CN106902079A - A kind of Loteprednol etabonate suspension eye drop composition - Google Patents
A kind of Loteprednol etabonate suspension eye drop composition Download PDFInfo
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- CN106902079A CN106902079A CN201510966566.4A CN201510966566A CN106902079A CN 106902079 A CN106902079 A CN 106902079A CN 201510966566 A CN201510966566 A CN 201510966566A CN 106902079 A CN106902079 A CN 106902079A
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- loteprednol etabonate
- crystal formation
- loteprednol
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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
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
A kind of Loteprednol etabonate suspension eye drop composition, contains the Loteprednol etabonate as active component, water, suspending agent and other auxiliary materials, described other auxiliary materials exist selected from one or more in pH adjusting agent, osmotic pressure regulator, surfactant, bacteriostatic agent, described Loteprednol etabonate with crystal form, and its X-ray powder diffraction is in θ=5.6 ° of the angle of diffraction 2,7.7 °, 11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, there is characteristic peak at 22.0 °.
Description
Technical field：
The present invention relates to a kind of ophthalmically acceptable suspension eye drops of glucocorticoid, more particularly to a kind of Loteprednol etabonate suspension drop
Ocular fluid composition and preparation method thereof.Belong to pharmaceutical technology field.
Background technology：
Loteprednol etabonate (CAS：82034-46-6, Loteprednol etabonate), it is a kind of new sugared cortical hormone
Element, by the development and production of PharmoS companies of the U.S., forms according to " soft medicine " principle design, Loteprednol etabonate suspension drop in 1998
Ocular fluid is ratified to list in the U.S., has listed afterwards and successively ophthalmically acceptable ointment and gel for eye use, for treating inflammation of eye section, especially fits
For eyelid and the medicine of the sensitive inflammation of the anterior steroidal of bulbar conjunctiva, cornea and eyeball and Post operation eye symptom.2005
Year, the compound Loteprednol etabonate/gernebcin suspension eye drops of FDA approval bausch ＆ lombs companyListing, is used for
Treatment intraocular cortex adrenaline hormone medicine responsive inflammatory conditions.
The crystal formation research work of current medicine has become more and more important, and the different polymorphics of a bulk drug can have
Different chemically and physically characteristics, including fusing point, chemical reactivity, apparent solubility, rate of dissolution, optically and mechanically property,
Vapour pressure and density, these characteristics can directly affect the treatment and/or production of bulk drug and preparation, and can influence preparation
Stability, solubility and bioavilability.Therefore, polymorphic can influence quality, security and the validity of pharmaceutical preparation.But
It is, currently without on the polymorphous research of Loteprednol etabonate and report.We are in exploitation Loteprednol etabonate bulk drug
When, its crystal formation situation is conducted in-depth research, find marketable material, eye drops and according to current conventional synthesis side
Method such as US4996335, Journal of Steorid Biochem Molecular Biology, 1991,38 (2)：149-
154th, Chinese pharmaceutical chemistry magazine, 2003, Vol.13, NO.5, P299, analytical chemistry research notes, 2005 volume 33,
P351-354, CN103249716, CN101942001, CN103183714 etc. disclosed method, the Loteprednol etabonate for obtaining
Loteprednol etabonate anhydride, and only a kind of crystal formation are, the present invention is referred to as crystal formation II.We filter to isolate it is commercially available according to
Carbon Loteprednol/gernebcin suspension eye dropsIn Loteprednol etabonate raw material, carry out X-ray powder diffraction survey
It is fixed, it is found that it is crystal formation II, we filter to isolate commercially available Loteprednol etabonate suspension eye drops(0.5% according to carbon
The ophthalmically acceptable supensoid agent of Loteprednol) andLoteprednol etabonate in (the ophthalmically acceptable supensoid agent of 0.2% Loteprednol etabonate)
Raw material, carries out X-ray powder diffraction measure, it is found that it is also crystal formation II.
Commercially available Loteprednol etabonate suspension eye drops is found through investigatingReplaced according to carbon chlorine with commercially available
Sprinkle promise/gernebcin suspension eye dropsStability is bad, and impurity increases quickly.For example：At 12 months
The maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) of Loteprednol etabonate is 0.44%, and the total miscellaneous of Loteprednol etabonate is
0.88%, 1.78% is risen to its maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) at 24 months, it is total miscellaneous to have reached
2.21%.The maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) of Loteprednol etabonate is 0.50% at 12 months, according to carbon
The total miscellaneous of Loteprednol is 0.92%, and 1.85% is risen to its maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) at 24 months,
It is total miscellaneous to have reached 2.26%.Therefore, preparing a kind of stability Loteprednol etabonate formulation products higher becomes extremely important.
