CN101137369A - Formulations for ocular treatment - 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 preparation that is used for the eye treatment

Technical field

This paper has described by delivering therapeutic agents treatment ophthalmic and disease, especially by to experimenter or experimenter eyes send method and the self-emulsifiable preparation that the self-emulsifiable preparation that comprises rapamycin is treated relevant degeneration of macula (" AMD ") of age.

Mutual reference with 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 rule awl 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), 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.Ophthal109:1232; 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 the method and formulation of moist AMD and treatment or prevention dryness 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 Inflam mation, 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 be used for reactive compound be delivered to back segment with treatment in long-acting method as the CNV of this class disease of AMD, macular edema, proliferative retinopathy and chronic inflammatory disease.

Rapamycin dissolubility in aqueous environments is very low.So, need dissolubility that preparation strengthens rapamycin so that more effectively it is delivered to aqueous environments, as zone, gastrointestinal tract and other aqueous environments between the vitreous body of eye, aqueous humor, sclera, conjunctiva, the CSC.

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 is raised the efficiency, and reduces side effect and general toxicity simultaneously.

Summary of the invention

Methods described herein and self-emulsifiable preparation allow to experimenter or experimenter's eyes delivering therapeutic agents and handle one or more above-mentioned difficulties.Unless context is pointed out on the contrary, expects that the experimenter that all Therapeutic Method can carry out comprises people experimenter.Similarly, methods described herein and self-emulsifiable preparation can be used for the multiple disease of sending multiple therapeutic agent and can be used to prevent and treating eyes in the time that prolongs.

This paper has described method and the self-emulsifiable preparation that is used for using to people experimenter rapamycin, and the amount of described rapamycin can effectively be treated or pre-moisture resistance AMD.This paper has described method and the self-emulsifiable preparation that is used for using to people experimenter rapamycin, and dryness AMD can effectively be treated or prevent to the amount of described rapamycin.This paper has described method and the self-emulsifiable preparation that is used for using to people experimenter rapamycin, and the transformation of dryness AMD hygrotropism AMD can effectively be treated or prevent to the amount of described rapamycin.

Describe in further detail as " detailed Description Of The Invention " part, also can use described method and self-emulsifiable preparation to be used for being used for the treatment of, preventing, suppressing moist AMD, postpone its generation or cause that it disappears to the experimenter or to the rapamycin of experimenter's eyes delivery treatments effective dose.In some modification, use described method and self-emulsifiable preparation to treat moist AMD.In some modification, use the pre-moisture resistance AMD of described method and self-emulsifiable preparation.In some modification, use treatment of described method and self-emulsifiable preparation or prevention dryness AMD.In some modification, use described method and self-emulsifiable preparation to be used to prevent dryness AMD to change moist AMD into.Described method and self-emulsifiable preparation also can be used for being used for the treatment of, preventing, suppressing CNV, postpone its generation or cause that it disappears to the experimenter or to the rapamycin of experimenter's eyes delivery treatments effective dose.Described method and self-emulsifiable preparation also can be used for to the 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 generating, postponing its generation or cause that it disappears.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 and self-emulsifiable preparation to be used for the treatment of, to prevent, to suppress moist AMD or dryness AMD, postpone its generation or cause that it disappears to the experimenter or to the therapeutic agent except that rapamycin of experimenter's eyes delivery treatments effective dose.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 analog, salt and ester.Also can use described method and self-emulsifiable preparation to be used for the treatment of, to prevent, to suppress CNV, postpone its generation or cause that it disappears to the experimenter or to the therapeutic agent of experimenter's eyes delivery treatments effective dose.Also can use described method and self-emulsifiable preparation to the experimenter or be used for the treatment of, prevent, suppress the eye medium vessels to the therapeutic agent of experimenter's eyes delivery treatments effective dose and generate, postpone its generation or cause that it disappears.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 ".

Described several formulations, route of administration and self-emulsifiable preparation in " detailed Description Of The Invention ", it can be used for other diseases or disease that the rapamycin of delivery treatments effective dose or other treatment agent be used for the treatment of, prevent, suppress moist AMD, dryness AMD, CNV, angiogenesis or eye, postpone its generation or cause that it disappears.

In some modification, self-emulsifiable preparation described herein medium with respect to its placement when inserting vitreous body forms milky or the albescent semicontinuous or nondispersive agglomerate of semisolid.

The route of administration that can be used for using self-emulsifiable preparation includes but not limited to that (1) place self-emulsifiable preparation by being expelled in the health aqueous medium, includes but not limited to be expelled to the zone between vitreous body, aqueous humor, sclera, conjunctivae and selerae and the conjunctiva; Or (2) dosage forms for oral administration self-emulsifiable preparation.Self-emulsifiable 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, ophthalmic, 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 self-emulsifiable preparation conjunctiva.In some modification, the self-emulsifiable preparation intravitreal administration.

Self-emulsifiable preparation described herein can be used for any aqueous medium, and they form emulsion therein.

Multiple self-emulsifiable preparation and method have been described, its be used for the treatment of, prevent, suppress moist AMD, dryness AMD, CNV, angiogenesis or eye other diseases or disease, postpone its generation or cause that it disappears.

A kind of self-emulsifiable preparation described herein comprises the self-emulsifiable preparation of rapamycin or other treatment agent.Self-emulsifiable preparation can own emulsifying in importing aqueous environments the time.Droplet in the emulsion can be generally any size, includes but not limited to up to 5 the droplet of 000nm.

In some modification, self-emulsifiable preparation comprises rapamycin, solvent and surfactant.As limiting examples, surfactant can be for non-ionic, and as cremophor EL, solvent can be fatty acid, as oleic acid, Imwitor742, Softigen767 or Capmuls PG8.Self-emulsifiable preparation can also comprise ethanol.

As limiting examples, self-emulsifiable preparation comprises rapamycin, cremophor EL, Capmuls PG8 and ethanol.

In some modification, self-emulsifiable preparation comprises rapamycin or another kind of therapeutic agent.This self-emulsifiable preparation can contain the rapamycin or the other treatment agent of any concentration usually, and this concentration is subjected to the restriction of rapamycin or other treatment agent dissolubility in this solvent.Operable multiple solvent and concentration are described in " detailed Description Of The Invention ".

Self-emulsifiable preparation described herein can be sent rapamycin or other treatment agent with the time period that prolongs.This class prolongs the system of limiting examples for the time period that prolongs rapamycin being delivered to the 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 treat, prevent, suppresses, postpones the degeneration of macula generation that the moist age is correlated with or be caused that it disappears in the experimenter.In some modification, self-emulsifiable preparation is used in relevant degeneration of macula of the moist age of time period internal therapy that prolongs.In some modification, self-emulsifiable preparation is used for pre-relevant degeneration of macula of moisture resistance age in the time period that prolongs.In some modification, use self-emulsifiable preparation prevention dryness AMD in the time period that prolongs to change moist AMD into.In a non-limiting instance, self-emulsifiable 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 experimenter's vitreous body, 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 ".

Concentration and dosage are described in " detailed Description Of The Invention ".

Summary of drawings

Fig. 1 has shown behind the intravitreal injection concentration of rapamycin in the vitreous body of lagophthalmos.

Invention is described in detail

This paper describes and relate to self-emulsifying preparation and the method that therapeutic agent is delivered to experimenter or experimenter's eye. These self-emulsifying preparations and method can be used for treatment, prevention, suppress, postpone disease and undesired illness in back segment occurs and it is disappeared, and described disease includes but are not limited to choroid neovascularization, macular degeneration, relevant macular degeneration (comprising moist AMD and dryness AMD), retinal vessel generation, chronic uveitis and other retina hyperplasia illnesss of age with undesired illness.

This paper describes (1) self-emulsifying preparation; (2) therapeutic agent, it uses self-emulsifying preparation described herein and method can be delivered to experimenter or experimenter's eyes; (3) can be by sending disease and the illness of therapeutic agent treatment; (4) send method of administration and the method for self-emulsifying preparation; (5) use described self-emulsifying preparation, by to experimenter or experimenter's eye, sending rapamycin, treat CNV and moist AMD or dryness AMD.

The degree of accuracy level that obtains when term used herein " approximately " refers to use methods described herein (as the method in embodiment).

The self-emulsifying preparation

As used herein, the self-emulsifying preparation refers to form the preparation of emulsion when with aqueous medium, contacting. Droplet in emulsion can be any size. The emulsion that the self-emulsifying preparation forms can include but not limited to for any type, microemulsion and the emulsion of receiving. A non-limiting example of self-emulsifying preparation is to form the preparation of oil-in-water type dispersion when with aqueous medium, contacting, and wherein by the surface-active agent molecule, stablizes dispersion.

A kind of self-emulsifying preparation described herein comprises therapeutic agent, solvent and surfactant. The surfactant component can comprise the combination of a kind of surfactant or surfactant. Solvent composition can comprise the combination of a kind of solvent or solvent. The therapeutic agent component can comprise the combination of a kind of therapeutic agent or therapeutic agent.

Attention exists overlapping between the composition that can be solvent and surfactant, therefore identical composition can be used as solvent or surfactant in some systems.

The self-emulsifying preparation also optionally comprises stabilizing agent, excipient, gelling agent, adjuvant, antioxidant and/or other compositions described herein. In a kind of preparation of description, surfactant is non-ionic.

This paper describes the self-emulsifying preparation be used to the therapeutic agent of sending the description of " therapeutic agent " part. Using self-emulsifying preparation described herein to send therapeutic agent can be used for treatment, prevention, suppresses, postpones the generation of the described disease of " disease and illness " part and illness or it is disappeared. Self-emulsifying preparation described herein can contain any therapeutic agent that " therapeutic agent " part is described, and includes but are not limited to rapamycin. Self-emulsifying preparation as herein described can comprise a kind of or more than a kind of therapeutic agent. Can use other self-emulsifying preparations the self-emulsifying preparation of clearly describing except this paper.

Described self-emulsifying preparation can strengthen therapeutic agent, include but not limited to the solubility of rapamycin, be used for improving sending of hydrotropism's environment, described water-based environment is such as intestines and stomach, vitreum, aqueous humor, conjunctiva, and the zone between CSC, perhaps other water-based environment. The solubility of this type of enhancing can cause the larger bioavailability of therapeutic agent. In addition, the solubility of this type of enhancing can also allow to increase the concentration of therapeutic agent (including but not limited to rapamycin), for example, by described self-emulsifying preparation, sends.

In some modification, therapeutic agent is approximately 0.1 to approximately 25% of preparation gross weight; Approximately 0.5 to approximately 20%; Approximately 1 to approximately 15%; Approximately 1.5 to approximately 10%; Or approximately 2 to approximately 8%; Approximately 3 to approximately 6%; Or the preparation gross weight approximately 5 to approximately 10%;

The a certain amount of 90-110% that refers to described amount of " approximately " of preparation component.

In some modification, solvent is approximately 2 to approximately 70% of preparation gross weight; Approximately 10 to approximately 60%; Approximately 25 to approximately 55%; Approximately 30 to approximately 50%; Or approximately 35 to approximately 45%; Approximately 2 to approximately 10%; Approximately 10 to approximately 20%; Approximately 20 to approximately 30%; Approximately 30 to approximately 40%; Approximately 40 to approximately 45%; Approximately 40 to approximately 45%; Approximately 45 to approximately 50%; Approximately 50 to approximately 60%; Or approximately 50 to approximately 70%.

