CN101810563B - Tacrolimus ophthalmic in-situ gel preparation and preparation method thereof - Google Patents

Abstract

The invention provides a tacrolimus ophthalmic in-situ gel preparation and a preparation method thereof, which micronizes medicaments or adopts the solid dispersion technology, the cyclodextrin inclusion technology or the like to obviously improve the solubility and then to prepare into an ophthalmic preparation which is in the liquid state in vitro and is in the gel state when being dropped into eyes. The invention is applicable to the treatment for preventing and curing ophthalmic corneal transplantation rejection, keratoconjunctivitis (KC), ocular allergic disorders and the like. The invention prepares tacrolimus into the ophthalmic in-situ gel for the first time. The ophthalmic gel is in the liquid state in vitro, the dosage can be easily and accurately controlled, the operation is convenient, and the ophthalmic gel can be uniformly spread when being dropped into eyes to form the gel. The ophthalmic gel can stay in eyes for long, can not be easily diluted by tears, can maintain the concentration of the effective medicaments, enhances the treatment effect, and has the advantages of less stimulation and good biocompatibility, thereby being an effective new ophthalmic medicine, being applicable to the clinic treatment and having extensive development prospect.

Description

Tacrolimus ophthalmic is used in body gel preparation and preparation method thereof

Technical field

The invention belongs to drug world, more specifically relate to a kind of tacrolimus ophthalmic and be used in body gel preparation and preparation method thereof.

Background technology

The keratopathy that a variety of causes causes is present domestic topmost blinding keratopathy, and annual number of patients reaches more than 1,000,000, and corneal graft is the main method of this type of disease of treatment, and the immunological rejection behind the corneal graft is present a great problem.Glucocorticoid is the main means of control postoperative graft-rejection, but its prolonged application not only can cause multiple complications, and often can not suppress the rejection of high-risk corneal transplantation postoperative effectively.In recent years ciclosporin A in the application of ophthalmology more and more widely, but ciclosporin eye drop solvent is an oiliness, it splashes into the eye back has very strong zest to eyes, the patient can not tolerate usually, and has allergic phenomena to take place.Clinical trial shows that the application of tacrolimus in transplanting such as the heart, lung, intestinal, bone marrow has better curative effect.It is treating LADA oculopathy, eye anaphylaxis illness simultaneously, and the immunological rejection after the corneal transplantation all has good curative effect.Its mechanism of action is similar with Ciclosporin A (CsA), and immunosuppressive activity is strong 100 times than Ciclosporin A, and the toxicity incidence rate is lower.

Tacrolimus (Tacrolimus, FK506) be Japanese scholar in 1984 building the novel immunosuppressant of from soil fungi, extracting in the rolling land district of a kind of Macrolide, by one and half ketone groups, α, β diketone base and 23 rings are formed, its molecular formula is C ₄₄H ₆₉NO ₁₂H ₂O, molecular weight are 822.5.Be white in color under the room temperature crystallization or crystalline powder, water insoluble, dissolubility 1～2 μ gml in the water ^-1, be dissolved in methanol, ethanol, acetone, chloroform, ethyl acetate, slightly be dissolved in hexane, petroleum ether.Be the lipophilic hydrophobicity, its fusing point is 127～129 ℃.

Its chemical constitution such as Fig. 1.

Its mechanism of action is to suppress lymphocyte activation through the activity that suppresses the relevant cell factor transcription factor.Tacrolimus is combined into FK506-FKBP12 with receptor protein FKBP12 earlier after getting into cell, and this complex combines and suppress its activity again with the calcineurin high-affinity, finally suppress transcribing of IL-2, blocking-up Ca ²⁺The activated channel of dependent cell, cell thereby be suppressed, thus bring into play powerful immunosuppressive action.

At present, the preparation that gone on the market is mainly oral formulations and injection, is Japanese import.But its whole body administration common adverse reactions have tremble, headache, infection, paraesthesia, neurotoxicity and renal function go down.Idol has that diarrhoea, serum creatinine increase, insomnia, blood glucose are increased, chest pain and other untoward reaction such as feel sick.Tacrolimus is prepared into ophthalmic preparation, has the characteristics of safety, efficient, no whole body toxic and side effects, and at present still anophthalmia go on the market with preparation.But this drug main will have problems as follows: tacrolimus is water insoluble, and the ophthalmic permeability is poor, is difficult to reach within the eye treatment level, makes its bioavailability lower, and how increasing its dissolubility is a major issue that must solve.Cyclodextrin inclusion technique can increase the dissolubility of insoluble drug, and eyes are not had zest, can promote the corneal permeability of medicine in the time of solubilising, is suitable as very much the adjuvant of preparation ophthalmic preparation.Meanwhile, cyclodextrin inclusion technique has certain effect to the curative effect of medication that improves poorly water-soluble.Because these medicines dissolubility in clathrate increases, thereby dosage can increase, and when clathrate contact with cornea, because free drug constantly release from dynamic equilibrium, absorption rate is slack-off, and the free drug that contacts with absorption site in the part increases.Add the eye irritation that cyclodextrin also can alleviate some drugs in the eye drop.This problem is chosen cyclodextrin inclusion technique and is prepared the tacrolimus cyclodextrin clathrate as intermediate, to increase dissolubility and the corneal permeability of tacrolimus in water, improves bioavailability, and then is prepared into eye and is used in the body gel.This gel for eye use external be liquid condition, splashing into behind the ophthalmic can uniform spreading, and forms gel.The solution gel property of transition of this uniqueness makes it have that preparation is simple, divided dose is accurate, easy to use, particularly the mucosal tissue affinity is strong, the holdup time is long with agents area, zest is little, advantages such as good biocompatibility.In addition, can more help the treatment of corneal allograft rejection and other immune associated ophthalmopathies guaranteeing to reduce dosage, minimizing systemic absorption and toxic and side effects under the pharmaceutically-active prerequisite.

Summary of the invention

The purpose of this invention is to provide a kind of tacrolimus ophthalmic and be used in body gel preparation and preparation method thereof, solve that tacrolimus is that oral formulations and injection bring problems such as the big toxic and side effects of human body in the prior art, the dissolubility of physical ability increase medicine in the middle of the tacrolimus wherein, this gel for eye use external be liquid condition; Dosage is control easily accurately, and is easy to use, and splashing into behind the ophthalmic can uniform spreading, and forms gel; Within the eye the time of staying longer, be difficult for being kept active drug concentration by the tear dilution; Enhancing treatment effect, and zest is little, good biocompatibility; Be that a kind of effective eye is used new drug, can be applied to clinically to have the wide development prospect.