The content of the invention：
To overcome the problems of the prior art, prepared with new Loteprednol etabonate crystal formation I the invention provides a kind of
Loteprednol etabonate suspension eye drops.At present, investigated by stability test, the brand-new Loteprednol etabonate crystal formation I is suspended
Suspension eye drops and commercially available Loteprednol etabonate suspension eye drip that eye drops is prepared with commercially available Loteprednol etabonate crystal formation II
LiquidWith commercially available Loteprednol etabonate/gernebcin suspension eye dropsCompare, stability is more preferable, and
Settling ratio is more preferable.
A kind of Loteprednol etabonate suspension eye drops, it is characterized in that containing the Loteprednol etabonate as active component, water,
Suspending agent and other auxiliary materials, described other auxiliary materials are selected from pH adjusting agent, osmotic pressure regulator, surfactant, bacteriostatic agent
One or more, described Loteprednol etabonate exists with crystal form, its X-ray powder diffraction the θ of the angle of diffraction 2=
5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, there is characteristic peak at 22.0 °.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that one or more additional work can also be contained
Property composition, the additional active ingredients be selected from hyaluronic acid, NSAIDs, antibiotic or hypotensive agents.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the NSAIDs is selected from indoles U.S.
It is pungent, nepafenac, C14H10Cl2NNaO2, pranoprofen, ketorolac tromethamine, flurbiprofen sodium；The preferred quinoline promise of antibiotic
Ketone, FQNS, aminoglycoside antibiotics；The hypotensive agents be selected from timolol, betaxolol, Bunolol,
Carteolol, metipranolol, vinegar first assistant amine brinzolamide or its salt.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the antibiotic is selected from TOB, celebrating greatly
Mycin, gatifloxacin, Ofloxacin, lavo-ofloxacin or its salt.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the antibiotic is TOB.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that being counted according to percent weight in volume (kg/L)
Calculate, the content of TOB is 0.3%.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that being counted according to percent weight in volume (kg/L)
Calculate, the content of Loteprednol etabonate is 0.2%~0.5%.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that being counted according to percent weight in volume (kg/L)
Calculate, the content of Loteprednol etabonate is 0.2% or 0.5%.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the suspending agent is selected from carboxymethylcellulose calcium
Sodium, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, carboxy vinyl polymer, dextrose
One or more in acid anhydride, PVP, Carbomer.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the suspending agent is polyvinylpyrrolidone.
A kind of described Loteprednol etabonate suspension eye drops, it is characterized in that described surfactant be selected from tween-
80th, Emulsifier EL-60 60, HCO60, polyethylene glycol-stearate, polyethylene glycol, lecithin,
One kind in sucrose ester, polyoxyethylene alkyl ether, polyoxy stearate, the polyoxypropylene diols of polyoxyethylene one, tyloxapol or
It is several.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that described surfactant is tyloxapol.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the bacteriostatic agent is selected from benzalkonium chloride, according to ground
Acid disodium, mosatil, benzethonium chloride, sorbic acid, phenmethylol, potassium sorbate, methyl p-hydroxybenzoate, para hydroxybenzene first
One or more in propyl propionate, chlorobutanol.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the bacteriostatic agent is selected from benzalkonium chloride, according to ground
Acid disodium or its mixture.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the osmotic pressure regulator is selected from glycerine, third
Glycol, sodium chloride, potassium chloride, D-sorbite, mannitol.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the osmotic pressure regulator is selected from glycerine or sweet
Dew alcohol.
A kind of described Loteprednol etabonate suspension eye drops, it is characterized in that the pH adjusting agent be selected from phosphoric acid and its salt,
Boric acid and its salt, citric acid and its salt, acetic acid and its salt, tartaric acid and its salt, sulfuric acid, hydrochloric acid, NaOH, potassium hydroxide,
Sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, tromethamine.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that the pH adjusting agent is selected from hydrochloric acid or hydrogen-oxygen
Change sodium.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that containing following percent weight in volume (kg/L)
Component：0.2~2% suspending agent, 0.01~0.025% bacteriostatic agent, 0.05~1% surfactant, 2~2.8%
Osmotic pressure regulator.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that containing following percent weight in volume (kg/L)
Component：2%~2.8% glycerine and/or propane diols, 0.1%~0.6% tyloxapol, 0.4%~1% polyethylene
Pyrrolidones K30.
Described a kind of Loteprednol etabonate suspension eye drops, it is characterized in that containing following percent weight in volume (kg/L)
Component：Benzalkonium chloride and/or natrium adetate, 0.01%~0.025%.
A kind of Loteprednol etabonate crystal formation I, it is characterized in that the X-ray powder diffraction of described crystal formation I the θ of the angle of diffraction 2=
5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, 22.0 °, there is characteristic peak at place, and it is with respect to diffracted intensity
Substantially it is respectively its detailed spectrogram as shown in Figure 2.The term " substantial ", it should be understood that the diffracted intensity of characteristic peak with
Crystal preparing technology, sample mounting procedure and measuring instrument difference can micro change, also should be of the invention
In the range of.Additionally, the difference and other factors of instrument may influence the θ values of the angle of diffraction 2, so the above-mentioned θ of the angle of diffraction 2 for having a characteristic peak
Value can change in existing value ± 0.2 °.
