CN101653413B - Tacrolimus ophthalmic emulsion and its preparation method - Google Patents
Tacrolimus ophthalmic emulsion and its preparation method Download PDFInfo
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- CN101653413B CN101653413B CN2009103077837A CN200910307783A CN101653413B CN 101653413 B CN101653413 B CN 101653413B CN 2009103077837 A CN2009103077837 A CN 2009103077837A CN 200910307783 A CN200910307783 A CN 200910307783A CN 101653413 B CN101653413 B CN 101653413B
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Abstract
The invention provides a tacrolimus ophthalmic emulsion and its preparation method, which belongs to the medicine preparation technical field and solve the problems of high toxic and side effects of tacrolimus oral preparation and injection to human body in the prior art. The emulsion is composed of tacrolimus, oil phase, an emulsifier, an auxiliary emulsifier, an osmotic pressure modifying agent, an antioxidant, a preservative, a pH modifying agent and an injection water, is prepared by an ultrasonic shearing emulsification or shearing-high pressure homogenization technology and is applied to treatment of ophthalmic corneal allograft rejection, keratoconjunctivitis sicca (KC) and ophthalmic anaphylactic disease. The invention prepares the tacrolimus into the ophthalmic emulsion for the first time, has the advantages of good biological compatibility, low stimulation to eyes and no toxic and side effects in the long-term application and can be applied clinically with wide development prospects.
Description
Technical field
The invention belongs to drug world, more specifically relate to a kind of tacrolimus ophthalmic emulsion 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 autoimmunity oculopathy, eye anaphylaxis illness simultaneously, and the immunological rejection after the corneal transplantation all has good curative effect.Its mechanism of action is similar to 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 is as follows:
The structural formula of tacrolimus
Its mechanism of action is to suppress lymphocyte activation by the activity that suppresses the relevant cell factor transcription factor.Tacrolimus is combined into FK506-FKBP12 with receptor protein FKBPl2 earlier after entering cell, and this complex combines with the calcineurin high-affinity and suppresses its activity, finally suppresses 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.
The tacrolimus eye drop is hospital-made oiliness eye drop at present.And oiliness is not suitable for the clinical treatment that directly applies to ocular disease.If it is directly splashed into eye, can produce stimulation and cause the dimness of vision and the viscosity sense of discomfort eye, also can increase the weight of some ocular disease, as xerophthalmia.
Summary of the invention
The purpose of this invention is to provide a kind of tacrolimus ophthalmic emulsion and preparation method thereof, tacrolimus is that oral formulations and injection bring problems such as the big toxic and side effects of human body in the solution prior art, tacrolimus is prepared into ophthalmic emulsion, it has good biocompatibility,, advantage such as life-time service have no side effect little to the eye zest, it is a kind of effective eye new drug, can be applied to clinically, have the wide development prospect.
Tacrolimus ophthalmic emulsion of the present invention is characterized in that: each raw material components of described tacrolimus ophthalmic emulsion comprises: tacrolimus 0.01～0.5g/ml; Oil phase 0.2～7.0g/ml; Emulsifying agent 0.1～10.0g/ml; Coemulsifier 0～2g/ml; Osmotic pressure regulator 0.1～10g/ml; Antioxidant 0～0.5g/ml; Antiseptic 0～0.6g/ml; PH regulator agent consumption is for regulating pH value to 5～9 of Emulsion; Surplus is a water for injection.
Remarkable advantage of the present invention is:
The present invention adopts safety, non-irritating surface activating agent as emulsifying agent, is fit to be applied to the eye sensitive part, has comfort level height, nonirritant, good biocompatibility, life-time service advantage such as have no side effect.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 ophthalmic emulsion with tacrolimus first, and ophthalmic emulsion 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.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 present invention adopts tacrolimus ophthalmic emulsion emulsion droplet mean diameter that ultrasonic shearing and high pressure homogenize prepared obtain less than 300nm, and preparation technology is simple, and repeatability is good; Proportion scale is proper, can obtain the microgranule of uniform particle diameter scope at 100nm; This system all has goodish thermodynamic stability, can sterilize repeatedly; Both be suitable for experimentation, be suitable for the big production of industry again.
Test shows through other drug: this system is suitable for using as the carrier of insoluble drug and carrier.