The tacrolimus ophthalmic that the present invention is used for treatments such as ophthalmic cornea graft-rejection, eye cornea and conjunctiva xerosis (KC), eye anaphylaxis illness is used in body gel single preparations of ephedrine, and its general tacrolimus ophthalmic by name is used in the body gel; English Tacrolimus In Situ Ophthalmic Gel by name; The Chinese phonetic alphabet is Takemosi Yanyong Zaitiningjiao.Medicine and main adjunct ingredient and the preparation of forming in following ratio that is applied to ophthalmology thereof; Wherein medicine is ground into impalpable powder or adopts solid dispersion technology or cyclodextrin inclusion technique to be prepared into the tacrolimus intermediate of high-dissolvability, adding ophthalmic gel base and other adjuvants are processed tacrolimus ophthalmic and are used in the body gel in the tacrolimus intermediate for preparing.

Tacrolimus ophthalmic of the present invention is used in the body gel preparation: said tacrolimus ophthalmic is used in the body gel preparation and contains the tacrolimus solid dispersion that water-soluble material is the high-dissolvability of carrier; According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; Said carrier material is polyvinylpyrrolidone, hydroxypropyl emthylcellulose, polyethylene glycols, poloxamer, Myrj 45, polyoxyethylene aliphatic alcohol ether, polyethylene glycol fatty acid glyceride, the mixture of one or more in saccharide or the organic acid.

The water-soluble material that contains of the present invention is the method for preparing that the tacrolimus ophthalmic of tacrolimus solid dispersion of the high-dissolvability of carrier is used in the body gel preparation; It is characterized in that: adopt solid dispersion technology to prepare the tacrolimus intermediate of high-dissolvability earlier, adding thickening agent and other adjuvants are processed tacrolimus ophthalmic and are used in the body gel in the tacrolimus intermediate for preparing.

Tacrolimus ophthalmic of the present invention is used in the body gel preparation: said tacrolimus ophthalmic is used in the tacrolimus clathrate that the body gel preparation contains with the cyclodextrin derivative high-dissolvability that is carrier; According to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; Said cyclodextrin derivative is one or more the mixture in beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, HP-, dihydroxypropyl-beta-schardinger dextrin-, glucose-beta-schardinger dextrin-, single succinyl-DM-, maleoyl-dimethyl-beta cyclodextrin, carboxymethyl cyclodextrin or the sulfoalkyl cyclodextrin.

Of the present invention containing with the cyclodextrin derivative is the method for preparing that the tacrolimus ophthalmic of tacrolimus clathrate of high-dissolvability of carrier is used in the body gel preparation; It is characterized in that: adopt cyclodextrin inclusion technique to prepare the tacrolimus intermediate of high-dissolvability earlier, adding thickening agent and other adjuvants are processed tacrolimus ophthalmic and are used in the body gel in the tacrolimus intermediate for preparing.

Of the present inventionly contain the method for preparing that the tacrolimus ophthalmic that is ground into the impalpable powder tacrolimus is used in the body gel preparation, it is characterized in that: earlier tacrolimus is ground into and adds thickening agent and other adjuvants behind the impalpable powder and process tacrolimus ophthalmic and be used in the body gel.

Remarkable advantage of the present invention is:

The present invention has overcome tacrolimus poorly water-soluble in the past; Problems such as the treatment window is narrow; Adopt solid dispersion technology or cyclodextrin inclusion technique or medicine such as is ground into behind the impalpable powder at solubilization method, significantly improve its dissolubility, thereby improve its bioavailability; Be prepared into then a kind of external for liquid condition, splash into the ophthalmic preparation of ophthalmic gel attitude.It is applied to the treatment of ophthalmic cornea graft-rejection, eye cornea and conjunctiva xerosis (KC), eye anaphylaxis illness etc.The present invention is prepared into eye with tacrolimus first and is used in the body gel, this gel for eye use external be liquid condition, dosage is accurately controlled easily, and is easy to use; Splashing into behind the ophthalmic can uniform spreading, and forms gel, within the eye the time of staying longer, be difficult for being diluted by tear; Can keep active drug concentration, enhancing treatment effect, and zest is little, good biocompatibility; Be that a kind of effective eye is used new drug, can be applied to clinically to have the wide development prospect.

Preferred cyclodextrin inclusion technique of the present invention is as the solubilization method of tacrolimus.Wherein, (HP-β-CD) solubilization to tacrolimus obviously is superior to other cyclodextrin derivative to HP-.With HP-β-CD is example, specifically inquires into the solubilization of cyclodextrin derivative to tacrolimus.The result shows, tacrolimus is had significant solubilization to HP-β-CD and along with the increase of HP-β-CD concentration, the dissolubility of medicine increases.In the time of 25 ℃, 5%HP-β-CD can make the dissolubility of tacrolimus in water increase 2.10 times; 50%HP-β-CD can make the dissolubility of tacrolimus in water increase 81.03 times.Along with the rising of temperature, the dissolubility of medicine also increases thereupon.When HP-β-CD mass concentration when being 50%, 25 ℃, 37 ℃ and 50 ℃ the dissolubility of tacrolimus be respectively 167.74,180.88 and 205.60 μ gml ^-1Tacrolimus-HP-(dissolubility (like table 1) of HP-β-CD).When HP-β-CD mass concentration less than 30%, greater than 5% o'clock, the effect that prepared cyclodextrin clathrate redissolves was better, and the dissolubility of tacrolimus can satisfy the requirement of preparation.Characteristic of the present invention is, adopts HP-to prepare the tacrolimus cyclodextrin clathrate, and its concentration range is 5%～30%.

The dissolubility of table 1 tacrolimus in variable concentrations HP-β-CD aqueous solution

Description of drawings

Fig. 1 is the structural formula of tacrolimus.