The preparation method of described Loteprednol etabonate crystal formation I, it is characterized in that being prepared using supercritical fluid technique, step
It is as follows：
(1) Loteprednol etabonate solution is configured：By 5g Loteprednol etabonates be completely dissolved at 50 DEG C 200ml acetone and
In the mixed solution of 10ml n-hexanes；
(2) the Loteprednol etabonate solution by step (1) middle configuration is connected with solution pump, and operating pressure is controlled to 10MPa；
(3) feed carbon dioxide：By the CO in steel cylinder2Supercritical fluid anti-solvent equipment system is input into by booster pump, is entered
Enter crystallization kettle, flow control controls 50 DEG C of start-up temperature in 10ml/min, and pressure is 10MPa；
(4) the Loteprednol etabonate solution by above-mentioned steps (1) middle configuration is set by solution pump through supercritical fluid anti-solvent
Nozzle is rapidly sprayed into crystallization kettle in standby system, and nozzle temperature is 50 DEG C, and its jet length is 5cm, and flow is controlled to 1.5ml/
Min, the operating time is 140min；It is continually fed into CO2Remaining solvent in crystallization kettle is cleaned；
(5) Loteprednol etabonate crystal formation I crystallizations are separated out；The Loteprednol etabonate separated out from solution is collected at crystallization kettle bottom
Crystal formation I.
Preparing for Loteprednol etabonate crystal formation I can also add crystal formation I's in the saturated solution M of Loteprednol etabonate
Crystal seed, cooling crystallization is obtained, the solution M by 1 parts by volume acetone, the n-hexane of 0.2~0.3 parts by volume, 0.2~0.3 body
The acetonitrile composition of product part.
Find under study for action, Loteprednol etabonate crystal formation II becomes more readily available, except the document mentioned in background technology
Outside the method for report, Loteprednol etabonate is dissolved in acetone, ethanol, methyl alcohol, tetrahydrofuran, dioxane, chloroform, dichloromethane
In one or more solvents in alkane, acetonitrile or isopropanol, either all be can obtain according to carbon using evaporative crystallization, crystallisation by cooling
Loteprednol crystal formation II.With acetone, ethanol, tetrahydrofuran or isopropanol as good solvent, with water, n-hexane, ether, stone
Oily ether, isopropyl ether etc. also can obtain Loteprednol etabonate crystal formation II as poor solvent when being crystallized using dissolved method.
Relative to the preparation of Loteprednol etabonate crystal formation II, the preparation of Loteprednol etabonate crystal formation I has certain to solvent
Selectivity, is found in surprise by studying us, mixed needed for recrystallization in the preparation method of above-mentioned Loteprednol etabonate crystal formation I
The volume ratio of acetone/n-hexane/acetonitrile is critically important in bonding solvent M, for example：When the volume ratio of acetone/n-hexane/acetonitrile is not upper
When stating scope, even if adding the crystal seed of Loteprednol etabonate crystal formation I, the product for obtaining is Loteprednol etabonate crystal formation II, for example
Comparative examples 1.On the other hand, the addition of the crystal seed of Loteprednol etabonate crystal formation I is also critically important, is being added without crystal seed, but its
In the case of his preparation condition identical, what is obtained is also Loteprednol etabonate crystal formation II, such as comparative examples 2.
From inventive embodiments 2 and inventive embodiments 3 as can be seen that the brand-new Loteprednol etabonate crystal formation I and existing
Anhydrous Loteprednol etabonate crystal formation II is compared, and obtained suspension eye drops is put in stability under identical prescription and preparation condition
There is more high stability, impurity increasess slowly, while main ingredient particle diameter is smaller, medicine reunion degree is lower, with more during putting
Settling ratio high.
Result table is investigated carrying out influence factor, accelerated test and 24 months room temperatures long-term stable experiment that keeps sample in addition
Bright, there are not significant changes in each detection projects of this Loteprednol etabonate crystal formation I (proterties, content, relevant material), with good
Stability, additionally carried out X-ray powder diffraction test, as a result show that crystal formation does not change, the crystal formation can keep
Good stability.
Powder diffraction instrument used is Rigaku D/max-2500 powder diffractometers in the present invention, is Rigaku company
Product.Laser Scattering Particle analyzer model：Mastersizer 2000.
