CN101237871A - Methods and compositions for the treatment of ocular disorders - Google Patents
Methods and compositions for the treatment of ocular disorders Download PDFInfo
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- CN101237871A CN101237871A CNA2006800289138A CN200680028913A CN101237871A CN 101237871 A CN101237871 A CN 101237871A CN A2006800289138 A CNA2006800289138 A CN A2006800289138A CN 200680028913 A CN200680028913 A CN 200680028913A CN 101237871 A CN101237871 A CN 101237871A
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Abstract
The invention provides methods and compositions for the delivery of lipophilic drugs that are useful for the treatment of various ophthahnological diseases, disorders, and pathologies, including the treatment of age-related macular degeneration, diabetic retinopathy, diabetic macular edema, cancer, and glaucoma.
Description
Related application data
The application enjoys the U.S. Patent application serial number of submitting on June 8th, 2,005 60/689 according to 35U.S.C. § 119 (e) request, 60/763 of submission on January 30th, 111 and 2006,537 priority intactly is incorporated herein by reference these documents full content separately.
Technical field
The present invention relates generally to oculopathy, and more particularly, be related to the ocular delivery composition prepared, in particular for the application of the preparation that is delivered to a rear portion.
Background technology
Usually one of difficulty that occurs in treatment oculopathy is effectively to pass through the intraocular delivery therapeutic agent.When by the intraocular delivery medicine, its generally diffusion removing from ocular tissue.Because medicine is sent pleasing to the eye inherent difficulty, so successfully treat normally difficulty of oculopathy.
Because the anatomical structure and the physiology characteristic thereof of eye, so drug targeting to suitable site of action normally is delivered to medicine one of challenge maximum in the eye.
Traditionally, local ophthalmic solution, suspension and semisolid have been used for the eye treatment preparation.The shortcoming relevant with using this class regular dosage form is that they show the thing availability deficiency of looking unfamiliar usually.More recent, researched and developed other medicament for the eyes delivery system.In these systems some comprises controlled release system, such as ocular inserts, nanoparticle, mucoadhesive polymer, water solublity medicine carrying thin film and liposome dosage form.The back has shown certain hope for one type, but the encapsulation medicine stability deficiency that shows.In addition, can effectively medicine be delivered to eye by the part instillation although confirmed Liposomal formulation, they can not describe and can use the delivery system that is suitable for the commodity application that medicine effectively is delivered to the necessary parameter in a rear portion.Therefore, the application of liposome dosage form only is limited.
Many present available eye medicinals exist quite to higher water solublity, and consider that usually medicine with limited solubility very or those think water-fast medicine instability, and in some cases, it are abandoned as further researching and developing.In these lipotropys and the water-insoluble drug some can have required treatment characteristic, and because its deliquescent problem, so it is utilized.Medicine at this apoplexy due to endogenous wind can have high-affinity to palladium cell membrane and lipotropy tissue, but is difficult to send because of its low aqueous solubility with in the difficulty of attempting giving to produce in their process.In these lipotropys and the water-insoluble drug some can have high-affinity to phospholipid, thereby make them be adapted to pass through liposome or phospholipid composite is sent, wherein medicine is not encapsulated in the water core of liposome, but the integral part of formation phospholipid substrate or immobilized artificial membrane.
Although be not illustrated in the general absorption process of ophthalmic as yet fully, as everyone knows at molecular characterization, have dependency between transporting and penetrating, it works in absorption process.Knownly between medicine is by biomembranous permeability and octanol-water partition coefficient, there is dependency.Use the rabbit corneal of chopping confirm LogP be 2.9 for beta-Blocking agent and corneal permeability the best thereof (referring to Schoenwald etc., 1983, J.Pharm.Sci., 72:1266).Regrettably, sending because of its low aqueous solubility or unsuitable pharmaceutical dosage form of this class lipophilic drugs is limited, particularly is being delivered at the moment.
Therefore, need and to have the lipid vesicle that becomes the lipid composition of forming by at least a phospholipid with water-insoluble preparation of pharmaceutical formulations of high-affinity to phospholipid.This based composition is not formerly illustrated as yet, but need, because they have high efficiency load and cause " seepage " to ignore with water than the height distribution of going into the lipid generation because of medicament distribution.
Summary of the invention
One embodiment of the invention provide the compositions for the treatment of various oculopathy, comprise medicine or its prodrug and the pharmaceutically acceptable carrier that is used for ocular delivery, and wherein said medicine is not a steroid molecule.Described medicine or its prodrug have and are no more than about 150
2, such as being lower than about 120
2Polar surfaces long-pending, for example, be no more than about 100
2Polar surfaces long-pending.Described medicine or its prodrug can further have under the pH of 4-8 scope and be lower than about 0.1mg/mL, such as be lower than about 0.05mg/mL under the pH of 4-8 scope, for example are lower than the water solublity of about 0.01mg/mL under the pH of 4-8 scope.Described medicine or its prodrug can also have under pH7.4 and be at least about 0.5 cLogD, such as being at least about 1, for example, are at least 2.Described medicine or its prodrug can have and be no more than about 1,000 dalton, such as being no more than about 900 dalton, for example are no more than about 800 daltonian molecular weight.The limited medicine of the present invention or some selection as known in the art and the physics and the chemical characteristic of prodrug are as shown in table 1.
Table 1
The medicine of some selection or the physicochemical characteristic of prodrug
| Chemical compound and characteristic | pH＝7.4 | mg/mL | The phospholipid affinity | |||||
| PSA | Lorentz-Lorenz molar refraction | Molal volume | IR | cLogD | Water solublity (pH5) | PC: medicine (mole) | Polarizability | |
| Acetazolamide | 151.66 | 45.95 | 127.39 | 1.64 | -0.55 | ＜1 | 18.22 | |
| Brimonidine | 62.2 | 68.42 | 160.3 | 1.8 | -0.39 | ＞2 | 27.12 | |
| III | 119.48 | 134.24 | 348.06 | 1.7 | -0.37 | 53.22 | ||
| Su11248 1) | 77.23 | 112.52 | 324.06 | 1.61 | 0.85 | ＞1 | 30∶1 | 44.61 |
| XXI *) | 144.06 | 97.88 | 228.43 | 1.8 | 0.93 | ＜＜0.1 | ＞100∶1 | 38.8 |
| Propranolol | 41.49 | 78.99 | 237.16 | 1.58 | 1.37 | ～0.1 | 31.31 | |
| XII | 139.74 | 145.38 | 385.74 | 1.68 | 0.14 | ＜＜0.1 | 100∶1 | 57.63 |
| Tropicamide | 53.43 | 82.2 | 244.83 | 1.59 | 1.15 | ＜1 | ＞2∶1 | 32.59 |
| I | 79.38 | 127.51 | 341 | 1.67 | 1.21 | ＜＜0.1 | 50.55 | |
| AP23464 2) | 102.74 | 133.99 | 351.01 | 1.69 | 1.42 | ＞0.1 | 53.12 | |
| CGP76775 3) | 89.43 | 127.62 | 338.86 | 1.68 | 1.92 | ＜0.1 | 50.59 | |
| XVII | 89.47 | 144.73 | 396.71 | 1.65 | 2.31 | ＜＜0.1 | 30∶1 | 57.38 |
| TAA 4) | 93.06 | 109.41 | 324.83 | 1.59 | 2.5 | ＜0.1 | 43.37 | |
| XV | 128.72 | 146.74 | 388.34 | 1.68 | 2.61 | ＜＜0.1 | 58.17 | |
| VII | 128.72 | 143.84 | 384.4 | 1.67 | 2.63 | ＜＜0.1 | 30∶1 | 57.02 |
| V | 83.4 | 135.27 | 357.51 | 1.68 | 2.71 | ＜＜0.1 | 30∶1 | 53.63 |
| The V-propionate | 89.47 | 149.37 | 413.22 | 1.64 | 2.84 | ＜＜0.1 | 59.21 | |
| XVI | 128.72 | 148.67 | 396.05 | 1.67 | 2.94 | ＜＜0.1 | 58.94 | |
| PP1 5) | 69.62 | 83.46 | 228.25 | 1.65 | 3.11 | ＜0.1 | 33.09 | |
| XX | 89.47 | 153.96 | 430.1 | 1.63 | 3.19 | ＜＜0.1 | 10∶1 | 61.03 |
| VIII | 102.36 | 163.13 | 435.72 | 1.67 | 3.24 | ＜＜0.1 | 64.67 | |
| AZM475271 6) | 77.97 | 127.97 | 353.72 | 1.64 | 3.26 | ＜＜0.1 | 50.73 | |
| XIII | 108.49 | 146.73 | 406.27 | 1.64 | 3.48 | ＜＜0.1 | ＜20∶1 | 58.17 |
| X | 89.47 | 158.6 | 446.28 | 1.63 | 3.54 | ＜＜0.1 | 10∶1 | 62.87 |
| IV | 63.17 | 138.15 | 379.68 | 1.65 | 3.56 | ＜＜0.1 | 10∶1 | 54.77 |
| XI | 63.17 | 138.29 | 371.03 | 1.67 | 3.61 | ＜＜0.1 | 10∶1 | 54.82 |
| Vatalanib | 50.7 | 101.95 | 260.61 | 1.71 | 3.79 | ＞2 | Unstable | 40.42 |
| XVIII | 134.79 | 173.51 | 469.09 | 1.66 | 4.43 | ＜＜0.1 | 30∶1 | 68.78 |
| VI | 89.47 | 165.04 | 442.5 | 1.67 | 4.5 | ＜＜0.1 | 10∶1 | 65.43 |
| The valeric acid dexamethasone | 100.9 | 123.71 | 382.35 | 1.56 | 4.55 | ＜＜0.1 | 49.04 | |
| SKI606 7) | 82.88 | 141.92 | 388.35 | 1.65 | 4.63 | ＜1 | 10∶1 | 56.26 |
| XIX | 89.47 | 169.86 | 458.77 | 1.66 | 4.96 | ＜＜0.1 | 67.34 | |
| PD180970 8) | 58.12 | 111.04 | 296.16 | 1.67 | 5.13 | ＜＜0.1 | 44.02 | |
| Cholesterol | 20.23 | 119.97 | 391.43 | 1.53 | 9.85 | ＜＜1 | ＞2∶1 | 47.56 |
| Tacrolimus (FK506) | 178.36 | 214.13 | 673.12 | 1.55 | 3.96 | ＜0.1 | 84.89 | |
| Cyclosporin A | 278.8 | 328.83 | 1183.63 | 1.47 | 3.35 | ＞1 | 130.36 |
Note: Roman number refers to the chemical compound of the application shown under those numerals
*)XXI refers to compounds X XI:
1)Sugen11248 refers to commercially available chemical compound
2)AP23464 refers to commercially available chemical compound
3)CGP76775 refers to commercially available chemical compound
4)TAA refers to commercially available chemical compound
5)PP1 refers to commercially available chemical compound
6)AZM475271 refers to commercially available chemical compound
7)SKI 606 refers to can be available from the chemical compound of Smith Kline Co.