The specific embodiment

It is that the tacrolimus ophthalmic of the tacrolimus solid dispersion of carrier is used in the body gel preparation that preparation contains with the water-soluble material:

The tacrolimus ophthalmic of tacrolimus solid dispersion that contains water-soluble material and be the high-dissolvability of carrier is used in body gel preparation method for preparing: adopt solid dispersion technology to prepare the tacrolimus intermediate of high-dissolvability earlier, in the tacrolimus intermediate for preparing, add responsive to temperature type gel-type vehicle and other adjuvants and process tacrolimus responsive to temperature type eye and be used in the body gel; Perhaps adopt pH responsive type gel-type vehicle to be prepared into tacrolimus pH responsive type eye and be used in the body gel; Perhaps adopt the ion-sensitive type gel-type vehicle to be prepared into tacrolimus ion-sensitive type eye and be used in the body gel; Perhaps adopt two kinds of machine-processed gel-type vehicles of different gellings to be prepared into tacrolimus mixed type eye and be used in the body gel.

Said preparation temperature responsive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of responsive to temperature type gel-type vehicles; The preparation of employing solid dispersion technology; Described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol; Water-solubility carrier material after the adding fusion, mix homogeneously stirs; Pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) be dissolved in the injection water at the tacrolimus intermediate, antiseptic, isoosmotic adjusting agent, the viscosifier that prepare; Stirring makes the solubilizing agent complete wetting, is placed in 2～8 ℃ of refrigerators, until the solution that obtains clear; The responsive to temperature type gel-type vehicle that slowly adds accurate weighing while stirring; Continue to stir and to make responsive to temperature type gel-type vehicle granule, put it into then in 2～8 ℃ the refrigerator and preserve more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution all by water-wet; Regulate pH5～9 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

Said preparation pH responsive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of pH responsive type gel-type vehicles; The preparation of employing solid dispersion technology; Described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol; Water-solubility carrier material after the adding fusion, mix homogeneously stirs; Pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) pH responsive type gel-type vehicle and the viscosifier with accurate weighing constantly add in an amount of injection water under the stirring; Continuing to stir makes the two granule all wetted; Placement is until the solution of being clarified, do not have agglomerate; Slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH2.5～6 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of pH responsive type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said pH responsive type gel-type vehicle is one or more the mixture among carbomer, cross-linked acrylic acid and derivant thereof, chitosan and derivant thereof, cellulose acetate-phthalate, cellulose acetate phthalate ester (CAP) or the Lacte.

Said preparation ion-sensitive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of ion-sensitive type gel-type vehicles; The preparation of employing solid dispersion technology; Described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol; Water-solubility carrier material after the adding fusion, mix homogeneously stirs; Pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) ion-sensitive type gel-type vehicle and the viscosifier with accurate weighing constantly add in an amount of injection water under the stirring, continue to stir to make the two granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring; Continue to stir until obtaining clarification, no agglomerate, finely dispersed solution, regulate pH5～9, filter with 220 mesh sieve cloth then with the pH regulator agent; Moisturizing is to total amount again; Pressure sterilizing, packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of ion-sensitive type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said ion-sensitive type gel-type vehicle is one or more the mixture in acetyl-removed gellan gum or alginate and the polysaccharide.

Said preparation mixed type eye is used in body gel preparation one:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of ion-sensitive type gel-type vehicles; The preparation of employing solid dispersion technology; Described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol; Water-solubility carrier material after the adding fusion, mix homogeneously stirs; Pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) the pH responsive type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring; Responsive to temperature type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring in addition; Continuing to stir makes pH responsive type gel-type vehicle granule all wetted; Placement is until the solution of being clarified, do not have agglomerate, the responsive to temperature type gel-type vehicle put into 2～8 ℃ refrigerator and preserved more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; Slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent prepare while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 2～1000 parts of ion-sensitive type gel-type vehicles; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said pH responsive type gel-type vehicle is one or more the mixture among carbomer, cross-linked acrylic acid and derivant thereof, chitosan and derivant thereof, cellulose acetate-phthalate, cellulose acetate phthalate ester (CAP) or the Lacte; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

Said preparation mixed type eye is used in body gel preparation two:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of ion-sensitive type gel-type vehicles; The preparation of employing solid dispersion technology; Described solid dispersion technology is solvent method, fusion method or solvent-fusion method: tacrolimus is dissolved in adequate amount of ethanol; Water-solubility carrier material after the adding fusion, mix homogeneously stirs; Pour out cooling rapidly, boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) the ion-sensitive type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring; Responsive to temperature type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring in addition; Continuing to stir makes ion-sensitive type gel-type vehicle granule all wetted; Placement is until the solution of being clarified, do not have agglomerate, the responsive to temperature type gel-type vehicle put into 2～8 ℃ refrigerator and preserved more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; Slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent prepare while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.Above raw material is according to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 2～1000 parts of ion-sensitive type gel-type vehicles; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said ion-sensitive type gel-type vehicle is one or more the mixture in acetyl-removed gellan gum or alginate and the polysaccharide thereof; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

It is that the tacrolimus ophthalmic of tacrolimus clathrate of carrier is used in the body gel preparation that preparation contains with the cyclodextrin derivative:

The tacrolimus ophthalmic of tacrolimus clathrate that contains cyclodextrin derivative and be the high-dissolvability of carrier is used in body gel preparation method for preparing: adopt cyclodextrin inclusion technique to prepare the tacrolimus intermediate of high-dissolvability earlier, in the tacrolimus intermediate for preparing, add responsive to temperature type gel-type vehicle and other adjuvants and process tacrolimus responsive to temperature type eye and be used in the body gel; Perhaps adopt pH responsive type gel-type vehicle to be prepared into tacrolimus pH responsive type eye and be used in the body gel; Perhaps adopt the ion-sensitive type gel-type vehicle to be prepared into tacrolimus ion-sensitive type eye and be used in the body gel; Perhaps adopt two kinds of machine-processed gel-type vehicles of different gellings to be prepared into tacrolimus mixed type eye and be used in the body gel.

Said preparation temperature responsive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) be dissolved in the injection water at the tacrolimus intermediate, antiseptic, isoosmotic adjusting agent, the viscosifier that prepare; Be placed in 2～8 ℃ of refrigerators; Until the solution that obtains clear, slowly add the responsive to temperature type gel-type vehicle of accurate weighing while stirring, continue stirring and make responsive to temperature type gel-type vehicle granule all by water-wet; Put it into then and preserve more than the 24h, in 2～8 ℃ the refrigerator until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH5～9 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

Said preparation pH responsive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) pH responsive type gel-type vehicle and the viscosifier with accurate weighing constantly add in an amount of injection water under the stirring; Continuing to stir makes the two granule all wetted; Placement is until the solution of being clarified, do not have agglomerate; Slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH2.5～6 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of pH responsive type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said pH responsive type gel-type vehicle is one or more the mixture among carbomer, cross-linked acrylic acid and derivant thereof, chitosan and derivant thereof, cellulose acetate-phthalate, cellulose acetate phthalate ester (CAP) or the Lacte.