Brief description of the drawings：
Fig. 1 is the X-ray powder diffraction spectrogram of Loteprednol etabonate crystal formation II obtained in comparative examples 1
Fig. 2 is the X-ray powder diffraction spectrogram of Loteprednol etabonate crystal formation I obtained in inventive embodiments 1-1
Fig. 3 is the connection of supercritical fluid anti-solvent equipment and schematic flow sheet in inventive embodiments 1-1
Wherein, 1 is Loteprednol etabonate solution, and 2 is solution pump, and 3 is nozzle, and 4 is crystallization kettle, and 5 is gas-liquid separation kettle, 6
It is gas discharge outlet, 7 is raffinate collector, and 8 is booster pump, and 9 is CO2, and P1 is equipment system pressure, and P2 is crystallization kettle work pressure
Power
Specific embodiment：
Below will by embodiment, the invention will be further described, these description be not present invention is made into
The restriction of one step.Those skilled in the art should be understood that the equivalent made to technical characteristic of the invention, or be correspondingly improved,
Still fall within protection scope of the present invention.
Commercially available Loteprednol etabonate bulk drug (anhydride, crystal formation II), purchased from Tianjin Tian Yao limited companies.
Replaced according to carbon chlorine using same lot number in following inventive embodiments 1 and comparative examples 1-13 and sprinkle raw material.
Content analysis method：
Loteprednol etabonate assay is analyzed with HPLC：
The chromatographic condition of HPLC is：Chromatographic column octadecylsilane chemically bonded silica
Mobile phase acetonitrile -0.1M glacial acetic acid (50：50)
Detection wavelength 254nm
The preparation of the Loteprednol etabonate crystal formation I of inventive embodiments 1
Inventive embodiments 1-1
(1) Loteprednol etabonate solution 1 is configured：By 5g Loteprednol etabonates be completely dissolved at 50 DEG C 200ml acetone and
In the mixed solution of 10ml n-hexanes；
(2) the Loteprednol etabonate solution 1 by step (1) middle configuration is connected with solution pump 2, and operating pressure is controlled to 10MPa；
(3) feed carbon dioxide：By the CO in steel cylinder2Supercritical fluid anti-solvent equipment system is input into by booster pump 8,
Into crystallization kettle 4, flow control controls 50 DEG C of start-up temperature in 10ml/min, and pressure is 10MPa；
By above-mentioned steps (1) middle configuration Loteprednol etabonate solution 1 by solution pump 2 through supercritical fluid anti-solvent
Nozzle 3 is rapidly sprayed into crystallization kettle 4 in equipment system, and nozzle temperature is 50 DEG C, and its jet length is 5cm；Flow is controlled to
1.5ml/min；Operating time is 140min；It is continually fed into CO2Remaining solvent in crystallization kettle 4 is cleaned；
(5) Loteprednol etabonate crystal formation I crystallizations are separated out；The Loteprednol etabonate separated out from solution is collected at crystallization kettle bottom 4
Crystal formation I.
Dried crystal is carried out into X-ray powder diffraction measure, characteristic peak positions is measured for 2 θ=5.6 °, 7.7 °,
11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, 22.0 °, as shown in Figure 2.
Loteprednol etabonate crystal formation I prepared by inventive embodiments 1-1 is done the crystal seed of inventive embodiments 1-2~1-5.
Inventive embodiments 1-2
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 20ml adds in the mixed solution of the acetonitrile of 20ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
Crystal seed prepared by a 1-1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, be cooled to 0~5 DEG C, filtering is dried, and will obtain
Crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °,
17.0 °, 18.8 °, 21.0 °, 22.0 °, confirm as Loteprednol etabonate crystal formation I.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.78；H, 6.75；Cl, 7.58
Inventive embodiments 1-3
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 20ml adds in the mixed solution of the acetonitrile of 30ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
Crystal seed prepared by a 1-1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, be cooled to 0~5 DEG C, filtering is dried, and will obtain
Crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °,
17.0 °, 18.8 °, 21.0 °, 22.0 °, confirm as Loteprednol etabonate crystal formation I.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.70；Cl, 7.60
Inventive embodiments 1-4
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 30ml adds in the mixed solution of the acetonitrile of 20ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
Crystal seed prepared by a 1-1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, be cooled to 0~5 DEG C, filtering is dried, and will
To crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=5.6 °, 7.7 °, 11.9 °, 14.1 °,
16.0 °, 17.0 °, 18.8 °, 21.0 °, 22.0 °, confirm as Loteprednol etabonate crystal formation I.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.81；H, 6.73；Cl, 7.63
Inventive embodiments 1-5
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 30ml adds in the mixed solution of the acetonitrile of 30ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
Crystal seed prepared by a 1-1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, be cooled to 0~5 DEG C, filtering is dried, and will obtain
Crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °,
17.0 °, 18.8 °, 21.0 °, 22.0 °, confirm as Loteprednol etabonate crystal formation I.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.91；H, 6.70；Cl, 7.55
The ophthalmically acceptable suspension stability test data comparative example of inventive embodiments 2
Patent CN200580016030 discloses commercially available product(the ophthalmically acceptable suspension of 0.5% Lotepredenol etabonate
Agent) prescription：
The commercially available product of table 1Prescription
* 25.0mg/mL glycerine, 96% equivalent to 24mg/mL (2.4W/W) glycerine, 100%.
