CN116407499A - Tacrolimus ophthalmic emulsion and preparation method thereof - Google Patents
Tacrolimus ophthalmic emulsion and preparation method thereof Download PDFInfo
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- CN116407499A CN116407499A CN202111682274.XA CN202111682274A CN116407499A CN 116407499 A CN116407499 A CN 116407499A CN 202111682274 A CN202111682274 A CN 202111682274A CN 116407499 A CN116407499 A CN 116407499A
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- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 title claims abstract description 83
- 229960001967 tacrolimus Drugs 0.000 title claims abstract description 80
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 title claims abstract description 80
- 239000000839 emulsion Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title abstract description 23
- 238000004945 emulsification Methods 0.000 title description 2
- 239000004359 castor oil Substances 0.000 claims abstract description 23
- 235000019438 castor oil Nutrition 0.000 claims abstract description 23
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 23
- 239000003921 oil Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 44
- 239000012071 phase Substances 0.000 claims description 43
- 238000002156 mixing Methods 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 claims description 16
- 229960004224 tyloxapol Drugs 0.000 claims description 16
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- 235000011187 glycerol Nutrition 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 238000000265 homogenisation Methods 0.000 claims description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 239000007764 o/w emulsion Substances 0.000 abstract description 4
- 210000004087 cornea Anatomy 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000004094 surface-active agent Substances 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 150000002500 ions Chemical class 0.000 abstract description 2
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- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
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- 238000003756 stirring Methods 0.000 description 6
- 230000001954 sterilising effect Effects 0.000 description 5
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- 230000000052 comparative effect Effects 0.000 description 4
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- 239000006196 drop Substances 0.000 description 3
- 238000002296 dynamic light scattering Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
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- 206010023332 keratitis Diseases 0.000 description 2
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 244000077995 Coix lacryma jobi Species 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
- 210000003837 chick embryo Anatomy 0.000 description 1
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- 239000004064 cosurfactant Substances 0.000 description 1
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- 238000009837 dry grinding Methods 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
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- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0011—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using physical methods
- A61L2/0017—Filtration
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and discloses a tacrolimus ophthalmic emulsion and a preparation method thereof. The invention provides an ophthalmic emulsion of tacrolimus, which is prepared into an oil-in-water emulsion by using the tacrolimus, wherein the used auxiliary materials are conventional auxiliary materials in an ophthalmic preparation. The oil-in-water emulsion can be spread on the surface of eye rapidly after administration, and oil drops in the emulsion form lipid layer on the surface of cornea, so as to stabilize tear film and prevent tear volatilization. Meanwhile, the medicine wrapped in the oil drops is slowly released from the oil drops under the action of tear ions, so that the residence time of the medicine on the ocular surface is prolonged. Meanwhile, castor oil is used as an oily solvent to obtain a finished emulsion product with higher stability. The invention also provides a preparation method of the tacrolimus ophthalmic emulsion, which has the advantages of less surfactant consumption, simple and feasible process, realization of industrial production, and basis for developing the tacrolimus ophthalmic preparation with simple and feasible process, better safety and higher bioavailability.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a tacrolimus ophthalmic emulsion and a preparation method thereof.
Background
Tacrolimus is a macrolide potent immunosuppressant isolated from fermentation medium of Streptomyces in 1984 by Japanese rattan Co. Its mechanism of action is similar to that of cyclosporin, but immunosuppression is 100 times stronger than that of cyclosporin. Has been widely used clinically for the treatment of transplant rejection and autoimmune diseases. At present, the tacrolimus mainly comprises injection, capsule, eye drops and other dosage forms. Is used for immune-related treatment after keratoconjunctivitis or cornea transplantation in the field of ophthalmology. 0.1% tacrolimus eye drops (Talymus) developed by Kagaku Kogyo Co., ltd., japan in 2008 are marketed for the treatment of catarrhal keratoconjunctivitis in spring. The commercially available tacrolimus eye drops are suspension, and the particle size of the suspension has a certain influence on bioavailability. Current techniques various methods are used to obtain tacrolimus microparticles, such as: dry milling, wet milling, anti-solvent recrystallization, and the like. The method can obtain tacrolimus particles to a certain extent, but has the problems of difficult industrial production, high production cost and the like due to more process steps, complex process and high equipment requirements. The current tacrolimus eye drops are mainly self-made oily eye drops in hospitals besides the commercial eye drops. However, these oily eye drops have low bioavailability, are irritating to the eyes and cause sticky discomfort to the eyes, and are generally intolerable to patients.