8)PD180970 refers to commercially available chemical compound
According to another embodiment of the invention, compositions comprises reactive compound or the medicine with structure A:
In structure A, A is can be separately independent be CH, N, NH, O, S, or fusion is so that form one of the ingredient of the ring of second ring, and wherein second ring can be aromatics, heteroaromatic, bicyclic aromatic or bicyclic aromatic heterocycle;
B can be separately independent for CH or fusion so that form the ingredient of the ring of second ring, wherein second ring can for aromatics, bicyclic aromatic or only first ring be the dicyclo of aromatics;
A
1Can be NRa, C (O), S (O), S (O)
2, P (O)
2, O, S or CR
aOne of, wherein R can be H, low alkyl group, branched alkyl, hydroxy alkyl, aminoalkyl, alkylthio, alkyl hydroxy, alkyl thiol or alkylamino, and if A wherein
1Be NR
a, if a=1 so is and A
1Be CR
a, a=2 so;
A
2Can be NR, C (O), S (O), S (O)
2, P (O)
2, one of O or S, condition is A
1With A
2Between to be connected chemically be correct;
R
0Can be one of H, low alkyl group or branched alkyl;
L
1Can be key, O, S, C (O), S (O), S (O)
2, NR
a, C
1-C
6One of alkyl; L
2Can be key, O, S, C (O), S (O), S (O)
2, C
1-C
6Alkyl, NR
aOne of; Or L
1And L
2Can be key each other;
R
b, R
d, R
eAnd R
rDo not exist separately or independent be H, C
1-C
6One of alkyl, cycloalkyl, branched alkyl, hydroxy alkyl, aminoalkyl, alkylthio, alkyl hydroxy, alkyl thiol or alkylamino;
P, q, m, r are separately independently for having the integer of 0 to 6 value;
R
bAnd R
dLump together and to be (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or
R
bAnd R
eLump together and to be (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or
R
dAnd R
fLump together and to be (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or
R
bAnd R
fLump together and to be (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
mOr (CH
2)
r-O-(CH
2)
mOne of; Or
R
dAnd R
eLump together and to be (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
m(CH
2)
r-O-(CH
2)
mOne of;
R
1Can be (CR
a)
m, (O) R ', C (O) N (R ') of O, N, S, C (O)
2, SO
3R ', OSO
2R ', SO
2R ', SOR ', PO
4R ', OPO
2R ', PO
3R ', PO
2R ' or have one of 3-6 unit heterocycle of one or more heteroatoms, wherein R ' can be one of hydrogen, low alkyl group, alkyl-hydroxyl, maybe can form the closed loop 3-6 unit heterocycle, branched alkyl and the branched alkyl hydroxyl that have one or more heteroatoms, wherein each R ' is independently under the situation of an above R ' existence;
R
2Can be phenyl, halogen, alkylamino, alkyl oxo, the CF of hydrogen, alkyl, branched alkyl, phenyl, replacement
3, sulfonamido, replacement sulfonamido, alkoxyl, alkylthio, sulfonate, sulphonic acid ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carbonyl oxygen base, acylamino-, urea groups, replacement carbonyl oxygen base, replacement acylamino-, replacement urea groups or have one of 3-6 unit heterocycle of one or more heteroatoms, additional condition is one or two substituent R
2May reside on the ring, and if have an above substituent R
2, these substituent groups are identical or different separately so;
R
3Can be hydrogen, alkyl, branched alkyl, alkoxyl, halogen, CF
3, cyano group, replacement one of alkyl, hydroxyl, alkyl hydroxy, sulfydryl, alkyl thiol, alkylthio, amino or aminoalkyl; And
N is the integer with the value between 1 and 5, and additional condition is if n 〉=2, R so
3Group and other R
3Group is independent separately.
According to another embodiment of the invention, compositions comprises reactive compound or medicine and pharmaceutically acceptable salt, hydrate, solvate, crystal form, N-oxide and each diastereomer with structure B:
In structure B, A can be selected from (CH) independently of one another
0-1, N, NH, O, S and fusion be so that form the ingredient of the ring of second ring, wherein second ring be selected from aromatics, heteroaromatic, bicyclic aromatic, bicyclic aromatic heterocycle or only first ring be the dicyclo of aromatics or heteroaromatic;
B can be selected from (CH) independently of one another
0-1, N, NH, O, S and fusion be so that form the ingredient of the ring of second ring, wherein second ring be selected from aromatics, heteroaromatic, bicyclic aromatic, bicyclic aromatic heterocycle or only first ring be the dicyclo of aromatics or heteroaromatic, additional condition is if B respectively does for oneself (CH)
0, R so
3Directly and the adjacent ring bonding;
R
0Can be selected from H and low alkyl group;
L can be selected from key and replacement or unsubstituted alkyl, alkenyl or alkynyl coupling part;
R
1Can be selected from C (R ')
3, OR ', N (R ')
2, NR ' C (O) R ', NR ' C (O) O (R '), NR ' C (O) N (R ')
2, SR ', C (O) (O) R ', C (O) R ', C (O) N (R ')
2, SO
3R ', OSO
2R ', SO
2R ', SOR ', S (O) N (R ')
2, (O) N (R ') of OS (O)
2, (O) N (R ') of S (O)
2, S (O) N (R ')
2, PO
4R ', OPO
2R ', PO
3R ', PO
2R ' and the 3-6 unit heterocycle that has one or more heteroatoms, wherein each hetero atom can carry R ' group arbitrarily thereon independently, wherein R ' is selected from hydrogen, low alkyl group, the alkyl that replaces, alkyl-hydroxyl, alkyl-the hydroxyl that replaces, sulfydryl-alkyl, the alkyl of sulfydryl-replacement, alkyl-sulfydryl, alkyl-the sulfydryl that replaces, aminoalkyl, the alkyl of amino-replacement, alkylamino, alkyl-the amino that replaces, branched alkyl, the alkyl of substitution in side chain, the branched alkyl hydroxyl, the alkyl hydroxy of substitution in side chain, side chain sulfo--alkyl, the alkyl of side chain sulfur-replacement, branched alkyl-sulfydryl, alkyl-the sulfydryl of substitution in side chain, the branched-amino alkyl, the alkyl of branched-amino-replacement, branched alkyl amino, alkyl-the amino of substitution in side chain and closed loop 3-6 unit's carbocyclic ring or heterocycle, wherein the substituent group on the alkyl of any described replacement comprises described closed loop 3-6 unit's carbocyclic ring or heterocycle, additional condition is that each hetero atom on the 3-6 unit heterocycle can carry R ' group arbitrarily thereon, additional condition is that the replacement on the alkyl of any described replacement comprises by non-carbon atom or any R ' group of being connected with described alkyl by carbon, and wherein in the situation that has an above R ' each R ' be independently;
R
2For being positioned at the substituent group on 5,6 or 8 of ring, wherein R
2Be selected from phenyl, halogen, side chain or non-branched-chain alkyl amino, side chain or non-branched-amino alkyl, side chain or non-branched-chain alkyl oxo, side chain or non-side chain oxygen base alkyl, side chain or non-side chain alkylthio, side chain or non-branched-chain alkyl sulfydryl, the CF of methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, isopentyl, phenyl, replacement
3, sulfonamido, replacement sulfonamido, sulfonate, sulphonic acid ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carbonyl oxygen base, acylamino-, urea groups, replacement carbonyl oxygen base, replacement acylamino-, replacement urea groups or directly or by group L and 5, the 3-6 unit's carbocyclic ring or the heterocycle of 6 or 8 connections, each hetero atom can carry R arbitrarily
2Group, additional condition are one, two or three substituent R
2May reside on the ring these substituent R
2Identical or different separately;
R
3Can be selected from hydrogen, alkyl, alkoxyl, halogen, CF
3, cyano group, the alkyl of replacement, hydroxyl, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, C (R ")
3, OR ", N (R ")
2, NR " C (O) R ", NR " C (O) NR ", R ", C (O) (O) R ", OC (O) R ", C (O) N (R ")
2, C (O), C (O) R ", OC (O) N (R ")
2, SO
3R ", OSO
2R ", SO
2R ", SOR ", PO
4R ", OPO
2R ", PO
3R ", PO
2R "; wherein R " has the first heterocycle of closed loop 3-6, branched alkyl, the branched alkyl hydroxyl of one or more heteroatoms for heteroaryl, low alkyl group, side chain low alkyl group, alkyl-hydroxyl, branched alkyl-hydroxyl, amino-alkyl, branched-amino-alkyl, alkyl-amino, branched alkyl-amino, sulfydryl-alkyl, side chain sulfydryl-alkyl, alkyl-sulfydryl, side chain sulfydryl-alkyl or the formation of the aryl of hydrogen, aryl, replacement, heteroaryl, replacement, is independently at above R of existence " situation in each R " wherein;
N is the integer with the value between 1 and 5, and additional condition is if n 〉=2, each R so
3Group and other R
3Group is independent,
Additional condition is if A respectively does for oneself (CH)
0, L is a key so;
Additional condition is if B respectively does for oneself (CH)
0, R so
3Can be above-mentioned non-hydrogen substituent group arbitrarily, 7 Direct Bonding of it and adjacent ring.
Another embodiment of the invention provides the method for treatment experimenter ophthalmic diseases, this method comprises the compositions of the experimenter that these needs are arranged being treated effective dose, said composition comprises reactive compound or medicine, comprise that with institute's array structure among this paper A or the B be exemplary compounds, described reactive compound or medicine have: a) be no more than about 150
2Polar surfaces long-pending; B) under the pH of 4-8 scope, be lower than the water solublity of about 0.1mg/mL; C) be to be at least about 0.5 cLogD 7.4 times at pH; And d) be no more than about 1,000 daltonian molecular weight, condition is that this medicine is not steroid molecule, treats described disease thus.
Another embodiment of the invention provides the preparation method for compositions, and said composition comprises reactive compound or the medicine with structure A or B.This method is included in and is with or without organic solvent and dissolves under existing or be partly dissolved described chemical compound or medicine; With comprise the polymeric matrix carrier with or do not mix with the moisture colloidal suspension of surface active ingredient; Remove organic solvent; Add penetrating agent; And with pH regulator to making described compositions be suitable for the value of administration.
Another embodiment of the invention provides the method that chemical compound is delivered to a rear portion, and this method comprises: the preparation preparation, and said preparation comprises the reactive compound with structure A or B or the medicine for the treatment of effective dose; And with described formulation delivered to the experimenter's eye that needs this class to send.
Another embodiment of the invention provides the method for identifying the chemical compound that is suitable for being delivered to eye, this method comprises by the eye drip administration and gives chemical compound, and after the eye drip administration, observe the distribution within the eye of described chemical compound, wherein said chemical compound is not a steroid molecule, identifies the chemical compound that is suitable for being delivered to eye thus.The chemical compound that uses in these class methods generally has and is no more than about 150
2, such as being lower than about 120
2, for example be no more than about 100
2Polar surfaces long-pending.This chemical compound further has under the pH of 4-8 scope and is lower than about 0.1mg/mL, such as be lower than about 0.05mg/mL under the pH of 4-8 scope, for example is lower than the water solublity of about 0.01mg/mL under the pH of 4-8 scope.This chemical compound is also to have for 7.4 times to be at least about 0.5 at pH, such as being at least about 1, for example is at least 2 cLogD.This chemical compound also has and is no more than about 1,000 dalton, such as being no more than about 900 dalton, for example, is no more than about 800 daltonian molecular weight.
Another embodiment of the invention provides goods, and it comprises: the bottle that comprises the compositions that comprises the reactive compound with structure A or B for the treatment of effective dose or medicine; And further comprise the description that is used to give described compositions.
Description of drawings
Accompanying drawing 1 is the infiltrative sketch map of the inductive ophthalmic of eye drip administration blocking VEGF of expression The compounds of this invention.
Accompanying drawing 2 is the sketch map of the topical prevention ophthalmic choroidal neovascularization (CNV) of The compounds of this invention VI in the CNV model that is illustrated in induced with laser.
Accompanying drawing 3 is pharmacokinetics (PK) data of expression use to the sketch map of the eye rear portion contact of the compound VI of C57BL/6 mice local instil (eye drop).
Accompanying drawing 4 is for representing PK schematic diagram data and the table to chemical compound V or VI concentration in the eye rear portion tissue behind local (eye drop) chemical compound V of instillation of mice or the VI.
Accompanying drawing 5 is for representing PK schematic diagram data and the table to the stable state choroid concentration of chemical compound V after three different plant species-rabbits, Canis familiaris L. and the local instillation compound VI of small test usefulness pig.
Accompanying drawing 6 is for representing the PK tables of data to eye contact in the eye rear portion after the local instillation compound VI of Dutch-Belted rabbit.
Describe in detail
As one man use as the following term of using among the application and definition term general and that IUPAC (International Union of Pure and Applied Chemistry) (IUPAC) is recommended:
" hetero atom " refers to arbitrarily non-carbon atom, for example N, O or S.
Term " aromatics " refers to because delocalization has significantly greater than the localization structure of inferring, such as the molecule body of the ring-type combination of the stability of kekule structures.
Term " heterocycle " refers at least one heteroatomic aromatic ring that comprises as defined above when being used for describing aromatic ring.
Term " heterocycle " is being not used in the ring-type that refers to non-aromatic group when describing aromatic ring (containing ring) group, and this cyclic group is made of about 14 carbon atoms of 3-and at least one above-mentioned hetero atom.
Term " heterocycle of replacement " refers to regard to aromatics and non-aromatic structure further with one or more following substituent heterocyclic radicals.
Term " alkyl " refers to the direct-connected or branched hydrocarbyl of monovalence with about 12 carbon atoms of 1-, for example, and methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, n-hexyl etc. Term " low alkyl group " refer to the alkyl with about 6 carbon atoms of 1-.
