CN105012231A - Good-stability eye-drop preparation containing PGF2alpha derivative and preparation method thereof - Google Patents
Good-stability eye-drop preparation containing PGF2alpha derivative and preparation method thereof Download PDFInfo
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Abstract
The invention provides a good-stability eye-drop preparation containing a PGF2alpha derivative. The eye-drop preparation comprises the PGF2alpha derivative serving as an active constituent and also comprises 15-hydroxy stearic acid polyglycol ester. It is surprised to find that after the 15-hydroxy stearic acid polyglycol ester serves as a solutizer of the PGF2alpha derivative (such as tafluprost) eye-drop preparation, the stability of active medicine is obviously improved; after the product is subjected to tests of the high temperature, the hard light, the acceleration stability and the long-term stability, compared with existing eye drops, the increase amount of related substances is obviously smaller, and the pharmacological activity and safety of the product are further guaranteed.
Description
Technical field
The present invention relates to a kind of PGF
2 αintraocular pressure lowering ophthalmic preparation had good stability of derivant and preparation method thereof.
Background technology
Glaucoma is that a kind of intraocular pressure raises the oculopathy of oppressing optic nerve and causing optic nerve lesion and visual disorder, principal character is Bulbi hypertonia, optic atrophy, defect of visual field and visual deterioration, one of main oculopathy of blinding, blind rate is about 10%, be only second to cataract, the diseases causing blindness be number two in the whole world.At present, about there are 6,680 ten thousand glaucoma patients in the world, estimate that there is 520 ten thousand to 670 ten thousand people therefore blinding in the whole world.Glaucoma is second largest ophthalmology common disease in China, and account for 14.36% of ophthalmic diseases, national prevalence is about 1% ~ 2%.
In recent years, the research of anti-glaucoma medicine has made great progress, derivatives of prostaglandins gradually substituted beta receptor blocking agent become the first-line treatment medicine of open angle glaucoma, Bulbi hypertonia and low-critical glaucoma, mainly comprise latanoprost, travoprost, bimatoprost and tafluprost.Derivatives of prostaglandins, reduces intraocular pressure mainly through increasing uveal scleral approach ah outflow, and minority medicine still has the function increasing trabecular reticulum ah outflow, and the intraocular pressure lowering effect of this type of medicine alone is better than other class medicine.Because the eye drop intraocular pressure lowering amplitude of derivatives of prostaglandins class is large, antihypertensive effect is better, and medication is convenient, and does not affect by intraocular pressure circadian, and usually once a day, mainly for primary open angle glaucoma, ocular hypertension, does not have obvious side effect.In addition, because the mechanism of action of this kind of anti-glaucoma medicine is different from other class anti-glaucoma medicine, synergism can be produced with other class anti-glaucoma medicine, also there is good reducing iop at night simultaneously, the fluctuation of Intraocular can be reduced, alleviate the infringement that intraocular pressure fluctuates to the visual field and optic nerve.Such medicine has become the first-line drug of open angle glaucoma, is also to think most potentiality and the most effective eye local intraocular pressure lowering medicine at present.
Tafluprost (Tafluprost, DE-085, MK2452) is a kind of novel PGF
2 αderivant, can strengthen its corneosclera permeability, changes into the activated carboxylic acid form of tool (AFP-172) and enter in aqueous humor after enzyme hydrolysis.AFP-172 by with prostaglandin F R acceptor interaction, promote that the aqueous humor between choroid sclera flows out, thus reach intraocular pressure lowering.
Because tafluprost biological activity is high, dosage is very little clinically, and the drug level of listing eye drop is 0.0015% (15 μ g/ml), and has stronger fat-soluble (nearly all PGF
2 αthe water solublity of derivant is all poor), may be attracted on resinae container and reduce dosage.In order to ensure tafluprost dosage clinically, Santen Pharmaceutical Co. Ltd. of Japan, Asahi Glass Co., Ltd by adding non-ionic surface active agent in eye drop, improve the dissolubility of derivatives of prostaglandins in water and significantly suppress its absorption on resinae container, and significantly can suppress the decomposition (see China Patent No.: application number 01815617.7) of derivatives of prostaglandins by adding antioxidant such as disodiumedetate or dibutyl hydroxy toluene., also point out in this patent, non-ionic surface active agent preferably uses polyoxyethylene sorbitan monoleate, HCO60 meanwhile, and wherein, the concentration of non-ionic surface active agent is 0.5% or following.In the tafluprost eye drop of Japan's listing, the non-ionic surface active agent used is polyoxyethylene sorbitan monoleate.
Summary of the invention
Intraocular pressure lowering ophthalmic preparation that the object of the present invention is to provide a kind of stability more good and preparation method thereof.
The invention provides a kind of intraocular pressure lowering ophthalmic preparation had good stability, in described ophthalmic preparation, comprise PGF
2 αderivant, as active component, also contains 15-hydroxy stearic acid macrogol ester.