In some modification, surfactant is approximately 2 to approximately 70% of preparation gross weight; Approximately 10 to approximately 60%; Approximately 25 to approximately 55%; Approximately 30 to approximately 50%; Or approximately 35 to approximately 45%; Approximately 2 to approximately 10%; Approximately 10 to approximately 20%; Approximately 20 to approximately 30%; Approximately 30 to approximately 40%; Approximately 40 to approximately 45%; Approximately 40 to approximately 45%; Approximately 45 to approximately 50%; Approximately 50 to approximately 60%; Or the preparation gross weight approximately 50 to approximately 70%.

The non-limiting example of self-emulsifying preparation be have gross weight approximately 0.1 to about 40% the thunderous handkerchief mycin of one or more therapeutic agents; Gross weight approximately 20% to about 80% solvent; Gross weight approximately 20% to the about self-emulsifying preparation of 80% surfactant. Said preparation can also choose wantonly comprise gross weight approximately 0 to approximately 40% cosurfactant, stabilizing agent, excipient, adjuvant, antioxidant, etc.

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

Therapeutic agent

Generally speaking, known or still to be found so far can be used for treating, prevent, suppress, postponing disease described herein and disease and take place or cause that its any chemical compound that disappears can be the therapeutic agent that is used for self-emulsifiable preparation described herein and method.

But operable therapeutic agent comprises by exempt from the chemical compound that the protein family member is worked in conjunction with cell protein.This compounds is known as " but in conjunction with exempting from proteic chemical compound ".But include but are not limited in conjunction with exempting from proteic chemical compound " limus " chemical compound family.Operable limus examples for compounds includes but are not limited to cyclophilin and FK506 conjugated protein (FKBPs), comprises sirolimus (sirolimus) (rapamycin) and water-soluble analogues SDZ-RAD (Novartis) thereof, TAFA-93 (Isotechnika), tacrolimus, everolimus, RAD-001 (Novartis), pimecrolimus, temsirolimus, CCI-779 (Wyeth), AP23841 (Ariad), AP23573 (Ariad) and ABT-578 (Abbott Laboratories).Operable Limus chemical compound analog and derivant include but not limited to be described in United States Patent (USP) 5,527,907; 6,376,517 and 6,329,386 and the chemical 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 chemical compound.

This paper term rapamycin, sirolimus and rapa 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; The bicyclo-rapamycin; The rapamycin dimer; Rapamycin monosilane ether; Rapamycin aromatic yl sulphonate and sulfamate, 31 and 42 monoesters and diester, 30-demethoxylation rapamycin, and Vezina etc., " Rapamycin (AY-22; 989), A New Antifungal Antibiotic.I.TaxonomyOf 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 AndCharacterization " 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 OfAcetate; Propionate; And Methionine Into Rapamycin By Streptomyceteshygroscopicus " J Nat Prod 54:167-177 (1991), WO92/05179, EP467606, 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 EthersOf Rapamycin " U.S. Patent number No.5,120,842; Failli etc., " Rapamycin42-Sulfonates And 42-(N-carboalkoxy) Sulfamates Useful AsImmunosuppressive Agents " U.S. Patent number 5,177,203; Nicolaou etc., " TotalSynthesis Of Rapamycin " J.Am.Chem.Soc.115:4419-4420 (1993); Romo etc., " Total Synthesis Of (-) Rapamycin Using An Evans-TishchenkoFragment Coupling " J.Am.Chem.Soc.115:7906-7907 (1993); With Hayward etc., " Total Synthesis Of Rapamycin Via A Novel Titanium-Mediated AldolMacrocyclization Reaction " J.Am.Chem.Soc., described other derivants of 115:9345-9346 (1993), each data is quoted as a reference in this paper integral body.

Can be used for Limus family compound treating, prevent, suppress, the postpone ophthalmic of angiogenesis mediation and disease (comprising the choroid neovascularization) take place or make in its self-emulsifiable preparation and method that disappears.Limus chemical compound family can be used for prevention, treatment, inhibition, delay AMD (comprising moist or dryness AMD) takes place or it is disappeared.Rapamycin can be used for preventing, treat, suppress, postpone the ophthalmic of angiogenesis mediation and disease (comprising the choroid neovascularization) takes place or it is disappeared.Rapamycin and rapamycin derivative and analog can be used for prevention, treatment, inhibition, delay AMD (comprising moist or dryness AMD) takes place or it is disappeared.

Operable other treatment agent is included in disclosed therapeutic agent in following patent and the publication, each data is quoted the open WO2004/027027 of its whole conduct: PCT at this paper, 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, authorizes Universityof 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 acid derivatives forvision and memory disorders, transferred GPI NIL Holdings, Inc; The open WO2004/028477 of PCT, on April 8th, 2004 is open, is entitled as Method subretinaladministration of therapeutics including steroids:method for localizingpharmadynamic action at the choroid and retina; And related methods fortreatment 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 deliverydevice, transferred Alcon Universal Ltd; U.S. Patent number 6, announced on March 30th, 713,081,2004, be entitled as Ocular therapeutic agent delivery device and methods formaking and using such devices, transfer Department of Health and HumanServices; U.S. Patent number 5,100 was announced, and was entitled as Methods ofinhibiting transplant rejection in mammals using rapamycin andderivatives and prodrugs thereof on March 31st, 899,1992.

Spendable other treatment agent comprises pyrrolidine, dithiocar-bamate (NF kB inhibitor); Squalamine; TPN470 analog and Amebacilin; PKC (Protein kinase C) inhibitor; Tie-1 and Tie-2 inhibitors of kinases; The vegf receptor kinase inhibitor; The Velcade of albuminous body inhibitor as being used to inject ^TM(bortezomib); 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-l integrin antagonist; Thiazolidinediones is as rosiglitazone (rosiglitazone) or troglitazone (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 (anecortave acetate); Acetonide; Omcilon (triamcinolone); 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 quinopril, captopril (captopril) and perindozril; MTOR inhibitor (target of rapamycin in mammal); 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 (deiminase); Epigallocatechin-3-epicatechol gallate (epigallocatechin-3-gallate); Cerivastatin (cerivastatin); Suramin (suramin) analog; VEGF trap molecule; Apoptosis inhibitor; Visudyne ^TM, snET2 and other photosensitizer, it can be used for photodynamic therapy (PDT); 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 NK4).

Spendable other treatment agent comprises antiinflammatory, includes but are not limited to on-steroidal antiinflammatory and steroid antiinflammatory.In some modification, can use the activating agent in self-emulsifiable preparation to be ace-inhibitor, the endogenous cell factor, the activating agent that influences basement membrane, the activating agent that influences endothelial cell growth, 2-adrenergic agonist components or blocker, cholinergic agonist or blocker, aldose reductase inhibitor, analgesic, anesthetis, anti-allergy agent, antibacterium medicine, antihypertensive, supercharging medicine (pressor), antiprotozoan agent, antiviral agent, antifungal, 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), beclometasone (beclomethasone), betamethasone (betamethasone), budesonide (budesonide), chloroprednisone (chloroprednisone), clobetasol (clobetasol), clobetasone (clobetasone), clocortolone (clocortolone), cloprednol (cloprednol), corticosterone (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), fluocinolone acetonide (fluocinolone acetonide), fluocinonide (fluocinonide), fluocortin butyl (fluocortinbutyl), fluocortolone (fluocortolone), fluorometholone (fluorometholone), fluperolone acetate (fluperolone acetate), fluprednylidene acetate (fluprednidene acetate), fluprednisolone (fluprednisolone), Cordran (flurandrenolide), Fluticasone Propionate (fluticasonepropionate), 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), prednisone (prednisone), W-4869 (prednival), methylene prednisolone (prednylidene), rimexolone (rimexolone), tixocortol (tixocortol), omcilon (triamcinolone), triamcinolone acetonide (triamcinoloneacetonide), benzene Qu An is DS (triamcinolone benetonide) how, triamcinolone hexacetonide (triamcinolone hexacetonide) and any derivant thereof.

In some modification, can use cortisone, dexamethasone, fluocinolone acetonide, hydrocortisone, methylprednisolone, prednisolone, prednisone and omcilon and derivant thereof.Self-emulsifiable preparation can comprise the combination of two or more steroid therapy agent.

In some modification, about by weight 0.05% to about 50% of self-emulsifiable preparation is formed in the steroid therapy agent.In some modification, steroid form self-emulsifiable preparation about by weight 0.05% to about 10%, between about 10% to 20%, between about 30% to about 40%, or about 40% to about 50%.