Term " alkyl of replacement " refers to further with one or more substituent alkyl, the aryloxy group of the heteroaryl of the aryl of the heterocycle of the cycloalkyl of described substituting group such as hydroxyl, alkoxyl, sulfydryl, cycloalkyl, replacement, heterocycle, replacement, aryl, replacement, heteroaryl, replacement, aryloxy group, replacement, halogen, cyano group, nitro, amino, acylamino-, aldehyde, acyl group, oxygen base acyl group, carboxyl, sulfonyl, sulfonamide, sulfonyl etc.
Term " alkenyl " refers to the have an appointment straight or branched alkyl of about 12 carbon atoms of 2-of at least one carbon-to-carbon double bond and band, and term " alkenyl of replacement " refers to further with one or more above-mentioned substituent alkenyls.
Term " alkynyl " refers to the have an appointment straight or branched alkyl of about 12 carbon atoms of 2-of at least one carbon-to-carbon triple bond and band, and term " alkynyl of replacement " refers to further with one or more above-mentioned substituent alkynyls.
Term " aryl " refers to band have an appointment aromatic group and the term of about 14 carbon atoms of 5-" aryl that replaces " refer to further with above-mentioned one or more substituent aryl.
Term " heteroaryl " refers to aromatic ring, and wherein ring structure is made of about 14 carbon atoms of 3-and at least one above-mentioned hetero atom, and term " heteroaryl of replacement " refers to further with one or more above-mentioned substituent heteroaryls.
Term " alkoxyl " refers to-the O-moieties, and wherein alkyl is such as above-mentioned definition, and term " alkoxyl of replacement " refers to further with one or more above-mentioned substituent alkoxyls.
Term " cycloalkyl " refers to the alkyl with about 8 carbon atoms of 3-of arranging as ring, and term " cycloalkyl of replacement " refers to further with one or more above-mentioned substituent cycloalkyl.
Term " alkylaryl " refers to aryl and the term of alkyl-replacement " alkylaryl that replaces " refer to further with one or more above-mentioned substituent alkylaryls.
Term " aryl alkyl " refers to alkyl and the term of aryl-replacement " aryl alkyl that replaces " refer to further with one or more above-mentioned substituent aryl alkyls.
Alkenyl and term " aromatic yl alkenyl of replacement " that term " aromatic yl alkenyl " refers to aryl-replacement refer to further with one or more above-mentioned substituent aromatic yl alkenyls.
Alkynyl and term " aromatic yl polysulfide yl of replacement " that term " aromatic yl polysulfide yl " refers to aryl-replacement refer to further with one or more above-mentioned substituent aryl.
Term " arlydene " refers to the divalent aromatic radical of about 14 carbon atoms of 5-and term " arlydene of replacement " and refers to further with one or more above-mentioned substituent arlydene.
Term " kinases " refers to the phosphate-based any enzyme that adds on the residue of protein of catalysis; For example serine and threonine kinase enzymatic are phosphate-based adds on serine and the threonine residues.
Term " treatment effective dose " refers to the biology that causes tissue, system, animal or human or the compound of medical response or the consumption of pharmaceutical composition that researcher, animal doctor, doctor or other clinicians seek, and described biology or medical response for example make blood vessel stasis (Vasculostasis) recover or keep or prevent blood vessel stasis to be endangered or loss; Reduce tumor load; Reduce the incidence of disease and/or the death rate.
Term " pharmaceutically acceptable " refers to and must and can not produce to its recipient carrier, diluent or the excipient of illeffects with other component compatibility of preparation.
Term " administration of compound " or " giving compound " refer to the effect that compound of the present invention or pharmaceutical composition are provided to the experimenter of needs treatment.
Term " antibody " refers to complete molecule and the fragment thereof of polyclone or monoclonal antibody, and is all if the Fab of associative list position determinant and F (ab ')2, Fv and SCA fragment.
Term " blood vessel stasis " refers to the homeostatic vascular function effect that causes the normal physiologic function of keeping.
Term " capillary stabilizer (vasculostatic agents) " refers to this activating agent, and this activating agent is sought wherein by forfeiture or the recovery of anti-hemostatic tube stasis or kept the situation that blood vessel stasis is compromised blood vessel stasis.
The term that term " clogD " uses in referring in the following software kit of following company arbitrarily: (1) ACD labs (Toronto Canada) ACD/physchem is software kit or analog in batches; Or 2) Comgenex/Compudrug (Sedona AZ) Pallas software or analog; Or (3) Syracuse Research Corporation (Syracuse NY) KOWWIN software or analog.
Embodiment of the present invention have been described pharmaceutical composition, comprise medicine (reactive compound) and the pharmaceutically acceptable carrier of effective treatment ocular disorders. The reactive compound that comprises in the composition can distribute and effectively treat ocular disorders, comprises that its treatment requires medicine or pro-drug to reach the ocular disorders at a rear portion. Operable medicine is not steroid molecule. Wherein require as follows to other that can be included in medicine in the present composition:
(a) described medicine or its pro-drug can have and be no more than about 150 2, such as being lower than about 120 2, for example be no more than about 100 2Polar surfaces long-pending;
(b) described medicine or its pro-drug can further have under the pH of 4-8 scope and be lower than about 0.1mg/mL, such as be lower than about 0.05mg/mL under 4-8 scope pH, for example are lower than the water-soluble of about 0.01mg/mL under 4-8 scope pH;
(c) described medicine or its pro-drug can be also to have for 7.4 times to be at least about 0.5 at pH, such as being at least about 1, for example are at least 2 cLogD;
(d) described medicine or its pro-drug can also have and be no more than about 1,000 dalton, such as being no more than about 900 dalton, for example, are no more than about 800 daltonian molecular weight.
The medicine that is suitable for the present invention's application can be any number of and combination in antiallergic, antimigraine, Antianemic Agents, bronchodilators, anodyne, antibiotic, leukotrienes inhibitor or antagonist, antihistamine, non-steroidal anti-inflammatory agents, antineoplastic, anticholinergic drug, arcotic, anti-tubercular drug, cardiovascular drug, agglutinin, the peptide class.
Satisfy the exemplary compound of above-mentioned requirements as hereinafter disclosing. One embodiment of the invention provide compound or its pharmaceutically acceptable salt, hydrate, solvate, crystalline form, N-oxide and each diastereoisomer of the pyrimidine derivates with structure A, and they are used for the treatment of various eye diseases, illness and pathology symptom.
In structure A, A can independently be CH, N, NH, O, S separately, or A for merging in order to form one of the part of the ring of second ring, wherein second ring can be aromatics, heteroaromatic, bicyclic aromatic or bicyclic aromatic heterocycle;
B can be separately independently for CH or fusion in order to form the part of the ring of second ring, wherein second ring can for aromatics, bicyclic aromatic or only first ring be the dicyclo of aromatics;
A
1Can be NRa, C (O), S (O), S (O)2、P(O)
2, O, S or CRaOne of, wherein R can be H, low alkyl group, branched alkyl, hydroxy alkyl, aminoalkyl, alkylthio, alkyl hydroxy, alkyl thiol or alkylamino, and if A wherein1Be NRa, a=1 so, and if A1Be CRa, a=2 so;
A
2Can be NR, C (O), S (O), S (O)2、P(O)
2, one of O or S, condition is A1With A2Between to be connected to chemically be correct;
R
0Can be one of H, low alkyl group or branched alkyl;
L
1Can be key, O, S, C (O), S (O), S (O)2、NR
a、C
1-C
6One of alkyl; L2Can be key, O, S, C (O), S (O), S (O)2、C
1-C
3Alkyl, NRaOne of; Or L1And L2Can be key together;
R
b，R
d，R
eAnd RfDo not exist separately or independent be H, C1-C
6One of alkyl, cycloalkyl, branched alkyl, hydroxy alkyl, aminoalkyl, alkylthio, alkyl hydroxy, alkyl thiol or alkylamino;
P, q, m, r are separately independently for having the integer of from 0 to 6 value;
R
bAnd RdBe combined and be (CH2)
m、(CH
2)
r-S-(CH
2)
m、(CH
2)
r-SO-(CH
2)
m、
(CH
2)
r-SO
2-(CH
2)
m、(CH
2)
r-NR
a-(CH
2)
mOr (CH2)
r-O-(CH
2)
mOne of; Or
R
bAnd ReBe combined and be (CH2)
m、(CH
2)
r-S-(CH
2)
m、(CH
2)
r-SO-(CH
2)
m、
(CH
2)
r-SO
2-(CH
2)
m、(CH
2)
r-NR
a-(CH
2)
mOr (CH2)
r-O-(CH
2)
mOne of; Or
R
dAnd RfBe combined and be (CH2)
m、(CH
2)
r-S-(CH
2)
m、(CH
2)
r-SO-(CH
2)
m、
(CH
2)
r-SO
2-(CH
2)
m、(CH
2)
r-NR
a-(CH
2)
mOr (CH2)
r-O-(CH
2)
mOne of; Or
R
bAnd RfBe combined and be (CH2)
m、(CH
2)
r-S-(CH
2)
m、(CH
2)
r-SO-(CH
2)
m、
(CH
2)
r-SO
2-(CH
2)
m、(CH
2)
r-NR
a-(CH
2)
mOr (CH2)
r-O-(CH
2)
mOne of; Or
R
dAnd ReBe combined and be (CH2)
m、(CH
2)
r-S-(CH
2)
m、(CH
2)
r-SO-(CH
2)
m、
(CH
2)
r-SO
2-(CH
2)
m、(CH
2)
r-NR
a-(CH
2)
m(CH2)
r-O-(CH
2)
mOne of;
R
1Can be (CRa)
m、O、N、S、C(O)(O)R′、C(O)N(R′)
2、SO
3R′、OSO
2R′、
SO
2R′、SOR′、PO
4R′、OPO
2R′、PO
3R′、PO
2R ' or with one of the 3-6 of one or more heteroatoms unit heterocycle, wherein R ' can be one of hydrogen, low alkyl group, alkyl-hydroxyl, maybe can form closed loop 3-6 unit heterocycle, branched alkyl and branched alkyl hydroxyl with one or more heteroatoms, wherein each R ' is independently in the situation that has an above R ';
R
2Can be phenyl, halogen, alkylamino, alkyl oxo, the CF of hydrogen, alkyl, branched alkyl, phenyl, replacement3, sulfonamido, replacement sulfonamido, alkoxyl, alkylthio, sulfonate, sulphonic acid ester, phosphate, phosphate, phosphonate, phosphonate ester, carbonyl oxygen base, acylamino-, urea groups, replacement carbonyl oxygen base, replacement acylamino-, replacement urea groups or with one of 3-6 unit heterocycle of one or more heteroatoms, additional condition is one or two substituent R2May reside on the ring, and if have an above substituent R2, these substituting groups are identical or different separately so;
R
3Can be hydrogen, alkyl, branched alkyl, alkoxyl, halogen, CF3, cyano group, replacement one of alkyl, hydroxyl, alkyl hydroxy, sulfydryl, alkyl thiol, alkylthio, amino or aminoalkyl; And
N is the integer with the value between 1 and 5, and additional condition is if n 〉=2, so each R3Group and other R3Group is independent.
The example of operable some concrete and nonrestrictive above-claimed cpd A comprise by under show the described chemical compound of structure I, II and III:
Another embodiment of the invention provides phentriazine derived compounds or its pharmaceutically acceptable salt, hydrate, solvate, crystal form, N-oxide and each diastereomer with structure B, and they are used for the treatment of various ocular disease, disease and pathology symptom.