Ophthalmic preparation of the present invention is liquid preparation or semi-solid preparation, can be eye drop, gel for eye use or other conventional dosage forms, can preferably use eye drop and gel for eye use in the present invention.In ophthalmic preparation of the present invention, solvent for use preferably uses water for injection, can avoid Ocular irritation as far as possible, certainly, when ensureing preparation security, also can use other solvents.
Further, described PGF
2 αderivant is selected from one or more the compositions in latanoprost, travoprost, bimatoprost and tafluprost.
Preferably, described PGF
2 αderivant is selected from tafluprost.
15-hydroxy stearic acid macrogol ester (Solutol HS15, Kolliphor HS15, Solutol HS15), record in European Pharmacopoeia (EP7.0), U.S. DMF, Deutscher Arzneibucs and British Pharmacopoeia, can be used for the solubilizing agent of ejection preparation.
Further, PGF in described ophthalmic preparation
2 αthe content of derivant is 0.001g/100ml ~ 0.01g/100ml.Preferred 0.0015g/100ml ~ 0.005g/100ml.
Further, in ophthalmic preparation, the content of 15-hydroxy stearic acid macrogol ester is 0.01g/100ml ~ 4.0g/100ml, preferred 0.03g/100ml ~ 1.0g/100ml, most preferably 0.05g/100ml ~ 0.1g/100ml.
Further, in every 10000ml ophthalmic preparation containing, for example the supplementary material of lower proportioning:
PGF
2 αderivant 0.15 ~ 0.5g, 15-hydroxy stearic acid macrogol ester 1 ~ 25g, stabilizing agent 3 ~ 10g, osmotic pressure regulator 85 ~ 485g, appropriate pH buffer agent and pH adjusting agent; PH buffer agent and pH adjusting agent regulate the pH value of ophthalmic preparation to be 5.0 ~ 8.0, and such as pH value is 5.0,5.5,6.0,7.0.
Preferably, ophthalmic preparation solvent for use is water for injection.
Described stabilizing agent is ethylenediaminetetraacetic acid or its esters; Described osmotic pressure regulator is selected from glycerol, mannitol, sorbitol, sodium chloride, glucose or lactose; Described pH buffer agent is selected from sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, potassium citrate, boric acid, monoethanolamine, diethanolamine, triethanolamine, acetic acid, sodium acetate or both above mixture; Described pH adjusting agent is sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, acetic acid, lactic acid or citric acid.
Wherein, the consumption that osmotic pressure regulator regulates suitably changes with the change of kind, as long as the osmotic pressure molar density ensureing ophthalmic preparation is 260 ~ 310mOsmol/kg, is preferably 270 ~ 290mOsmol/kg.
Further, described stabilizing agent is one or both the combination in disodium edetate, sodium calcium edetate.Described pH buffer agent is sodium dihydrogen phosphate or potassium dihydrogen phosphate.Described pH adjusting agent is sodium hydroxide, potassium hydroxide or hydrochloric acid.
Further, described pH buffer agent and pH adjusting agent regulate the pH value of ophthalmic preparation to be preferably 5.5 ~ 6.0.
Further, in described ophthalmic preparation without antibacterial.
Certainly, in described ophthalmic preparation, also can contain antibacterial, as long as these antibacterial ensure eye safety, can preferably use benzalkonium chloride, benzalkonium bromide.
Further, in described ophthalmic preparation, the content of antibacterial is 0.001g/100ml ~ 1.0g/100ml, preferred 0.001g/100ml ~ 0.2g/100ml, most preferably 0.001g/100ml ~ 0.01g/100ml.
Further, described ophthalmic preparation also can contain macromolecule non-ionic surface active agent, thickening agent is or/and bioadhesive polymer, these macromolecule non-ionic surface active agents, thickening agent is or/and bioadhesive polymer can be selected to prepare gel or other conventional materials with semi-solid preparation, as poloxamer (Poloxamer), carbomer (Carbomer), hydroxypropyl emthylcellulose (HPMC), polyvinyl alcohol (PVA) etc., but be not limited to above-mentioned different materials, gel for eye use or other requirements with semi-solid preparation is prepared as long as can meet.
Present invention also offers the preparation method of above-mentioned ophthalmic preparation, it comprises following operating procedure:
(1) by constituent content sampling each in ophthalmic preparation;
(2) get 15-hydroxy stearic acid macrogol ester heating and melting or after being dissolved in water, add PGF
2 αderivant, after dissolving, adds pharmaceutically acceptable solvent or/and ophthalmic preparation prepared by adjuvant.
Further, the preparation method of described ophthalmic preparation, comprises following operating procedure:
A, by each constituent content sampling in ophthalmic preparation;
B, get 15-hydroxy stearic acid macrogol ester, be heated to molten condition or add appropriate (as 2 ~ 300ml) water for injection dissolve, add PGF
2 αderivant, is stirred to and dissolves completely, obtains PGF
2 αderivant aqueous premix;
C, by PGF
2 αderivant aqueous premix is added in the water for injection of 3000 ~ 9000ml, add stabilizing agent, pH buffer agent, osmotic pressure regulator again, stirring makes dissolve completely and mix, solution ph is regulated to be 5.0 ~ 8.0 by pH adjusting agent, inject water to 10000ml, filtration sterilization, fill, obtains ophthalmic preparation.