Other limiting examples of operable therapeutic agent include but are not limited to anesthetis, analgesics, cell traffic/migration inhibitor, as Colchicine, Changchun new city vincristine, cytochalasin B and related compound; Carbonic anhydrase inhibitors is as acetazolamide (acetazolamide), methazolamide (methazolamide), daranide (dichlorphenamide), acetazolamide (diamox) and neuroprotective such as nimodipine and related compound; Antibiotic such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, Gramicidin, cefalexin, oxytetracycline, chloromycetin, rifampicin, ciprofloxacin, aminoglycoside, gentamycin, erythromycin and penicillin, quinolinones, ceftazidime, vancomycin imines penem (vancomycine imipeneme); Antifungal such as amphotericin B, croconazole, ketoconazole and miconazole (miconazole); Antibacterial agent such as sulfonamides (sulfonamides), sulfadiazine (sulfadiazine), sulfacetamide (sulfacetamide), sulfamethizole (sulfamethizole) and sulfafurazole (sulfisoxazole), nitrofural (nitrofurazone) and sodium propionate; Antiviral agent such as idoxuridine (idoxuridine), trifluorothymidine (trifluorothymidine), trifluridine (trifluorouridine), acyclovir (acyclovir), ganciclovir (ganciclovir), cidofovir (cidofovir), interferon, DDI, AZT, Foscanet (foscamet), vidarabine (vidarabine), irbavirin, protease inhibitor and anti-cytomegalovirus agent; Anti-allergy agent such as sodium cromoglicate (sodium cromoglycate), antazoline (antazoline), methapyriline, chlorphenamine (chlorpheniramine), cetirizine (cetirizine), neo-antergan (pyrilamine) and pheniramine (prophenpyridamine); Synthetic glucocorticoid and mineralocorticoid and the more general hormone form (DHEA, Progesterone, estrogen) of coming from cholesterol metabolism; Nonsteroidal anti-inflammatory agent, for example Salicylate, indomethacin (indomethacin), ibuprofen (ibuprofen), diclofenac, flurbiprofen (flurbiprofen), adjoin sieve former times health (piroxicam) and COX2 inhibitor; Antitumor agent such as carmustine (carmustine), cisplatin (cisplatin), fluorouracil; Amycin, asparaginase, azacitidine (azacitidine), azathioprine (azathioprine), bleomycin, busulfan (busulfan), carboplatin (carboplatin), carmustine, chlorambucil (chlorambucil), cyclophosphamide (cyclophosphamide), cyclosporin, cytosine arabinoside, dacarbazine (dacarbazine), actinomycin D (dactinomycin), daunorubicin (daunorubicin), doxorubicin (doxorubicin), estramustine (estramustine), etoposide (etoposide), etretinate (etretinate), filgrastin (filgrastin), fluorodeoxyuridine (floxuridine), fludarabine (fludarabine), fluorouracil, florxymesterone, flutamide (flutamide), goserelin (goserelin), hydroxyurea (hydroxyurea), ifosfamide (ifosfamide), leuprorelin acetate (leuprolide), levamisole (levamisole), limustine, chlormethine (nitrogen mustard), melphalan (melphalan), mercaptopurine (mercaptopurine), methotrexate (methotrexate), mitomycin (mitomycin), mitotane (mitotane), pentostatin (pentostatin), group's pool bromine alkane (pipobroman), plicamycin (plicamycin), procarbazine (procarbazine), leulkine (sargramostin), streptozotocin (streptozocin), tamoxifen (tamoxifen), paclitaxel (taxol), teniposide (teniposide), thioguanine, uracil mustard (uracil mustard), vinblastine (vinblastine), vincristine (vincristine) and vindesine (vindesine); Immune drug such as vaccine and immunostimulant; Insulin, calcitonin, parathyroid hormone and peptide and vassopressin hypothalamic releasing factor; Beta-adrenergic blocking agent such as timolol (timolol), levobunolol (levobunolol) and betaxolol (betaxolol); Cytokine, interleukin and somatomedin, epidermal growth factor, fibroblast growth factor, platelet derived growth factor, transforming growth factor, ciliary nerve nutrition somatomedin, glial cell derived neurotrophic factor, NGF, EPO, PLGF, cranial nerve somatomedin (BNGF), VEGF (VEGF) and at monoclonal antibody or its fragment of this class somatomedin; Antiinflammatory such as hydrocortisone, dexamethasone, fluocinolone acetonide, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone and omcilon; Decongestant such as phenylephrine (phenylephrine), naphazoline (naphazoline) and tetrahydrazoline; Miotic and anticholinergic such as pilocarpine (pilocarpine), carbachol (carbachol), diisopropyl fluorophosphate (DFP) (di-isopropylfluorophosphates), iodate diethoxyphosphinylthiocholine (phospholine iodine) and demecarium bromide (demecarium bromide); Iridodilator such as atropine sulfate, cyclopentolate (cyclopentolate), melyltropeine (homatropine), scopolamine (scopolamine), tropicamide (tropicamide), eucatropine (eucatropine); Sympathomimetic such as epinephrine and vasoconstrictor and vasodilation, anticoagulant (anticlotting agents) is as heparin, antifibrin is former, plasmin (fibrinolysin), anticoagulant kinase (anticlotting activase), antidiabetic comprises acetohexamide (acetohexamide), chlorpropamide (chlorpropamide), glipizide (glipizide), glibenclamide (glyburide), tolazamide (tolazamide), tolbutamide (tolbutamide), insulin and aldose reductase inhibitor, hormone, peptide, nucleic acid, sugar, lipid, glycolipid, glycoprotein and other macromole comprise endocrine hormone such as pituitrin, insulin, the insulin relative growth factor, thyroxine, growth hormone; Heat shock protein; Immunne response dressing agent such as muramyldipeptide, cyclosporin, interferon (comprise α-, β-and gamma interferon), interleukin-22, cytokine, FK506 (a kind of epoxy-pyrido-oxa-azacyclo-tricosene-tetraketone also is known as tacrolimus), tumor necrosis factor, pentostatin, Thymopentin (thymopentin), transforming factor β 2, erythropoietin (erythropoetin); Anti-new raw albumen (for example anti-VEGF, interferon), antibody (monoclonal, polyclone, humanization etc.) or antibody fragment, oligomerization is fit, fit and genetic fragment (oligonucleotide, plasmid, ribozyme, siRNA (SiRNA), nucleic acid fragment, peptide), immunomodulator such as endoxan (endoxan), Thalidomide, zitazonium; Antithrombotic and vasodilation such as rtPA, urokinase, fibrinolysin; Nitric oxide donors, nucleic acid, dexamethasone, cyclosporin A, azathioprine, brequinar (brequinar), gusperimus (gusperimus), the fast cry of certain animals of 6-coloured glaze base, mizoribine (mizoribine), rapamycin, tacrolimus (FK-506), folacin (9,10-dimethylpteroylglutamic acid for example, edatrexate (edatrexate), methotrexate, piritrexim (piritrexim), Pteropterin (pteropterin), Tomudex , trimetrexate (trimetrexate)), purine analogue (cladribine (cladribine) for example, fludarabine (fludarabine), Ismipur, ITG (thiamiprine), thiaguanine), pyrimidine analogue (ancitabine (ancitabine) for example, azacitidine, the 6-azauridine, carmofur (carmofur), cytosine arabinoside, doxifluridine (doxifluridine), emitefur (emitefur) Shan Yu arabinose pyridine (enocitabine), fluorodeoxyuridine, fluorouracil, gemcitabine, tegafur (tegafur)), fluocinolone acetonide, triaminolone, NSC 24345, fluorometholone, medrysone (medrysone) and prednisolone.In some modification, immunosuppressant is a dexamethasone.In other modification, immunosuppressant is a cyclosporin A.

In other 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 angiogenesis or neovascularization (particularly choroid neovascularization) or make its therapeutic agent that disappears and therapy.In some modification, use extra therapeutic agent or therapy for treating angiogenesis or neovascularization (particularly CNV).The therapeutic agent that this class is extra and the limiting examples of therapy comprise pyrrolidine, dithiocar-bamate (dithiocarbamate) (NF kB inhibitor); Squalamine; TPN470 analog and Amebacilin; PKC (Protein kinase C) inhibitor; Tie-l 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-l 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 self-emulsifiable 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 self-emulsifiable preparation and method to treat described disease and disease.

In some modification, using the disease of therapeutic agent described herein and self-emulsifiable preparation and method treatment or disease is not the disease or the disease of eye.

Following list of references (every kind of complete being incorporated herein by reference) has shown one or more preparations, include but not limited to the rapamycin preparation, and rapamycin of multiple dosage and the purposes that the other treatment agent is used for the treatment of multiple disease or disease have been described for it: the US that on February 9th, 2005 submitted to

60/651,790, title FORMULATIONS FOR OCULAR TREATMENT, attorney docket 57796-30002.00; The US60/664 that on February 9th, 2005 submitted to, 040, attorney docket 57796-30004.00, title LIQUID FORMULATIONS FOR TREATMENTOF DISEASES OR CONDITIONS; The US60/664 that March 21 in 2005 submitted to, 119, attorney docket 57796-30005.00, title DRUG DELIVERY SYSTEMS FORTREATMENT OF DISEASES OR CONDITIONS; The US60/664 that March 21 in 2005 submitted to, 306, attorney docket 57796-30006.00 title IN SITU GELLINGFORMULATIONS AND LIQUID FORMULATIONS FORTREATMENT OF DISEASES OR CONDITIONS; The US_ that submitted on February 9th, 2006/_, title FORMULATIONS FOR O CULAR TREATMENT, attorney docket 57796-20002.00; Submitted on February 9th, 2006 _/_, attorney docket 57796-20004.00, title LIQUID FORMULATIONS FOR TREATMENT OFDISEASES OR CONDITIONS; US2005/0187241, and US2005/0064010.

Generally speaking, to using the treatment of therapeutic agent described herein and self-emulsifiable preparation and method, prevention, inhibition, delay to take place or causing that any ophthalmic or the disease that disappear can be taken place or cause to disappear by treatment, prevention, inhibition, delay.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 self-emulsifiable preparation described herein and method to treat, 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 self-emulsifiable preparation described herein and method to treat, 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 (arteryocclusion), carotid artery obstruction disease (carotid obstructive disease), sicklemia (Sickle Cellanemia), eales disease (Eales disease), myopia (myopia), chronic detachment of retina (chronic retinal detachment), hyperviscosity syndrome (hyperviscositysyndromes), toxoplasmosis (toxoplasmosis), wound (trauma), polypoid (the sick polypoidal choroidal of choroidal artery vasculopathy), laser therapy infectious-related complication (post-lasercomplications), the complication of ICSC (complications ofidiopathic central serous chorioretinopathy), choroid inflammation complication (complications of choroidal inflammatory conditions), rubescent (rubeosis), with rubescent relevant disease (canthus neovascularization), neovascular glaucoma (neovascularglaucoma), 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 for the treatment of, prevent or postpone the generation of CNV, include but not limited to have in an eye CNV in experimenter's the another eye of AMD.In some modification, preparation described herein and pharmaceutical preparation are used for the treatment of, prevent or postpone to have the generation of CNV in experimenter's the another eye of moist AMD or AMD in an eye.In some modification, preparation described herein and pharmaceutical preparation comprise the limus chemical compound, include but 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 eye 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 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, be administered under preparation and the pharmaceutical preparation conjunctiva and have 20/40 or the eye of 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 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, be administered under preparation and the pharmaceutical preparation conjunctiva and have 20/40 or the eye of better vision.In some modification, preparation described herein and pharmaceutical preparation are applied, and the 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 or pharmaceutical preparation treatment, in the treatment or after the treatment, the 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 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 self-emulsifiable preparation described herein and method can treat, suppress, postpone its generation or make its a kind of disease that disappears is moist AMD.In some modification, use self-emulsifiable preparation described herein 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.

Self-emulsifiable preparation described herein 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.

Self-emulsifiable preparation described herein (including but are not limited to the self-emulsifiable preparation that contains rapamycin) also can be used for treating, prevent, suppress, postponing the generation of relevant disease of panimmunity and disease or it is disappeared, 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, self-emulsifiable preparation described herein (including but are not limited to the self-emulsifiable preparation that contains rapamycin) is used for the treatment of panimmunity relevant disease and disease, 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.Self-emulsifiable preparation described herein (including but are not limited to the self-emulsifiable preparation that contains rapamycin) useful as immunosuppressants.Self-emulsifiable preparation described herein (including but are not limited to the self-emulsifiable preparation that contains rapamycin) can be used for treating, prevent, suppressing or postpones 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, self-emulsifiable preparation described herein is 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 was disappeared, self-emulsifiable preparation described herein can be used by number of ways known in the art, includes but are not limited to by Orally administered when being used for the treatment of, preventing, suppressing, postponing.

General is used and can be finished by oral self-emulsifiable preparation.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 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 the standard of determining of angiogenesis and/or 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.Therapeutic agent can be administered to mammalian subject.Therapeutic agent can be administered to people experimenter.Therapeutic agent can be administered to the veterinary animal experimenter.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 WO2004/027027 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 ResearchFoundation February 7 nineteen ninety-five; U.S. Patent number 6,376 was announced on April 23rd, 517,2003, was entitled as Pipecolicacid derivatives for vision and memory disorders, transferred GPI NILHoldings, Inc; The open WO2004/028477 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 transfers Innorx, Inc; U.S. Patent number 6,416 was announced on July 9th, 777,2002, was entitled as Ophthalmic drug delivery device, transferred Alcon Universal Ltd; U.S. Patent number 6, announced on March 30th, 713,081,2004, be entitled as Ocular therapeutic agent deliverydevice and methods for making and using such devices, transfer Departmentof Health and 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 American Home Products Corp., with Application No. 60/503,840 and 10/945,682.