Description of drawings
Fig. 1 is embodiment 1 tacrolimus ophthalmic emulsion A particle size distribution figure.
Fig. 2 is embodiment 2 tacrolimus ophthalmic emulsion B particle size distribution figure.
Fig. 3 is embodiment 3 tacrolimus ophthalmic emulsion C particle size distribution figure.
The specific embodiment
Tacrolimus ophthalmic emulsion of the present invention, component and content mass ratio, tacrolimus 0.01～0.5g/ml; Oil phase 0.2～7.0g/ml; Emulsifying agent 0.1～10.0g/ml; Coemulsifier 0～2g/ml; Osmotic pressure regulator 0.1～10g/ml; Antioxidant 0～0.5g/ml; Antiseptic 0～0.6g/ml; PH regulator agent consumption is for regulating pH value to 5～9 of Emulsion; Surplus is a water for injection.Wherein said oil phase is one or more the mixture in Oleum Ricini, Semen Maydis oil, olive oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, walnut oil, Oleum Helianthi or the medium chain length fatty acid triglyceride; Described tacrolimus and oil phase mass ratio are 1: 20～1: 0.2; Described emulsifying agent is that soybean lecithin, Ovum Gallus domesticus Flavus lecithin, fatty acid monoglyceride, triglycerin fat acid esters, polyglycereol stearate, sucrose monolaurate, fatty acid Pyrusussuriensis are smooth, one or more mixture of Polysorbate, polyoxyethylene fatty acid ester class, polyoxyethylene aliphatic alcohol ether class or poloxalkol apoplexy due to endogenous wind; Described coemulsifier is one or more the mixture in methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, glyceryl monostearate, stearic acid or the stearyl alcohol; Described osmotic pressure regulator is one or more the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol; Described pH regulator agent is one or more the mixture in sodium hydroxide and/or hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, triethanol ammonium, borate buffer or the phosphate buffer; Described antioxidant is vitamin E; Described antiseptic is one or more the mixture in chlorobutanol, phenethanol, phenoxyethanol, three pears acid, thimerosal, edetate sodium, benzalkonium chloride, benzalkonium bromide, phenylmercuric nitrate, Benzene Chloride first hydrocarbon ammonia solution, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben etc.
The preparation method of tacrolimus ophthalmic emulsion of the present invention: adopt ultrasonic emulsification pretreatment or shearing-high pressure homogenize prepared, its operating procedure is: (1) takes by weighing oil phase, antioxidant stirs, as solution 1.;
(2) emulsifying agent, coemulsifier are added solution 1. in, be heated to 70 ℃, be stirred to emulsifying agent, coemulsifier all after the dissolving, add tacrolimus, continue heated and stirred to tacrolimus and dissolve fully, 2. as solution;
(3) osmotic pressure regulator, antiseptic are added in the entry, be heated to 70 ℃, stir, 3. as solution;
(4) under magnetic agitation, 2. solution slowly splashed into solution 3. in, drip off back restir 5～10min, be transferred to high-shearing dispersion emulsifying machine, 10000rmin
-1High speed dispersion forms colostrum;
(5) colostrum is again through ultrasonic emulsification pretreatment 5～15min; Perhaps colostrum is added in the high pressure homogenizer, collect emulsion, promptly get breast eventually through high pressure homogenize;
(6) dilute the volume that is settled to described concentration with water for injection, regulate pH value to 5～9 with the pH regulator agent; Prepared Emulsion is filtered with 220 wire screen, sterilize behind the inflated with nitrogen, packing promptly gets tacrolimus ophthalmic emulsion.
(7) obtained tacrolimus ophthalmic emulsion is with 100 ℃ of flowing steam sterilizations, time 15～45min; Perhaps obtained product is sterilized with Co60, time 15～60min; Perhaps obtained product 0.45 filtering with microporous membrane.
The representational embodiment of preparation of the present invention is provided below, and these embodiment only are used to illustrate the present invention, and protection domain are not caused restriction.