Said preparation ion-sensitive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) ion-sensitive type gel-type vehicle and the viscosifier with accurate weighing constantly add in an amount of injection water under the stirring, continue to stir to make the two granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring; Continue to stir until obtaining clarification, no agglomerate, finely dispersed solution, regulate pH5～9, filter with 220 mesh sieve cloth then with the pH regulator agent; Moisturizing is to total amount again; Pressure sterilizing, packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of ion-sensitive type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said ion-sensitive type gel-type vehicle is one or more the mixture in acetyl-removed gellan gum or alginate and the polysaccharide thereof.

Said preparation mixed type eye is used in body gel preparation one:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) the pH responsive type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring, continues to stir to make pH responsive type gel-type vehicle granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Responsive to temperature type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring in addition, the responsive to temperature type gel-type vehicle is put into 2～8 ℃ refrigerator and is preserved more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; With responsive to temperature type gel-type vehicle and pH responsive type gel-type vehicle mix homogeneously, slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH2.5～6 with the pH regulator agent; Filter with 220 mesh sieve cloth then, moisturizing is to total amount again, pressure sterilizing; Packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 2～1000 parts of ion-sensitive type gel-type vehicles; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said pH responsive type gel-type vehicle is one or more the mixture among carbomer, cross-linked acrylic acid and derivant thereof, chitosan and derivant thereof, cellulose acetate-phthalate, cellulose acetate phthalate ester (CAP) or the Lacte; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

Said preparation mixed type eye is used in body gel preparation two:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) the ion-sensitive type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring, continues to stir to make ion-sensitive type gel-type vehicle granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Responsive to temperature type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring in addition, the responsive to temperature type gel-type vehicle is put into 2～8 ℃ refrigerator and is preserved more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; With responsive to temperature type gel-type vehicle and pH responsive type gel-type vehicle mix homogeneously, slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH5～9 with the pH regulator agent; Filter with 220 mesh sieve cloth then, moisturizing is to total amount again, pressure sterilizing; Packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 2～1000 parts of ion-sensitive type gel-type vehicles; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said ion-sensitive type gel-type vehicle is one or more the mixture in acetyl-removed gellan gum or alginate and the polysaccharide thereof; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

Preparation contains the tacrolimus ophthalmic that is ground into impalpable powder and is used in the body gel preparation:

Contain the tacrolimus ophthalmic that is ground into impalpable powder and be used in body gel preparation method for preparing: earlier tacrolimus is ground into impalpable powder, crosses 220 mesh sieves, add responsive to temperature type gel-type vehicle and other adjuvants respectively and process tacrolimus responsive to temperature type eye and be used in the body gel; Perhaps adopt pH responsive type gel-type vehicle to be prepared into tacrolimus pH responsive type eye and be used in the body gel; Perhaps adopt the ion-sensitive type gel-type vehicle to be prepared into tacrolimus ion-sensitive type eye and be used in the body gel; Perhaps adopt two kinds of machine-processed gel-type vehicles of different gellings to be prepared into tacrolimus mixed type eye and be used in the body gel.

Said preparation temperature responsive type eye is used in the body gel preparation:

Antiseptic, isoosmotic adjusting agent, the viscosifier of getting recipe quantity are dissolved in the injection water; Be placed in 2～8 ℃ of refrigerators; Until the solution that obtains clear, slowly add the responsive to temperature type gel-type vehicle of accurate weighing while stirring, continue stirring and make responsive to temperature type gel-type vehicle granule all by water-wet; Put it into then and preserve more than the 24h, in 2～8 ℃ the refrigerator until obtaining clarification, no agglomerate, finely dispersed gel-type vehicle; The tacrolimus of recipe quantity is ground into impalpable powder, crosses 220 mesh sieves, gradation is ground in the substrate, stirs, and regulates pH5～9 with the pH regulator agent, and then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.According to mass fraction: 1 part of tacrolimus; 0.2～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, Metagin, second or the propyl ester etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

Said preparation pH responsive type eye is used in the body gel preparation:

The pH responsive type gel-type vehicle and the viscosifier of accurate weighing are constantly added in an amount of injection water under the stirring, and continuation is stirred and is made the two granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; The tacrolimus of recipe quantity is ground into impalpable powder; Cross 220 mesh sieves, gradation is ground in the substrate, stirs; Slowly add antiseptic, isoosmotic adjusting agent while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH2.5～6 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of pH responsive type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said pH responsive type gel-type vehicle is one or more the mixture among carbomer, cross-linked acrylic acid and derivant thereof, chitosan and derivant thereof, cellulose acetate-phthalate, cellulose acetate phthalate ester (CAP) or the Lacte.

Said preparation ion-sensitive type eye is used in the body gel preparation:

The ion-sensitive type gel-type vehicle and the viscosifier of accurate weighing are constantly added in an amount of injection water under the stirring, and continuation is stirred and is made the two granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; The tacrolimus of recipe quantity is ground into impalpable powder, crosses 220 mesh sieves, gradation is ground in the substrate; Stir, slowly add antiseptic, isoosmotic adjusting agent while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH5～9 with the pH regulator agent, filter with 220 mesh sieve cloth then, moisturizing is to total amount again; Pressure sterilizing, packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of ion-sensitive type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said ion-sensitive type gel-type vehicle is one or more the mixture in acetyl-removed gellan gum or alginate and the polysaccharide thereof.