Chinese patent CN101653413B discloses an ophthalmic emulsion of tacrolimus which, although the process is easy, requires terminal sterilization to achieve sterility. In practical experiments, tacrolimus is found to be unstable to heat, and related substances are obviously increased, the content is reduced and the stability of the product is deteriorated when terminal sterilization is used.
Chinese patent CN107929235B discloses an ophthalmic preparation in the form of microemulsion, which is clear and transparent, and has a simple preparation method, but the auxiliary materials added in the prescription are too many in variety, and have more surfactant and cosurfactant, and the biocompatibility and safety toxic and side effects of the organism are to be studied deeply.
How to prepare the tacrolimus ophthalmic preparation with simple and easy process, better safety, higher stability and bioavailability becomes the problem to be solved in the prior art.
Disclosure of Invention
In view of the above, the invention provides a tacrolimus ophthalmic emulsion and a preparation method thereof, which can improve patient compliance, realize industrialized mass production and realize sterile tacrolimus ophthalmic preparations through sterilization and filtration, so as to solve the problems of complex preparation process, poor stability of the obtained product, excessive types of auxiliary materials added in the prescription and the like of the existing tacrolimus ophthalmic preparations.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides tacrolimus ophthalmic emulsion which comprises the following components: tacrolimus, castor oil, tyloxapol, an osmotic pressure regulator, a pH regulator and water;
the mass ratio of the tacrolimus to the castor oil to the tyloxapol to the osmotic pressure regulator is 0.05-0.08:2:0.2-2:2-2.5;
the dosage of the pH regulator is that the pH of the tacrolimus ophthalmic emulsion is 4.5-5.5;
the water is used in an amount such that the concentration of tacrolimus is 0.2-1 g/L.
Preferably, the osmotic pressure regulator is one of glycerol, sodium chloride and sorbitol.
Preferably, the pH regulator is hydrochloric acid solution or sodium hydroxide solution.
Preferably, the concentration of the hydrochloric acid solution is 0.1 to 0.3M, and the concentration of the sodium hydroxide solution is 0.1 to 0.3M.
The invention also provides a preparation method of the tacrolimus ophthalmic emulsion, which comprises the following steps:
(1) Preparing an oil phase: mixing tacrolimus, castor oil and tyloxapol to obtain an oil phase;
(2) Preparing an aqueous phase: mixing an osmotic pressure regulator with water to obtain a water phase;
(3) Adding the oil phase into the water phase to obtain an oil water phase; purifying the oil-water phase to obtain a treated oil-water phase; mixing the treated oil-water phase with a pH regulator to obtain the tacrolimus ophthalmic emulsion.
Preferably, in the step (1), the mixing temperature is 50-80 ℃ and the mixing time is 15-30 min.
Preferably, the purification in the step (3) includes a shearing treatment and a homogenizing treatment.
Preferably, the shearing rate of the shearing treatment is 7500-8500 r/min, and the shearing time is 10-20 min.
Preferably, the homogenizing treatment is performed by micro-jet; the pressure of the homogenizing treatment is 20000-23000 PSI.
Preferably, the oil-water phase treated in the step (3) is mixed with a pH regulator and then filtered; the filtration employed a 0.22 μm filtration membrane.