In structure B and pharmaceutically acceptable salt, hydrate, solvate, crystal form, N-oxide and each diastereomer, A can be selected from (CH) independently of one another
0-1, N, NH, O, S and fusion be so that form the ingredient of the ring of second ring, wherein second ring be selected from aromatics, heteroaromatic, bicyclic aromatic, bicyclic aromatic heterocycle or only first ring be the dicyclo of aromatics or heteroaromatic;
B can be selected from (CH) independently of one another
0-1, N, NH, O, S and fusion be so that form the ingredient of the ring of second ring, wherein second ring be selected from aromatics, heteroaromatic, bicyclic aromatic, bicyclic aromatic heterocycle or only first ring be the dicyclo of aromatics or heteroaromatic, additional condition is if B respectively does for oneself (CH)
0, R so
3Directly and the adjacent ring bonding;
R
0Can be selected from H and low alkyl group;
L can be selected from key and replacement or unsubstituted alkyl, alkenyl or alkynyl coupling part;
R
1Can be selected from C (R ')
3, OR ', N (R ')
2, NR ' C (O) R ', NR ' C (O) O (R '), NR ' C (O) N (R ')
2, SR ', C (O) (O) R ', C (O) R ', C (O) N (R ')
2, SO
3R ', OSO
2R ', SO
2R ', SOR ', S (O) N (R ')
2, (O) N (R ') of OS (O)
2, (O) N (R ') of S (O)
2, S (O) N (R ')
2, PO
4R ', OPO
2R ', PO
3R ', PO
2R ' and the 3-6 unit heterocycle that has one or more heteroatoms, wherein each hetero atom can carry R ' group arbitrarily thereon independently, wherein R ' is selected from hydrogen, low alkyl group, the alkyl that replaces, alkyl-hydroxyl, alkyl-the hydroxyl that replaces, sulfydryl-alkyl, the alkyl of sulfydryl-replacement, alkyl-sulfydryl, alkyl-the sulfydryl that replaces, aminoalkyl, the alkyl of amino-replacement, alkylamino, alkyl-the amino that replaces, branched alkyl, the alkyl of substitution in side chain, the branched alkyl hydroxyl, the alkyl hydroxy of substitution in side chain, side chain sulfo--alkyl, the alkyl of side chain sulfur-replacement, branched alkyl-sulfydryl, alkyl-the sulfydryl of substitution in side chain, the branched-amino alkyl, the alkyl of branched-amino-replacement, branched alkyl amino, alkyl-the amino of substitution in side chain and closed loop 3-6 unit's carbocyclic ring or heterocycle, wherein the substituent group on the alkyl of any described replacement comprises described closed loop 3-6 unit's carbocyclic ring or heterocycle, additional condition is that each hetero atom on the 3-6 unit heterocycle can carry R ' group arbitrarily thereon, additional condition is that the replacement on the alkyl of any described replacement comprises by non-carbon atom or any R ' group of being connected with described alkyl by carbon, and wherein in the situation that has an above R ' each R ' be independently;
R
2For being positioned at the substituent group on 5,6 or 8 of ring, wherein R
2Be selected from phenyl, halogen, side chain or non-branched-chain alkyl amino, side chain or non-branched-amino alkyl, side chain or non-branched-chain alkyl oxo, side chain or non-side chain oxygen base alkyl, side chain or non-side chain alkylthio, side chain or non-branched-chain alkyl sulfydryl, the CF of methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, isopentyl, phenyl, replacement
3, sulfonamido, replacement sulfonamido, sulfonate, sulphonic acid ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carbonyl oxygen base, acylamino-, urea groups, replacement carbonyl oxygen base, replacement acylamino-, replacement urea groups or directly or by group L and 5, the 3-6 unit's carbocyclic ring or the heterocycle of 6 or 8 connections, each hetero atom can carry R arbitrarily
2Group, additional condition are one, two or three substituent R
2May reside on the ring these substituent R
2Identical or different separately;
R
3Can be selected from hydrogen, alkyl, alkoxyl, halogen, CF
3, cyano group, the alkyl of replacement, hydroxyl, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, C (R ")
3, OR ", N (R ")
2, NR " C (O) R ", NR " C (O) NR ", R ", C (O) (O) R ", OC (O) R ", C (O) N (R ")
2, C (O), C (O) R ", OC (O) N (R ")
2, SO
3R ", OSO
2R ", SO
2R ", SOR ", PO
4R ", OPO
2R ", PO
3R ", PO
2R "; wherein R " has the first heterocycle of closed loop 3-6, branched alkyl, the branched alkyl hydroxyl of one or more heteroatoms for heteroaryl, low alkyl group, side chain low alkyl group, alkyl-hydroxyl, branched alkyl-hydroxyl, amino-alkyl, branched-amino-alkyl, alkyl-amino, branched alkyl-amino, sulfydryl-alkyl, side chain sulfydryl-alkyl, alkyl-sulfydryl, side chain sulfydryl-alkyl or the formation of the aryl of hydrogen, aryl, replacement, heteroaryl, replacement, is independently at above R of existence " situation in each R " wherein;
N is the integer with the value between 1 and 5, and additional condition is if n 〉=2, each R so
3Group and other R
3Group is independent,
Additional condition is if A respectively does for oneself (CH)
0, L is a key so;
Additional condition is if B respectively does for oneself (CH)
0, R so
3Can be above-mentioned non-hydrogen substituent group arbitrarily, its 7 Direct Bonding direct and adjacent ring.
Operablely include, but are not limited to down show chemical compound (IV) to (XX) by described some typical compound of structure B:
Embodiment of the present invention provide the method for treatment experimenter ophthalmic diseases, comprise the compositions of the present invention of the experimenter that these class treatment needs are arranged being treated effective dose, treat described disease thus.
Be the administration for the treatment of concrete ophthalmic diseases, pathology symptom and disease or reversing described disease or reducing this sick side effect or alleviate the risk design team compound of this disease development.The limiting examples of described disease, pathology symptom and disease comprises the degeneration of macula relevant with the age (AMD), does AMD, diabetic retinopathy, diabetic macular edema, cancer and glaucoma.Some compositions of the present invention can be used for the treatment of some ophthalmic diseases, pathology symptom and disease, but not necessarily is used for the treatment of other this class disease, pathology symptom and disease.For example, some compositions is suitable for treating AMD, but is not suitable for treating glaucoma, and vice versa.Those skilled in the art can determine whether chemical compound is suitable for treating specific ophthalmic diseases, pathology symptom and disease.
Many immunology factors can relate to the degeneration of macula relevant with the age (AMD) and other oculopathy.Possible situation be exist in the drusen deposit that forms in the macula lutea before AMD inflammation that immunocyte and complement can further activate the contribution disease cause of disease by way of.A kind of this class is by way of can be for raising and activated macrophage, and they further worsen intraocular inflammation and may cause choroidal neovascularization.Medicine of the present invention or prodrug can have and are used for the treatment of the immunomodulatory properties that has the unbalance disease of immunne response when administration by having effect in the immunne response arm one or more.This effect can be directly at immunocyte, as MHC I and II type, macrophage, T cell, B cell, mastocyte etc. or when the administration by changing, strengthen or reduce the individual human specific cell factor or chemotactic factor carries out.
In order to give embodiment of the present invention, compositions is mixed with eye drop, solution, suspension, Emulsion, gel or the ointment that comprises the reactive compound for the treatment of effective dose.The typical medication of compositions described herein comprises local delivery, is delivered to a rear portion, the interior or administration near the eyes of vitreous body.Those skilled in the art can determine to be suitable for concrete patient's dosage and therapeutic scheme.As a limiting examples, can with every day 1 to 4 time frequency or weekly 1 to 4 time spot seldom be mixed with the compositions of eye drop.
The medicine that comprises in the preparation of the present invention can be for lipophilic and can be various kinase whose inhibitor.Suppressible kinase whose limiting examples comprises Janus family kinase (Jak), Src family kinase, vegf receptor family kinase, pdgf receptor family kinase, Eph receptor family kinases and FGF receptor family kinases.
Suppressible kinase whose other limiting examples comprises: casein kinase (CK2); CK2; CK2 α; CK2 β; People CK2 (alpha subunit); People CK2 (β subunit); People CK2 (holoenzyme complex); Zea mays CK2; Akt/PKB:Akt, Aktl, Aktl (non-activity), Akt2, Akt3, PKB, PKB α, PKB α (non-activity), PKB β, PKB γ; Map kinase is by way of ERK, ERK1, ERK2, JNK2, JNK2 α, MAP2 K1, MAPK1, MAPK 3, MAPKK1, MAPKK6, MEK1, MKK1, MKK6, p38, p38 (non-activity), p38a/SAPK2a, SAPK1, SAPK2, comprise Ras and Raf with these with relevant by way of in other kinases; With various other kinases, as at ABL, ARK5, Aurora-A, Aurora-B, Aurora-C, BRK, CaMKII, CDK1/B, CDK2/A, CDK2/E, CDK3/E, CDK4/D1, CDK5/p35NCK, CDK6/D1, CDK7/H/MAT1, CDK9/CycT, CHK1, CHK2, c-KIT, c-MET, COT, CSK, DAPK1, EGFR, EPHA, EPHB, ERBB2, ERBB4, FAK, FGF-R, FGR, FLK1, FLT3, GSK3 β, HER2, IGF1-R, IKK β, INS-R, ITK, JAK2, JAK3, JNK3, KDR, KIT, LCK, LYN, MET, MST4, MUSK, NEK2, NEK6, NLK, PAK, PDGFR, PDK1, PIM, PKC α, PKC β, PKC δ, PKC ε, PKCeta, PKC γ, PKC ι, PKC μ, PKG, PLK1, PRK1, PRKX, PTK2, RET, ROCK2, S6K4, SAK, SGK, SRC, SYK, thymidine kinase TK1, TIE2, VEGFR1, VEGFR2, VEGFR3, ZAP70 or arbitrarily other relate to mediation relate to that vascular leakage or blood vessel take place or the kinases of inflammatory reaction in.
Except that above-mentioned reactive compound and pharmaceutically acceptable carrier, also following compositions, wetting agent, cataract preventive, RNAi molecule, antisense molecule, peptide class, polynucleotide, protein, micromolecular compound, vegf receptor antagonist, antiinflammatory, oxygen free radical scavenger, tonicity agent, comfortable promoter, solubilisation aids, antioxidant, stabilizing agent and the NO inhibitor that further comprises antiviral agent, antibiotic, reduction intraocular pressure of compositions of the present invention.
The whole bag of tricks can be used to prepare compositions of the present invention.In one embodiment, dissolve fully in the presence of the organic solvent or be partly dissolved described medicine or prodrug being with or without; Mix with the moisture colloidal suspension that comprises the polymeric matrix carrier, contains or do not contain surface active ingredient subsequently.Organic solvent (if use) can be removed then, penetrating agent can be added; And can be with pH regulator to making described compositions be suitable for the value of administration.This method can also be chosen wantonly and comprise and add aseptic filler or by filtering or autoclaving is sterilized, or lyophilization or spray drying, or before use dry preparation is dissolved again, or the combination of this class optional step.
In another embodiment, used medicine or prodrug can be mixed with the moisture colloidal suspension that comprises the polymeric matrix carrier, so that formation colloidal suspension, for example have and be lower than 5 μ m, suspension such as the mean particle size that is lower than about 1 μ m, add penetrating agent subsequently, subsequently with pH regulator to the scope that is suitable for administration.If desired, this method can also be chosen wantonly and comprise and add aseptic filling or by filtering or autoclaving is sterilized, or lyophilization or spray drying, or before use dry preparation is dissolved again, or the combination of this class optional step.
Compositions of the present invention can be mixed with the colloidal suspension of water disperse.The lipid that comprises in this class suspension can be surfactant.Can be used for some limiting examples phospholipid (phospholipids), phosphatidylcholine class, cuorin class, fatty acid, PHOSPHATIDYL ETHANOLAMINE class and phospholipid (phosphatides) in the lipid of preparation of the present invention.This class colloidal suspension further is included in the polymer that can form suspension when being included in the medicine merging in the compositions, for example lyophily polymer.Some limiting examples that can be used to form the polymer of this class suspension comprises: cellulose derivative, such as hydroxypropyl emthylcellulose (HPMC), carboxymethyl cellulose (CMC), methylcellulose (MC), hydroxyethyl-cellulose (HEC), amylose and derivant, amylopectin and derivant, glucosan and derivant, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA); And acrylate copolymer, such as the derivant of poly-(acrylic acid) or poly-(methacrylic acid), as HEMA, carbomer (from Noveon or similar polymer).Colloidal suspension of the present invention can also comprise the surface active ingredient as the wetting agent/dispersant that fully tolerates within the eye.The limiting examples of surfactant is mainly non-ionic surface active agent, as Tai Luoshabai, polyethylene glycols and derivant, as PEG400, PEG1500, PEG20000, poloxamer 407, poloxamer 188, tween 80 and polysorbate20.These surface active ingredients can use separately or with other surface active ingredient coupling or with above-mentioned lipid and polymer coupling.
These compositionss can comprise one or more antiseptic, such as benzalkonium chloride, alkyldimethyl benzylammonium chloride, cetab, cetylpyridinium chloride, benzene degree bromine ammonium, benzethonium chloride, thimerosal, chlorobutanol, benzylalcohol, phenyl phenol (phenoxyethanol), phenethanol, sorbic acid, para hydroxybenzene carbamoyl methyl and propyl p-hydroxybenzoate, chlorhexidine, digluconate or EDTA.