Said preparation mixed type eye is used in body gel preparation one:

The pH responsive type gel-type vehicle of accurate weighing is constantly added in an amount of injection water under the stirring, and continuation is stirred and is made pH responsive type gel-type vehicle granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Responsive to temperature type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring in addition, the responsive to temperature type gel-type vehicle is put into 2～8 ℃ refrigerator and is preserved more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; With responsive to temperature type gel-type vehicle and pH responsive type gel-type vehicle mix homogeneously, the tacrolimus of recipe quantity is ground into impalpable powder, cross 220 mesh sieves, gradation is ground in the substrate; Stir, slowly add antiseptic, isoosmotic adjusting agent while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH2.5～6 with the pH regulator agent, filter with 220 mesh sieve cloth then, moisturizing is to total amount again; Pressure sterilizing, packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 2～1000 parts of ion-sensitive type gel-type vehicles; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said pH responsive type gel-type vehicle is one or more the mixture among carbomer, cross-linked acrylic acid and derivant thereof, chitosan and derivant thereof, cellulose acetate-phthalate, cellulose acetate phthalate ester (CAP) or the Lacte; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

Said preparation mixed type eye is used in body gel preparation two:

The ion-sensitive type gel-type vehicle of accurate weighing is constantly added in an amount of injection water under the stirring, and continuation is stirred and is made ion-sensitive type gel-type vehicle granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Responsive to temperature type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring in addition, the responsive to temperature type gel-type vehicle is put into 2～8 ℃ refrigerator and is preserved more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; With responsive to temperature type gel-type vehicle and ion-sensitive type gel-type vehicle mix homogeneously, slowly add tacrolimus impalpable powder, antiseptic, the isoosmotic adjusting agent of mistake 220 mesh sieves that prepare while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH2.5～6 with the pH regulator agent; Filter with 220 mesh sieve cloth then, moisturizing is to total amount again, pressure sterilizing; Packing promptly gets.According to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 2～1000 parts of ion-sensitive type gel-type vehicles; 2～1000 parts of responsive to temperature type gel-type vehicles.Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said ion-sensitive type gel-type vehicle is one or more the mixture in acetyl-removed gellan gum or alginate and the polysaccharide thereof; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

Tacrolimus ophthalmic of the present invention is used in the physicochemical character of body gel:

External be liquid, splashing into ophthalmic becomes gel, viscosity reduces with the increase of external carbuncle.

It is a kind of in external one-tenth liquid condition that tacrolimus ophthalmic of the present invention is used in the body gel preparation, splashes into the ophthalmic preparation of ophthalmic gel attitude.Its toxicity is low, and zest is little, good biocompatibility, and patient's compliance and toleration improve in section.Development and exploitation that tacrolimus ophthalmic is used in the body gel preparation have following advantage: for liquid condition, dosage is accurately control, easy to use easily, and be easy to sprawl after splashing into ophthalmic external for (1) these article.(2) eye of the present invention is used in the body gel and on rheology, is plasticity or pseudoplastic behavior character, and viscosity reduces with nictation, and use feeling is comfortable, when not batting an eyelid, can recover viscosity again.(3) the tacrolimus gel for eye use directly acts on the affected part, can play a role fully effectively, can reduce GI irritation, neurotoxicity and other side effect that oral drugs cause.(4) compare with conventional dosage forms commonly used, have unrivaled advantage.Compare with eye drop, tacrolimus ophthalmic is used in the body gel preparation and is difficult for by the tear dilution, and prolong drug helped medicine and keeps higher concentration at anterior corneal surface in the holdup time of eye, increased the medication amount through cornea, improved bioavailability of medicament; Compare with eye ointment, tacrolimus ophthalmic is used in body gel good water solubility, cleans easily, not pollution clothes.On the other hand, tacrolimus ophthalmic is used in the body gel and does not cause the visual field fuzzy, uses the back to form the gas-pervious reticular membrane of one deck, all can use round the clock.This Products Development is successful, not only can fill up the blank of domestic and international ophthalmic remedy, also can bring good society and economic benefit.

The representational embodiment of preparation of the present invention is provided below, and these embodiment only are used to explain the present invention, and protection domain are not caused restriction.

Embodiment

Embodiment 1 tacrolimus responsive to temperature type eye is used in the preparation of body gel

Tacrolimus	0.05g
		HP-	0.70g
Poloxamer 407 (P407)	20.0g
		Poloxamer 188 (P188)	10.3g
Sodium chloride	0.9g
		Benzalkonium bromide	0.02g
Using the 0.1mol/L sodium hydroxide to regulate pH is 8
		Add water to full dose	100g

Preparation technology:

Get tacrolimus and be dissolved in the small amount of ethanol solution, on one side ultrasonic one side slowly join in the HP-aqueous solution, ultrasonic 40min, lyophilized overnight promptly gets.Tacrolimus hydroxypropyl-beta-cyclodextrin inclusion, sodium chloride, the benzalkonium bromide of recipe quantity are dissolved in the injection water, are placed in 2～8 ℃ of refrigerators, until the solution that obtains clear; The poloxamer that slowly adds accurate weighing while stirring continue to stir and to make the poloxamer granule all by water-wet, puts it into then in 2～8 ℃ the refrigerator to preserve more than the 24h; Until obtaining clarification, no agglomerate, finely dispersed solution, using the 0.1mol/L sodium hydroxide to regulate pH is 8, filters with 220 mesh sieve cloth then; Moisturizing is to total amount again; Pressure sterilizing, packing promptly gets.

Embodiment 2 tacrolimus responsive to temperature type eyes are used in the preparation of body gel

Preparation technology:

Get tacrolimus and be dissolved in the small amount of ethanol solution, slowly join in the HP-aqueous solution while stir, continue to stir 2h, lyophilized overnight promptly gets.Tacrolimus hydroxypropyl-beta-cyclodextrin inclusion, sodium chloride, ethyl hydroxybenzoate and the hydroxypropyl emthylcellulose (E50) of recipe quantity are dissolved in the injection water, are placed in 2～8 ℃ of refrigerators, until the solution that obtains clear; The PEG-PLGA that slowly adds accurate weighing while stirring continues stirring and makes the PEG-PLGA grain all by water-wet, puts it into then and preserves more than the 24h in 2～8 ℃ of refrigerators; Until obtaining clarification, no agglomerate, finely dispersed solution, using the 0.1mol/L sodium hydroxide to regulate pH is 8, filters with 220 mesh sieve cloth then; Moisturizing is to total amount again; Pressure sterilizing, packing promptly gets.

Embodiment 3 tacrolimus pH responsive type eyes are used in the preparation of body gel

Tacrolimus	0.05g
		Polyethylene glycol 6000	20.0g
Carbomer (NF940)	2.0g
		Methylcellulose	0.8g
Glycerol	0.8g
		Methyl hydroxybenzoate	0.03g
Propylparaben	0.03g
		Using the 0.1mol/L triethanolamine to regulate pH is 4
Add water to full dose	100g

Preparation technology:

Getting tacrolimus is dissolved in the small amount of ethanol solution; After treating that polyethylene glycol 6000 is heated to fusion in 60～70 ℃ of water-baths; Mixing, vigorous stirring also is poured over fused mass and forms thin layer on the corrosion resistant plate, makes it to be cooled to rapidly solid; Again this solid is positioned over 24h in 25～40 ℃ of vacuum drying ovens, promptly gets.The carbomer and the methylcellulose of accurate weighing are constantly added in an amount of injection water under the stirring; Continuing to stir makes the two granule all wetted; Placement is until the solution of being clarified, do not have agglomerate; Slowly add tacrolimus solid dispersion, glycerol, methyl hydroxybenzoate, the propylparaben for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH4 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.