In step C, the addition of water for injection should ensure 15-hydroxy stearic acid macrogol ester is dissolved completely.
Further, the preparation method of described ophthalmic preparation, it also can comprise following operating procedure:
(1) by constituent content sampling each in ophthalmic preparation;
(2) get 15-hydroxy stearic acid macrogol ester, be heated to molten condition or add appropriate (as 2 ~ 300ml) water for injection dissolve, add PGF
2 αderivant, is stirred to PGF
2 αderivant is dissolved completely, obtains PGF
2 αderivant aqueous premix;
(3) by PGF
2 αderivant aqueous premix is added to the consoluet solution of poloxamer, or fully swelling after carbomer solution in, add stabilizing agent, pH buffer agent, osmotic pressure regulator again, stir, regulate solution ph to be 5.0 ~ 8.0 by pH adjusting agent, inject water to 10000ml, filtration sterilization, fill, obtains ophthalmic preparation.
Further, the preparation method of described ophthalmic preparation, it also can comprise following operating procedure:
(1) by constituent content sampling each in ophthalmic preparation;
(2) get 15-hydroxy stearic acid macrogol ester, be heated to molten condition or add appropriate (as 2 ~ 300ml) water for injection dissolve, add PGF
2 αderivant, is stirred to PGF
2 αderivant is dissolved completely, obtains PGF
2 αderivant aqueous premix;
(3) by PGF
2 αderivant aqueous premix is added to the consoluet solution of poloxamer, or fully swelling after carbomer solution in, add antibacterial, stabilizing agent, pH buffer agent, osmotic pressure regulator again, stir, regulate solution ph to be 5.0 ~ 8.0 by pH adjusting agent, inject water to 10000ml, filtration sterilization, fill, obtains ophthalmic preparation.
The present invention is surprised to find that, using 15-hydroxy stearic acid macrogol ester as PGF
2 αafter the solubilizing agent of derivant (as tafluprost) ophthalmic preparation, significantly improve the stability of active medicine, product is after high temperature, high light, accelerated stability and long-term stable experiment, its related substance recruitment is obviously few compared with existing eye drop, has ensured drug activity and the safety of product further; In drug safety, the present invention is using 15-hydroxy stearic acid macrogol ester as PGF
2 αthe solubilizing agent of derivant (as tafluprost) ophthalmic preparation, the former triturate of tafluprost eye drop containing polyoxyethylene sorbitan monoleate in gained eye drop and prior art is in same level, to animals administer position all without obvious stimulation.
Detailed description of the invention
Embodiment 1: the preparation of the multiple dose tafluprost ophthalmic preparation of bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.16g |
| 15-hydroxy stearic acid macrogol ester | 5.0g |
| Disodium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Glycerol | 225.0g |
| Benzalkonium chloride | 0.1g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium chloride and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium chloride in water being about 10%; Get 15-hydroxy stearic acid macrogol ester to add 2.5ml water for injection and stir evenly, dissolve, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 4000ml, add 10% benzalkonium chloride in water, disodium edetate, sodium dihydrogen phosphate, glycerol again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.5 ~ 6.0, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill is in the medicinal eye drop bottle of 5ml Low Density Polyethylene (loading amount is 2.5ml), add middle plug and enclosing cover, screw, obtain the multiple dose eye drop of bacteriostatic agent.
The preparation of the multiple dose tafluprost ophthalmic preparation of embodiment 2 bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.20g |
| 15-hydroxy stearic acid macrogol ester | 8.0g |
| Sodium calcium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Glycerol | 225.0g |
| Benzalkonium chloride | 0.5g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium chloride and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium chloride in water being about 10%; Get 15-hydroxy stearic acid macrogol ester and add the dissolving of 50ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 8000ml, add 10% benzalkonium chloride in water, sodium calcium edetate, sodium dihydrogen phosphate, glycerol again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.8 ~ 6.6, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill is in the medicinal eye drop bottle of 5ml polypropylene (loading amount is 2.5ml), add middle plug and enclosing cover, screw, obtain the multiple dose eye drop of bacteriostatic agent.
The preparation of the multiple dose tafluprost ophthalmic preparation of embodiment 3 bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.50g |
| 15-hydroxy stearic acid macrogol ester | 20.0g |
| Disodium edetate | 5.0g |
| Sodium dihydrogen phosphate | 40.0g |
| Sodium chloride | 85.0g |
| Benzalkonium chloride | 1.0g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium chloride and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium chloride in water being about 10%; Get 15-hydroxy stearic acid macrogol ester and add the dissolving of 200ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The benzalkonium chloride in water of 10%, disodium edetate, sodium dihydrogen phosphate, sodium chloride are joined in the water for injection of 7000ml, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 6.0 ~ 6.5, add the aqueous premix of tafluprost, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill is in the medicinal eye drop bottle of 5ml polypropylene (loading amount is 2.5ml), add middle plug and enclosing cover, screw, obtain the multiple dose eye drop of bacteriostatic agent.