The self-emulsifiable preparation that is used for delivering therapeutic agents

Unless spell out in the context on the contrary, expect that any or multiple therapeutic agent as herein described can be used for self-emulsifiable preparation as herein described.Unless spell out in the context on the contrary, expect that any or multiple self-emulsifiable preparation as herein described can be used for the treatment of, prevents, suppresses or postpone the generation of any or multiple disease as herein described or disease.

In some modification, self-emulsifiable preparation is solution before using.In some modification, self-emulsifiable preparation likens to and is the longer time of the preparation stabilization of Emulsion.

" aqueous medium " used herein or " aqueous environments " are medium or the environment that contains at least about 50% water.

The example of aqueous medium includes but are not limited to zone, aqueous humor, the gastric juice between vitreous body, extracellular fluid, conjunctiva, sclera, the CSC and comprises 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.

This paper has described the therapeutic agent how self-emulsifiable preparation can be used to send the generation of disease described in effective treatment, prevention, inhibition, delay " disease and the disease " part or disease or cause the amount that it disappears, and comprises and describes the prolongation release how self-emulsifiable preparation can be used for the treatment of agent.

" 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 the 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 use self-emulsifiable preparation to the animal model of purpose disease or disease, and observing effect.

The therapeutic agent of delivery treatments effective dose can be realized or by using twice or the self-emulsifiable preparation of multidose is realized by the single administration self-emulsifiable preparation in the time that prolongs.As this type of limiting examples of repeatedly using, the therapeutic dose of rapamycin is kept the generation that was used for the treatment of, prevents, suppresses, postpones moist AMD in three months or make its disappear can be by using the delivery treatments amount potion self-emulsifiable preparation 3 months, or finish by the self-emulsifiable preparation that order is used multiple dose.The optimal dose strategy will depend on the kinetics of sending of the therapeutic dose of the therapeutic agent that need be sent and its time that need be sent and self-emulsifiable preparation.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 to be used for the treatment of, to prevent, to suppress, to postpone 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 preparation 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 preparation, the release that this class is delayed can be useful.Treated, prevent, suppress, postpone its generation and 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 this period of delay before therapeutic agent delivery began.Also can be possible other period of delay.According to the instruction of this paper, spendable delayed release preparation is that to be proficient in the personnel of this technology known.

Usually, can the be following any self-emulsifiable preparation preparation of therapeutic agent, described self-emulsifiable preparation can be to experimenter or the experimenter's eye therapeutic agent with required delivery cycles delivery treatments effective dose.

The solubilising of therapeutic agent

Operable a kind of preparation is that therapeutic agent is dissolved in the preparation in the solvent.Usually, any solvent with required effect can be used, and therapeutic agent is dissolved in wherein and can be applied to the experimenter.Usually, can use the dissolved therapeutic agent of any concentration with required effect.Solvent can be the mixture of single solvent or solvent.The type of solvent and solution can be known for technical staff in the medicine delivery technique.Solvent composition can be that single solvent maybe can be the mixture of solvent.Solvent is that the technical staff is known in the medicine delivery technique.Consult for example Remington:The Science andPractice of Pharmacy, the 20th edition, Lippincott Williams ﹠amp; Wilkins; The 20th edition (on December 15th, 2000); Ansel ' s Pharmaceutical Dosage Forms and DrugDelivery Systems, the 8th edition, Lippincott Williams ﹠amp; Wilkins (in August, 2004); Handbook Of Pharmaceutical Excipients 2003, American PharmaceuticalAssociation, Washington, DC, USA and Pharmaceutical Press, London, UK; And Strickley, solubilizing Excipients in Oral and InjectableFormulations, Pharmaceutical Research, the 21st volume, No.2, in February, 2004.

Spendable solvent include but are not limited to following one or more: 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 PEG300 and PEG400) 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).

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 Captex100, Captex300, Captex355, Miglyol810, Miglyol812, Miglyol818, Miglyol829 and Dynacerin660.The commercial propylene glycol ester compositions that can buy comprises Captex200 and Miglyol840 etc.Commercially available prod Capmul MCM is one of many possible medium chain mixture that contains monoglyceride and diglyceride.

Other solvents comprise naturally occurring oil, as 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).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, Imwitor742, 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, polysorbitan20, Cavitron, various molecular weights includes but are not limited to PEG300 and PEG400.

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

The solvent that is used for self-emulsifiable 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 limiting examples that can be used for the solvent of self-emulsifiable preparation as herein described included but are not limited to any solvent described herein, 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 PEG300 and PEG400) and Pegylation; Gattefosse) any one or more; any one or more combination of front, or any one or more analog or derivant of front.

Other solvents include but are not limited to C ₆-C ₂₄Fatty acid, oleic acid, Imwitor742, Capmul, F68, F68 (Lutrol), PLURONICS (include but are not limited to PLURONICS F108, F127 and F68, poloxamer, Jeffamines), Tetronics, F127, beta-schardinger dextrin-, CMC, polysorbitan20, Cavitron, softigen767, captisol and Oleum sesami.

The additive method that can be used for dissolving rapamycin is described in Solubilization of Rapamycin, Int ' lJ.Pharma such as P.Simamora 213 (2001) 25-29, 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 contain the rapamycin with desired effect of arbitrary concentration usually.Rapamycin solution can be 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.Those skilled in the art can find to identify that according to this paper instruction the solvent that is used for rapamycin is conventional.

Surfactant

Usually, the combination of any surfactant or surfactant can be used for self-emulsifiable preparation described herein, condition be surfactant when with preparation in other combination of components the time obtain self-emulsifiable preparation.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 or amphoteric surfactant, condition be surfactant when with preparation in other combination of components the time obtain self-emulsifiable preparation.

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 aqueous 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, NIKKOL HCO-35, MKKOL HCO-40, NIKKOL HCO-60 (from NikkoChemicals Co.Ltd.); CREMOPHOR (from BASF) is as CREMOPHORRH40, CREMOPHOR RH60, CREMOPHOR EL, TWEENS (from ICIChemicals), for example polysorbas20, tween 21, polysorbate40, polysorbate60, Tween 80, sorbimacrogol oleate100, CREMOPHOR RH 410, CREMOPHOR RH 455 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 Tagat0 (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-oleate; Alcohol ethoxylate is as Brij type emulsifying agent; The propenoxylated block copolymer of ethoxylation is as poloxamer; The macrogol ester of fatty acid is as PEG300 glyceryl linoleate or Labrafil2125CS, PEG300 olein or Labrafil M1944CS, PEG400 caprylic/capric glyceride or Labrasol and PEG300 caprylic/capric glyceride or Softigen767; Cremophors is as Cremophor E, CREMOPHORE EL or Cremophor EL, Cremophor EL-P, Cremophor RH4OP, polyoxyl 40 hydrogenated castor oil, Cremophor RH40; Polyoxyethylene 60 castor oil hydrogenated or Cremophor RH60, single caprylic/capric glyceride are as Campmul CM10; 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 Span20, aromatic (Tritons ), PEG-glyceride (PECEOL ^TM), PEG-PPG (polypropylene glycol) copolymer (PLURONICS includes but are not limited to PLUROMCS F108, F127 and F68, poloxamer, Jeffamines), Tetronics, polyglycereol, PEG-tocopherol, PEG-LICOL6-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 Gelucire44/14; 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 GELUCIRE44/14 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 (PEG400 monostearate), Myrj 52 (PEG1750 monostearate) and Oleum menthae.

In some modification, also can 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 Maisine35-1 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 M1944CS is an example of surfactant, and wherein said preparation contains the mixture of glyceryl glycol ester and macrogol ester.

The surfactant that is used for rapamycin

The limiting examples that can be used for the surfactant of rapamycin includes but are not limited to be had greater than 10,11,12,13 or the surfactant of 14HLB.A non-limiting instance is Cremophor EL.Many other surfactants are possible, as top " surfactant " part in those.As mentioned above, some solvents are useful as surfactants also.This area routine techniques personnel can find to identify that according to this paper instruction it is conventional which kind of surfactant can be used for rapamycin.

Pharmaceutical preparation

Unless context spells out on the contrary, pharmaceutical preparation can comprise any self-emulsifiable preparation described herein.

Preparation described herein can also comprise multiple other components that are suitable for use in the pharmaceutical preparation.This type of component for example comprises, stabilizing agent.The stabilizing agent that is 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.Attention is overlapping for existing between the composition of stabilizing agent and the composition for solvent or surfactant, and identical composition can be brought into play more than a kind of effect.

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, 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; PVP, PVA, wax etc.

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

Operable gellant includes but 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, tragakanta, terra, pectin, tamarind, larch arabinogalactan, alginate, Semen sophorae, xanthan gum, starch, aluminium-magnesium silicate, tragakanta, polyvinyl alcohol, gellan gum, hydrocolloid admixture and polyvidone.

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.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 addition, pharmaceutical preparation described herein also is intended to be used to produce medicine, and this medicine is used for treating disease described herein or disease according to one or more methods described herein.

The preparation 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 and self-emulsifiable 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 softigen767, polyoxyethylene sorbitan monoleate, PLURONICS, Tetronics, Miglyol and Transcutol.

Can randomly be added in the pharmaceutical preparation described herein 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 addition, can add heavy-gravity polymer in preparation, assist location is placed and is handled with easy in sclera.In some purposes of self-emulsifiable preparation, can in sclera, form bag by surgical operation, so that accept the injection of self-emulsifiable 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 Labmill8000 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 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.

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 in advance and is used for the treatment of ophthalmic diseases or treatment of conditions agent, 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 rapamycin is housed in advance.In some modification, the small size applicator is equipped with the self-emulsifiable preparation that contains 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 self-emulsifiable preparation.

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 one or more preparations that contain one or more therapeutic agents of liquid form in advance, includes but are not limited to the liquid absorption member that comprises rapamycin, comprises rapamycin and Polyethylene Glycol and randomly also comprise the liquid absorption member (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

Methods described herein and self-emulsifiable preparation can be used by one or more route of administration described herein.

In some modification, self-emulsifiable preparation described herein 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, preparation described herein and method 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.

When using certain volume, be appreciated that there is certain inaccuracy in the accuracy of 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 up to 20% or more.Hamilton HPLC type syringe be it is generally acknowledged degree of accuracy in 10%, and recommends to be used to or less than 10 μ l volumes.