Compositions of the present invention can be mixed with salt form.Pharmaceutically acceptable non-toxic salts comprises the salt (with free carboxy or other anionic group) of alkali addition, they can be derived from inorganic base, such as, the hydroxide of sodium, potassium, ammonium, calcium or ferrum for example, and organic base, such as 2-aminopropane., trimethylamine, 2-ethylamino-ethanol, histidine procaine etc.This class salt can also be as the salt formation of the sour addition that forms with any free cations group, and general and mineral acid, such as, for example hydrochloric acid, sulphuric acid or phosphoric acid, or organic acid, such as formation such as acetic acid, citric acid, p-methyl benzenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, mandelic acid.Salt of the present invention comprises that all example hydrochloric acids, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid etc. make the amine salt of amino protonated formation by using mineral acid.Salt of the present invention also comprises by using appropriate organic, makes the amine salt of amino protonated formation such as p-methyl benzenesulfonic acid, acetic acid etc.It is available for those skilled in the art that concern is used to implement extra excipient of the present invention, for example at United StatesPharmacopoeia Vol.XXII and National Formulary Vol.XVII, U.S.Pharmacopoeia Convention, Inc., Rockville, those that can find among the MD (1989) are incorporated herein by reference the related content of these documents.In addition, the present invention includes the polymorphic of chemical compound described herein.
Another embodiment of the invention provides the method for treatment ophthalmic diseases, comprises the compositions of the present invention of the experimenter that these class treatment needs are arranged being treated effective dose, and this method is undertaken by described compositions is delivered to the salt rear portion.Send in order to carry out this class, preparation can be the eye drop form.This method may further include and gives inhibitors of kinases, such as Src family kinase, vegf receptor family kinase, pdgf receptor family kinase, Eph receptor family kinases or the kinase whose inhibitor of FGF receptor family.
According to another embodiment of the invention, can identify the chemical compound that is suitable for being delivered to eye.Identify in order to carry out this class, give chemical compound to eye and after the eye drip administration, observe the distribution of ophthalmic chemical compound that identify the chemical compound that is suitable for being delivered to eye thus, condition is that candidate compound is not steroid molecule by the eye drip administration.The chemical compound that is used for these class methods has and is no more than about 150
2, such as being lower than about 120
2, for example be no more than about 100
2Polar surfaces long-pending.This chemical compound further has under the pH of 4-8 scope and is lower than about 0.1mg/mL, such as be lower than about 0.05mg/mL under the pH of 4-8 scope, for example is lower than the water solublity of about 0.01mg/mL under the pH of 4-8 scope.This chemical compound is also to have for 7.4 times to be at least about 0.5 at pH, such as being at least about 1, for example is at least 2 cLogD.This chemical compound also has and is no more than about 1,000 dalton, such as being no more than about 900 dalton, for example, is no more than about 800 daltonian molecular weight.
Another embodiment of the invention provides goods.These goods can comprise bottle, container, pipe, arrow-necked bottle, dropper and/or syringe, wherein comprise as described hereinly to be used for the compositions that comprises reactive compound of ocular delivery and to may further include the description that is used to give described compositions.
It is for further illustration advantages and features of the invention that the following example is provided, and is not used for limiting scope of the present invention but do not specify.By to confirming that from the eye effect of some chemical compound of the present invention with by pharmacokinetic analysis the representational result who sends can find in the accompanying drawings to the ocular tissue rear portion.
Embodiment 1. is based on the system of the colloidal suspension of the inclusion compound (V) of the continuous lipid of water
Be equipped with
By getting the 18mg chemical compound (V) of HCl salt form, with 550mg dimyristoyl phosphatidyl choline (DMPC), 2412mg 2.9% mixed with propylene glycol and use the sonicator probe in controlled temperature bath the homogenize preparation based on the colloidal suspension of the continuous lipid of water.Use 35 μ L0.1N NaOH that pH regulator is further carried out supersound process with whole uniformities to 5-6 and with said composition.The gained preparation is carried out aseptic filtration by 0.22 μ m PVDF syringe filter.
Perhaps, use high pressure homogenize homogenize medicine.If desired, before homogenize, use lipid in water by means of organic solvent, such as ethanol or chloroform predissolve medicine.If desired, the gained preparation can also be carried out autoclaving so that aseptic in the final container.If desired, can add antiseptic, such as Benzalkonii Chloridum.
By getting the 37.6mg chemical compound (XI) of HCl salt form, with 550mg dimyristoyl phosphatidyl choline (DMPC), 2412mg 2.9% mixed with propylene glycol and use the sonicator probe in controlled temperature bath the homogenize preparation based on the water disperse colloidal suspension of lipid.Use the enuatrol of 15 μ L50mg/mL in deionized water that pH regulator is further carried out supersound process with whole uniformities to 5-6 and with said composition.The gained preparation is carried out aseptic filtration by 0.22 μ m PVDF syringe filter.
Perhaps, use high pressure homogenize homogenize medicine.If desired, before homogenize, use lipid in water by means of organic solvent, such as ethanol or chloroform predissolve medicine.If desired, the gained preparation can also be carried out autoclaving so that aseptic in the final container.If desired, can add antiseptic, such as Benzalkonii Chloridum.
As embodiment 1 preparation preparation, but use chemical compound (XI) but not chemical compound (V).With chemical compound (XI) as eye drop administration (1%API, 50 μ L), BID, 3 days.During behind single dose the 3rd day, put to death rabbit, extract and gather various ocular tissues (retina, choroid, horny layer etc.).After organizing homogenize and acetonitrile precipitation, use LC/MS/MS to measure in-house concentration.Use the WINNONLIN program to carry out the PK data analysis.The concentration of chemical compound V in choroid similar between 2 kinds of preparations (in μ M level).Long half time was to approximate 8 hours.
To be used for this experiment as the preparation of the inclusion compound (V) of embodiment 1 preparation.Dosage with 0.5% is to rabbit topical administration 50 μ l chemical compounds (V) (QD, 1 day).Gather ocular tissue, such as choroid, retina, sclera and cornea and mensuration concentration.Choroid concentration is told 4 times of retina concentration.Half-life is about 2 double-lengths.
Preparation comprises the colloidal suspension based on the continuous lipid of water of the active component of 1% dosage through the following steps: get the 13mg chemical compound (VI) as free alkali, at about 50-60 ℃ with there is 830mg in 5% glucose and 36 μ L 1N HCl, to comprise homogenize in the presence of the solution of 0.125%HPMC 4KM, up to the clarifying translucent colloid solution of acquisition.Adding the lipid vesicle of the saturated S-PC of 205mg18% (PL90H) in 2.9% propylene glycol then flocculates so that reduce colloid as stabilizing agent.The supersound process sample and by add 24 μ L 1N NaOH with pH regulator to pH4.5-6.Filter by sonication or the further homogenize sample of high pressure homogenize and by 0.45 μ m PVDF syringe filter.Osmolarity is 319mmol ul.
Can choose wantonly and not use surfactant (being phospholipid) to obtain above-mentioned preparation.In this class situation, may need to keep electric charge suitable on the granule by introducing counter ion counterionsl gegenions, described counter ion counterionsl gegenions are adsorbed on the particle surface and thereon and are maintained, and wherein enough pH can reduce flocculation.
Preparation comprises the colloidal suspension based on the continuous lipid of water of the active component of 0.5% dosage through the following steps: get the 13mg chemical compound (VI) as free alkali, at about 50-60 ℃ with there is 1620mg in 5% glucose and 36 μ L 1N HCl, to comprise homogenize in the presence of the solution of 0.125%HPMC 4KM, up to the clarifying translucent colloid solution of acquisition.Adding the lipid vesicle of the saturated S-PC of 384mg18% (PL90H) in 2.9% propylene glycol then flocculates so that reduce colloid as stabilizing agent.The supersound process sample and by add 24 μ L 1N NaOH with pH regulator to pH4.5-6.Filter by sonication or the further homogenize sample of high pressure homogenize and by 0.45 μ m PVDF syringe filter.Osmolarity is 293mmolal.
Can choose wantonly and not use surfactant (being phospholipid) to obtain above-mentioned preparation.In this class situation, may need to keep electric charge suitable on the granule by introducing counter ion counterionsl gegenions, described counter ion counterionsl gegenions are adsorbed on the particle surface and thereon and are maintained, and wherein enough pH can reduce flocculation.
Embodiment 7. is based on the system of the colloidal suspension of the inclusion compound (VI) of the continuous lipid of water
Be equipped with
To be diluted to final weight be the colloidal suspension based on the continuous lipid of water that 982mg obtains to comprise the active component of 0.2% dosage by getting the 382mg preparation that comprises 0.5% chemical compound (VI) and being used in 0.125%HPMC 4KM in 5% glucose.Gained mixture appropriateness is carried out sonication to guarantee uniformity.Regulate pH to obtaining final pH 4.8.Sample is filtered by 0.45 μ m PVDF syringe filter.Osmolarity is 282mmolal.
Can choose wantonly and not use surfactant (being phospholipid) to obtain above-mentioned preparation.In this class situation, may need to keep electric charge suitable on the granule by introducing counter ion counterionsl gegenions, described counter ion counterionsl gegenions are adsorbed on the particle surface and by this way and are maintained, and wherein enough pH can reduce flocculation.
Use preparation as forfeiture preparation among the embodiment 5.Rat pup is given 10 μ L eye drops of the chemical compound (VI) of 0.2,0.5 or 1% single dose.Gather ocular tissue so that use LC/MS/MS to carry out chemical compound (V) analysis in different time points.Average A UC in choroid is at 0.2-1% dosage, yet in retina, concentration shows as nonlinear.The half-life of chemical compound (V) is 5-8 hour in choroid.
Embodiment 9. is based on the system of the colloidal suspension of the inclusion compound (X) of the continuous lipid of water
Be equipped with
By using the continuous colloidal suspension of water that comprises the active component of 0.5% dosage as 51mg chemical compound (X) preparation of mesylate, about 50-60 ℃ and have 7.06g 5% glucose and in comprise homogenize in the presence of the solution of 0.25%HPMC 4KM, up to the clarifying translucent colloid solution of acquisition.Regulate pH so that obtain the final pH4.7 that measures by adding 1N NaOH.Filter by sonication or the further homogenize sample of high pressure homogenize and by 0.45 μ m PVDF syringe filter.Final osmolarity is 285mmolal.
Acquisition comprises the continuous colloidal suspension of water of the active component of 0.5% dosage through the following steps: get 44mg chemical compound (X), about 50-60 ℃ and have 4.2g 5% glucose solution with in 5% glucose and 23.8 μ L 5N HCl solution, 36 μ L 1N HCl, comprise homogenize in the presence of the solution of 1.38g 0.5%HPMC 4KM, up to the clarifying translucent colloid solution of acquisition.Adding the lipid vesicle of 1.23g 18% saturated S-PC (PL90H) in 2.9% propylene glycol then flocculates so that reduce colloid as stabilizing agent.The supersound process sample and by add 50 μ L 1N NaOH with pH regulator to pH4.5-6.Filter by sonication or the further homogenize sample of high pressure homogenize and by 0.45 μ m PVDF syringe filter.Osmolarity is 297mmolal.
Embodiment 11. does not use the comprise chemical combination of surfactant preparation based on the continuous lipid of water
The colloidal suspension of thing (VIII)
Obtain to comprise the continuous colloidal suspension of water of the active component of 0.5% dosage through the following steps: get the chemical compound (VIII) of 35.6mg free alkali form and at about 50-60 ℃ with there is 5.04g in 5% glucose, to comprise homogenize in the presence of the solution of 0.5%HPMC 4KM, up to the clarifying translucent colloid solution of acquisition.Actual final pH is 6.68.Sample is filtered by 0.45 μ m PVDF syringe filter.Osmolarity is 322mmolal.
Use the preparation of preparation described in embodiment 9 and 11.With chemical compound (X) with (VIII) as eye drop (50 μ L) administration, as dosage, be QD, 3 days, or BID, 3 days.Behind choroid, do not detect chemical compound (VIII) concentration in the retina.After chemical compound (X) administration in choroid the concentration of chemical compound (V) very can to reproduce (380-513nM) and half-life be 7-14 hour.
Retina concentration changes according to the difference of used preparation.The cLogD of chemical compound (VIII) under pH7.4 is 0.14, and is 3.54 with regard to chemical compound (X).According to above-mentioned to identical dosage regimen shown in the chemical compound (X), at prodrug compound (VIII) by local delivery at the moment, but from retina and choroid, be not recovered to the API (chemical compound (V)) of detection limit.