The preparation of the multiple dose tafluprost ophthalmic preparation of embodiment 4 bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.15g |
| 15-hydroxy stearic acid macrogol ester | 1.0g |
| Disodium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Mannitol | 475.0g |
| Benzalkonium chloride | 0.1g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium chloride and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium chloride in water being about 10%; Get 15-hydroxy stearic acid macrogol ester to be incubated under 30 DEG C ~ 35 DEG C conditions and to make it be in molten condition, add tafluprost, stirring and evenly mixing, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 7000ml, add 10% benzalkonium chloride in water, disodium edetate, sodium dihydrogen phosphate, mannitol again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 6.2 ~ 7.0, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill is in the medicinal eye drop bottle of 5ml Low Density Polyethylene (loading amount is 2.5ml), add middle plug and enclosing cover, screw, obtain the multiple dose eye drop of bacteriostatic agent.
The preparation of the multiple dose tafluprost ophthalmic preparation of embodiment 5 bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.16g |
| 15-hydroxy stearic acid macrogol ester | 5.0g |
| Disodium edetate | 5.0g |
| Potassium dihydrogen phosphate | 20.0g |
| Glycerol | 225.0g |
| Benzalkonium bromide | 0.1g |
| Potassium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium bromide and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium bromide aqueous solution being about 10%; Get 15-hydroxy stearic acid macrogol ester and add the dissolving of 100ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 4000ml, add 10% benzalkonium bromide aqueous solution, disodium edetate, potassium dihydrogen phosphate, glycerol again, stirring makes dissolve completely and mix, with 0.1mol/L potassium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.0 ~ 6.0, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill is in the medicinal eye drop bottle of 5ml Low Density Polyethylene (loading amount is 2.5ml), add middle plug and enclosing cover, screw, obtain the multiple dose eye drop of bacteriostatic agent.
The preparation of the embodiment 6 not single dose tafluprost ophthalmic preparation of bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.15g |
| 15-hydroxy stearic acid macrogol ester | 5.0g |
| Disodium edetate | 5.0g |
| Sodium citrate | 20.0g |
| Glycerol | 225.0g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get 15-hydroxy stearic acid macrogol ester and add the dissolving of 80ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 5000ml, disodium edetate, sodium citrate, glycerol again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.8 ~ 6.5, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill, in the medicinal eye drop bottle of 1ml polypropylene (loading amount is 0.3ml), obtains the single dose eye drop of not bacteriostatic agent.
The preparation of the embodiment 7 not single dose tafluprost ophthalmic preparation of bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.16g |
| 15-hydroxy stearic acid macrogol ester | 3.5g |
| Disodium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Glucose | 485.0g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get 15-hydroxy stearic acid macrogol ester and add the dissolving of 50ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 8000ml, disodium edetate, sodium dihydrogen phosphate, glucose again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.5 ~ 6.2, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill, in the medicinal eye drop bottle of 1ml polypropylene (loading amount is 0.3ml), obtains the single dose eye drop of not bacteriostatic agent.
The preparation of the embodiment 8 not single dose tafluprost ophthalmic preparation of bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.16g |
| 15-hydroxy stearic acid macrogol ester | 5.0g |
| Disodium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Sorbitol | 225.0g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get 15-hydroxy stearic acid macrogol ester and add the dissolving of 35ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 5000ml, disodium edetate, sodium dihydrogen phosphate, sorbitol again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.8 ~ 6.6, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill, in the medicinal eye drop bottle of 1ml polypropylene (loading amount is 0.4ml), obtains the single dose eye drop of not bacteriostatic agent.
The preparation of the embodiment 9 not single dose tafluprost ophthalmic preparation of bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.16g |
| 15-hydroxy stearic acid macrogol ester | 15.0g |
| Sodium calcium edetate | 5.0g |
| Potassium citrate | 40.0g |
| Glycerol | 220.0g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get 15-hydroxy stearic acid macrogol ester and be incubated under 30 DEG C ~ 35 DEG C conditions and make it be in molten condition, add tafluprost, stirring and evenly mixing, obtains the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 8500ml, sodium calcium edetate, potassium citrate, glycerol again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.5 ~ 6.0, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill, in the medicinal eye drop bottle of 1ml polypropylene (loading amount is 0.3ml), obtains the single dose eye drop of not bacteriostatic agent.
The preparation of the embodiment 10 not single dose tafluprost ophthalmic preparation of bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.20g |
| 15-hydroxy stearic acid macrogol ester | 8.0g |
| Disodium edetate | 5.0g |
| Boric acid | 20.0g |
| Glycerol | 225.0g |
| Sodium hydroxide | In right amount |
| Acetic acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get 15-hydroxy stearic acid macrogol ester and add the dissolving of 30ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 3000ml, disodium edetate, boric acid, glycerol again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 1mol/L acetum regulates medicinal liquid pH value to be about 5.8 ~ 6.2, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill, in the medicinal eye drop bottle of 1ml polypropylene (loading amount is 0.4ml), obtains the single dose eye drop of not bacteriostatic agent.