Embodiment 1
| A/g | B/g | C/g | Dg/ | |
| Tacrolimus | 0.05 | 0.1 | 0.25 | 0.5 |
| Injection medium chain length fatty acid triglyceride (MCT) | 0.7 | 2.5 | 4.5 | 7.0 |
| Oleum Ricini | 0.2 | 1.0 | 1.2 | 3.0 |
| Ovum Gallus domesticus Flavus lecithin (S100) | 0.1 | 1.0 | 1.5 | 5.0 |
| Glycerol | 1.8 | 2.2 | 3.0 | 3.5 |
| Benzalkonium bromide | 0.01 | 0.01 | 0.02 | 0.02 |
| Vitamin E | 0.01 | 0.01 | 0.02 | 0.02 |
| Use 0.1molL -1Sodium hydroxide is regulated pH value | 7.0-8.0 | 7.0-8.0 | 7.0-8.0 | 7.0-8.0 |
| Water for injection is to full dose | 100ml | 100ml | 100ml | 100ml |
Preparation technology:
Take by weighing Oleum Ricini, MCT, vitamin E and stir, 1. as solution.In adding recipe quantity Ovum Gallus domesticus Flavus lecithin (S100) 1., be heated to 70 ℃, be stirred to Ovum Gallus domesticus Flavus lecithin all after the dissolving, add tacrolimus, continue heated and stirred to tacrolimus and dissolve fully, 2. as solution.Glycerol, benzalkonium bromide are added in the suitable quantity of water, be heated to 70 ℃, 3. as solution.Under magnetic agitation, 2. solution slowly splashed into solution 3. in, drip off back restir 5min, be transferred to high-shearing dispersion emulsifying machine, 10000rmin
-1High speed dispersion forms colostrum.Colostrum promptly gets breast eventually again through ultrasonic shearing homogenize 10min.Be settled to recipe quantity with the water for injection dilution, with 0.1molL
-1Sodium hydroxide is regulated pH value to 7.0～8.0.Prepared Emulsion is filtered with 220 mesh sieve cloth, sterilize behind the inflated with nitrogen, packing, promptly.
Embodiment 2
| A/g | B/g | C/g | D/g | |
| Tacrolimus | 0.05 | 0.1 | 0.25 | 0.5 |
| Olive oil | 0.7 | 2.5 | 4.5 | 7.0 |
| Soybean lecithin | 0.1 | 1.0 | 1.5 | 5.0 |
| Glycerol | 1.8 | 2.2 | 3.0 | 3.5 |
| Phenylmercuric acetate | 0.01 | 0.01 | 0.02 | 0.02 |
| Vitamin E | 0.01 | 0.01 | 0.02 | 0.02 |
| Regulate pH value with phosphate buffer | 8.0-8.5 | 8.0-8.5 | 8.0-8.5 | 8.0-8.5 |
| Water for injection is to full dose | 100ml | 100ml | 100ml | 100ml |
Preparation technology:
Take by weighing olive oil, vitamin E stirs, as solution 1..In adding the recipe quantity soybean lecithin 1., be heated to 70 ℃, be stirred to soybean lecithin all after the dissolving, add tacrolimus, continue heated and stirred to tacrolimus and dissolve fully, 2. as solution.Glycerol, phenylmercuric acetate are added in the suitable quantity of water, be heated to 70 ℃, 3. as solution.Under magnetic agitation, 2. solution slowly splashed into solution 3. in, drip off back restir 5min, be transferred to high-shearing dispersion emulsifying machine, 10000rmin
-1High speed dispersion forms colostrum.Colostrum promptly gets breast eventually again through the high pressure homogenizer homogenize.Be settled to recipe quantity with the water for injection dilution, regulate pH value to 8.0～8.5 with phosphate buffer.Prepared Emulsion is filtered with 220 mesh sieve cloth, sterilize behind the inflated with nitrogen, packing, promptly.
Embodiment 3
Preparation technology:
Take by weighing Oleum sesami, vitamin E stirs, as solution 1..In adding the recipe quantity polyoxyethylene 20 sorbitan monooleate 1., be heated to 70 ℃, be stirred to polyoxyethylene 20 sorbitan monooleate all after the dissolving, add tacrolimus, continue heated and stirred to tacrolimus and dissolve fully, 2. as solution.(HPMC) puts into suitable quantity of water with hydroxypropyl emthylcellulose, is heated to 70 ℃, stirs, again glycerol, the acid of three pears are added in the HPMC solution, and mixing, as solution 3..Under magnetic agitation, 2. solution slowly splashed into solution 3. in, drip off back restir 5min, be transferred to high-shearing dispersion emulsifying machine, 10000rmin
-1High speed dispersion forms colostrum.Colostrum promptly gets breast eventually again through ultrasonic shearing homogenize 10min.Be settled to recipe quantity with the water for injection dilution, regulate pH value to 7.6～8.2 with borate buffer.Prepared Emulsion is filtered with 220 mesh sieve cloth, sterilize behind the inflated with nitrogen, packing, promptly.