With reference to above-mentioned prescription, 0.5% Loteprednol etabonate crystal formation I ophthalmic suspensions (a groups) and 0.5% is prepared for
Loteprednol etabonate (crystal formation II) ophthalmic suspension (b groups), and for stability and settling ratio and commercially available product
(0.5% Lotepredenol etabonate ophthalmic suspension,Group) compare.A groups employ micronizing and are replaced according to carbon chlorine
Sprinkle promise crystal formation I, d (0.1)=2.501 μm, d (0.5)=5.275 μm, d (0.9)=10.758 μm.B groups employ micronizing according to
Carbon Loteprednol crystal formation II, size distribution is d (0.1)=2.512 μm, d (0.5)=5.232 μm, d (0.9)=10.456 μm.
The preparation method of two groups of suspensions is：
1. the water for injection for taking recipe quantity 60% is heated to 80 DEG C, adds auxiliary material, and stirring is to being completely dissolved；
2. in hundred grades of environment with 0.22 μm of filtering with microporous membrane twice；
3. add bacterium to examine qualified main ingredient, with homogenizer 30 minutes；
4. pH value is adjusted to 5.3-5.6 or so with 0.1M hydrochloric acid and/or 0.1M NaOH；
5. full dose is added water to, is stirred evenly, cross 200 mesh sieves, be stirred continuously in hundred grades of environment filling to low density polyethylene (LDPE) bottle
In.
2.1 stability
By Loteprednol etabonate crystal formation I groups (a groups) and Loteprednol etabonate crystal formation II groups (b groups) in embodiment 2 25
Store 24 months under DEG C ± 2 DEG C/40%RH ± 5%RH, high spot reviews relevant material, settling ratio, the grain of Loteprednol etabonate
Degree situation of change, it is specific as follows：
2.1.1 the relevant materials of Loteprednol etabonate crystal formation I/ Loteprednol etabonate crystal formations II investigate result
Respectively survey storage 0 when, 12 months and the relevant material after 24 months, measure result and see the table below, from result, 25
Storage is respectively adopted Loteprednol etabonate crystal formation I and Loteprednol etabonate is brilliant after 24 months under DEG C ± 2 DEG C/40%RH ± 5%RH
Sample prepared by type II, the relevant material of Loteprednol etabonate has growth, but uses prepared by Loteprednol etabonate crystal formation I
Sample, maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) and total miscellaneous growth are smaller in the relevant material of Loteprednol etabonate, compared with
Loteprednol etabonate crystal formation II groups and commercially available product are more stable.Maximum in following table it is single it is miscellaneous be PJ-91.
The relevant material of the Loteprednol etabonate of table 2 investigates result
2.1.2 the settling ratio of Loteprednol etabonate crystal formation I/ Loteprednol etabonate crystal formations II
50ml liquids are taken with 50ml tool plug graduated cylinders, close plug is firmly shaked 1 minute, writes down suspended matter elemental height H0, is stood
3 hours, the final height H of suspended matter is write down, settling ratio=H/H0 was determined with 24 months when 0, as a result see the table below, by tying
Fruit understands, after being stored 24 months under 25 DEG C of ± 2 DEG C/40%RH ± 5%RH, with the sample prepared using Loteprednol etabonate crystal formation II
The settling ratio of product and 24 months commercial samples to the effect phase is compared, the sedimentation of the sample prepared using Loteprednol etabonate crystal formation I
It is more stable during placement than higher.
The settling ratio of table 3 investigates result
2.1.3 the particle diameter of Loteprednol etabonate crystal formation I/ Loteprednol etabonate crystal formations II
As a result we see the table below using laser particle analyzer is at 0 and detects within 24 months sample particle diameter respectively, can by result
Know, when 0, the sample particle diameter that Loteprednol etabonate crystal formation I and Loteprednol etabonate crystal formation II preparations are respectively adopted is basically identical, warp
After being stored 24 months under 25 DEG C of ± 2 DEG C/40%RH ± 5%RH, the Loteprednol etabonate in two groups of samples has an aggregation, but according to
Particle diameter is more compared with sample and the commercial samples of 24 months prepared by crystal formation II for the particle diameter of sample prepared by carbon Loteprednol crystal formation I
Small, stability is more preferable.
The laser particle analyzer of table 4 determines Loteprednol etabonate particle size results (μm)
The Loteprednol etabonate ophthalmic suspension of inventive embodiments 3 is prepared and stability
The prescription of table 5
Inventive embodiments 3-1a~3-10a employ micronizing Loteprednol etabonate crystal formation I, size distribution be d (0.1)=
2.501 μm, d (0.5)=5.275 μm, d (0.9)=10.758 μm.3-1b~3-10b groups employ micronizing according to carbon chlorine for sprinkling
Promise crystal formation II, size distribution is d (0.1)=2.512 μm, d (0.5)=5.232 μm, d (0.9)=10.456 μm.