The preparation of the embodiment 11 not single dose tafluprost ophthalmic preparation of bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.16g |
| 15-hydroxy stearic acid macrogol ester | 25.0g |
| Disodium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Sodium chloride | 85.0g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get 15-hydroxy stearic acid macrogol ester and add the dissolving of 150ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined in the water for injection of 9000ml, disodium edetate, sodium dihydrogen phosphate, sodium chloride again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 6.2 ~ 7.0, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill, in the medicinal eye drop bottle of 1ml polypropylene (loading amount is 0.3ml), obtains the single dose eye drop of not bacteriostatic agent.
The preparation of the multiple dose latanoprost for eyes preparation of embodiment 12 bacteriostatic agent
Prescription:
| Composition | Consumption |
| Latanoprost | 0.5g |
| 15-hydroxy stearic acid macrogol ester | 2.0g |
| Disodium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Mannitol | 475.0g |
| Benzalkonium chloride | 0.1g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium chloride and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium chloride in water being about 10%; Get 15-hydroxy stearic acid macrogol ester to be incubated under 30 DEG C ~ 35 DEG C conditions and to make it be in molten condition, add latanoprost, stirring and evenly mixing, obtain the aqueous premix containing latanoprost.The aqueous premix of latanoprost is joined in the water for injection of 7000ml, add 10% benzalkonium chloride in water, disodium edetate, sodium dihydrogen phosphate, mannitol again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 6.2 ~ 8.0, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill is in the medicinal eye drop bottle of 5ml Low Density Polyethylene (loading amount is 2.5ml), add middle plug and enclosing cover, screw, obtain the multiple dose eye drop of bacteriostatic agent.
The preparation of the multiple dose travoprost ophthalmic preparation of embodiment 13 bacteriostatic agent
Prescription:
| Composition | Consumption |
| Travoprost | 0.4g |
| 15-hydroxy stearic acid macrogol ester | 1.0g |
| Disodium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Sodium chloride | 85.0g |
| Benzalkonium chloride | 0.1g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium chloride and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium chloride in water being about 10%; Get 15-hydroxy stearic acid macrogol ester to be incubated under 30 DEG C ~ 35 DEG C conditions and to make it be in molten condition, add travoprost, stirring and evenly mixing, obtain the aqueous premix containing travoprost.The aqueous premix of travoprost is joined in the water for injection of 7000ml, add 10% benzalkonium chloride in water, disodium edetate, sodium dihydrogen phosphate, sodium chloride again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.2 ~ 6.2, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill is in the medicinal eye drop bottle of 4ml Low Density Polyethylene (loading amount is 1.5ml), add middle plug and enclosing cover, screw, obtain the multiple dose eye drop of bacteriostatic agent.
The preparation of the multiple dose tafluprost ophthalmic preparation of embodiment 14 bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.15g |
| 15-hydroxy stearic acid macrogol ester | 2.0g |
| Disodium edetate | 5.0g |
| Poloxamer188 | 1500.0g |
| PEG400 | 50.0g |
| Benzalkonium chloride | 0.1g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium chloride and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium chloride in water being about 10%; Get 15-hydroxy stearic acid macrogol ester to add 15ml water for injection and stir evenly, dissolve, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined under cryogenic in consoluet poloxamer188 solution, add 10% benzalkonium chloride in water, disodium edetate, PEG400 again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.5 ~ 6.0, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill, sealing, obtain the multiple dose ophthalmic preparation of bacteriostatic agent.
The preparation of the multiple dose tafluprost ophthalmic preparation of embodiment 15 bacteriostatic agent
Prescription:
| Composition | Consumption |
| Tafluprost | 0.15g |
| 15-hydroxy stearic acid macrogol ester | 4.0g |
| Sodium calcium edetate | 5.0g |
| Sodium dihydrogen phosphate | 20.0g |
| Carbomer-940 | 40.0g |
| HPMC E50 | 150.0g |
| Benzalkonium chloride | 0.5g |
| Sodium hydroxide | In right amount |
| Hydrochloric acid | In right amount |
| Water for injection | Add to 10000ml |
Method for making: get benzalkonium chloride and add in 9 times of water gagings, stirs and makes to dissolve completely and mix homogeneously, obtain the benzalkonium chloride in water being about 10%; Get 15-hydroxy stearic acid macrogol ester and add the dissolving of 50ml water for injection, add tafluprost, be stirred to tafluprost and dissolve completely, obtain the aqueous premix containing tafluprost.The aqueous premix of tafluprost is joined through fully swelling and dissolve Carbomer-940 and HPMC E50 solution in, add 10% benzalkonium chloride in water, sodium calcium edetate, sodium dihydrogen phosphate again, stirring makes dissolve completely and mix, with 0.1mol/L sodium hydroxide solution or/and 0.1mol/L hydrochloric acid solution regulates medicinal liquid pH value to be about 5.8 ~ 7.5, add to the full amount of water for injection, mixing, 0.22 μm of membrane filtration is degerming, fill, sealing, obtain the multiple dose ophthalmic preparation of bacteriostatic agent.