Embodiment 4
| A/g | B/g | C/g | D/g | |
| Tacrolimus | 0.05 | 0.1 | 0.25 | 0.5 |
| Oleum Helianthi | 0.7 | 2.5 | 4.5 | 7.0 |
| Ovum Gallus domesticus Flavus lecithin (E80) | 0.1 | 1.0 | 1.5 | 5.0 |
| Tween-80 | 2 | 5 | 10 | 15 |
| Sodium chloride | 0.9 | 0.8 | 0.9 | 0.5 |
| Benzene Chloride first hydrocarbon ammonia solution | 0.01 | 0.01 | 0.02 | 0.02 |
| Vitamin E | 0.01 | 0.01 | 0.02 | 0.02 |
| Use 0.1molL -1Sodium hydroxide is regulated pH value | 7.0-8.0 | 7.0-8.0 | 7.0-8.0 | 7.0-8.0 |
| Water for injection is to full dose | 100ml | 100ml | 100ml | 100ml |
Preparation technology:
Take by weighing Oleum Helianthi, Tween-80, vitamin E and stir, 1. as solution.In adding recipe quantity Ovum Gallus domesticus Flavus lecithin (E80) 1., be heated to 70 ℃, be stirred to Ovum Gallus domesticus Flavus lecithin (E80)) all after the dissolving, add tacrolimus, continue heated and stirred to tacrolimus and dissolve fully, 2. as solution.Sodium chloride, Benzene Chloride first hydrocarbon ammonia solution are added in the suitable quantity of water, be heated to 70 ℃, 3. as solution.Under magnetic agitation, 2. solution slowly splashed into solution 3. in, drip off back restir 5min, be transferred to high-shearing dispersion emulsifying machine, 10000rmin
-1High speed dispersion forms colostrum.Colostrum promptly gets breast eventually again through the emulsifying of extra high pressure homogenize machine.Be settled to recipe quantity with the water for injection dilution, with 0.1molL
-1Sodium hydroxide is regulated pH value to 7.0～8.0.Prepared Emulsion is filtered with 220 mesh sieve cloth, sterilize behind the inflated with nitrogen, packing, promptly.
| A/g | B/g | C/g | D/g | |
| Tacrolimus | 0.05 | 0.1 | 0.25 | 0.5 |
| Injection medium chain length fatty acid triglyceride (MCT) | 0.7 | 2.5 | 4.5 | 7.0 |
| Soybean oil | 0.2 | 1.0 | 1.2 | 3.0 |
| Ovum Gallus domesticus Flavus lecithin (S100) | 0.1 | 1.0 | 1.5 | 5.0 |
| Sodium chloride | 0.9 | 0.8 | 0.9 | 0.5 |
| Phenethanol | 0.3 | 0.3 | 0.5 | 0.5 |
| Ethyl hydroxybenzoate | 0.01 | 0.01 | 0.02 | 0.03 |
| Vitamin E | 0.01 | 0.01 | 0.02 | 0.02 |
| Use 0.1molL -1Sodium hydroxide is regulated pH value | 7.8-8.5 | 7.8-8.5 | 7.8-8.5 | 7.8-8.5 |
| Water for injection is to full dose | 100ml | 100ml | 100ml | 100ml |
Preparation technology:
Take by weighing soybean oil, MCT, vitamin E and stir, 1. as solution.In adding recipe quantity Ovum Gallus domesticus Flavus lecithin (S100) 1., be heated to 70 ℃, be stirred to Ovum Gallus domesticus Flavus lecithin (S100) all after the dissolving, add tacrolimus, continue heated and stirred to tacrolimus and dissolve fully, 2. as solution.Sodium chloride, phenethanol, ethyl hydroxybenzoate are added in the suitable quantity of water, be heated to 70 ℃, 3. as solution.Under magnetic agitation, 2. solution slowly splashed into solution 3. in, drip off back restir 5min, be transferred to high-shearing dispersion emulsifying machine, 10000rmin
-1High speed dispersion forms colostrum.Colostrum promptly gets breast eventually again through the high pressure homogenizer homogenize.Be settled to recipe quantity with the water for injection dilution, with 0.1molL
-1Sodium hydroxide is regulated pH value to 7.8～8.5.Prepared Emulsion is filtered with 220 mesh sieve cloth, sterilize behind the inflated with nitrogen, packing, promptly.