The main ingredient composition contained in embodiment 3-1a~3-7a is Loteprednol etabonate crystal formation I, and inventory is 2.0g, real
It is Loteprednol etabonate crystal formation II to apply the main ingredient composition contained in a 3-1b~3-7b, and inventory is 2.0g, preparation method ginseng
See embodiment 2.
The main ingredient composition contained in inventive embodiments 3-8a is Loteprednol etabonate crystal formation I and TOB, is replaced according to carbon chlorine
The inventory for sprinkling promise crystal formation I is 5.0g, and the inventory of TOB is 3.0g；The main ingredient composition contained in inventive embodiments 3-8b
It is Loteprednol etabonate crystal formation II and TOB, the inventory of Loteprednol etabonate crystal formation II is 5.0g, the throwing of TOB
Doses is 3.0g.The preparation method of embodiment 3-8 is：
1. the water for injection for taking recipe quantity 60% is heated to 80 DEG C, adds auxiliary material and TOB, and stirring is to being completely dissolved；
2. in hundred grades of environment with 0.22 μm of filtering with microporous membrane twice；
3. add bacterium to examine qualified main ingredient, with homogenizer 30 minutes；
4. pH value to 5.7-5.9 is adjusted with 0.1M hydrochloric acid and/or 0.1M NaOH；
5. full dose is added water to, is stirred evenly, cross 200 mesh sieves, be stirred continuously in hundred grades of environment, it is filling to low density polyethylene (LDPE) bottle
In (with commercially available productPackaging material is identical).
The main ingredient composition contained in embodiment 3-9a is Loteprednol etabonate crystal formation I and lavo-ofloxacin hydrochloride, according to carbon chlorine
Inventory for bold and vigorous promise crystal formation I is 5.0g, and the inventory of lavo-ofloxacin hydrochloride is 3.05g, is contained in embodiment 3-9b
Main ingredient composition is Loteprednol etabonate crystal formation II and lavo-ofloxacin hydrochloride, and the inventory of Loteprednol etabonate crystal formation II is
5.0g, the inventory of lavo-ofloxacin hydrochloride is 3.05g.Preparation method reference implementation example 3-8.
The main ingredient composition contained in embodiment 3-10a is Loteprednol etabonate crystal formation I and gatifloxacin, Loteprednol etabonate
The inventory of crystal formation I is 5.0g, and the inventory of gatifloxacin is 3.0g, and the main ingredient composition contained in embodiment 3-10b is according to carbon
Loteprednol crystal formation II and gatifloxacin, the inventory of Loteprednol etabonate crystal formation II is 5.0g, and the inventory of gatifloxacin is
3.0g.Preparation method reference implementation example 3-8.
3.1 stability
By Loteprednol etabonate crystal formation I groups (a groups) in embodiment 3-1~3-10 and Loteprednol etabonate crystal formation II groups (b
Group) under 25 DEG C of ± 2 DEG C/40%RH ± 5%RH store 24 months, due to the compound sample of above-mentioned 3-8~3-10 in, except according to
Carbon Loteprednol other main ingredients are complete molten, Loteprednol etabonate is to be suspended, therefore high spot reviews Loteprednol etabonate
Relevant material, settling ratio, granularity situation of change, it is specific as follows：
3.1.1 the relevant material of Loteprednol etabonate investigates result
Respectively survey storage 0 when, 12 months and the relevant material after 24 months, measure result and see the table below, from result, 25
Storage is respectively adopted Loteprednol etabonate crystal formation I and Loteprednol etabonate is brilliant after 24 months under DEG C ± 2 DEG C/40%RH ± 5%RH
Sample prepared by type II, the relevant material of Loteprednol etabonate has growth, but uses prepared by Loteprednol etabonate crystal formation I
Sample, maximum single miscellaneous (17 β carboxylic acid things, code name PJ-91) and total miscellaneous growth are smaller in the relevant material of Loteprednol etabonate, compared with
Loteprednol etabonate crystal formation II groups are more stable.Maximum in following table it is single it is miscellaneous be PJ-91.
The relevant material of the Loteprednol etabonate of table 6 investigates result
3.1.2 the settling ratio of Loteprednol etabonate
50ml liquids are taken with 50ml tool plug graduated cylinders, close plug is firmly shaked 1 minute, writes down suspended matter elemental height H0, is stood
3 hours, the final height H of suspended matter is write down, settling ratio=H/H0 was determined with 24 months when 0, as a result see the table below, by tying
Fruit understands, after being stored 24 months under 25 DEG C of ± 2 DEG C/40%RH ± 5%RH, with the sample prepared using Loteprednol etabonate crystal formation II
The settling ratio of product is compared, and the settling ratio of the sample prepared using Loteprednol etabonate crystal formation I is higher, more steady during placement
It is fixed.