Below by way of test example, beneficial effect of the present invention is described.
The comparison of sample is prepared in the different types of solubilizing agent of test example 1
Tafluprost is water-soluble hardly, in order to increase its dissolubility, investigates the impact of different types of solubilizing agent on preparation.Polyoxyethylene sorbitan monoleate, PEG400, polyoxyl 40 hydrogenated castor oil, poloxamer and 15-hydroxy stearic acid macrogol ester is used to prepare tafluprost eye drop for solubilizing agent respectively.
Concrete operations are: get tafluprost 15mg and solubilizing agent (5g PEG400, other solubilizing agent consumptions are 1g) mix and blend 30min is (if solubilizing agent is solid or semisolid, first solubilizing agent is dissolved in the water of 5 times amount) make premixed drug solutions, add in 1000ml water, ultrasonic 10min also stirs constantly, observes character; After 0.22 μm of membrane filtration, measure sign content and the related substance thereof of tafluprost in solution.
The chromatographic condition of tafluprost assay and Related substances separation:
Chromatographic column: Agilent Zorbax SB-C18 (250 × 4.6mm, 3.5 μm, Agilent Technologies of the U.S.); Mobile phase: 20mmol/L potassium dihydrogen phosphate (containing the alpha-cyclodextrin of 0.1mmol/L, adjusting pH to 4.5 with phosphoric acid)-acetonitrile; Determined wavelength is 200nm; Column temperature is 50 DEG C; Flow velocity is 1.0ml/min.
Assay method: it is appropriate that precision takes tafluprost reference substance, precision measures sample solution, prepares reference substance solution, need testing solution, contrast solution respectively.Precision measures need testing solution, reference substance solution, each 100 μ l of contrast solution respectively, injection liquid chromatography, record chromatogram, by external standard method with calculated by peak area tafluprost content, and by external standard method with the ratio of each impurity of calculated by peak area and tafluprost labelled amount.
Experimental result is in table 1:
Table 1 variety classes solubilizing agent result of the test
Experimental result shows, when polyoxyethylene sorbitan monoleate, polyoxyl 40 hydrogenated castor oil, poloxamer, 15-hydroxy stearic acid macrogol ester are as solubilizing agent, tafluprost all can be made to dissolve completely, and PEG400 solubilizing effect is poor.In addition, its related substances when 15-hydroxy stearic acid macrogol ester is solubilizing agent in solution is lower, and its to have hemolytic activity low, on the drug solution viscosity of dissolving almost without impact, therefore, select 15-hydroxy stearic acid macrogol ester as solubilizing agent, there is obvious advantage.
The tafluprost eye drop of test example 2 containing 15-hydroxy stearic acid macrogol ester and the tafluprost eye drop influence factor contrast test containing polyoxyethylene sorbitan monoleate
1, instrument, reagent
Agilent1200 high performance liquid chromatograph (Agilent company of the U.S.); CP225DSARTORIOUS 100,000/electronic balance (German Sai Duolisi balance); Thunder magnetic PHS-3C acidometer (Shanghai Precision Scientific Apparatus Co., Ltd).
Tafluprost reference substance (self-control, content 99.5%); E-isomer control product (self-control, content 97.7%), benzalkonium chloride reference substance.Acetonitrile (chromatographically pure, Chemical Reagent Co., Ltd., Sinopharm Group); Potassium dihydrogen phosphate (analytical pure, Tianjin Bo Di Chemical Co., Ltd.), water is redistilled water; Other reagent such as phosphoric acid is analytical pure.
Containing the tafluprost eye drop (embodiment of the present invention 1) of 15-hydroxy stearic acid macrogol ester, containing the tafluprost eye drop (tafluprost eye drop TAPROS, lot number TP1119, Santen Pharmaceutical Co. Ltd.) of polyoxyethylene sorbitan monoleate
2, chromatographic condition
Tafluprost assay and Related substances separation: chromatographic column: Agilent Zorbax SB-C18 (250 × 4.6mm, 3.5 μm, Agilent Technologies of the U.S.); Mobile phase: 20mmol/L potassium dihydrogen phosphate (containing the alpha-cyclodextrin of 0.1mmol/L, adjusting pH to 4.5 with phosphoric acid)-acetonitrile; Determined wavelength is 200nm; Column temperature is 50 DEG C; Flow velocity is 1.0ml/min.
Benzalkonium chloride assay: chromatographic column: Agilent Zorbax CN (150 × 4.6mm, 5 μm, Agilent Technologies of the U.S.); Mobile phase: 20mmol/L sodium dihydrogen phosphate (containing 0.2% triethylamine, adjusting pH to 4.5 with phosphoric acid)-acetonitrile; Determined wavelength is 210nm; Column temperature is 35 DEG C; Flow velocity is 1.5ml/min.