Tacrolimus ophthalmic emulsion is to the irritant experiment of rabbit eye
1 experiment material
Experiment medicine: 1. 0.05% tacrolimus ophthalmic emulsion (embodiment 1); 2. 0.05% tacrolimus Oleum Ricini eye drop.
Laboratory animal: cleaning level white rabbit, male and female half and half, body weight 1.5～2.5kg is available from animal reproduction field, Jiangning District Green Dragon mountain, Nanjing.The animal subject eyes guarantee no any irritation, inflammatory reaction and ocular injury.
2 test methods
With the rabbit is animal pattern, according to chemicals zest, anaphylaxis and hemolytic investigative technique guideline, estimates the mucous membrane irritation of responsive gel for eye use of tacrolimus body temperature and tacrolimus Oleum Ricini eye drop with the eye irritation test method(s).
Get 8 of rabbit, male and female half and half, no ophthalmic is divided into two groups at random: tacrolimus ophthalmic emulsion group and tacrolimus Oleum Ricini eye drop group.Adopt animal consubstantiality left and right sides self matching type, a branch hole eyeball splashes into tacrolimus ophthalmic emulsion and each 100 μ l of tacrolimus Oleum Ricini eye drop, and opposite side splashes into normal saline 100 μ l in contrast.Make the passive closed 10s of lagophthalmos after the administration, medicinal liquid is had fully with the part contact.Administration every day 3 times, 2 weeks of successive administration.Before administration every day and after the last administration 1,2,4,24,48 and 72h eye is checked.Eye irritant reaction standards of grading corneal, iris and conjunctiva by table 1 are marked respectively.The irritant reaction score value addition of cornea, iris and conjunctiva of each animal gets total mark observing time with each, and one group integration summation divided by number of animals, is promptly got the last score value of this animal subject to eye irritation.Press the evaluation criterion of table 2 then, judge whether preparation has zest.
Table 1 an irritant reaction standards of grading
Table 2 eye irritation evaluation criterion
| The comprehensive mean scores of eye irritation | Zest is estimated |
| 0～3 | Nonirritant |
| 4～8 | Slight zest |
| 9～12 | The moderate zest |
| 13～16 | The intensity zest |
3 experimental results
Each experimental period point lagophthalmos stimulates score value to see Table 3.
Each experimental period point lagophthalmos of table 3 stimulates score value
Result of the test shows that tacrolimus ophthalmic emulsion successive administration 14d is to the eye nonirritant.Behind the tacrolimus Oleum Ricini eye drop successive administration 14d, iris, conjunctival congestion, blepharoedema, secretions makes whole eye district moist, judges that through standards of grading tacrolimus Oleum Ricini eye drop has zest to eye.
Claims (7)
1. tacrolimus ophthalmic emulsion, it is characterized in that: each raw material components of described tacrolimus ophthalmic emulsion comprises: tacrolimus 0.01～0.5 g/ml; Oil phase 0.2～7.0 g/ml; Emulsifying agent 0.1～10.0 g/ml; Coemulsifier 0～2 g/ml; Osmotic pressure regulator 0.1～10 g/ml; Antioxidant 0～0.5 g/ml; Antiseptic 0～0.6 g/ml; PH regulator agent consumption is for regulating pH value to 5～9 of Emulsion; Surplus is a water for injection; Described oil phase is more than one the mixture in Oleum Ricini, Semen Maydis oil, olive oil, soybean oil, Oleum sesami, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, walnut oil, Oleum Helianthi or the medium chain length fatty acid triglyceride; Described emulsifying agent is that soybean lecithin, Ovum Gallus domesticus Flavus lecithin, fatty acid monoglyceride, triglycerin fat acid esters, polyglycereol stearate, sucrose monolaurate, fatty acid Pyrusussuriensis are smooth, more than one mixture of Polysorbate, polyoxyethylene fatty acid ester class, polyoxyethylene aliphatic alcohol ether class or poloxalkol apoplexy due to endogenous wind; Described coemulsifier is more than one the mixture in methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, glyceryl monostearate, stearic acid or the stearyl alcohol.