Embodiment 4 tacrolimus pH responsive type eyes are used in the preparation of body gel

Tacrolimus	0.05g
		Polyvinylpyrrolidone K30	30.0g
The cellulose acetate phthalate ester	0.3g
		Glucose	0.8g
Methyl hydroxybenzoate	0.03g
		Propylparaben	0.03g
Using the 0.1mol/L sodium hydroxide to regulate pH is 6
		Add water to full dose	100g

Preparation technology:

Getting tacrolimus is dissolved in the small amount of ethanol solution; After treating that polyvinylpyrrolidone K30 is heated to fusion in 60～70 ℃ of water-baths; Mixing, vigorous stirring also is poured over fused mass and forms thin layer on the corrosion resistant plate, makes it to be cooled to rapidly solid; Again this solid is positioned over 24h in 25～40 ℃ of vacuum drying ovens, promptly gets.The cellulose acetate phthalate ester of accurate weighing is constantly added in an amount of injection water under the stirring; Continuing to stir makes its granule all wetted; Placement is until the solution of being clarified, do not have agglomerate; Slowly add tacrolimus solid dispersion, glucose, methyl hydroxybenzoate, the propylparaben for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH4 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets.

Embodiment 5 tacrolimus ion-sensitive type eyes are used in the preparation of body gel

Tacrolimus	0.05g
		Go acetyl-removed gellan gum	0.6g
Sodium chloride	0.8g
		Benzalkonium chloride	0.03g
Using the 0.1mol/L sodium hydroxide to regulate pH is 8
		Add water to full dose	100g

Preparation technology:

The acetyl-removed gellan gum of going of accurate weighing is constantly added in an amount of injection water under the stirring, and continuation is stirred and is made it wetted, and placement is until the solution of being clarified, do not have agglomerate; The tacrolimus of recipe quantity is ground into impalpable powder, crosses 220 mesh sieves, gradation is ground in the substrate; Stir, slowly add benzalkonium chloride, sodium chloride while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH 8 with the 0.1mol/L sodium hydroxide, filter with 220 mesh sieve cloth then, moisturizing is to total amount again; Pressure sterilizing, packing promptly gets.

Embodiment 6 tacrolimus responsive to temperatures and ion-sensitive mixed type eye are used in the preparation of body gel

Tacrolimus	0.05g
		Single succinyl-DM-	1.5g
Poloxamer 407 (P407)	14.0g
		Sodium alginate	0.1g
Sodium chloride	0.8g
		Benzalkonium chloride	0.02g
Using the 0.1mol/L sodium hydroxide to regulate pH is 8
		Add water to full dose	100g

Preparation technology:

Get tacrolimus and be dissolved in the small amount of ethanol solution, slowly join in single succinyl-DM-aqueous solution while stir, continue to stir 2h, lyophilized overnight promptly gets.The sodium alginate of accurate weighing is constantly added in an amount of injection water under the stirring, and continuation is stirred and is made its granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; In addition the poloxamer 407 of accurate weighing is constantly stirred down and add in an amount of injection water, put it in 2～8 ℃ the refrigerator and preserve more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; With poloxamer 407 and sodium alginate soln mix homogeneously, slowly add tacrolimus cyclodextrin clathrate, benzalkonium chloride, the sodium chloride for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH8 with the 0.1mol/L sodium hydroxide; Filter with 220 mesh sieve cloth then, moisturizing is to total amount again, pressure sterilizing; Packing promptly gets.

The responsive mixed type eye of embodiment 6 tacrolimus responsive to temperatures and pH is used in the preparation of body gel

Preparation technology:

Getting tacrolimus is dissolved in the small amount of ethanol solution; After treating that Myrj 45 is heated to fusion in 60～70 ℃ of water-baths; Mixing, vigorous stirring also is poured over fused mass and forms thin layer on the corrosion resistant plate, makes it to be cooled to rapidly solid; Again this solid is positioned over 24h in 25～40 ℃ of vacuum drying ovens, promptly gets.The carbomer 1342P NF of accurate weighing is constantly added in an amount of injection water under the stirring, and continuation is stirred and is made its granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; In addition the poloxamer 407 of accurate weighing is constantly stirred down with poloxamer 188 and add in an amount of injection water, put it in 2～8 ℃ the refrigerator and preserve more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; With poloxamer 407, poloxamer 188 and carbomer 1342PNF solution mix homogeneously, slowly add tacrolimus solid dispersion, methyl hydroxybenzoate, the sodium chloride for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH6 with the 0.1mol/L sodium hydroxide; Filter with 220 mesh sieve cloth then, moisturizing is to total amount again, pressure sterilizing; Packing promptly gets.

The inherent body gel of tacrolimus ophthalmic suppresses the pharmacodynamic experiment of rabbit cornea graft-rejection:

The present invention has set up rabbit allogeneic penetrating keratoplasty animal model, tacrolimus ophthalmic is used in the body gel is applied topically in the rabbit cornea transplantation model, inquires into the inhibitory action of its corneal post-transplantation immunological rejection.This experimental selection ciclosporin eye drop is observed the curative effect that tacrolimus ophthalmic is used in the body gel as positive control drug.