In some modification, the volume that is administered to the Vitrea self-emulsifiable preparation described herein of lagophthalmos or experimenter's eye is 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 self-emulsifiable preparation described herein that is administered to lagophthalmos or experimenter's vitreum is less than about 20 μ l.In some modification, the volume that is administered to Vitrea self-emulsifiable preparation described herein is less than about 10 μ l.In some modification, the volume of self-emulsifiable preparation described herein that is administered to lagophthalmos or experimenter's vitreum 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 self-emulsifiable preparation described herein in lagophthalmos or the experimenter's vitreum is between about 1 μ l and about 10 μ l.In some modification, the volume that is administered to the self-emulsifiable preparation described herein in lagophthalmos or the experimenter's vitreum is between about 1 μ l and about 5 μ l.In some modification, the volume that is administered to the self-emulsifiable preparation described herein in lagophthalmos or the experimenter's vitreum is between about 1 μ l and about 5 μ l.In some modification, the volume that is administered to the self-emulsifiable 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 self-emulsifiable preparation described herein of lagophthalmos or 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 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 self-emulsifiable preparation described herein that is administered to lagophthalmos or experimenter's eye under the conjunctiva is less than about 20 μ l.In some modification, the volume of preparation described herein that is administered to lagophthalmos or experimenter's eye under the conjunctiva is less than about 10 μ l.In some modification, the volume that is administered to the self-emulsifiable preparation described herein of lagophthalmos or 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 500 μ l, between about 500 μ l and about 700 μ l, between about 700 μ l and about 900 μ l, between about 800 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 self-emulsifiable preparation described herein that is administered to lagophthalmos or experimenter's eye under the conjunctiva is between about 1 μ l and about 10 μ l.In some modification, the volume of self-emulsifiable preparation described herein that is administered to lagophthalmos or experimenter's eye under the conjunctiva is between about 1 μ l and about 5 μ l.In some modification, the volume of self-emulsifiable preparation described herein that is administered to lagophthalmos or experimenter's eye under the conjunctiva is between about 1 μ l and about 5 μ l.In some modification, the volume of self-emulsifiable preparation described herein that is administered to lagophthalmos or 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 contains the Polyethylene Glycol that is not more than about 250 μ l.In some modification, liquid preparation described herein contains and is not more than about 250 μ l, is not more than about 200 μ l, is not more than about 150 μ l, is not more than about 125 μ l, is not more than about 100 μ l, is not more than about 75 μ l, is not more than about 50 μ l, is not more than about 25 μ l, is not more than about 20 μ l, is not more than about 15 μ l, is not more than about 10 μ l, is not more than about 7.5 μ l, is not more than about 5 μ l, is not more than about 2.5 μ l, is not more than about 1.0 μ l or is not more than the Polyethylene Glycol of about 0.5 μ l.The preparation that contains Polyethylene Glycol can contain for example PEG300 or PEG400.

In some modification, self-emulsifiable preparation described herein in a period of time, includes but not limited to be applied in mutual 1 hour a plurality of conjunctiva upper/lower positions mutually.Be not bound by theory, think that this type of is repeatedly used, allow than using bigger accumulated dose under the single dose conjunctiva as the potential limited ability of multiple injection owing to topical ophthalmic tissue absorption larger volume.

" retina choroid " used herein and " retina tela chorioidea " are synonyms, and are meant the bonded retina and the tela chorioidea of eye.

" under the conjunctiva " used herein places or injection is meant placement or injection between CSC.

As limiting examples, self-emulsifiable preparation described herein and method can with treat effectively, prevent, postpone CNV, moist AMD, dryness AMD take place or make its amount that disappears and persistent period be applied 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, moist AMD and dryness AMD take place or it is disappeared can be different, and can be different for variant site of delivery.The description of the exemplary approach of sending for the retina medicine near the eyes, see Periocular routes for retinal drug delivery, Raghava etal. (2004), Expert Opin.Drug Deliv.1 (1): 99-114 is with its complete being incorporated herein by reference.

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.

The route of administration that can be used for using self-emulsifiable preparation includes but are not limited to (for example by injection) self-emulsifiable preparation is placed experimenter's aqueous medium, includes but are not limited to place (for example by injection) experimenter's eye.But the self-emulsifiable 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 self-emulsifiable preparation that comprises 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 drug formulation.For example, use in the program at one, the surgeon forms bag in the sclera of eye, and the self-emulsifiable preparation that will contain therapeutic agent then is 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) self-emulsifiable 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.

Self-emulsifiable 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.

Some that can be used for sending self-emulsifiable preparation described herein are modified to passes through injected delivery.In the method, the self-emulsifiable preparation injectable advances the experimenter, or is injected in experimenter's eye or near the position the eye, for delivery to experimenter or experimenter's eye.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 routes for 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.

The site that self-emulsifiable 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 self-emulsifiable preparation includes but are not limited to injection.

Self-emulsifiable preparation described herein can be delivered to the multiple position in eye zone so that can delivering therapeutic agents, includes but not limited to ophthalmic or sends near the eyes; Be delivered between vitreous body, aqueous humor, sclera, conjunctiva, the CSC, retina tela chorioidea, macula lutea, near the eyes tissue, tenons district and in or near other zones or other environment.Send site and route of administration above having described other, as the whole body approach.

The self-emulsifiable preparation that comprises therapeutic agent can use multiple program directly to be delivered to eyes, described method includes but not limited to such program, wherein (1) uses syringe and the agent of hypodermic needle administering therapeutic, (2) with the agent of custom-designed device injection for curing, (3) before the injection for curing agent, operation forms bag in sclera, as the container of therapeutic agent or therapeutic drug formulation.For example, use in the program at one, the surgeon forms bag in the sclera of eye, and the preparation that will contain therapeutic agent then is 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) preparation that will comprise 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.

In the vitreous body and send rapamycin under the conjunctiva and be used for the treatment of, prevent, suppress, postpone the generation of AMD or cause that it disappears

In some modification that this paper describes, to comprise and send or be delivered to the vitreous body that the experimenter includes but not limited to people experimenter's eye under the self-emulsifiable preparation conjunctiva of rapamycin, treat as observed CNV in AMD to treat, prevent, suppress, to postpone the generation of eye medium vessels or it is disappeared, to include but are not limited to.In some modification, use self-emulsifiable preparation treatment eye medium vessels to generate, 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.

Can be delivered to eye (including but not limited to 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 will depend on the disease of being studied (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 and preparation and can be used for people and veterinary purpose, include but not limited to that laboratory animal, laboratory animal, house pet or agricultural go up important 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.

When therapeutic agent was rapamycin, self-emulsifiable preparation can be used for sending in vitreous body or the rapamycin of the amount of remaining valid.In a limiting examples, think that sending rapamycin can be used for the treatment of moist AMD to obtain about 10pg/ml in vitreous body to the delivery system of about 2 μ g/ml rapamycin concentrations.When the intravitreal administration rapamycin, the continuous Emulsion bolus (bolus) of initial application has been got rid of in the calculating of rapamycin concentrations in the vitreous body.In another limiting examples, think that sending rapamycin can be used for the treatment of moist AMD to obtain about 0.01pg/ml in the retina choroid to the delivery system of about 10ng/mg rapamycin concentrations.The therapeutic agent of other treatment effective dose also is possible, and can easily determine according to instruction those skilled in the art of this paper.

When therapeutic agent was rapamycin, self-emulsifiable preparation described herein and other delivery systems can be used for experimenter or experimenter's eyes are sent the rapamycin of doses.In a limiting examples, think that containing the 20 μ g that have an appointment can be used for the treatment of moist AMD or dryness AMD to the delivery system of the initial dosage of about 4mg.Operable other dosage delivered are described in " detailed Description Of The Invention ".

The rapamycin that can be used for a kind of concentration of methods described herein is to organize level that the concentration of about 0.01pg/ml or pg/mg or more rapamycins is provided.In some modification, use a kind of dosage, it provides about 0.1pg/ml or ng/mg organizing on level, about 1pg/ml or ng/mg, about 0.01ng/ml or ng/mg or more than, about 0.1ng/ml or ng/mg, about 0.5ng/ml or ng/mg, about 1ng/ml or ng/mg, about 2ng/ml or ng/mg, about 3ng/ml or ng/mg, about 5ng/ml or ng/mg, about 10ng/ml or ng/mg, about 15ng/ml or ng/mg, about 20ng/ml or ng/mg, about 30ng/ml or ng/mg, about 50ng/ml or ng/mg, about 100ng/ml or ng/mg, about 200ng/ml or ng/ml, about 300ng/ml or ng/mg, about 400ng/ml or ng/mg, about 500ng/ml or ng/mg, about 1 μ g/ml or μ g/mg, about 10 μ g/ml or μ g/mg, about 50 μ g/ml or μ g/mg, about 100 μ g/ml or μ g/mg, about 150 μ g/ml or μ g/mg, about 200 μ g/ml or μ g/mg, about 250 μ g/ml or μ g/mg, about 300 μ g/ml or μ g/mg, about 350 μ g/ml or μ g/mg, about 400 μ g/ml or μ g/mg, about 450 μ g/ml or μ g/mg, or any one or more of about 400 μ g/ml or μ g/mg.Those skilled in the art will know according to the instruction of this paper depends on how route of administration and the persistent period utilized obtain suitable concentration.

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

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

In some modification, people experimenter used contain the 1 μ g that has an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 5mg amount.In some modification, people experimenter used contain the 20 μ g that have an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 4mg amount.In some modification, people experimenter used contain the 20 μ g that have an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 1.2mg amount.In some modification, people experimenter used contain the 10 μ g that have an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 0.5mg amount.In some modification, people experimenter used contain the 10 μ g that have an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 90 μ g amount.In some modification, people experimenter used contain the 60 μ g that have an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 120 μ g amount.In some modification, people experimenter used contain the 100 μ g that have an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 400 μ g amount.In some modification, people experimenter used contain the 400 μ g that have an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 1mg amount.In some modification, people experimenter used contain the 1mg that has an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 5mg amount.In some modification, people experimenter used contain the 3mg that has an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 7mg amount.In some modification, people experimenter used contain the 5mg that has an appointment and be used for the treatment of moist AMD to the self-emulsifiable preparation described herein of the rapamycin of about 10mg amount.

In some modification, people experimenter used contain the 1 μ g that has an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 5mg amount.In some modification, people experimenter used contain the 20 μ g that have an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 4mg amount.In some modification, people experimenter used contain the 20 μ g that have an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 1.2mg amount.In some modification, people experimenter used contain the 10 μ g that have an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 0.5mg amount.In some modification, people experimenter used contain the 10 μ g that have an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 90 μ g amount.In some modification, people experimenter used contain the 60 μ g that have an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 120 μ g amount.In some modification, people experimenter used contain the 100 μ g that have an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 400 μ g amount.In some modification, people experimenter used contain the 400 μ g that have an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 1mg amount.In some modification, people experimenter used contain the 1mg that has an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 5mg amount.In some modification, people experimenter used contain the 3mg that has an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 7mg amount.In some modification, people experimenter used contain the 5mg that has an appointment and be used for pre-moisture resistance AMD to the self-emulsifiable preparation described herein of the rapamycin of about 10mg amount.

In some modification, people experimenter used contain the 1 μ g that has an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 5mg amount.In some modification, people experimenter used contain the 20 μ g that have an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 4mg amount.In some modification, people experimenter used contain the 20 μ g that have an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 1.2mg amount.In some modification, people experimenter used contain the 10 μ g that have an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 0.5mg amount.In some modification, people experimenter used contain the 10 μ g that have an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 90 μ g amount.In some modification, people experimenter used contain the 60 μ g that have an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 120 μ g amount.In some modification, people experimenter used contain the 100 μ g that have an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 400 μ g amount.In some modification, people experimenter used contain the 400 μ g that have an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 1mg amount.In some modification, people experimenter used contain the 1mg that has an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 5mg amount.In some modification, people experimenter used contain the 3mg that has an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 7mg amount.In some modification, people experimenter used contain the 5mg that has an appointment and be used for the treatment of dryness AMD to the self-emulsifiable preparation described herein of the rapamycin of about 10mg amount.