The settling ratio of table 7 investigates result
3.1.3 the particle diameter of Loteprednol etabonate
We have detected at 0 and respectively embodiment 3-1~3-10 samples for 24 months using laser particle analyzer, as a result see below
Table, from result, when 0, is respectively adopted sample particle diameter prepared by Loteprednol etabonate crystal formation I and Loteprednol etabonate crystal formation II
Basically identical, after being stored 24 months under 25 DEG C of ± 2 DEG C/40%RH ± 5%RH, the Loteprednol etabonate in two groups of samples has
Aggregation, but the particle diameter of the sample of Loteprednol etabonate crystal formation II preparations particle diameter compared with sample prepared by crystal formation II is smaller, surely
It is qualitative more preferable.
The laser particle analyzer of table 8 determines Loteprednol etabonate particle size results (μm)
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 1
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 20ml adds in the mixed solution of the acetonitrile of 40ml
To 50 DEG C, heat filtering filters off insoluble matter to heat, is cooled to 30 DEG C (if there is crystal to separate out, taking supernatant liquor), is subsequently adding invention real
Crystal seed prepared by a 1-1 is applied, insulated and stirred 30 minutes separates out a large amount of crystal, is cooled to 0~5 DEG C, filters, vacuum drying at room temperature,
The crystal that will be obtained carries out X-ray powder diffraction measure, measures characteristic peak positions for 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °,
14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °, as shown in Figure 1.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.78；H, 6.75；Cl, 7.58
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 2
The acetone that 5g Loteprednol etabonates add 100ml is taken, the n-hexane of 20ml adds in the mixed solution of the acetonitrile of 20ml
To 50 DEG C, heat filtering filters off insoluble matter, cooling crystallization, filtering, vacuum drying at room temperature, the Loteprednol etabonate crystal that will be obtained to heat
X-ray powder diffraction measure is carried out, characteristic peak positions is measured for 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °,
16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.70；Cl, 7.60
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 3
Take the anhydrous Loteprednol etabonates of 5g to be dissolved in the 50ml absolute ethyl alcohols of heat, heat filtering elimination insoluble matter, cooling crystallization,
Filtering, dry, the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=
7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.81；H, 6.73；Cl, 7.63
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 4
Take the anhydrous Loteprednol etabonates of 5g to be dissolved in the 70ml methyl alcohol of heat, heat filtering filters off insoluble matter, cooling crystallization, mistake
Filter, dry, the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=
7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.91；H, 6.70；Cl, 7.55
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 5
Take 5g Loteprednol etabonates to be dissolved in the 60ml isopropanols of heat, heat filtering elimination insoluble matter, cooling crystallization, filtering,
Dry, the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=7.1 °,
9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.85；H, 6.73；Cl, 7.54
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 6
Take the 150ml acetone-petroleum ethers (V that 5g Loteprednol etabonates are dissolved in heat：V=2：1) in, heat filtering filters off insoluble
Thing, cooling crystallization is filtered, dried, and the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measures feature
Peak position is set to 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.88；H, 6.76；Cl, 7.57
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 7
Take 5g Loteprednol etabonates and add 100ml acetone, in the mixed solution of 10ml water, be heated to 50 DEG C, heat filtering filter
Insoluble matter is removed, dried crystal is utilized Karl_Fischer method measured moisture content, confirmed by cooling crystallization, filtering, vacuum drying at room temperature
It is Loteprednol etabonate without hydrate.The Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measures feature
Peak position is set to 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.92；H, 6.74；Cl, 7.57
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 8
Take 5g Loteprednol etabonates and add 100ml acetone, in the mixed solution of 30ml water, be heated to 50 DEG C, heat filtering filter
Insoluble matter is removed, dried crystal is utilized Karl_Fischer method measured moisture content, confirmed by cooling crystallization, filtering, vacuum drying at room temperature
It is Loteprednol etabonate without hydrate.The Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measures feature
Peak position is set to 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.90；H, 6.73；Cl, 7.57
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 9
Take commercially available product(the ophthalmically acceptable supensoid agent of 0.5% Loteprednol etabonate), filtering, much filtrate is washed, vacuum
Drying at room temperature, Karl_Fischer method measured moisture content is utilized by dried crystal, confirms as Loteprednol etabonate without hydrate.Will
To Loteprednol etabonate crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=7.1 °, 9.2 °,
11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.70；Cl, 7.60
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 10
Take commercially available product(0.5% Loteprednol etabonate/0.3% gernebcin suspension eye drops), filtering, will leach
Thing wash, vacuum drying at room temperature, by dried crystal utilize Karl_Fischer method measured moisture content, confirm as Loteprednol etabonate without
Hydrate.The Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=
7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.70；Cl, 7.60
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 11
Take tetrahydrofuran-n-hexane (V that 5g Loteprednol etabonates are dissolved in hot 40ml:V=3.3：1) in mixed solvent,
Heat filtering filters off insoluble matter, and cooling crystallization is filtered, dried, and the Loteprednol etabonate crystal that will be obtained carries out X-ray powder diffraction
Determine, measure characteristic peak positions for 2 θ=7.1 °, 9.2 °, 11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.81；H, 6.72；Cl, 7.60
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 12
Take 5g Loteprednol etabonates to be dissolved in the 100ml anhydrous propanones of heat, heat filtering filters off insoluble matter, cooling crystallization, mistake
Filter, dry, the crystal that will be obtained carries out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=7.1 °, 9.2 °,
11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.80；H, 6.73；Cl, 7.64
The preparation of the anhydrous Loteprednol etabonate crystal formation II of comparative examples 13
Take commercially available product(the ophthalmically acceptable supensoid agent of 0.2% Loteprednol etabonate), filtering, much filtrate is washed, vacuum
Drying at room temperature, Karl_Fischer method measured moisture content is utilized by dried crystal, confirms as Loteprednol etabonate without hydrate.Will
To Loteprednol etabonate crystal carry out X-ray powder diffraction measure, measure characteristic peak positions for 2 θ=7.1 °, 9.2 °,
11.5 °, 13.7 °, 14.1 °, 15.5 °, 16.3 °, 18.6 °, 19.7 °.