Experimental program is following:

(1) foundation of penetrating keratoplasty model: 10min auricular vein injection air is put to death donor rabbits before the art, drills through with diameter 6.25mm trepan to supply the eye central cornea to plant sheet, puts in a small amount of 1% hyaluronate sodium subsequent use.It is the art eye that all recipient rabbits are all selected right eye, and 3d art eye drips and uses the levofloxacin eye drop, every day 4 times before the operation.Slit lamp examination before the art, solving skill eye situation.Recipient rabbits intramuscular injection chlore-ammonia ketone (50mgkg ^-1) and stable (2.5mgkg ^-1) mixed liquor anaesthetize sb. generally.15min starting point PILO eye drop and 1% tetracain hydrochloride eye drop are each 3 times before the Rhizoma Atractylodis Macrocephalae, at interval 5min.The routine disinfection drape, the sterile working.Under operating microscope, get 6.25mm cornea central authorities holostrome and plant sheet and implant 6.0mm cornea central authorities penetrance plant bed immediately, drip 2 heparin sodium injections, with 10-0 import nylon wire interrupted suture 16 pins, toe-in does not bury.Art finishes injects a small amount of viscoelastic agent (1% hyaluronate sodium) in the anterior chamber, form the anterior chamber.Subconjunctival injection dexamethasone sodium phosphate injection and atropine sulfate injection drip the levofloxacin eye drop, and margo palpebrae is sewed up.Postoperative 1d removes the margo palpebrae suture, postoperative 3d local conventional levofloxacin eye drop every day 4 times used, 1% atropine eye drop and Tropicamide and Phenylephrine eye drop, every day 2 times.Behind the 3d according to the different eye drops of packet applications.

(2) experimental animal divides into groups and administration: corneal transplantation postoperative the 3rd day, and get rid of because the operation factor causes infection, hyphema, obliteratio camerae anterior or postoperative generation iris incarceration, hyphema and lenticular opacity eye, and in time replenish animal.Be divided into 4 groups at random, 8 every group, A group: normal saline group (negative control group); B group: ciclosporin eye drop group; C group: tacrolimus Oleum Ricini eye drop group; D group: the responsive gel for eye use group of tacrolimus body temperature.Each group is used the eye drop eye drip all from postoperative beginning in the 3rd day, and every day 3 times, each 100 μ l take place until rejection.

(3) observational technique and index: postoperative rose on the 1st, under slit lamp, observed the situation of corneal graft every day, and muddiness, edema and three indexs of new vessels are marked, and standards of grading are seen table 2.Three item rating sums be the same day rejection index (rejection index, RI).When RI >=6, be regarded as immunological rejection and take place, the record corneal graft time-to-live.

Table 2 corneal transplantation postoperative rejection standards of grading

(4) statistical procedures: adopt the SPSS14.0 of statistical software to carry out statistical analysis; Use one factor analysis of variance (One-WayANOVA) the relatively difference of the difference of each observation index, RI and the difference of respectively organizing corneal graft survival natural law between each group, P＜0.05 is for there being statistical significance.

The result:

The scoring of each group rabbit cornea post-transplantation being planted sheet muddiness, edema, new vessels in 10 days compares.Find from table 3 analysis of statistical data:

1. each group of corneal transplantation postoperative 10 days is planted the sheet muddiness and is had significant difference (F=7.694; P=0.001), plant the sheet edema have significant difference (F=4.667, P=0.009); Plant sheet new vessels not statistically significant (F=0.569; P=0.640), the RI value have significant difference (F=12.242, P=0.000).

2. with the normal saline matched group relatively, each medication group plant the sheet muddiness all obviously alleviate (P=0.000, P=0.05, P=0.001).Compare difference not statistically significant (P＞0.05) between each medication group.

3. with the normal saline matched group relatively, each medication group plant the sheet edema all obviously alleviate (P=0.020, P=0.02, P=0.006).Compare difference not statistically significant (P＞0.05) between each medication group.

4. with the normal saline matched group relatively, each medication group RI value all obviously reduce (P=0.000, P=0.000, P=0.000).Compare difference not statistically significant (P＞0.05) between each medication group.

The scoring that table 3 corneal transplantation postoperative was planted sheet muddiness, edema, new vessels in 10 days is (x ± s) relatively

Divide into groups	Plant the sheet muddiness	Plant the sheet edema	Plant the sheet new vessels	RI
					Negative control group	2.62±0.74	1.88±0.64	1.38±0.52	5.88±1.12
Ciclosporin eye drop group	1.38±0.52**	1.25±0.46**	1.12±0.64	3.75±0.46**
					Tacrolimus Oleum Ricini eye drop group	1.50±0.53**	1.00±0.53**	1.25±0.71	4.00±0.76**
The responsive gel for eye use group of tacrolimus body temperature	1.81±0.74**	1.12±0.35**	1.50±0.53	4.12±0.64**

Compare * * P＜0.01 with normal saline group identical parameters

Each group rabbit cornea is planted the sheet time-to-live to be compared.The laboratory observation time is 100d.Data statistic analysis is found from table 4, and each is organized the corneal graft life span and compares with the normal saline group, all has significant difference (P＜0.01).Wherein normal saline group corneal graft life span is the shortest, and other respectively organize corneal graft life span not statistically significant.The result shows that the responsive gel for eye use of 0.05% tacrolimus body temperature can significantly suppress the immunological rejection that rabbit cornea is transplanted, with listing ciclosporin eye drop curative effect zero difference.

Table 4 is respectively organized rabbit cornea and is planted the sheet time-to-live

Group	The corneal graft time-to-live (d)	±s
			Negative control group	12、9、8、13、10、11、11、13	10.88±1.81
Ciclosporin eye drop group	100、100、100、100、100、100、100、100	100±0**
			Tacrolimus Oleum Ricini eye drop group	100、100、100、100、100、100、100、100	100±0**
The responsive gel for eye use group of tacrolimus body temperature	100、100、100、100、100、100、100、100	100±0**

Annotate: * * compares with the normal saline group, P＜0.01

Claims (3)

1. a tacrolimus ophthalmic is used in the body gel; It is characterized in that: medicine tacrolimus and adjuvant are prepared into the tacrolimus intermediate of high-dissolvability, in the tacrolimus intermediate for preparing, add ophthalmic gel base and other adjuvants and process tacrolimus ophthalmic and be used in the body gel;

It is the tacrolimus clathrate of carrier that said tacrolimus ophthalmic is used in that the body gel contains with the cyclodextrin derivative, according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; Said cyclodextrin derivative is one or more the mixture in beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, HP-, dihydroxypropyl-beta-schardinger dextrin-, glucose-beta-schardinger dextrin-, single succinyl-DM-, maleoyl-dimethyl-beta cyclodextrin, carboxymethyl cyclodextrin or the sulfoalkyl cyclodextrin.