Compared with the prior art, the invention has the following beneficial effects:
(1) The tacrolimus is prepared into the oil-in-water emulsion, and the used auxiliary materials are conventional auxiliary materials in the ophthalmic preparation. The oil-in-water emulsion can be spread on the surface of eye rapidly after administration, and oil drops in the emulsion form lipid layer on the surface of cornea, so as to stabilize tear film and prevent tear volatilization. Simultaneously, the medicine wrapped in the oil drops is slowly released from the oil drops under the action of tear ions, so that the residence time of the medicine on the ocular surface is prolonged;
(2) The invention provides a tacrolimus ophthalmic emulsion capable of filtering and sterilizing, which contains more than 90% of water, has lower viscosity, can easily pass through a 0.22 mu m filter membrane, can realize sterile filtration, and avoids the increase of tacrolimus related substances caused by terminal sterilization;
(3) According to the preparation method, the castor oil is used as an oil core, the tacrolimus is dissolved in the castor oil, so that the tacrolimus has good compatibility with the castor oil, and the stability of the preparation is improved;
(4) The tacrolimus ophthalmic emulsion disclosed by the invention has the advantages of less surfactant dosage, simple and feasible process and capability of realizing industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing the particle size distribution of tacrolimus ophthalmic emulsion obtained in example 1 of the present invention;
FIG. 2 is a graph showing the particle size distribution of tacrolimus ophthalmic emulsion obtained in example 2 of the present invention;
FIG. 3 is a graph showing the particle size distribution of tacrolimus ophthalmic emulsion obtained in example 3 of the present invention.
Detailed Description
The invention provides tacrolimus ophthalmic emulsion which comprises the following components: tacrolimus, castor oil, tyloxapol, an osmotic pressure regulator, a pH regulator and water;
in the invention, the mass ratio of the tacrolimus, the castor oil, the tyloxapol and the osmotic pressure regulator is preferably 0.05-0.08:2:0.2-2:2-2.5, and more preferably 0.06-0.07:2:0.3-1.5:2.1-2.3;
in the present invention, the pH adjuster is preferably used in an amount such that the pH of the tacrolimus ophthalmic emulsion is 4.5 to 5.5, and more preferably such that the pH of the tacrolimus ophthalmic emulsion is 4.7 to 5.2;
in the present invention, the amount of water to be used is preferably such that the concentration of tacrolimus is 0.2 to 1g/L, more preferably such that the concentration of tacrolimus is 0.4 to 0.8g/L.
In the present invention, the osmotic pressure regulator is preferably one of glycerin, sodium chloride, and sorbitol, and more preferably glycerin or sorbitol.
In the present invention, the pH adjuster is preferably a hydrochloric acid solution or a sodium hydroxide solution, and more preferably a hydrochloric acid solution.
In the present invention, the concentration of the hydrochloric acid solution is preferably 0.1 to 0.3M, more preferably 0.15 to 0.2M; the concentration of the sodium hydroxide solution is preferably 0.1 to 0.3M, more preferably 0.15 to 0.2M.
The invention also provides a preparation method of the tacrolimus ophthalmic emulsion, which comprises the following steps:
(1) Preparing an oil phase: mixing tacrolimus, castor oil and tyloxapol to obtain an oil phase;
(2) Preparing an aqueous phase: mixing an osmotic pressure regulator with water to obtain a water phase;
(3) Adding the oil phase into the water phase to obtain an oil water phase; purifying the oil-water phase to obtain a treated oil-water phase; mixing the treated oil-water phase with a pH regulator to obtain the tacrolimus ophthalmic emulsion.
In the present invention, the mixing temperature in the step (1) is preferably 50 to 80 ℃, and more preferably 55 to 75 ℃; the mixing time is preferably 15 to 30 minutes, more preferably 18 to 25 minutes.
In the present invention, the purification in the step (3) includes a shearing treatment and a homogenizing treatment, including the steps of:
mixing and shearing the oil-water phase at the speed of 7500-8500 r/min for 10-20 min to obtain colostrum;
the sheared colostrum is homogenized for 4 times under 20000-23000 PSI pressure by micro-jet.
In the present invention, the shear rate of the shearing treatment is preferably 7500 to 8500r/min, more preferably 7800 to 8200r/min; the shearing time is preferably 10 to 20 minutes, more preferably 12 to 15 minutes.
In the present invention, the homogenization treatment is performed by a micro-jet, and the pressure of the homogenization treatment is preferably 20000 to 23000PSI, more preferably 21000 to 22000PSI.
In the invention, the oil-water phase treated in the step (3) is mixed with a pH regulator and then filtered; the filtration employed a 0.22 μm filtration membrane.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The components are as follows:
the preparation method comprises the following steps:
heating, mixing and stirring tacrolimus, castor oil and tyloxapol at 60 ℃ for 20 minutes to dissolve the tacrolimus, the castor oil and the tyloxapol into a clear state;
mixing and stirring glycerol and water for injection to obtain a water phase;
the oil-water phase is sheared and mixed for 10min at a high speed of 8000r/min to obtain colostrum, the colostrum is subjected to micro-jet and 20000PSI homogenization for 4 times, the pH value is regulated to 4.98 by 0.1M hydrochloric acid solution, and the emulsion finished product is obtained after filtration by a 0.22 mu M injector.