In some modification, people experimenter used contain the 1 μ g that has an appointment and be used for the treatment of angiogenesis to the self-emulsifiable preparation described herein of the rapamycin of about 5mg amount, include but not limited to the choroid neovascularization.In some modification, people experimenter used contain the 20 μ g that have an appointment and be used for the treatment of angiogenesis to the self-emulsifiable preparation described herein of the rapamycin of about 4mg amount, include but not limited to the choroid neovascularization.In some modification, to people experimenter use contain have an appointment 20 μ g to about 1.2mg, about 10 μ g arrive about 0.5mg, about 10 μ g to 90 μ g, about 60 μ g to 120 μ g; About 100 μ g to 400 μ g, about 400 μ g to 1mg, about 1mg to 5mg, the self-emulsifiable preparation described herein of about 3mg rapamycin of amount to 7mg or about 5mg to 10mg is used for the treatment of angiogenesis, includes but not limited to the choroid neovascularization.

In some modification,, contain the self-emulsifiable preparation of gross weight about 0.5% to the rapamycin of about 6% concentration to using under people experimenter's conjunctiva by using the self-emulsifiable preparation described herein of about 0.1 μ l to about 200 μ l.In some modification,, contain the self-emulsifiable preparation of gross weight about 0.5% to the rapamycin of about 4% concentration to using under people experimenter's conjunctiva by using the self-emulsifiable preparation described herein of about 1 μ l to about 50 μ l.In some modification,, contain the self-emulsifiable preparation of gross weight about 1.5% to the rapamycin of about 3.5% concentration to using under people experimenter's conjunctiva by using the self-emulsifiable preparation described herein of about 1 μ l to about 15 μ l.In some modification, by using the described herein self-emulsifiable preparation of about 1 μ l, to using the self-emulsifiable preparation of the rapamycin that contains about 2% concentration of gross weight under people experimenter's conjunctiva to about 15 μ l.

In some modification,, contain the self-emulsifiable preparation of 0.5 μ g of having an appointment to the rapamycin of about 4mg amount to using under people experimenter's conjunctiva by using the self-emulsifiable preparation described herein of about 0.1 μ l to about 200 μ l.In some modification,, contain the self-emulsifiable preparation of 5 μ g of having an appointment to the rapamycin of about 2mg amount to using under people experimenter's conjunctiva by using the self-emulsifiable preparation described herein of about 1 μ l to about 100 μ l.In some modification,, contain the self-emulsifiable preparation of 5 μ g of having an appointment to the rapamycin of about 1mg amount to using under people experimenter's conjunctiva by using the self-emulsifiable preparation described herein of about 1 μ l to about 50 μ l.In some modification,, contain the self-emulsifiable preparation of 15 μ g of having an appointment to the rapamycin of about 500 μ g amount to using under people experimenter's conjunctiva by using the self-emulsifiable preparation described herein of about 1 μ l to about 25 μ l.In some modification,, contain the self-emulsifiable preparation of 20 μ g of having an appointment to the rapamycin of about 300 μ g amount to using under people experimenter's conjunctiva by using the self-emulsifiable preparation described herein of about 1 μ l to about 15 μ l.

In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of gross weight about 0.5% to the rapamycin of about 6% concentration by using the self-emulsifiable preparation described herein of about 0.1 μ l to about 200 μ l.In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of gross weight about 0.5% to the rapamycin of about 4% concentration by using the self-emulsifiable preparation described herein of about 1 μ l to about 50 μ l.In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of gross weight about 1.5% to the rapamycin of about 3.5% concentration by using the self-emulsifiable preparation described herein of about 1 μ l to about 15 μ l.In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of the rapamycin of about 2% concentration of gross weight by using the self-emulsifiable preparation described herein of about 1 μ l to about 15 μ l.

In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of 2 μ g to the rapamycin of about 4mg amount of having an appointment by using the self-emulsifiable preparation described herein of about 0.1 μ l to about 200 μ l.In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of 20 μ g to the rapamycin of about 2mg amount of having an appointment by using the self-emulsifiable preparation described herein of about 1 μ l to about 100 μ l.In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of 20 μ g to the rapamycin of about 1mg amount of having an appointment by using the self-emulsifiable preparation described herein of about 1 μ l to about 50 μ l.In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of 20 μ g to the rapamycin of about 500 μ g amount of having an appointment by using the self-emulsifiable preparation described herein of about 1 μ l to about 25 μ l.In some modification,, people experimenter's intravitreal administration is contained the self-emulsifiable preparation of 20 μ g to the rapamycin of about 300 μ g amount of having an appointment by using the self-emulsifiable preparation described herein of about 1 μ l to about 15 μ l.

In some modification, self-emulsifiable preparation is described as containing the amount of the therapeutic agent that is equal to the rapamycin amount at this paper.Described therapeutic agent component can also be expressed as the concentration that is equal to rapamycin.As used herein, the amount of the therapeutic agent that " is equal to rapamycin " or concentration refer to the amount or the concentration of therapeutic agent, it has and be used for the treatment of, prevent, postpone or suppress disease or situation, includes but not limited to the interior effect of body that the concrete dosage of the rapamycin of disease disclosed herein and situation is roughly the same.

Those skilled in the art can determine that based on the instruction of this paper how many amounts or the given therapeutic agent of concentration are 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); And US2005/0187241.

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.

In some modification, people experimenter used to contain be equal to the as herein described self-emulsifiable preparation of about 1 μ g to the amount of the therapeutic agent of about 5mg rapamycin amount, be used for the treatment of moist AMD.In some modification, people experimenter is used about 1 μ g arrives the therapeutic agent of about 0.5mg rapamycin amount to about 5mg, about 20 μ g to about 1.2mg, about 10 μ g the amount of therapeutic agent of amount that is equal to, be used for the treatment of moist AMD, people experimenter is used about 10 μ g to 90 μ g, about 60 μ g are to 120 μ g; People experimenter is used about 100 μ g to 400 μ g, and about 400 μ g are to 1mg; In some modification, people experimenter is used the amount of about 1mg to the therapeutic agent of 5mg rapamycin amount that be equal to; In some modification, people experimenter is used the amount of about 3mg to the therapeutic agent of 7mg rapamycin amount that be equal to; In some modification, people experimenter is used the amount of about 5mg to the therapeutic agent of 10mg rapamycin amount that be equal to.

In some modification, people experimenter used to contain be equal to the as herein described self-emulsifiable preparation of about 1 μ g to the amount of the therapeutic agent of about 5mg rapamycin amount, be used for the treatment of dryness AMD.In some modification, people experimenter used be equal to about 20 μ g arrive the therapeutic agent of about 0.5mg rapamycin amount to about 4mg, about 20 μ g to about 1.2mg, about 10 μ g amount, be used for the treatment of dryness AMD; People experimenter is used about 10 μ g to 90 μ g, and about 60 μ g are to 120 μ g; People experimenter is used about 100 μ g to 400 μ g, and about 400 μ g are to 1mg; In some modification, people experimenter is used the amount of about 400 μ g to the therapeutic agent of 1mg rapamycin amount that be equal to; In some modification, people experimenter is used the amount of about 1mg to the therapeutic agent of 5mg rapamycin amount that be equal to; In some modification, people experimenter is used the amount of about 3mg to the therapeutic agent of 7mg rapamycin amount that be equal to; In some modification, people experimenter used be equal to the amount of about 5mg to the therapeutic agent of 10mg rapamycin amount, be used for the treatment of dryness AMD.

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

In some modification, per 3 or more months, per 6 or more months, per 9 or more months, per 12 or more months or longer time intravitreal administration one or more preparations described herein, with one or more of treatment choroid neovascularization, moist AMD, dryness AMD, or pre-moisture resistance 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, per 12 or more months or the longer time conjunctiva, with one or more of treatment choroid neovascularization, moist AMD, dryness AMD, or pre-moisture resistance AMD.

In some modification, per 3 or more months, per 6 or more months, per 9 or more months, per 12 or more months or longer time intravitreal administration any one or more rapamycin preparation described herein, with one or more of treatment choroid neovascularization, moist AMD, dryness AMD, or pre-moisture resistance AMD.In some modification, use one or more rapamycin preparations described herein under per 3 or more months, per 6 or more months, per 9 or more months, per 12 or more months or the longer time conjunctiva, with one or more of treatment choroid neovascularization, moist AMD, dryness AMD, or pre-moisture resistance AMD.In some modification, the effect of rapamycin last till it in ocular tissue by LCMS measurable during outside.

Sending of therapeutic agent described herein can for example be sent with about 1ng/ days to about 100 μ g/ days dosage range or with the dosage that is higher or lower than this scope, depends on route of administration and persistent period.In some modification of the self-emulsifiable preparation that is used for methods described herein, with about 0.1 μ g/ days to about 10 μ g/ days dosage range delivering therapeutic agents.In some modification of the preparation that is used for methods described herein, with about 1 μ g/ days to about 5 μ g/ days dosage range delivering therapeutic agents.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.

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.

By injecting the level of organizing of preparation realization described herein

When therapeutic agent was rapamycin, self-emulsifiable preparation can be used for sending in vitreous body or the rapamycin of the amount of remaining valid.In a limiting examples, think to be used for the treatment of moist AMD with the delivery system that can in vitreous body, provide about 1pg/ml to send rapamycin to the amount of about 2 μ g/ml rapamycin concentrations.When the intravitreal administration rapamycin, the continuous Emulsion bolus (bolus) of initial application has been got rid of in the calculating of rapamycin concentrations in the vitreous body.In another limiting examples, think that sending rapamycin can be used for the treatment of moist AMD to obtain about l pg/mg in retina or choroid to the delivery system of about 1ng/mg rapamycin concentrations.Instruction those skilled in the art according to this paper can easily determine other valid density.

This paper has described self-emulsifiable preparation, and it demonstrates and removes spectrum in the body with one or more following features.This removing spectrum is inject self-emulsifiable preparation in lagophthalmos eyeball vitreous body after, the removing spectrum of removing in this therapeutic agent body.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.

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 (Betadin e).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, F.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.

" 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.

Behind the intravitreal injection of lagophthalmos 5 hours, the average percent removing causes comparing with the level of the back 1 hour vitreous body internal therapy of injection agent in the body, about 70% to about 150%, more generally about 90% to about level of treatment agent of 130%, more generally about 110% to about 120% in the vitreous body.Behind the intravitreal injection of lagophthalmos 5 hours, the average percent of vitreous body internal therapy agent was compared with the level of the back 1 hour vitreous body internal therapy of injection agent, can less than about 150%, more generally less than about 120%.