2. according to the described tacrolimus ophthalmic emulsion of claim 1, it is characterized in that: described osmotic pressure regulator is more than one the mixture in sodium chloride, glucose, mannitol, glycerol, sorbitol or the propylene glycol.
3. according to the described tacrolimus ophthalmic emulsion of claim 1, it is characterized in that: described pH regulator agent is more than one the mixture in sodium hydroxide or hydrochloric acid, citric acid, sodium citrate, glacial acetic acid, triethanol ammonium, borate buffer or the phosphate buffer.
4. according to the described tacrolimus ophthalmic emulsion of claim 1, it is characterized in that wherein said antioxidant is vitamin E.
5. according to the described tacrolimus ophthalmic emulsion of claim 1, it is characterized in that wherein said antiseptic is more than one the mixture in chlorobutanol, phenethanol, phenoxyethanol, three pears acid, thimerosal, edetate sodium, benzalkonium chloride, benzalkonium bromide, phenylmercuric nitrate, Benzene Chloride first hydrocarbon ammonia solution, methyl hydroxybenzoate, ethyl hydroxybenzoate or the propylparaben.
6. preparation method as claim 1,2,3,4 or 5 described tacrolimus ophthalmic emulsions, it is characterized in that: adopt ultrasonic emulsification pretreatment or shearing-high pressure homogenize prepared, according to described proportioning raw materials, operating procedure is:
(1) take by weighing oil phase, antioxidant stirs, as solution 1.;
(2) emulsifying agent, coemulsifier are added solution 1. in, be heated to 70 ℃, be stirred to emulsifying agent, coemulsifier all after the dissolving, add tacrolimus, continue heated and stirred to tacrolimus and dissolve fully, 2. as solution;
(3) osmotic pressure regulator, antiseptic are added in the entry, be heated to 70 ℃, stir, 3. as solution;
(4) under magnetic agitation, 2. solution slowly splashed into solution 3. in, drip off back restir 5～10min, be transferred to high-shearing dispersion emulsifying machine, 10000 rmin
-1High speed dispersion forms colostrum;
(5) colostrum is again through ultrasonic emulsification pretreatment 5～15min; Perhaps colostrum is added in the high pressure homogenizer, collect emulsion, promptly get breast eventually through high pressure homogenize;
(6) dilute the volume that is settled to described concentration with water for injection, regulate pH value to 5～9 with the pH regulator agent; Prepared Emulsion is filtered with 220 wire screen, sterilize behind the inflated with nitrogen, packing promptly gets tacrolimus ophthalmic emulsion.
7. the preparation method of tacrolimus ophthalmic emulsion according to claim 6 is characterized in that, obtained product is with 100 ℃ of flowing steam sterilizations, time 15～45min; Perhaps obtained product is sterilized with Co60, time 15～60min; Perhaps obtained product 0.45 filtering with microporous membrane.
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| CN104274406B (en) * | 2014-10-23 | 2017-06-16 | 西安远大德天药业股份有限公司 | A kind of injection tacrolimus fat emulsion and preparation method thereof |
| CN112569187B (en) * | 2019-09-27 | 2022-04-12 | 武汉科福新药有限责任公司 | Tacrolimus nano eye emulsion and preparation method thereof |
| CN113521003B (en) * | 2021-03-09 | 2022-06-28 | 山西利普达医药科技有限公司 | Ophthalmic composition and preparation method and application thereof |
| CN115089548B (en) * | 2022-07-19 | 2023-08-08 | 河南省人民医院 | Sterile tacrolimus solution type eye drops and preparation method thereof |
| CN116077421B (en) * | 2023-01-03 | 2023-12-12 | 江苏知原药业股份有限公司 | Tacrolimus ointment and preparation method thereof |
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