Embodiment 13. does not use the comprise chemical combination of surfactant preparation based on the continuous lipid of water
The colloidal suspension of thing (VI)
Acquisition comprises the continuous colloidal suspension of water of the active component of 1% dosage through the following steps: get 50mg chemical compound (VI), subsequently at about 50-60 ℃ with there is 4.06g in 5% mannitol, 90 μ L 1N HCl and 3mL ethanol, to comprise homogenize in the presence of the solution of 0.5%HPMC 4KM, up to the clarifying translucent colloid solution of acquisition.Final by adding 112 μ L0.1N NaOH with the physiological pH of pH regulator to suitable 4.5-6.Ethanol evaporation and frozen soln with postlyophilization, use 3.7g DI water to dissolve then again and filter by 0.45 μ m PVDF syringe filter.
Embodiment 14. chemical compounds (VI) are in the medicine generation in the Dutch-Belted rabbit behind the topical
Dynamics research
Use the preparation of preparation as described in example 13 above.To rabbit topical administration chemical compound (VI) (50 μ L), be BID 3 days or 3 days dosage of QD (1% dosage).Detected concentration higher (in μ M scope) and be linear between described 2 kinds of dosages in the tissue of eye rear portion.
To comprise the continuous colloidal suspension of water as the 51.1mg chemical compound (IV) of HCl salt mixes with 830mg phosphatidylcholine (from the PL90G of American Lecithin) and is dissolved in 2.5mL ethanol, be concentrated into dried (in high vacuum) subsequently, use 7.1g 2.9%w/v propylene glycol (USP)+12 μ L 1N NaOH to suspend again, use the homogenize of sonicator probe, add 0.3mL 0.9%NaCl subsequently and use 0.1N HC1 pH regulator to 5.5.The gained preparation is carried out aseptic filtration by 0.22 μ m PVDF syringe filter.Osmolarity is 314mmolal.
Embodiment 16. is based on the system of the colloidal suspension of the inclusion compound (XI) of the continuous lipid of water
Be equipped with
To comprise the continuous colloidal suspension of water as the 51.8mg chemical compound (XI) of HCl salt mixes with 810mg phosphatidylcholine (from the PL90G of American Lecithin) and is dissolved in 2.5mL ethanol, be concentrated into dried (in high vacuum) subsequently, use 7.1g 2.9%w/v propylene glycol (USP)+12 μ L 1N NaOH to suspend again, use the homogenize of sonicator probe, add 0.3mL 0.9%NaCl subsequently and use 0.1N HCl pH regulator to 5.5.The gained preparation is carried out aseptic filtration by 0.22 μ m PVDF syringe filter.Osmolarity is 320mmolal.
Embodiment 17. is based on the system of the colloidal suspension of the inclusion compound (V) of the continuous lipid of water
Be equipped with
To comprise the continuous colloidal suspension of water as the 50.6mg chemical compound (V) of HCl salt mixes with 1516mg phosphatidylcholine (from the PL90G of American Lecithin) and is dissolved in 2.5mL ethanol, be concentrated into dried (in high vacuum) subsequently, use 6.492.9%w/v propylene glycol (USP)+12 μ L 1N NaOH to suspend again, use the homogenize of sonicator probe, add 0.3mL 0.9%NaCl subsequently and use 0.1N HCl pH regulator to 5.5.The gained preparation is carried out aseptic filtration by 0.22 μ m PVDF syringe filter.Osmolarity is 330mmolal.
Embodiment 18. is based on the colloidal suspension of the inclusion compound (VII) of the continuous lipid of water
Preparation
To comprise the colloidal suspension based on the continuous lipid of water as the 51.2mg chemical compound (VII) of HCl salt mixes with 1521mg phosphatidylcholine (from the PL90G of American Lecithin) and is dissolved in 2.5mL ethanol, be concentrated into dried (in high vacuum) subsequently, use 6.4g 2.9%w/v propylene glycol (USP)+12 μ L 1N NaOH to suspend again, use the homogenize of sonicator probe, add 0.3mL 0.9%NaCl subsequently and use 0.1N HCl pH regulator to 5.5.The gained preparation is carried out aseptic filtration by 0.22 μ m PVDF syringe filter.Osmolarity is 334mmolal.
Embodiment 19. chemical compounds (VII), V), (XI) and (IV) behind topical
Pharmacokinetic in the Dutch-Belted rabbit
Use the preparation that described in embodiment 15-18, prepares.With 0.5% dosage (BID) with chemical compound (IV), (XI), (V) and (VII) to lagophthalmos topical (50 μ L/ eye) 5 days.In 1,7 the eye amount of contact when measuring stable state during with 24 hours.For the Cmax in 598 and 572 choroid in the 208-290ng/ml scope.The result is summarised in the accompanying drawing 6.
Preparation comprises the continuous colloidal suspension of water of active component of 1% dosage through the following steps: get as the 50mg chemical compound (VI) of free alkali and at about 50-60 ℃ with there is 4.06g to comprise homogenize in the presence of the solution of 0.5%HPMC 4KM in 5% mannitol, 90 μ L1N HCl and 3mL ethanol, up to the clarifying translucent colloid solution of acquisition.Final by adding 112 μ L0.1N NaOH with the value of pH regulator to suitable 4.5-6.Ethanol evaporation and frozen soln with postlyophilization, use the 3.7g deionized water to dissolve then again and filter by 0.45 μ m PVDF syringe filter.
Embodiment 21. uses the comprise chemical combination of lipid surfactant preparation based on the continuous lipid of water
The colloidal suspension of thing (V)
To comprise the colloidal suspension based on the continuous lipid of water as the 31.16mg chemical compound (V) of HCl salt mixes with 970mg phosphatidylcholine (from the PL90G of American Lecithin) and is dissolved in 2mL ethanol, be concentrated into dried (in high vacuum) subsequently, use 2.7g2.9%w/v propylene glycol (USP)+12 μ L1N NaOH to suspend again, use the homogenize of sonicator probe, add 0.2mL 0.9%NaCl.Final pH is 6.1.The gained preparation is carried out aseptic filtration by 0.22 μ m PVDF syringe filter.Osmolarity is 335mmolal.
Efficacy study in the embodiment 22. retinal edema eye models behind the eye drip
The auxiliary agent that will prepare described in embodiment 20 and 21 is used for these research.Mice is given the part eye drop (every day 1 time or 3 times) or the chemical compound (VI) (single eye drop) of chemical compound (V).After 1-2 hour, VEGF is passed through to inject in the vitreous body little rathole.After 1 hour, the azovan blue dyestuff is injected the tail vein by intravenous.After about 4 hours, put to death animal, blood sampling and excision eye.Measure the inductive retina permeability of determining by ophthalmic albumin leakage of VEGF-.
After QD gave chemical compound (V), the retina seepage had been suppressed 50%, yet the result does not have significance,statistical.After TID gave chemical compound (V), the retina seepage had been suppressed～80% (p＜0.00003).Give chemical compound (VI) back retina seepage at QD and suppressed (100%) (p＜0.00002) fully.
Embodiment 23. uses the comprise chemical combination of lipid surfactant preparation based on the continuous lipid of water
The colloidal suspension of thing (V)
To comprise the colloidal suspension based on the continuous lipid of water as the 15.29mg chemical compound (V) of HCl salt mixes with 471mg phosphatidylcholine (from the PL90G of American Lecithin) and is dissolved in 1mL ethanol, be concentrated into dried (in high vacuum) subsequently, use 4.5g2.3%w/v propylene glycol (USP)+40 μ L0.1N NaOH to suspend again, use the homogenize of sonicator probe, finally add 0.125mL 0.9%NaCl.Final pH is 5.5.The gained preparation is carried out aseptic filtration by 0.22 μ m PVDF syringe filter.Osmolarity is 255mmolal.
The preparation of the suspension of embodiment 24. chemical compounds (V) in 5% glucose
To mix with the hydrogenant phosphatidylcholine of 3mg (PL90H) as the 34.70mg chemical compound (V) of HCl salt and be suspended in 5% glucose to final weight be 3g.So that reduce the granular size of 5-10 mu m range, and use 1N NaOH that final pH is adjusted to 5.5 said composition sonication 2 hours.With 5% glucose this suspension is diluted to final drug level 3mg active component/mL.Be delivered to rat with the sample heat sterilization and by the eye drip administration.
Preparation described in the preparation embodiment 23 and 24.First kind of preparation is the water Mass colloid system based on lipid, and second kind of suspension that preparation is the micron size of same medicine in water.
Sample in the effect test of embodiment 26 chemical compounds (VI) inhibition choroidal neovascularization
Preparation
128mg chemical compound (V) is mixed with the suspension of 7g 26%w/v phosphatidylcholine (from the PL90G of AmericanLecithin) in 2.6% propylene glycol and 360 μ L 1N HCl, use the homogenize in psychrolusia of sonicator probe extremely translucent.Add 100 μ L0.9%NaCl and 138 μ L 1N NaOH then, so that with pH regulator to 5.65.The gained preparation is carried out aseptic filtration by 0.245 μ m PVDF syringe filter.Osmolarity is 372mmolal.
Sample in the effect test of embodiment 27 chemical compounds (VI) inhibition choroidal neovascularization
Preparation
50mg chemical compound (V) is mixed with the suspension of 4g 18%w/v phosphatidylcholine (from the PL90G of AmericanLecithin) in 2.6% propylene glycol and 136 μ L 1N HCl, use the homogenize in psychrolusia of sonicator probe extremely translucent.Add 54 μ L 1N NaOH then, so that with pH regulator to 5.8.The gained preparation is carried out aseptic filtration by 0.245 μ m PVDF syringe filter.Osmolarity is 443mmolal.
The preparation of embodiment 28 lipid vesicle control samples
Use sonicator probe (can use the high pressure homogenizer) homogenize 2689mg phosphatidylcholine (from the PL90G of American Lecithin) in psychrolusia to filter by 0.45 μ m PVDF syringe filter to translucent.
Embodiment 29. chemical compounds (VI) topical oozes choroidal neovascularization and retina
The inhibition of leaking
Use the preparation that described in embodiment 26-28, prepares.Test compounds (VI) in choroidal artery takes place is obviously wherein used the induction of vascular generation of breaking of the C57BL/6 mice Bruch's membrane of induced with laser.
Give and to send three 532nm diode lasers on 9,12 and 3 o ' clock positions of female C57BL/6J mice in 4-5 age in week (n=10 only/group) utmost point behind retina and solidify and burn.Behind laser burn, as directed with carrier or chemical compound (V) processing mice.After 2 weeks, analyze the flat fixture of choroid (flatmounts) so that the new vessels of identification fluorescence staining forms and calculate the gross area that new vessels forms in each retina to the glucosan and the use image analysis software of mice perfusion fluorescein-labelling.The result show with 50 μ g/ eye administered compound (VI) show comparison in the same old way product reduce about 47% (p＜0.0001) and with 150 μ g/ eye administered compound (VI) show comparison in the same old way product reduce by about 35% (p＜0.006).The result is summarised in the accompanying drawing 2.
After embodiment 30. gives rabbit, small test with pig and the local instillation chemical compound of Canis familiaris L. bilateral (VI)
Contact chemical compound (V) and research (VI)
Compositions and the evaluation of preparation embodiment 30-A-30-F as described below.
Preparation 30-A (1% chemical compound (VI) in the 5%PL90H/0.2%HPMC glucose)
Preparation
(SIGMA 40-60cps) disperses 181.82mg chemical compound (VI) with 102 μ L5N HCl, mixes simultaneously and heating (～50 ℃), till translucent at flushing 0.5%HPMC in the sterilized water (SWFI) to use 6.7g.Add then 8.2g 9% hydrogenated soy phosphatidyl choline (PL90H-American Lecithin Co) in water dispersion liquid and 60 μ L 2N NaOH solution so as with pH regulator to 5.3-6.Use sonicator probe (GE-130 type) homogenize compositions, use 491mg glucose (EP/BP/USP level, Fisher Scientific) that osmolarity is adjusted to about 230-240mOsm then.Product is filtered by 0.45 μ m PVDF syringe filter (Millipore), use 0.22 μ m PVDF syringe filter (Millipore) to filter subsequently.
Preparation 30-B is (in 0.2% poloxamer 407/0.3%HPMC/3.5% glucose 1%
Chemical compound (V)) preparation
Use 5.89g to disperse 107.09mg chemical compound (VI) among 0.5%HPMC (40-60cps) and the 54.4 μ L 5N HCl in sterilized water (SWFI), mix simultaneously and heat (～50 ℃), till clarifying in flushing.Add 1.6g 1%Lutrol F127 (BASF) solution and 109 μ L 2N NaOH then so as with pH regulator to 5.3-6.Use sonicator probe (GE-130 type) homogenize compositions, use 261mg glucose (EP/BP/USP level, Fisher Scientific) that osmolarity is adjusted to about 283mOsm then.Product is filtered by 0.22 μ m PVDF syringe filter (Millipore).