The final emulsion had a pH of 4.98, an average particle size of 200.1nm and a PdI of 0.147 as determined by dynamic light scattering (Malvern Nano ZS 90).
The emulsion finished product prepared in example 1 was subjected to stability test, and the results are shown in Table 1.
TABLE 1 stability test results of emulsion finished product prepared in example 1
As can be seen from Table 1, the emulsion product prepared by the invention is stable in 30d particle size, content and related substances, and no obvious fluctuation occurs.
Example 2
The components are as follows:
the preparation method comprises the following steps:
heating, mixing and stirring tacrolimus, castor oil and tyloxapol at 60 ℃ for 20 minutes to dissolve the tacrolimus, the castor oil and the tyloxapol into a clear state;
mixing and stirring glycerol and water for injection to obtain a water phase;
the oil-water phase is sheared and mixed for 10min at a high speed of 7800r/min to obtain colostrum, the colostrum is subjected to micro-jet and 20000PSI homogenization for 4 times, the pH value is regulated to be 5.02 by using 0.1M hydrochloric acid solution, and the emulsion finished product is obtained after filtration by using a 0.22 mu M injector.
The emulsion finished product has pH value of 5.02, average particle diameter of 161.8nm and PdI of 0.178 measured by dynamic light scattering (Malvern Nano ZS 90), and the particle diameter, content and related substances are basically stable after being placed for 30 days.
Example 3
The components are as follows:
the preparation method comprises the following steps:
heating, mixing and stirring tacrolimus, castor oil and tyloxapol at 60 ℃ for 20 minutes to dissolve the tacrolimus, the castor oil and the tyloxapol into a clear state;
mixing and stirring glycerol and water for injection to obtain a water phase;
the oil-water phase is sheared and mixed for 10min at a high speed of 8200r/min to obtain colostrum, the colostrum is subjected to micro-jet, 23000PSI is homogenized for 4 times, the pH value is regulated to be 5.02 by using 0.1M hydrochloric acid solution, and the emulsion finished product is obtained after the filtration by using a 0.22 mu M injector.
The emulsion finished product has pH value of 5.02, average particle diameter of 155.5nm and PdI of 0.167 measured by dynamic light scattering (Malvern Nano ZS 90), and the particle diameter, content and related substances are basically stable after being placed for 30 days.
Comparative example 1
The components are as follows:
the preparation method comprises the following steps:
MCT, cetammonium chloride and tacrolimus are heated and stirred at 60 ℃ to be dissolved to prepare an oil phase. Tyloxapol is dissolved in water, and glycerin and 0.01M sodium hydroxide solution are added and stirred to prepare a water phase. Pouring the oil phase into the water phase, mixing and shearing the oil phase and the water phase for 10min, and filtering the colostrum with a homogenizer with 0.22 μm to obtain the emulsion finished product.
The emulsion finished product prepared in comparative example 1 was subjected to stability test, and the results are shown in Table 2.
TABLE 2 stability test results of the emulsion product of comparative example 1
As is clear from Table 2, the emulsion obtained in comparative example 1 had a reduced emulsion content and poor sample stability.
Eye irritation test was performed on the emulsion products obtained in example 1 and example 3:
eye irritation test was performed on the emulsion products obtained in example 1 and example 3 with 0.1% of a commercially available tacrolimus eye drop (trade name: talymus):
results: the emulsion products obtained in example 1 and example 3 were not significantly irritating to the market in the chick embryo chorioallantoic membrane assay (HET-CAM).
The solubility and compatibility of tacrolimus in different oily solvents were tested:
excess tacrolimus was weighed into various oily solvents, stirred overnight at room temperature, and the supernatant was centrifuged to measure the saturated solubility of tacrolimus in various oily solvents, and the results are shown in tables 3 and 4.