2. a tacrolimus ophthalmic as claimed in claim 1 is used in the method for preparing of body gel; It is characterized in that: adopt cyclodextrin inclusion technique to prepare the tacrolimus intermediate of high-dissolvability earlier, adding responsive to temperature type gel-type vehicle and other adjuvants are processed tacrolimus responsive to temperature type eye and are used in the body gel in the tacrolimus intermediate for preparing; Perhaps adopt pH responsive type gel-type vehicle to be prepared into tacrolimus pH responsive type eye and be used in the body gel; Perhaps adopt the ion-sensitive type gel-type vehicle to be prepared into tacrolimus ion-sensitive type eye and be used in the body gel; Perhaps adopt two kinds of machine-processed gel-type vehicles of different gellings to be prepared into tacrolimus mixed type eye and be used in the body gel.

3. be used in the method for preparing of body gel according to the tacrolimus ophthalmic described in the claim 2, it is characterized in that:

Said preparation temperature responsive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) be dissolved in the injection water at the tacrolimus intermediate, antiseptic, isoosmotic adjusting agent, the viscosifier that prepare; Be placed in 2～8 ℃ of refrigerators; Until the solution that obtains clear, slowly add the responsive to temperature type gel-type vehicle of accurate weighing while stirring, continue stirring and make responsive to temperature type gel-type vehicle granule all by water-wet; Put it into then and preserve more than the 24h, in 2～8 ℃ the refrigerator until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH5～9 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets;

Above raw material is according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of responsive to temperature type gel-type vehicles; Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides;

Said preparation pH responsive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) pH responsive type gel-type vehicle and the viscosifier with accurate weighing constantly add in an amount of injection water under the stirring; Continuing to stir makes the two granule all wetted; Placement is until the solution of being clarified, do not have agglomerate; Slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH2.5～4 with the pH regulator agent, then with the filtration of 220 mesh sieve cloth, moisturizing is to total amount again, pressure sterilizing, and packing promptly gets;

Above raw material is according to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of pH responsive type gel-type vehicles; Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said pH responsive type gel-type vehicle is one or more the mixture among carbomer, cross-linked acrylic acid and derivant thereof, chitosan and derivant thereof, cellulose acetate-phthalate, cellulose acetate phthalate ester (CAP) or the Lacte;

Said preparation ion-sensitive type eye is used in the body gel preparation:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) ion-sensitive type gel-type vehicle and the viscosifier with accurate weighing constantly add in an amount of injection water under the stirring, continue to stir to make the two granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring; Continue to stir until obtaining clarification, no agglomerate, finely dispersed solution, regulate pH5～9, filter with 220 mesh sieve cloth then with the pH regulator agent; Moisturizing is to total amount again; Pressure sterilizing, packing promptly gets;

Above raw material is according to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 0～1000 part of viscosifier; 2～1000 parts of ion-sensitive type gel-type vehicles; Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said viscosifier are one or more the mixture in hydroxypropyl emthylcellulose, methylcellulose, polyvidone or the polyvinyl alcohol; Said ion-sensitive type gel-type vehicle is one or more the mixture in acetyl-removed gellan gum or alginate and the polysaccharide thereof;

Said preparation mixed type eye is used in body gel preparation one:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) the pH responsive type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring, continues to stir to make pH responsive type gel-type vehicle granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Responsive to temperature type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring in addition, the responsive to temperature type gel-type vehicle is put into 2～8 ℃ refrigerator and is preserved more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; With responsive to temperature type gel-type vehicle and pH responsive type gel-type vehicle mix homogeneously, slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH2.5～6 with the pH regulator agent; Filter with 220 mesh sieve cloth then, moisturizing is to total amount again, pressure sterilizing; Packing promptly gets;

Above raw material is according to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 2～1000 parts of ion-sensitive type gel-type vehicles; 2～1000 parts of responsive to temperature type gel-type vehicles; Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said pH responsive type gel-type vehicle is one or more the mixture among carbomer, cross-linked acrylic acid and derivant thereof, chitosan and derivant thereof, cellulose acetate-phthalate, cellulose acetate phthalate ester (CAP) or the Lacte; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides;

Said preparation mixed type eye is used in body gel preparation two:

(1) the first tacrolimus intermediate of preparation high-dissolvability: the raw material of said preparation tacrolimus intermediate comprises: according to mass fraction: 1 part of tacrolimus; 5～600 parts of cyclodextrin derivative; The preparation of employing cyclodextrin inclusion technique; Described cyclodextrin inclusion technique is paddling process, microwave method or supercritical ultrasonics technology: tacrolimus and cyclodextrin derivative are dissolved in adequate amount of ethanol; Sonic oscillation 5～60min; Rotary Evaporators is 20～60 ℃ of solvent evaporated, and boulton process or freeze-drying are prepared into the tacrolimus intermediate of high-dissolvability;

(2) the ion-sensitive type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring, continues to stir to make ion-sensitive type gel-type vehicle granule all wetted, and placement is until the solution of being clarified, do not have agglomerate; Responsive to temperature type gel-type vehicle with accurate weighing constantly adds in an amount of injection water under the stirring in addition, the responsive to temperature type gel-type vehicle is put into 2～8 ℃ refrigerator and is preserved more than the 24h, until obtaining clarification, no agglomerate, finely dispersed solution; With responsive to temperature type gel-type vehicle and ion-sensitive type gel-type vehicle mix homogeneously, slowly add tacrolimus intermediate, antiseptic, the isoosmotic adjusting agent for preparing while stirring, continue to stir until obtaining clarification, no agglomerate, finely dispersed solution; Regulate pH5～9 with the pH regulator agent; Filter with 220 mesh sieve cloth then, moisturizing is to total amount again, pressure sterilizing; Packing promptly gets;

Above raw material is according to mass fraction: 1 part of tacrolimus; 5～600 parts of water-solubility carrier materials; 0～6 part of antiseptic; 2～200 parts of isoosmotic adjusting agent; 2～1000 parts of ion-sensitive type gel-type vehicles; 2～1000 parts of responsive to temperature type gel-type vehicles; Said pH regulator agent is to adopt sodium hydroxide, or one or more the mixture in hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, boric acid, triethanol ammonium or the phosphate buffer; Said antiseptic is one or more the mixture in chlorobutanol, thimerosal, benzalkonium chloride, benzalkonium bromide, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben; Said isoosmotic adjusting agent is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Said ion-sensitive type gel-type vehicle is one or more the mixture in acetyl-removed gellan gum or alginate and the polysaccharide thereof; Said responsive to temperature type gel-type vehicle is poloxamer, polyethylene glycol-lactic acid block copolymer (PEG-PLGA (PLA)-PEG), ethylhydroxyethylcellulose or gather one or more the mixture in (N-isopropyl) acrylic acid amides.

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