Preparation 30-C (0.5% chemical combination in the 5%DMPC/0.2%HPMC/3.7% glucose
Thing (V)) preparation
Use 3.5g 0.5%HPMC E 50 and 27.2 μ L 5N HCl dispersion 49.5mg chemical compound (VI) in SWFI, mix simultaneously and heating (～50 ℃), till clarification.Add 16 μ L 2N NaOH then, mix simultaneously, add 4.3g 9%DMPC dispersion liquid and 38.4 μ L 2N NaOH subsequently in case with pH regulator to 5.3-6.Use sonicator homogenize compositions, use the 294mg glucose that osmolarity is adjusted to about 230-240mOsm then.End product is filtered by 0.45 μ m syringe filter.
Preparation 30-D (1% chemical combination in the 6%DMPC/0.13%HPMC/3.6% glucose
Thing (V)) preparation
Use 1.1g 0.5%HPMC E50 and 27.2 μ L 5N HCl dispersion 50.52mg chemical compound (VI) in SWFI, mix simultaneously and heating (～50 ℃), till clarification.Add 2.67g 9%DMPC dispersion liquid and 54.4 μ L 2N NaOH solution then, so as with pH regulator to 5.3-6.Use sonicator homogenize compositions, use the 147mg glucose that osmolarity is adjusted to about 230-240mOsm then, filter by 0.45 μ m filter subsequently.
Preparation 30-E (1% chemical compound (V)/5%PL90H/0.2%HPMC/3.5% glucose)
Preparation
Use 6.7g 0.5%HPMC (40-60cps) and 102 μ L 5N HCl dispersion 181.82mg chemical compound (VI) in SWFI, mix simultaneously and heating (～50 ℃), till clarification.Add then 8.2g 9% hydrogenated soybean PC (PL90H) in SWFI suspension and carry out sonication, add 60 μ L2N NaOH then so as with pH regulator to 5.3-5.8.Use sonicator probe (GE-130 type) homogenize compositions, use 491mg glucose (EP/BP/USP level, Fisher Scientific) that osmolarity is adjusted to about 260mOsm and passes through the filtration of 0.22 μ m PVDF syringe filter (Millipore) then.
Preparation 30-F (1% chemical compound (V)/0.2% Tai Luoshabai/0.3%HPMC/3.5% Fructus Vitis viniferae
Sugar) preparation
Use 10.96g 0.5%HPMC (40-60cps) and 102 μ L 5N HCl dispersion 186.15mg chemical compound (VI) in SWFI, mix simultaneously and heating (～50 ℃), till clarification.Add 3.123g 1% Tai Luoshabai solution and 210 μ L2N NaOH solution then so as with pH regulator to 5.0-5.5.Use sonicator probe (GE-130 type) homogenize compositions, use 493.6mg glucose (EP/BP/USP level, Fisher Scientific) that osmolarity is adjusted to about 260mOsm and passes through the filtration of 0.22 μ m PVDF syringe filter (Millipore) then.Test and estimate the preparation 30-A-30-F of preparation as mentioned above then.
The eye toleration of the chemical compound (VI) of embodiment 31 preparations
Chemical compound (V) preparation (1% chemical compound (VI)/1%HPMC/3.5% glucose/0.2% Thailand
The preparation of Luo Shabai/0.005%BAK/0.025%EDTA)
Use 55g 0.5%HPMC (40-60cps) and 529 μ L 5N HCl dispersion 989mg compound VI in SWFI, mix simultaneously and heating (～50 ℃), till clarification.Add the solution of 87.5g 3.5mg/mL Tai Luoshabai in 0.5%HPMC then, use 5.18g glucose (EP/BP/USP level, Fisher Scientific) that osmolarity is adjusted to about 256mOsm and add 1081 μ L2N NaOH in case with pH regulator to 5.0-5.5.Use Avestin C5 homogenate, filter by 0.45 μ m filter then, use 0.22 μ mPES syringe filter (Millipore) to filter subsequently.In the 103.05g preparation, add 516 μ L 1%BAK solution and 516 μ L 5%EDTA.
Carrier is (at 1%HPMC/3.5% glucose/0.2% Tai Luoshabai/0.005%
0.012% carminic acid among the BAK/0.025%EDTA) preparation
55.24g 1%HPMC (40-60cps) is mixed in SWFI and 529 μ L 5N HCl.Add solution and the 1324 μ L2N NaOH solution of 87g 0.35% Tai Luoshabai in 1%HPMC then.Add the 18.53mg carminic acid and use 1N NaOH, use the 5.16g glucose that osmolarity is adjusted to 246 then pH regulator to 7.4.738 μ L 1%BAK and 738 μ L 5%EDTA are joined in the 147g solution so that with pH regulator to 7.4, subsequently by the filtration of 0.22PES filter.0.9% saline solution is used as (B/Braun) negative control.
Embodiment 32 a series of chemical compounds by topical (eye drip) intraocular delivery extremely
C57b1/6 mice eye rear portion
A series of chemical compounds are mixed with and isoosmotic 1% drug substance in 0.2% Tai Luoshabai/1%HPMC of glucose.The pH of preparation is according to the difference of every kind of chemical compound characteristic and in the 5-7.4 scope.Analyze the amount of drug substance when giving after preparation and the administration in the end 2 and 7 hours by topical to the c57b1/6 mice.Extraction is organized and is detected by LC/MS/MS.
Although described the present invention with reference to the foregoing description, accessible is that modification and variation comprise within the spirit and scope of the present invention.Therefore, the present invention is only limited by following claims.
Claims (63)
1. compositions, it comprises:
Medicine or its prodrug and the pharmaceutically acceptable carrier that is used for ocular delivery, wherein said medicine has:
A) be no more than about 150
2Polar surfaces long-pending;
B) under the scope pH of 4-8, be lower than the water solublity of about 0.1mg/mL;
C) be to be at least about 0.5 cLogD 7.4 times at pH; With
D) be no more than about 1,000 daltonian molecular weight,
Condition is that described medicine is not a steroid molecule.
2. the described compositions of claim 1, wherein said medicine have and are no more than about 120
2Polar surfaces long-pending.
3. the described compositions of claim 2, wherein said medicine have and are no more than about 100
2Polar surfaces long-pending.
4. any described compositions among the claim 1-3, wherein said medicine has the water solublity that is lower than about 0.05mg/mL.
5. the described compositions of any claim 4, wherein said medicine has the water solublity that is lower than about 0.01mg/mL.
6. the described compositions of claim 1, wherein said medicine have and are at least about 1 cLogD.
7. the described compositions of claim 1, wherein said medicine have and are at least about 2 cLogD.
8. the described compositions of claim 1, wherein said medicine have and are no more than about 900 daltonian molecular weight.
9. the described compositions of claim 1, wherein said medicine have and are no more than about 800 daltonian molecular weight.
10. the described compositions of claim 1, wherein said medicine or prodrug are selected from antiallergic agent, antimigraine, anti-anemic drug, bronchodilator, analgesic, antibiotic, leukotriene inhibitor or antagonist, antihistaminic, non-steroid class antiinflammatory, antineoplastic agent, anticholinergic, anesthetics, antitubercular agent, cardiovascular drug, agglutinin, peptide class and combination thereof.
11. the described compositions of claim 1, wherein said medicine or prodrug are inhibitors of kinases.
12. the described compositions of claim 11, wherein said kinases are selected from Janus family kinase (Jak), Src family kinase, vegf receptor family kinase, pdgf receptor family kinase, Eph receptor family kinases and FGF receptor family kinases.
13. the described compositions of claim 1, wherein said medicine or prodrug are lipophilic.
14. the described compositions of claim 1, wherein by in the vitreous body or near the eyes with described formulation delivered to an eye rear portion.
15. the described compositions of claim 1, wherein said preparation are eye drop.
16. the described compositions of claim 1 further comprises the chemical compound of the compositions, wetting agent, cataract preventive, vegf receptor inhibitor, antiinflammatory, oxygen free radical scavenger and the NO inhibitor that are selected from antiviral agent, antibiotic, reduction intraocular pressure.
17. the described compositions of claim 1 further comprises surface active ingredient.
18. the described compositions of claim 17, wherein said surface active ingredient are selected from phospholipid, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE class, cuorin, fatty acid, phospholipid and non-ionic surface active agent.
19. the described compositions of claim 18, wherein said non-ionic surface active agent is selected from: Tai Luoshabai; Polyethylene glycols and derivant are as PEG400, PEG1500, PEG20000; Poloxamer 407; Poloxamer 188; Tween 80; And polysorbate20.
20. the described compositions of claim 1, wherein said medicine or prodrug are not used for the treatment of glaucoma.
21. the described compositions of claim 18, wherein said medicine or prodrug are not used for the treatment of glaucoma.
22. the described compositions of claim 1, wherein said composition is suitable for treating the pathology situation of eye, and it is selected from the degeneration of macula relevant with the age, diabetic retinopathy, diabetic macular edema, cancer and glaucoma.
23. the described compositions of claim 1, wherein said medicine or its prodrug comprise chemical compound and pharmaceutically acceptable salt, hydrate, solvate, crystal form, N-oxide and each diastereomer with structure A:
Wherein A is selected from CH, N, NH, O and S independently of one another, or A is for merging so that form the ingredient of the ring of second ring, and wherein second ring is selected from aromatics, heteroaromatic, bicyclic aromatic and bicyclic aromatic heterocycle;
B separately independently for CH or fusion so that form the ingredient of the ring of second ring, wherein second ring be selected from aromatics, bicyclic aromatic and only first ring be the dicyclo of aromatics;
A
1Be selected from NR
a, C (O), S (O), S (O)
2, P (O)
2, O, S and CR
a, wherein R is selected from H, low alkyl group, branched alkyl, hydroxy alkyl, aminoalkyl, alkylthio, alkyl hydroxy, alkyl thiol and alkylamino, and if A wherein
1Be NR
a, if a=1 so is and A
1Be CR
a, a=2 so;
A
2Be selected from NR, C (O), S (O), S (O)
2, P (O)
2, O and S, condition is A
1With A
2Between to be connected chemically be correct;
R
0Be selected from H, low alkyl group and branched alkyl;
L
1Be selected from key, O, S, C (O), S (O), S (O)
2, NR
aAnd C
1-C
6Alkyl; L
2Be selected from key, O, S, C (O), S (O), S (O)
2, C
1-C
6Alkyl and NR
aOr L
1And L
2Lump together the formation key;
R
b, R
d, R
eAnd R
fDo not exist separately or be independently selected from H, C
1-C
6Alkyl, cycloalkyl, branched alkyl, hydroxy alkyl, aminoalkyl, alkylthio, alkyl hydroxy, alkyl thiol and alkylamino;
P, q, m, r are separately independently for having the integer of from 0 to 6 numerical value;
R
bAnd R
dLump together to form and be selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart; Or
R
bAnd R
eLump together to form and be selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart; Or
R
dAnd R
fLump together to form and be selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart; Or
R
bAnd R
fLump together to form and be selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
m(CH
2)
1-O-(CH
2)
mPart; Or
R
dAnd R
eForm each other and be selected from (CH
2)
m, (CH
2)
r-S-(CH
2)
m, (CH
2)
r-SO-(CH
2)
m, (CH
2)
r-SO
2-(CH
2)
m, (CH
2)
r-NR
a-(CH
2)
m(CH
2)
r-O-(CH
2)
mPart;
R
1Be selected from (CR
a)
m, (O) R ', C (O) N (R ') of O, N, S, C (O)
2, SO
3R ', OSO
2R ', SO
2R ', SOR ', PO
4R ', OPO
2R ', PO
3R ', PO
2R ' and the 3-6 unit heterocycle that has one or more heteroatoms, wherein R ' is selected from hydrogen, low alkyl group and alkyl-hydroxyl, or R ' is for being selected from the part of the closed loop 3-6 unit heterocycle, branched alkyl and the branched alkyl hydroxyl that have one or more heteroatoms, and wherein each R ' is independently under the situation of an above R ' existence;
R
2Be selected from phenyl, halogen, alkylamino, alkyl oxo, the CF of hydrogen, alkyl, branched alkyl, phenyl, replacement
3, sulfonamido, replacement sulfonamido, alkoxyl, alkylthio, sulfonate, sulphonic acid ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carbonyl oxygen base, acylamino-, urea groups, replacement carbonyl oxygen base, replacement acylamino-, replacement urea groups and have the 3-6 unit heterocycle of one or more heteroatoms, additional condition is one or two substituent R
2May reside on the ring, and if have an above substituent R
2, these substituent groups are identical or different separately so;
R
3Be selected from hydrogen, alkyl, branched alkyl, alkoxyl, halogen, CF
3, cyano group, replacement alkyl, hydroxyl, alkyl hydroxy, sulfydryl, alkyl thiol, alkylthio, amino and aminoalkyl; And
N is the integer with the value between 1 and 5, and additional condition is if n 〉=2, each R so
3Group and other R
3Group is independent.