Behind the intravitreal injection of lagophthalmos 24 hours, the average percent removing causes comparing with the level of the back 1 hour vitreous body internal therapy of injection agent in the body, about 50% to about 110%, more generally about 60% to about level of treatment agent of 100%, more generally about 70% to about 90% in the vitreous body.Behind the intravitreal injection of lagophthalmos 5 hours, the average percent of vitreous body internal therapy agent was compared with the level of the back 1 hour vitreous body internal therapy of injection agent, can less than about 110%, more generally less than about 90%.

Behind the intravitreal injection of lagophthalmos 72 hours, the average percent removing causes comparing with the level of the back 1 hour vitreous body internal therapy of injection agent in the body, about 0.1% to about 20%, more generally about 1% to about level of treatment agent of 10%, more generally about 3% to about 7% in the vitreous body.Behind the intravitreal injection of lagophthalmos 5 hours, the average percent of vitreous body internal therapy agent was compared with the level of the back 1 hour vitreous body internal therapy of injection agent, can less than about 20%, more generally less than about 10%.

Behind the intravitreal injection of lagophthalmos 168 hours, the average percent removing causes comparing with the level of the back 1 hour vitreous body internal therapy of injection agent in the body, about 0.01% to about 10%, more generally about 0.1% to about level of treatment agent of 5%, more generally about 0.1% to about 1% in the vitreous body.Behind the intravitreal injection of lagophthalmos 5 hours, the average percent of vitreous body internal therapy agent was compared with the level of the back 1 hour vitreous body internal therapy of injection agent, can less than about 5%, more generally less than about 1%.

Described self-emulsifiable preparation, average percent is removed and the feature of comparing below having in 1 hour behind the lagophthalmos intravitreal injection in its body: the level of injecting back 5 hours therapeutic agents is less than about 150%; The level of injecting back 24 hours therapeutic agents is less than about 100%; The level of injecting back 72 hours therapeutic agents is less than about 25%; The level of injecting back 168 hours therapeutic agents is less than about 1%.

In some modification, self-emulsifiable preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation at least about 3 days, at least about 6 days, at least about 9 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is at least about 10ng/mL in the lagophthalmos vitreous body.In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation at least about 3 days, at least about 6 days, at least about 9 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is at least about 100ng/mL in the lagophthalmos vitreous body.In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation at least about 3 days, at least about 6 days, at least about 9 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is at least about 1 μ g/mL in the lagophthalmos vitreous body.In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation at least about 3 days, at least about 6 days, at least about 9 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is at least about 10 μ g/mL in the lagophthalmos vitreous body.In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation at least about 3 days, at least about 6 days, at least about 9 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is at least about 100 μ g/mL in the lagophthalmos vitreous body.In some modification, therapeutic agent is a rapamycin.

In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation 1 day at least about 2 days, at least about 4 days, at least about 6 days, at least about 8 days, at least about 10 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent arrives about 10 μ g/mL for about 10ng/mL in the lagophthalmos vitreous body.In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation 1 day at least about 2 days, at least about 4 days, at least about 6 days, at least about 8 days, at least about 10 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent arrives about 10 μ g/mL for about 100ng/mL in the lagophthalmos vitreous body.In some modification, therapeutic agent is a rapamycin.

" 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 that different time is measured in the correlation time section and the difference between the minima are less than 10 times.

In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation 1 day at least about 2 days, at least about 4 days, at least about 6 days, at least about 8 days, at least about 10 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is roughly constant at the value place greater than about 10ng/mL in the lagophthalmos vitreous body.In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation 1 day at least about 2 days, at least about 4 days, at least about 6 days, at least about 8 days, at least about 10 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is roughly constant at the value place greater than about 100ng/mL in the lagophthalmos vitreous body.In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation 1 day at least about 2 days, at least about 4 days, at least about 6 days, at least about 8 days, at least about 10 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is roughly constant greater than the value place of about 1 μ g/mL in the lagophthalmos vitreous body.In some modification, liquid preparation is delivering therapeutic agents when being expelled to the lagophthalmos vitreous body, obtain behind lagophthalmos applicating liquid preparation 1 day at least about 2 days, at least about 4 days, at least about 6 days, at least about 8 days, at least about 10 days, at least about 12 days or at least about 15 days, the mean concentration of therapeutic agent is roughly constant greater than the value place of about 10 μ g/mL in the lagophthalmos vitreous body.In some modification, therapeutic agent is a rapamycin.

Described self-emulsifiable preparation, the average percent removing was compared with injection and had following feature in back 1 hour in its body: the level of injecting back 5 hours therapeutic agents is less than about 125%; The level of injecting back 24 hours therapeutic agents is less than about 90%; The level of injecting back 72 hours therapeutic agents is less than about 10%; The level of injecting back 168 hours therapeutic agents is less than about 0.5%.

Described self-emulsifiable preparation, the average percent removing was compared with injection and had following feature in back 1 hour in its body: the level of injecting back 5 hours therapeutic agents is greater than about 90%; The level of injecting back 24 hours therapeutic agents is greater than about 70%; The level of injecting back 72 hours therapeutic agents is greater than about 5%; The level of injecting back 168 hours therapeutic agents is greater than about 0.1%.

For the generation for the treatment of, prevent, suppress, postpone some disease or disease or cause that it disappears, can wish in the time period that prolongs, to keep the therapeutic agent of delivery treatments effective dose.Depend on treat, prevent, suppress, postpone to take place or cause that disease or the disease that disappears, the time period of this delay can reach for 1 week, reached for 2 weeks, reached for 3 weeks, reach 1 month, reach 3 months, reach 6 months, reach 9 months or reach 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 self-emulsifiable preparation, and described self-emulsifiable preparation is kept the concentration of therapeutic agent in the eye in the time that prolongs, and 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 use a kind of self-emulsifiable preparation in the time that prolongs, or finishes by the self-emulsifiable preparation of using two or more dosage.The limiting examples of repeatedly using as this class is kept the therapeutic dose of rapamycin and was used for the treatment of moist in three months or dryness AMD can be by using a kind of self-emulsifiable preparation of 3 months of delivery treatments amount, or uses multiple self-emulsifiable preparation by order and finish.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 determine spendable administration strategy.

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 preparation 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 preparation, the release that this class is delayed can be useful.According to therapeutic agent of being sent and/or the disease and the disease of being treated or preventing, 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 described and according to the instruction of this paper at this paper, spendable other delayed release preparations will be proficient in this technology personnel clearly.

The method for preparing self-emulsifiable preparation

Can be used to prepare self-emulsifiable preparation described herein, a kind of non-limiting method that includes but not limited to comprise the self-emulsifiable preparation of rapamycin is, cool off said preparation by mixed solvent, therapeutic agent and surfactant under the temperature that raises at room temperature or a little then together up to obtaining relative limpid solution.Additive that other are optional such as above-mentioned those can mix with said preparation.Can use additive method, and according to the instruction of this paper, these methods will be that those skilled in the art are familiar with.

Send rapamycin in the vitreous body and be used for the treatment of AMD

In modification more described herein, the vitreous body that the self-emulsifiable preparation that will comprise rapamycin is delivered to eye with prevention, treatment, suppress, postpone the eye medium vessels and generate or cause that it disappears, as prevention, treatment, suppress, postpone as in AMD observed CNV generation or cause that it disappears.Shown that rapamycin suppresses the CNV in rat and the mouse model, as describing in the U. S. application number 10/665,203, with its complete being incorporated herein by reference.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 and self-emulsifiable preparation can be used for people and veterinary purpose and is used for other possible animal.For sending rapamycin to the people to suppress the situation of CNV, the chemical compound that has shown a kind of amount of suppression is to organize level that the amount of about 10ng/ml is provided.The rapamycin of this concentration and higher and lower concentration can be used for method described herein.A kind of concentration that can be used for the rapamycin of method described herein is to organize level that the about 1ng/ml or the concentration of rapamycin still less are provided; Operable another concentration is to organize level that about 2ng/ml or concentration still less are provided, and operable another concentration is to organize level that about 3ng/ml or concentration still less are provided; Operable another concentration is to organize level that about 5ng/ml or concentration still less are provided; Operable another concentration is to organize level that about 10ng/ml or concentration still less are provided; Operable another concentration is to organize level that about 15ng/ml or concentration still less are provided; Operable another concentration is to organize level that about 20ng/ml or concentration still less are provided; Operable another concentration is to organize level that about 30ng/ml or concentration still less are provided; Operable another concentration is to organize level that about 50ng/ml or concentration still less are provided.One skilled in the art will know that instruction, depend on how the route of administration of utilization and persistent period obtain suitable concentration according to this paper.

Sending of disclosed therapeutic agent can be for example, and with the about 1 pik/kg/ days dosage ranges to about 300mg/kg/ days (about experimenter's body weight), the dosage that perhaps is higher or lower than this scope was sent, and depends on route of administration and persistent period.In the certain methods of using self-emulsifiable preparation described herein, with about 1 pik/kg/ days to about 1mg/kg/ days dosage range delivering therapeutic agents.The dosage that is used for the treatment of the multiple therapeutic agent of multiple disease described herein and disease can be by using clinical trial optimization.

Self-emulsifiable preparation described herein can be used in the time that prolongs to eye, especially Yan aqueous medium, include but not limited to, the rapamycin of the zone between vitreous body, aqueous humor, sclera, conjunctiva, CSC and other aqueous environments delivery treatments effective doses, with treatment, prevention, suppress, postpone the generation of CNV or cause that it disappears, thereby can be used for the treatment of, prevent, suppress, postpone the generation of moist or dryness AMD or cause that it disappears.Think by changing some features of self-emulsifiable preparation described herein, the position of the component, formulation delivered that includes but not limited to self-emulsifiable preparation in the eye, include but not limited between vitreous body or the CSC, with the volume of using, self-emulsifiable preparation described herein can be used in the time period of multiple prolongation to the rapamycin of eye delivery treatments effective dose, comprise the delivery treatments amount greater than about 1 week, greater than about 2 weeks, greater than about 3 weeks, greater than about 1 month, greater than about 3 months, greater than about 6 months, greater than about 9 months, greater than about 1 year.

When to the rapamycin of experimenter's administering therapeutic effective dose of suffering from moist AMD, rapamycin can treat, suppress moist AMD or cause disappearing of moist AMD.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.

This paper has described self-emulsifiable preparation, and it demonstrates and removes spectrum in the body with one or more following features.This removing spectrum is inject self-emulsifiable preparation in lagophthalmos eyeball vitreous body after, the removing spectrum of removing in this rapamycin body.The volume of lagophthalmos is about 30-40% of human eye.The amount of rapamycin 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.

Injected back 5 hours, average percent is removed and is caused comparing with the level of rapamycin in back 1 hour vitreous body of injection in the body, and about 70% to about 150%, more generally about 90% arrives about rapamycin levels of 130%, more generally about 110% to about 120% in the vitreous body.Injected back 5 hours, in the vitreous body in back 1 hour vitreous body of the average percent of rapamycin and injection the level of rapamycin compare, can less than about 150%, more generally less than about 120%

Injected back 24 hours, average percent is removed and is caused comparing with the level of rapamycin in back 1 hour vitreous body of injection in the body, and about 50% to about 110%, more generally about 60% arrives about rapamycin levels of 100%, more generally about 70% to about 90% in the vitreous body.Injected back 5 hours, in the vitreous body in back 1 hour vitreous body of the average percent of rapamycin and injection the level of rapamycin compare, can less than about 100%, more generally less than about 90%.