3, assay method
It is appropriate that precision takes tafluprost reference substance, precision measures sample solution, prepares reference substance solution, need testing solution, contrast solution respectively.Precision measures need testing solution, reference substance solution, each 100 μ l of contrast solution respectively, injection liquid chromatography, record chromatogram, by external standard method with calculated by peak area tafluprost content, and by external standard method with the ratio of each impurity of calculated by peak area and tafluprost labelled amount.
Precision measures this product and each 100 μ l of benzalkonium chloride reference substance solution, respectively injection liquid chromatography, and record chromatogram, according to the content of calculated by peak area benzalkonium chloride.
4, measurement result
With reference to " chemicals stability study technological guidance principle " and " Chinese Pharmacopoeia " version in 2010 two annex XIX C " crude drug and pharmaceutical preparation stability test guideline ", carry out factors influencing to this product embodiment 1 sample (lot number 20130401) and TAPROS (lot number TP1119), factors influencing Comparative result is in table 2, table 3.
Experimental condition: high temperature 60 DEG C ± 2 DEG C, illumination 4500Lux ± 500Lux;
Inspection target: character, pH value, content, related substance, benzalkonium chloride content.
Table 2 embodiment 1 sample (lot number 20130401) factors influencing result
The former triturate of table 3 (lot number TP1119) factors influencing result
The tafluprost eye drop of test example 3 containing 15-hydroxy stearic acid macrogol ester and the tafluprost eye drop stability comparative study containing polyoxyethylene sorbitan monoleate
With reference to the related request of " chemicals stability study technological guidance principle " and " Chinese Pharmacopoeia " version in 2010 two annex XIX C " crude drug and pharmaceutical preparation stability test guideline ", (lot number is C130413 to have investigated the tafluprost eye drop containing 15-hydroxy stearic acid macrogol ester respectively, specification is 0.0375mg:2.5ml) and containing the tafluprost eye drop (TAPROS of polyoxyethylene sorbitan monoleate, lot number TP1126, Santen Pharmaceutical Co. Ltd.) within 6 months, carry out drug substance stable Journal of Sex Research in 25 DEG C of placements, 6 months, 40 DEG C placements.
Test apparatus, chromatographic condition, assay method are identical with test example 2.
Inspection target is: character, pH value, content and related substance, the results are shown in Table 4, table 5, table 6, table 7:
Table 4 embodiment 1 sample (lot number C130413) Accelerated stability test investigates result
Table 5 embodiment 1 sample (lot number C130413) stability long term test investigates result
The former triturate of table 6 (lot number TP1126) Accelerated stability test investigates result
The former triturate of table 7 (lot number TP1126) stability long term test investigates result
Above-mentioned result of the test shows, uses the tafluprost eye drop stable in properties that Solutol HS-15 is prepared for solubilizing agent, and the Functionality, quality and appealing design of more former triturate TAPROS (lot number TP1119).
In drug safety, be in same level with prior art after the present invention changes prescription, to animals administer position all without obvious stimulation.By " Chemical induced irritation, anaphylaxis and hemolytic investigative technique guideline " (guideline is numbered: [H] GPT4-1, in March, 2005), selection new zealand rabbit is laboratory animal, carry out eye drop administration irritation test, containing the tafluprost eye drop (embodiment of the present invention 1 of 15-hydroxy stearic acid macrogol ester, lot number is C130413, specification is 0.0375mg:2.5ml) (Santen Pharmaceutical Co. Ltd. produces with the former triturate of tafluprost eye drop containing polyoxyethylene sorbitan monoleate, lot number is TP1113, specification is 0.0375mg:2.5ml) irritation test result consistent, successive administration to animals administer position all without obvious stimulation.
Claims (11)
1. one kind comprises PGF
2 αthe intraocular pressure lowering ophthalmic preparation had good stability of derivant, is characterized in that: comprise PGF in described ophthalmic preparation
2 αderivant, as active component, also contains 15-hydroxy stearic acid macrogol ester.
2. ophthalmic preparation according to claim 1, is characterized in that: described PGF
2 αderivant is selected from one or more the compositions in latanoprost, travoprost, bimatoprost and tafluprost.
3. ophthalmic preparation according to claim 1, is characterized in that: described ophthalmic preparation is liquid preparation or semi-solid preparation, wherein PGF
2 αthe content of derivant is 0.001g/100ml ~ 0.01g/100ml; In described ophthalmic preparation, the content of 15-hydroxy stearic acid macrogol ester is 0.01g/100ml ~ 4.0g/100ml, preferred 0.03g/100ml ~ 1.0g/100ml, most preferably 0.05g/100ml ~ 0.1g/100ml.
4. ophthalmic preparation according to claim 3, is characterized in that: PGF in described ophthalmic preparation
2 αthe content of derivant is 0.0015g/100ml ~ 0.005g/100ml.
5. the ophthalmic preparation according to claim 3 or 4, is characterized in that: containing, for example the supplementary material of lower proportioning in the every 10000ml of described ophthalmic preparation:
PGF
2 αderivant 0.15 ~ 0.5g, 15-hydroxy stearic acid macrogol ester 1 ~ 25g, stabilizing agent 3 ~ 10g, osmotic pressure regulator 85 ~ 485g, appropriate pH buffer agent and pH adjusting agent; PH buffer agent and pH adjusting agent regulate the pH value of ophthalmic preparation to be 5.0 ~ 8.0.