24. the described compositions of claim 23, wherein said medicine or its prodrug are selected from Compound I, II and III:
25. the described compositions of claim 24, wherein said medicine or its prodrug are Compound I:
26. the described compositions of claim 24, wherein said medicine or its prodrug are Compound I I:
27. the described compositions of claim 24, wherein said medicine or its prodrug are compound III:
28. the described compositions of claim 1, wherein said medicine or its prodrug comprise chemical compound and pharmaceutically acceptable salt, hydrate, solvate, crystal form, N-oxide and each diastereomer with structure B:
Wherein:
Wherein A is selected from (CH) independently of one another
0-1, N, NH, O, S and fusion be so that form the ingredient of the ring of second ring, wherein second ring be selected from aromatics, heteroaromatic, bicyclic aromatic, bicyclic aromatic heterocycle or only first ring be the dicyclo of aromatics or heteroaromatic;
B is selected from (CH) independently of one another
0-1, N, NH, O, S and fusion be so that form the ingredient of the ring of second ring, wherein second ring be selected from aromatics, heteroaromatic, bicyclic aromatic, bicyclic aromatic heterocycle or only first ring be the dicyclo of aromatics or heteroaromatic, additional condition is if each B is (CH)
0, R so
3Directly and the adjacent ring bonding;
R
0Be selected from H and low alkyl group;
L is selected from key and replacement or unsubstituted alkyl, alkenyl or alkynyl coupling part;
R
1Be selected from C (R ')
3, OR ', N (R ')
2, NR ' C (O) R ', NR ' C (O) O (R) ', NR ' C (O) N (R ')
2, SR ', C (O) (O) R ', C (O) R ', C (O) N (R ')
2, SO
3R ', OSO
2R ', SO
2R ', SOR ', S (O) N (R ')
2, (O) N (R ') of OS (O)
2, (O) N (R ') of S (O)
2, S (O) N (R ')
2, PO
4R ', OPO
2R ', PO
3R ', PO
2R ' and the 3-6 unit heterocycle that has one or more heteroatoms, wherein each hetero atom can carry R ' group arbitrarily thereon independently, wherein R ' is selected from hydrogen, low alkyl group, the alkyl that replaces, alkyl-hydroxyl, alkyl-the hydroxyl that replaces, sulfydryl-alkyl, the alkyl of sulfydryl-replacement, alkyl-sulfydryl, alkyl-the sulfydryl that replaces, aminoalkyl, the alkyl of amino-replacement, alkylamino, alkyl-the amino that replaces, branched alkyl, the alkyl of substitution in side chain, the branched alkyl hydroxyl, the alkyl hydroxy of substitution in side chain, side chain sulfo--alkyl, the alkyl of side chain sulfur-replacement, branched alkyl-sulfydryl, alkyl-the sulfydryl of substitution in side chain, the branched-amino alkyl, the alkyl of branched-amino-replacement, branched alkyl amino, alkyl-the amino of substitution in side chain and closed loop 3-6 unit's carbocyclic ring or heterocycle, wherein the substituent group on the alkyl of any described replacement comprises described closed loop 3-6 unit's carbocyclic ring or heterocycle, additional condition is that each hetero atom on the 3-6 unit heterocycle can carry R ' group arbitrarily thereon, additional condition is that the replacement on the alkyl of any described replacement comprises by non-carbon atom or any R ' group of being connected with described alkyl by carbon, and wherein in the situation that has an above R ' each R ' be independently;
R
2For being positioned at the substituent group on 5,6 or 8 of ring, wherein R
2Be selected from methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, isopentyl, phenyl, replacement phenyl, halogen, side chain or non-branched-chain alkyl amino,, side chain or non-branched-amino alkyl, side chain or non-branched-chain alkyl oxo, side chain or non-branched alkoxy, side chain or non-side chain alkylthio, side chain or non-branched-chain alkyl sulfydryl, CF
3, sulfonamido, replacement sulfonamido, sulfonate, sulphonic acid ester, phosphate, phosphate ester, phosphonate, phosphonate ester, carbonyl oxygen base, acylamino-, urea groups, replacement carbonyl oxygen base, replacement acylamino-, replacement urea groups or directly or the first carbocyclic ring of 3-6 or the heterocycle that are connected with 5,6 or 8 by group L, each hetero atom can carry R arbitrarily independently
2Group, additional condition are one, two or three substituent R
2May reside on the ring these substituent R
2Identical or different separately;
R
3Be selected from hydrogen, alkyl, alkoxyl, halogen, CF
3, cyano group, the alkyl of replacement, hydroxyl, aryl, the aryl of replacement, heteroaryl, the heteroaryl of replacement, heterocycle, C (R ")
3, OR ", N (R ")
2, NR " C (O) R ", NR " C (O) NR ", R ", C (O) (O) R ", OC (O) R ", C (O) N (R ")
2, C (O), C (O) R ", 0C (O) N (R ")
2, SO
3R ", OSO
2R ", SO
2R ", SOR ", PO
4R ", OPO
2R ", PO
3R ", PO
2R "; wherein R " has the first heterocycle of closed loop 3-6, branched alkyl, the branched alkyl hydroxyl of one or more heteroatoms for heteroaryl, low alkyl group, side chain low alkyl group, alkyl-hydroxyl, branched alkyl-hydroxyl, amino-alkyl, branched-amino-alkyl, alkyl-amino, branched alkyl-amino, sulfydryl-alkyl, side chain sulfydryl-alkyl, alkyl-sulfydryl, side chain sulfydryl-alkyl or the formation of the aryl of hydrogen, aryl, replacement, heteroaryl, replacement, is independently at above R of existence " situation in each R " wherein;
N is the integer with the value between 1 to 5, and additional condition is if n 〉=2, R so
3Group and other R
3Group is independent separately,
Additional condition is if A respectively does for oneself (CH)
0, L is a key so;
Additional condition is if B respectively does for oneself (CH)
0, R so
3Be the above-mentioned any substituent group except hydrogen, 7 Direct Bonding of it and adjacent ring.
29. the described compositions of claim 28, wherein said medicine or its prodrug comprise the chemical compound that is selected from compound IV-XX:
30. the described compositions of claim 28, wherein said medicine or its prodrug inclusion compound V:
31. the described compositions of claim 28, wherein said medicine or its prodrug inclusion compound VI:
32. the described compositions of claim 28, wherein said medicine or its prodrug comprise the chemical compound that is selected from compound VIII, IX, X, XVII and XIX:
33. the described compositions of claim 28, wherein said medicine or its prodrug inclusion compound XII:
34. comprising, the described compositions of claim 28, wherein said medicine or its prodrug be selected from compound VI I, the chemical compound of XV and XVI:
35. the described compositions of claim 28, wherein said medicine or its prodrug inclusion compound XIV:
36. the described compositions of claim 28, wherein said medicine or its prodrug inclusion compound XVIII:
37. the described compositions of claim 28, wherein said medicine or its prodrug inclusion compound XI:
38. the described compositions of claim 1 further comprises the carrier based on polymer that can form colloidal suspension with described medicine or prodrug.
39. the described compositions of claim 38, wherein said polymer are the lyophily polymer.
40. the described compositions of claim 38, wherein said polymer are selected from cellulose derivative, amylopectin and derivant thereof, glucosan and derivant thereof, poly-(vinylpyrrolidone), poly-(vinyl alcohol), poly-(acrylic acid) derivant, poly-(methacrylic acid) derivant and combination thereof.
41. the described compositions of claim 40, wherein said cellulose derivative is selected from methylcellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, carboxymethyl cellulose, starch, amylase and derivant thereof.
42. the method for treatment experimenter ophthalmic diseases comprises the compositions of the experimenter that these needs are arranged being treated the claim 1 of effective dose, treats this disease thus.
43. the described method of claim 42, wherein said ophthalmic diseases are selected from the degeneration of macula relevant with the age, diabetic retinopathy diabetic macular edema, cancer and glaucoma.
44. the described method of claim 42 is wherein by giving described compositions to the eye rear portion in the vitreous body or near the eyes.
45. the described method of claim 42, wherein said compositions are the eye drop preparation form.
46. the described method of claim 45, wherein the surface to eye gives described compositions, every day or about weekly 1 to 4 time.
47. the described method of claim 42 wherein gives described compositions to the experimenter with exsiccant degeneration of macula relevant with the age.
48. the described method of claim 42 wherein gives described compositions so that reduce the risk of ophthalmic diseases development.
49. the described method of claim 42, further comprise and give pharmaceutically acceptable material, it is selected from compositions, wetting agent, cataract preventive, vegf receptor antagonist, antiinflammatory, oxygen free radical scavenger and the NO inhibitor of antiviral agent, antibiotic, reduction intraocular pressure.
50. the described method of claim 42, wherein said pharmaceutically acceptable material is the vegf receptor inhibitor.
51. the described method of claim 42 further comprises and is selected from RNAi molecule, antisense molecule, peptide, micromolecular compound, polynucleotide and proteinic molecule.
52. the described method of claim 42 wherein is mixed with the preparation that is selected from solution, gel, suspension, Emulsion and ointment with described compositions.
53. the described method of claim 42, wherein said compositions further comprises pharmaceutically acceptable material, and it is selected from tonicity agent, comfortable promoter, solubilisation aids, antioxidant and stabilizing agent.
54. the method for compositions of preparation claim 1 comprises:
Be with or without in the presence of the organic solvent dissolving or be partly dissolved described medicine;
Mix with the moisture colloidal suspension that comprises the polymeric matrix carrier, contains or do not contain surface active ingredient;
If suitable, randomly remove organic solvent;
Add penetrating agent; And
With pH regulator to making described compositions be suitable for the value of administration.
55. the method for compositions of preparation claim 1 comprises:
Described medicine or prodrug mixed with the moisture colloidal suspension that comprises the polymeric matrix carrier so that form have the colloidal suspension that is lower than 5 μ m mean particle sizes;
Add penetrating agent; And
With pH regulator to making described compositions be suitable for the value of administration.
56. any described method in claim 54 and 55, at least a in further comprising the following steps:
Add aseptic filler;
Sterilize by filtration or autoclaving;
Lyophilization;
Spray drying; Or
Before use dry preparation is dissolved again.
57. comprise the goods of the bottle of the compositions that contains claim 1.
58. the described goods of claim 57 further comprise the description that gives described compositions.
59. chemical compound is delivered to the method at a rear portion, comprise preparation contain claim 1 compositions preparation and said preparation is delivered to the eye that needs the experimenter that this class sends.
60. the described method of claim 59, wherein said preparation are the eye drop dosage form.
61. the described method of claim 59, wherein said compositions comprises inhibitors of kinases.
62. the described method of claim 61, wherein said kinases are selected from Src family kinase, vegf receptor family kinase, pdgf receptor family kinase, Eph receptor family kinases, FGF receptor family kinases and Janus family kinase.
63. identify the method for the chemical compound be suitable for being delivered to a rear portion, comprise:
(a) give chemical compound by the eye drip administration; And
(b) observe the distribution of chemical compound in eye after the eye drip administration, wherein this chemical compound is the medicine or the prodrug of claim 1,
Identify the chemical compound that is suitable for being delivered to eye thus.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68911105P | 2005-06-08 | 2005-06-08 | |
| US60/689,111 | 2005-06-08 | ||
| US60/763,537 | 2006-01-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101237871A true CN101237871A (en) | 2008-08-06 |
Family
ID=39921063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800289138A Pending CN101237871A (en) | 2005-06-08 | 2006-06-07 | Methods and compositions for the treatment of ocular disorders |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101237871A (en) |
-
2006
- 2006-06-07 CN CNA2006800289138A patent/CN101237871A/en active Pending
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Application publication date: 20080806 |