Injected back 72 hours, average percent is removed and is caused comparing with the level of rapamycin in back 1 hour vitreous body of injection in the body, and about 0.1% to about 20%, more generally about 1% arrives about rapamycin levels of 10%, more generally about 3% to about 7% in the vitreous body.Injected back 5 hours, in the vitreous body in back 1 hour vitreous body of the average percent of rapamycin and injection the level of rapamycin compare, can less than about 20%, more generally less than about 10%.

Injected back 168 hours, average percent is removed and is caused comparing with the level of rapamycin in back 1 hour vitreous body of injection in the body, and about 0.01% to about 10%, more generally about 0.1% arrives about rapamycin levels of 5%, more generally about 0.1% to about 1% in the vitreous body.Injected back 5 hours, in the vitreous body in back 1 hour vitreous body of the average percent of rapamycin and injection the level of rapamycin compare, can less than about 5%, more generally less than about 1%.

Described self-emulsifiable preparation, the average percent removing was compared with injection and had following feature in back 1 hour in its body: the level of injecting back 5 hours rapamycins is less than about 150%; The level of injecting back 24 hours rapamycins is less than about 100%; The level of injecting back 72 hours rapamycins is less than about 25%; The level of injecting back 168 hours rapamycins is less than about 1%.

Described self-emulsifiable preparation, the average percent removing was compared with injection and had following feature in back 1 hour in its body: the level of injecting back 5 hours rapamycins is less than about 125%; The level of injecting back 24 hours rapamycins is less than about 90%; The level of injecting back 72 hours rapamycins is less than about 10%; The level of injecting back 168 hours rapamycins is less than about 0.5%.

Described self-emulsifiable preparation, the average percent removing was compared with injection and had following feature in back 1 hour in its body: the level of injecting back 5 hours rapamycins is greater than about 90%; The level of injecting back 24 hours rapamycins is greater than about 70%; The level of injecting back 72 hours rapamycins is greater than about 5%; The level of injecting back 168 hours rapamycins is greater than about 0.1%.

Embodiment

Unless context has explanation in addition, the part that is by weight of part, molecular weight is a mean molecule quantity, and temperature is degree centigrade, and pressure is or near atmospheric pressure.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 200proof ethanol of CA.When using rapamycin, it is from LC laboratories, Woburn, MA or Chunghwa Chemical Synthesis ﹠amp; Biotech Co., LTD (CCSB), Taipei Hsien, Taiwan, ROC.When using PEG400, it is from The DowChemical Company, New Milford, CT.W/w refers to the final weight of the weight of specific components with respect to preparation.

Embodiment 1-preparation and sign contain the self-emulsifiable preparation of rapamycin

1.47% rapamycin w/w is dissolved among the 11.77% ethanol w/w, then mixes with 43.44%Cremophor EL w/w and 43.44%Capmuls PG8w/w gentleness.Said preparation is translucent.When the vitreous body of contact aqueous medium such as water or lagophthalmos, the microemulsion that preparation forms and become " muddy " or " lactous ", nondispersive agglomerate is opposite with forming.

Embodiment 2-contains the self-emulsifiable preparation of rapamycin to the intravitreal injection of eye

The 50 μ l preparations of describing among the embodiment 1 are expelled in the vitreous body of New Zealand (New Zealand) white rabbit eye.Analyze the wherein concentration of remaining rapamycin with (zone that the comprises the self-emulsifiable preparation injection) homogenate of whole vitreous body and at 1,5,24,72 and 168 hour.Quality by the rapamycin that will measure is calculated Vitrea mean concentration divided by the Vitrea volume of being analyzed.This analysis is undertaken by liquid chromatography-mass spectrometry (LCMS).Each time point is represented two rabbits meansigma methods of eyes (four eyes of each time point) separately.

Be respectively about 347, about 401, about 273, about 18 and about 1 μ g/ μ l in the mean concentration of 1,5,24,72 and 168 hour rapamycin.These results show in Fig. 1.

Embodiment 3-preparation and sign contain the self-emulsifiable preparation of rapamycin

Rapamycin is dissolved in 100% ethanol, then mixes with Caprol MPGO and Softigen767 gentleness.Final percentage ratio by gross weight is 2%w/w rapamycin, 4%w/w ethanol, 47%w/w Caprol MPGO and w/w47%Softigen767.

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.

Claims (40)

1. the method for the degeneration of macula that treatment people's age is relevant, this method comprises uses self-emulsifiable preparation to experimenter's eyes, and this self-emulsifiable preparation comprises the therapeutic agent of relevant degeneration of macula effective dose of treatment age.

2. the method for claim 1, wherein said self-emulsifiable preparation is sent a certain amount of described therapeutic agent when time in the vitreous body that is expelled to lagophthalmos, described amount is enough to be implemented in self-emulsifiable preparation is applied to behind the lagophthalmos at least about in 7 days time period, and the mean concentration of therapeutic agent is equal to the rapamycin concentrations at least about 0.001ng/ml in the retina choroid of lagophthalmos.

3. the method for claim 2, wherein said self-emulsifiable preparation is sent a certain amount of described therapeutic agent when time in the vitreous body that is expelled to lagophthalmos, described amount is enough to be implemented in self-emulsifiable preparation is applied to behind the lagophthalmos at least about in 7 days time period, and the mean concentration of therapeutic agent is equal to the rapamycin concentrations at least about 0.01ng/ml in the retina choroid of lagophthalmos.

4. the method for claim 3, wherein said self-emulsifiable preparation is sent a certain amount of described therapeutic agent when time in the vitreous body that is expelled to lagophthalmos, described amount is enough to be implemented in self-emulsifiable preparation is applied to behind the lagophthalmos at least about in 7 days time period, and the mean concentration of therapeutic agent is equal to the rapamycin concentrations at least about 0.1ng/ml in the retina choroid of lagophthalmos.

5. the method for claim 2, wherein said self-emulsifiable preparation is sent a certain amount of described therapeutic agent when time in the vitreous body that is expelled to lagophthalmos, described amount is enough to be implemented in self-emulsifiable preparation is applied to behind the lagophthalmos at least about in 7 days time period, and the mean concentration of therapeutic agent is equal to the rapamycin concentrations at least about 1ng/ml in the retina choroid of lagophthalmos.

6. the process of claim 1 wherein that but described therapeutic agent is in conjunction with exempting from proteic chemical compound.

7. the process of claim 1 wherein that described therapeutic agent is selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and its analog, salt and ester.

8. the method for claim 7, wherein said therapeutic agent is a rapamycin.

9. the process of claim 1 wherein the aqueous medium that described self-emulsifiable preparation is placed experimenter's eye.

10. the method for claim 9 wherein places described self-emulsifiable preparation the vitreous body of experimenter's eye.

11. the method for claim 9 wherein places described self-emulsifiable preparation between the CSC of experimenter's eye.

12. the process of claim 1 wherein that described self-emulsifiable preparation also comprises solvent.

13. the method for claim 12, wherein said self-emulsifiable preparation also comprises surfactant.

14. the method for claim 13, wherein said glass or plastic containers.

15. the method for claim 14, wherein said non-ionic surface active agent have the HLB value greater than about 10.

16. the method for claim 15, wherein said non-ionic surface active agent is CremophorEL.

17. the method for claim 12, wherein said solvent is a fatty acid.

18. the method for claim 12, wherein said solvent are selected from oleic acid, Imwitor 742, Softigen767 or Capmuls PG8.

19. treatment people's the disease or the method for disease, this method comprises uses the self-emulsifiable preparation that comprises a certain amount of rapamycin to people experimenter's eyes, and the amount of described rapamycin can effectively be treated one or more of choroid neovascularization, iris neovascularization, degeneration of macula, moist AMD, dryness AMD, uveitis, anaphylaxis conjunctivitis, xerophthalmia, glaucoma, retinitis pigmentosa, central retinal vein occlusion disease, macular edema, diabetic retinopathy and corneal transplantation disease.

20. the method for claim 19, wherein rapamycin exists with the amount of the moist AMD of effective treatment.

21. the method for claim 19, wherein rapamycin exists with the amount of effectively pre-moisture resistance AMD.

22. the method for claim 20 or 21 wherein places self-emulsifiable preparation the vitreous body of experimenter's eye.

23. the method for claim 20 or 21 wherein places self-emulsifiable preparation between the CSC of experimenter's eye.

24. the method for claim 22, wherein self-emulsifiable preparation contains the 20 μ g that have an appointment to about 4mg.

25. the method for claim 23, wherein self-emulsifiable preparation contains the 20 μ g that have an appointment to about 4mg.

26. the method for claim 22 or 23, wherein self-emulsifiable preparation contains the 20 μ g that have an appointment to about 1mg.

27. self-emulsifiable preparation, but proteic chemical compound is exempted from its combination that comprises the amount of the moist AMD of effective treatment, dryness AMD or CNV; Solvent and surfactant are wherein prepared the aqueous medium that this self-emulsifiable preparation is used for being placed on experimenter's eye.

28. self-emulsifiable preparation, but proteic chemical compound is exempted from its combination that comprises the amount of the moist AMD of effective prevention; Solvent and surfactant are wherein prepared the aqueous medium that this self-emulsifiable preparation is used for being placed on experimenter's eye.

29. the self-emulsifiable preparation of claim 28, wherein said chemical compound are selected from rapamycin, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, CCI-779, AP23841, ABT-578 and its analog, salt and ester.

30. the self-emulsifiable preparation of claim 29, wherein said chemical compound is a rapamycin.

31. the self-emulsifiable preparation of claim 30, wherein this self-emulsifiable preparation is sent the rapamycin of the amount of effective treatment experimenter median nexus film neovascularization when being applied to the experimenter.

32. the self-emulsifiable preparation of claim 30, wherein this self-emulsifiable preparation is sent the rapamycin of the amount of the degeneration of macula that the moist age is relevant among effective treatment experimenter when being applied to the experimenter.

33. the self-emulsifiable preparation of claim 30, wherein this self-emulsifiable preparation is sent the rapamycin of the amount of the degeneration of macula that the moist age is relevant among effective prevention experimenter when being applied to the experimenter.

34. the self-emulsifiable preparation of claim 30, wherein said glass or plastic containers.

35. the self-emulsifiable preparation of claim 30, wherein said surfactant have the HLB value greater than about 10.

36. the self-emulsifiable preparation of claim 30, wherein said solvent is a fatty acid.

37. the self-emulsifiable preparation of claim 30, wherein said solvent are selected from oleic acid, Imwitor 742, Softigen 767 or Capmuls PG8.

38. the self-emulsifiable preparation of claim 34, wherein said non-ionic surface active agent are Cremophor EL.

39. the self-emulsifiable preparation of claim 34, wherein said self-emulsifiable preparation contain 0.1 to the 5%w/w rapamycin; About 40 to 50%w/w solvent; With 40 to the non-ionic surface active agent of 50%w/w.

40. the self-emulsifiable preparation of claim 39, it also comprises ethanol.