TABLE 3 results of solubility and compatibility tests of Tacrolimus in different oily solvents
| Sequence number | Oily solvent | Solubility at room temperature (mg/g) |
| 1 | Soybean oil | 0.83 |
| 2 | Japanese soybean oil | 1.38 |
| 3 | Coix seed oil | 1.73 |
| 4 | Castor oil | 19.21 |
| 5 | MCT (Medium chain triglyceride) | 18.35 |
TABLE 4 compatibility of FK506 (tacrolimus) in MCT (medium chain triglycerides) and castor oil (10 d)
Also under chromatographic conditions, tacrolimus has fewer impurities in castor oil, which is similar to commercially available formulations, producing more impurities in MCT; the compatibility test results show that the tacrolimus has excellent compatibility with castor oil and poor compatibility with MCT.
As can be seen from fig. 1 to 3, the tacrolimus ophthalmic emulsion obtained by the invention has uniform particle size distribution, no agglomeration phenomenon occurs, and the stability of the tacrolimus ophthalmic emulsion is strong.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The tacrolimus ophthalmic emulsion is characterized by comprising the following components: tacrolimus, castor oil, tyloxapol, an osmotic pressure regulator, a pH regulator and water;
the mass ratio of the tacrolimus to the castor oil to the tyloxapol to the osmotic pressure regulator is 0.05-0.08:2:0.2-2:2-2.5;
the dosage of the pH regulator is that the pH of the tacrolimus ophthalmic emulsion is 4.5-5.5;
the water is used in an amount such that the concentration of tacrolimus is 0.2-1 g/L.
2. The tacrolimus ophthalmic emulsion of claim 1 wherein the osmotic pressure regulator is one of glycerin, sodium chloride, sorbitol.
3. The tacrolimus ophthalmic emulsion according to claim 2, characterized in that the pH-adjusting agent is a hydrochloric acid solution or a sodium hydroxide solution.
4. The tacrolimus ophthalmic emulsion according to claim 3, characterized in that the concentration of the hydrochloric acid solution is between 0.1 and 0.3M and the concentration of the sodium hydroxide solution is between 0.1 and 0.3M.
5. The method for preparing the tacrolimus ophthalmic emulsion according to any one of claims 1 to 4, characterized by comprising the following steps:
(1) Preparing an oil phase: mixing tacrolimus, castor oil and tyloxapol to obtain an oil phase;
(2) Preparing an aqueous phase: mixing an osmotic pressure regulator with water to obtain a water phase;
(3) Adding the oil phase into the water phase to obtain an oil water phase; purifying the oil-water phase to obtain a treated oil-water phase; mixing the treated oil-water phase with a pH regulator to obtain the tacrolimus ophthalmic emulsion.
6. The method of preparing an ophthalmic tacrolimus emulsion according to claim 5, wherein the mixing temperature in the step (1) is 50-80 ℃ and the mixing time is 15-30 min.
7. The method of preparing an ophthalmic emulsion of tacrolimus according to claim 5, wherein the purification in step (3) comprises a shearing treatment and a homogenizing treatment.
8. The method for preparing tacrolimus ophthalmic emulsion according to claim 7, wherein the shearing rate of the shearing treatment is 7500-8500 r/min and the shearing time is 10-20 min.
9. The method for preparing an ophthalmic tacrolimus emulsion according to claim 7 or 8, characterized in that said homogenization treatment is carried out by means of microjet; the pressure of the homogenizing treatment is 20000-23000 PSI.
10. The method for preparing an ophthalmic tacrolimus emulsion according to any one of claims 5 to 8, characterized in that the aqueous oily phase treated in step (3) is filtered after mixing with a pH regulator; the filtration employed a 0.22 μm filtration membrane.