6. ophthalmic preparation according to claim 5, is characterized in that: described stabilizing agent is ethylenediaminetetraacetic acid or its esters; Described osmotic pressure regulator is selected from glycerol, mannitol, sorbitol, sodium chloride, glucose or lactose; Described pH buffer agent is selected from sodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, sodium citrate, potassium citrate, boric acid, monoethanolamine, diethanolamine, triethanolamine, acetic acid, sodium acetate or both above mixture; Described pH adjusting agent is sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, acetic acid, lactic acid or citric acid.
7. ophthalmic preparation according to claim 5, is characterized in that: described stabilizing agent is one or both the combination in disodium edetate, sodium calcium edetate; Described pH buffer agent is sodium dihydrogen phosphate or potassium dihydrogen phosphate; Described pH adjusting agent is sodium hydroxide, potassium hydroxide or hydrochloric acid.
8. ophthalmic preparation according to claim 5, is characterized in that: pH buffer agent and pH adjusting agent regulate the pH value of ophthalmic preparation to be 5.5 ~ 6.0.
9. the ophthalmic preparation according to claim 1 ~ 8 any one, it is characterized in that: also containing antibacterial in described ophthalmic preparation, described antibacterial is selected from benzalkonium chloride, benzalkonium bromide, in described ophthalmic preparation, the content of antibacterial is 0.001g/100ml ~ 1.0g/100ml, preferred 0.001g/100ml ~ 0.2g/100ml, most preferably 0.001g/100ml ~ 0.01g/100ml.
10. the ophthalmic preparation according to claim 1 ~ 8 any one, is characterized in that: described ophthalmic preparation also contains macromolecule non-ionic surface active agent, thickening agent or/and bioadhesive polymer.
11. the preparation method of ophthalmic preparation described in claim 1 ~ 10 any one, is characterized in that: it comprises following operating procedure:
(1) by constituent content sampling each in ophthalmic preparation;
(2) get 15-hydroxy stearic acid macrogol ester heating and melting or after being dissolved in water, add PGF
2 αderivant, after dissolving, adds pharmaceutically acceptable solvent or/and ophthalmic preparation prepared by adjuvant.
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| CN110799188A (en) * | 2017-06-22 | 2020-02-14 | 健康制药有限责任公司 | Ophthalmic formulations based on tropicamide |
| CN111346050A (en) * | 2020-03-11 | 2020-06-30 | 四川禾亿制药有限公司 | Dibazol hydrochloride eye drops and preparation method thereof |
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| CN105380901A (en) * | 2015-11-18 | 2016-03-09 | 侯宇华 | Tafluprost eye drop and preparation method thereof |
| CN105380901B (en) * | 2015-11-18 | 2018-07-17 | 侯宇华 | A kind of tafluprost eye drops and preparation method thereof |
| WO2018033854A1 (en) * | 2016-08-15 | 2018-02-22 | Santen Pharmaceutical Co., Ltd. | Ophthalmic composition and a method for treating ocular hypertension and glaucoma |
| CN110799188B (en) * | 2017-06-22 | 2023-05-26 | 梅迪维斯责任有限公司 | Ophthalmic formulations based on topiramate |
| CN110799188A (en) * | 2017-06-22 | 2020-02-14 | 健康制药有限责任公司 | Ophthalmic formulations based on tropicamide |
| CN110237031B (en) * | 2018-07-12 | 2022-02-11 | 尼科斯股份有限公司 | Ophthalmic composition comprising nitric oxide releasing prostamide |
| CN111249228A (en) * | 2018-07-12 | 2020-06-09 | 尼科斯股份有限公司 | Ophthalmic composition comprising nitric oxide releasing prostamide |
| CN111249228B (en) * | 2018-07-12 | 2022-05-03 | 尼科斯股份有限公司 | Ophthalmic composition comprising nitric oxide releasing prostamide |
| CN110237031A (en) * | 2018-07-12 | 2019-09-17 | 尼科斯股份有限公司 | Ophthalmic composition comprising discharging nitric oxide production forefront amide |
| CN111346050A (en) * | 2020-03-11 | 2020-06-30 | 四川禾亿制药有限公司 | Dibazol hydrochloride eye drops and preparation method thereof |
| CN111840225A (en) * | 2020-08-12 | 2020-10-30 | 王信 | Eye drop for treating glaucoma and preparation method thereof |
| CN111840225B (en) * | 2020-08-12 | 2021-09-14 | 陈丽娜 | Eye drop for treating glaucoma and preparation method thereof |
| JP2022120120A (en) * | 2022-06-13 | 2022-08-17 | 東亜薬品株式会社 | OPHTHALMOLOGIC AQUEOUS COMPOSITION AND METHOD FOR INHIBITING DECREASE IN CONTENT OF PROSTAGLANDIN F2α DERIVATIVE |
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