein (FKBP), TAFA-93, RAD-001, temsirolimus, AP23573,7-table-rapamycin, 7-sulfidomethyl-rapamycin, 7-table-trimethoxyphenyl-rapamycin, 7-table-sulfidomethyl-rapamycin, 7-demethoxylation-rapamycin, 32-demethoxylation-rapamycin, 2-demethylation-rapamycin, the monoester derivates of rapamycin, the diester deriv of rapamycin, rapamycin 27-oxime; The 42-oxo analog of rapamycin; The bicyclo-rapamycin; The rapamycin dimer; Rapamycin monosilane ether; Rapamycin aromatic yl sulphonate, rapamycin sulfamate, 31 and 42 monoesters, 31 and 42 diester, 30-demethoxylation rapamycin and pharmaceutically acceptable prodrug, analog, salt and ester.

15. the liquid preparation of claim 14, wherein therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester.

16. the method for the degeneration of macula that the moist age is relevant among the treatment people experimenter, described method comprises by ophthalmic or sends claim 7,9,11 from certain volume to people experimenter, 13 and 15 each the liquid preparations of using near the eyes that described preparation contains the rapamycin of the amount of the degeneration of macula that the moist age is relevant among effective treatment people experimenter.

17. the method for the degeneration of macula that the moist age is relevant among the prevention people experimenter, described method comprises by ophthalmic or sends claim 7,9,11 from certain volume to people experimenter, 13 and 15 each the liquid preparations of using near the eyes that described preparation contains the rapamycin of the amount of the degeneration of macula that the moist age is relevant among effective prevention people experimenter.

18. the method for claim 16, wherein said liquid preparation also comprises Polyethylene Glycol, and wherein the volume of liquid preparation is administered to people experimenter by placing in the vitreous body, and the volume of liquid preparation contains the Polyethylene Glycol that is less than 100 μ L.

19. the method for claim 16, wherein said liquid preparation also comprises Polyethylene Glycol, and wherein the volume of liquid preparation is administered to people experimenter by placing between the CSC, and the volume of liquid preparation contains the Polyethylene Glycol that is less than 150 μ L.

20. the method for claim 17, wherein said liquid preparation also comprises Polyethylene Glycol, and wherein the volume of liquid preparation is administered to people experimenter by placing between the CSC, and the volume of liquid preparation contains the Polyethylene Glycol that is less than 150 μ L.

21. the method for the degeneration of macula that the moist age is relevant among the treatment people experimenter, described method comprises by ophthalmic or sends near the eyes people experimenter is used the liquid preparation that contains the effective dose therapeutic agent that described therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester; And wherein liquid preparation has one or more and is selected from following feature: the therapeutic agent of sending q.s when (1) liquid preparation is injected into the lagophthalmos vitreous body, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.01ng/mg at least; Send the therapeutic agent of q.s when (2) liquid preparation is injected into the lagophthalmos vitreous body, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos vitreous body internal therapy agent is equal to the rapamycin concentrations of 1000ng/ml at least; Send the therapeutic agent of q.s when (3) liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of the vitreous body internal therapy agent of lagophthalmos is equal to the rapamycin concentrations of 0.01ng/ml at least; Send the therapeutic agent of q.s when (4) liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.001ng/mg at least; Form nondispersive agglomerate when (5) liquid preparation is injected in the lagophthalmos vitreous body.

22. the method for the degeneration of macula that the moist age is relevant among the prevention people experimenter, described method comprises by ophthalmic or sends near the eyes people experimenter is used the liquid preparation that contains the effective dose therapeutic agent that described therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester; And wherein liquid preparation has one or more and is selected from following feature: the therapeutic agent of sending q.s when (1) liquid preparation is injected into the lagophthalmos vitreous body, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.01ng/mg at least; Send the therapeutic agent of q.s when (2) liquid preparation is injected into the lagophthalmos vitreous body, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos vitreous body internal therapy agent is equal to the rapamycin concentrations of 1000ng/ml at least; Send the therapeutic agent of q.s when (3) liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of the vitreous body internal therapy agent of lagophthalmos is equal to the rapamycin concentrations of 0.01ng/ml at least; Send the therapeutic agent of q.s when (4) liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.001ng/mg at least; Form nondispersive agglomerate when (5) liquid preparation is injected in the lagophthalmos vitreous body.

23. the method for claim 22, wherein people experimenter is accredited as under the highly dangerous that is in the degeneration of macula that the moist age of development is relevant in the eye, and described eye is used described liquid preparation.

24. the method for claim 23, wherein people experimenter suffers from relevant degeneration of macula of dryness age at least one eye.

25. the method for claim 23, wherein people experimenter suffers from relevant degeneration of macula of moist age in an eye, and liquid preparation is applied in the eye of not suffering from relevant degeneration of macula of moist age.

26. the method for the degeneration of macula that the dryness age is relevant among the treatment people experimenter, described method comprises by ophthalmic or sends near the eyes people experimenter is used the liquid preparation that contains the effective dose therapeutic agent that described therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester; And wherein liquid preparation has one or more and is selected from following feature: the therapeutic agent of sending q.s when (1) liquid preparation is injected into the lagophthalmos vitreous body, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.01ng/mg at least; Send the therapeutic agent of q.s when (2) liquid preparation is injected into the lagophthalmos vitreous body, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos vitreous body internal therapy agent is equal to the rapamycin concentrations of 1000ng/ml at least; Send the therapeutic agent of q.s when (3) liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of the vitreous body internal therapy agent of lagophthalmos is equal to the rapamycin concentrations of 0.01ng/ml at least; Send the therapeutic agent of q.s when (4) liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.001ng/mg at least; Form nondispersive agglomerate when (5) liquid preparation is injected in the lagophthalmos vitreous body.

27. prevention suffers from the method for the degeneration of macula that the moist age is relevant among the people experimenter of relevant degeneration of macula of dryness age, described method comprises that the people experimenter to suffering from relevant degeneration of macula of dryness age uses the liquid preparation that contains the effective dose therapeutic agent, and described therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and officinal salt thereof and ester; Wherein send and use this liquid preparation by ophthalmic or periphery, wherein liquid preparation has one or more and is selected from following feature: the therapeutic agent of sending q.s when (1) liquid preparation is injected into the lagophthalmos vitreous body, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.01ng/mg at least; Send the therapeutic agent of q.s when (2) liquid preparation is injected into the lagophthalmos vitreous body, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos vitreous body internal therapy agent is equal to the rapamycin concentrations of 1000ng/ml at least; Send the therapeutic agent of q.s when (3) liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of the vitreous body internal therapy agent of lagophthalmos is equal to the rapamycin concentrations of 0.01ng/ml at least; Send the therapeutic agent of q.s when (4) liquid preparation is injected between the lagophthalmos CSC, described amount can be implemented in behind the applicating liquid preparation in time period of 30 days at least, and the mean concentration of lagophthalmos retina tela chorioidea internal therapy agent is equal to the rapamycin concentrations of 0.001ng/mg at least; Form nondispersive agglomerate when (5) liquid preparation is injected in the lagophthalmos vitreous body.

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