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Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070105761A1 (en) * | 2005-11-09 | 2007-05-10 | Combinatorx, Incorporated | Methods, compositions, and kits for the treatment of opthalmic disorders |
| CN101014317A (en) * | 2004-11-09 | 2007-08-08 | 诺瓦加利制药公司 | Ophthalmic Emulsions Containing Immunosuppressants |
| CN101132768A (en) * | 2004-12-15 | 2008-02-27 | 伊兰制药国际有限公司 | Nanoparticle tacrolimus formulation |
| CN101653413A (en) * | 2009-09-25 | 2010-02-24 | 宋洪涛 | Tacrolimus ophthalmic emulsion and its preparation method |
| JP2012011566A (en) * | 2010-06-29 | 2012-01-19 | Fujifilm Corp | Method for manufacturing nozzle plate, ink jet head and ink jet recorder, and nozzle formation method |
| KR20120041812A (en) * | 2010-08-06 | 2012-05-03 | 영남대학교 산학협력단 | Composition of solid pharmaceutical preparation containing tacrolimus using self-microemulsifying drug delivery system |
| CN102985087A (en) * | 2010-07-23 | 2013-03-20 | 丸宝株式会社 | Tacrolimus-containing oil-in-water type creamy composition |
| CN104382848A (en) * | 2014-10-20 | 2015-03-04 | 齐鲁制药有限公司 | Tacrolimus suspending eye drop liquid and preparation method thereof |
| US20160074321A1 (en) * | 2013-03-27 | 2016-03-17 | Comprehensive Drug Enterprises, Ltd. | Ophthalmic composition, method for preparing the same, and use of the same |
| CN107753419A (en) * | 2017-10-18 | 2018-03-06 | 江苏知原药业有限公司 | Tacrolimus external preparation |
| CN107929235A (en) * | 2016-10-13 | 2018-04-20 | 沈阳兴齐眼药股份有限公司 | A kind of ophthalmically acceptable preparation of tacrolimus and preparation method thereof |
| CN112569187A (en) * | 2019-09-27 | 2021-03-30 | 武汉科福新药有限责任公司 | Tacrolimus nano eye emulsion and preparation method thereof |
| CN113577024A (en) * | 2021-08-20 | 2021-11-02 | 山西利普达医药科技有限公司 | Ophthalmic composition and preparation method and application thereof |
-
2021
- 2021-12-29 CN CN202111682274.XA patent/CN116407499B/en active Active
Patent Citations (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101014317A (en) * | 2004-11-09 | 2007-08-08 | 诺瓦加利制药公司 | Ophthalmic Emulsions Containing Immunosuppressants |
| CN101132768A (en) * | 2004-12-15 | 2008-02-27 | 伊兰制药国际有限公司 | Nanoparticle tacrolimus formulation |
| US20070105761A1 (en) * | 2005-11-09 | 2007-05-10 | Combinatorx, Incorporated | Methods, compositions, and kits for the treatment of opthalmic disorders |
| CN101653413A (en) * | 2009-09-25 | 2010-02-24 | 宋洪涛 | Tacrolimus ophthalmic emulsion and its preparation method |
| JP2012011566A (en) * | 2010-06-29 | 2012-01-19 | Fujifilm Corp | Method for manufacturing nozzle plate, ink jet head and ink jet recorder, and nozzle formation method |
| CN102985087A (en) * | 2010-07-23 | 2013-03-20 | 丸宝株式会社 | Tacrolimus-containing oil-in-water type creamy composition |
| KR20120041812A (en) * | 2010-08-06 | 2012-05-03 | 영남대학교 산학협력단 | Composition of solid pharmaceutical preparation containing tacrolimus using self-microemulsifying drug delivery system |
| US20160074321A1 (en) * | 2013-03-27 | 2016-03-17 | Comprehensive Drug Enterprises, Ltd. | Ophthalmic composition, method for preparing the same, and use of the same |
| CN104382848A (en) * | 2014-10-20 | 2015-03-04 | 齐鲁制药有限公司 | Tacrolimus suspending eye drop liquid and preparation method thereof |
| CN107929235A (en) * | 2016-10-13 | 2018-04-20 | 沈阳兴齐眼药股份有限公司 | A kind of ophthalmically acceptable preparation of tacrolimus and preparation method thereof |
| CN107753419A (en) * | 2017-10-18 | 2018-03-06 | 江苏知原药业有限公司 | Tacrolimus external preparation |
| CN112569187A (en) * | 2019-09-27 | 2021-03-30 | 武汉科福新药有限责任公司 | Tacrolimus nano eye emulsion and preparation method thereof |
| CN113577024A (en) * | 2021-08-20 | 2021-11-02 | 山西利普达医药科技有限公司 | Ophthalmic composition and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 高燕;张颖;符海娟;李佳;: "他克莫司眼用微乳的制备及载药量测定方法", 国际药学研究杂志, no. 05, 30 May 2017 (2017-05-30), pages 453 - 460 * |
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