Molecular formula：C24H31ClO7
Elemental Analysis theory：C, 61.73；H, 6.69；Cl, 7.59
Elementary analysis measured value：C, 61.81；H, 6.71；Cl, 7.60.
Claims (10)
1. a kind of Loteprednol etabonate suspension eye drop composition, it is characterized in that containing as active component according to carbon chlorine for sprinkling
Promise, water, suspending agent and other auxiliary materials, described other auxiliary materials are selected from pH adjusting agent, osmotic pressure regulator, surfactant, suppression
One or more in microbial inoculum, described Loteprednol etabonate exists with crystal form, and its X-ray powder diffraction is in the θ of the angle of diffraction 2
=5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, there is characteristic peak at 22.0 °.
2. a kind of Loteprednol etabonate suspension eye drop composition as claimed in claim 1, it is characterized in that can also be contained
Plant or several additional active components, the additional active ingredients are selected from hyaluronic acid, NSAIDs, antibiotic or drop eye
Pressing.
3. a kind of Loteprednol etabonate suspension eye drop composition as described in claim 1 and 2, it is characterized in that according to weighing body
Product percentage (kg/L) is calculated, and the content of Loteprednol etabonate is 0.2%~0.5%.
4. a kind of Loteprednol etabonate suspension eye drop composition as claimed in claim 3, it is characterized in that according to bulking value
Percentage (kg/L) is calculated, and the content of Loteprednol etabonate is 0.2% or 0.5%.
5. a kind of Loteprednol etabonate suspension eye drop composition as described in claim 1,2,4 is any, it is characterized in that described
Suspending agent is selected from sodium carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl
One or more in alcohol, carboxy vinyl polymer, dextran, PVP, Carbomer.
6. a kind of Loteprednol etabonate suspension eye drop composition as described in claim 1,2,4 is any, it is characterized in that described
Surfactant be selected from Tween-80, Emulsifier EL-60 60, HCO60, polyethylene glycol-tristearin
Acid esters, polyethylene glycol, lecithin, sucrose ester, polyoxyethylene alkyl ether, polyoxy stearate, the polyoxypropylene two of polyoxyethylene one
One or more in alcohol, tyloxapol.
7. a kind of Loteprednol etabonate suspension eye drop composition as described in claim 1,2,4 is any, it is characterized in that described
Bacteriostatic agent be selected from benzalkonium chloride, natrium adetate, mosatil, benzethonium chloride, sorbic acid, phenmethylol, potassium sorbate, to hydroxyl
One or more in yl benzoic acid methyl esters, propylparaben, chlorobutanol.
8. a kind of Loteprednol etabonate suspension eye drop composition as described in claim 1,2,4 is any, it is characterized in that described
Osmotic pressure regulator is selected from one or more in glycerine, propane diols, sodium chloride, potassium chloride, D-sorbite, mannitol.
9. a kind of Loteprednol etabonate suspension eye drop composition as described in claim 1,2,4 is any, it is characterized in that described
PH adjusting agent be selected from phosphoric acid and its salt, boric acid and its salt, citric acid and its salt, acetic acid and its salt, tartaric acid and its salt, sulfuric acid,
One kind or several in hydrochloric acid, NaOH, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acid carbonate, saleratus, tromethamine
Kind.
10. a kind of Loteprednol etabonate crystal formation I, it is characterized in that the X-ray powder diffraction of described crystal formation I the θ of the angle of diffraction 2=
5.6 °, 7.7 °, 11.9 °, 14.1 °, 16.0 °, 17.0 °, 18.8 °, 21.0 °, there is characteristic peak at 22.0 °.
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Application publication date: 20170630 |