CN101966144A - Preparation and application of olopatadine in-situ gel - Google Patents
Preparation and application of olopatadine in-situ gel Download PDFInfo
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- 229960004114 olopatadine Drugs 0.000 title claims abstract description 87
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 title claims abstract description 87
- 238000002360 preparation method Methods 0.000 title claims abstract description 45
- 238000011065 in-situ storage Methods 0.000 title claims abstract description 16
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 35
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 35
- 210000003928 nasal cavity Anatomy 0.000 claims abstract description 22
- 239000003814 drug Substances 0.000 claims abstract description 18
- 229920001992 poloxamer 407 Polymers 0.000 claims abstract description 16
- 229940044476 poloxamer 407 Drugs 0.000 claims abstract description 16
- 229920001993 poloxamer 188 Polymers 0.000 claims abstract description 14
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- 229940085237 carbomer-980 Drugs 0.000 claims abstract description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 6
- 230000007704 transition Effects 0.000 claims description 29
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- 208000036284 Rhinitis seasonal Diseases 0.000 claims description 2
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- 238000000034 method Methods 0.000 description 20
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- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 3
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- HVRLZEKDTUEKQH-NOILCQHBSA-N Olopatadine hydrochloride Chemical compound Cl.C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 HVRLZEKDTUEKQH-NOILCQHBSA-N 0.000 description 2
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new dosage form of olopatadine in the technical field of medicines, in particular to the preparation and an application of olopatadine in-situ gel. The invention is characterized in that the preparation is a solution in a non-physiological state and is converted into gel in a physical state. Olopatadine temperature-sensitive gel is prepared by systematically investigating shaft materials and properly proportioning poloxamer 407 (F127 for short) and poloxamer 188 (F68 for short). Olopatadine pH-sensitive gel is prepared by adjusting the consumption of carbomer 980 and hydroxypropyl methyl cellulose (HPMC). The preparations can be applied through the eyes or nasal cavity, the residence time of the drug in the administration parts is greatly prolonged, bioavailability is increased, curative effect is improved, and the preparation has ideal application prospects.
Description
Technical field
The present invention relates to the novel form of olopatadine kind eye usefulness or nasal cavity applied medicine thing, it is being solution at non-physiological state, physiological status changes the preparation and the application of gel mutually into, and exactly it is the preparation method and the clinical indication of olopatadine temperature and the responsive gel of pH.Said preparation has prolonged medicine greatly in eye (or nasal cavity) holdup time, has improved bioavailability, has improved curative effect, and ideal application prospect is arranged.
Background technology
Olopatadine is mast cell stabilizers and relative selectivity histamine H 1-receptor antagonist.All can suppress I type type in live body and the experiment in vitro.Olopatadine is to alpha-adrenergic receptor, and dopamine receptor, muscarine I type and II receptor and 5-hydroxytryptamine receptor do not have to act on.At present, the Olopatadine formulations of selling on the market mainly is eye drop, olopatadine nasal spray.Wherein, because eyelid blinks and the diluting effect of tear, and eye drop is got rid of rapidly by nasolacrimal duct, and its bioavailability is less than 1% often, need to increase administration number of times and keep drug effect after eye drop uses.The eye with or nasal cavity be carrier with the hydrophilic high molecular material often with gel, better biocompatibility is arranged, be semi-solid preparation, but the action time of prolong drug, the minimizing administration number of times, but dosage is wayward.
Eye has following characteristics with (or nasal cavity) with situ-gel: 1. have unique the hydrophilic three-dimensional net structure and the favorable tissue compatibility; 2. Du Te solution-gel conversion character make its have concurrently preparation simple, easy to use, with agents area advantages such as particularly strong, holdup time of mucous membrane tissue affinity is long, prolonged release time of medicine, keep the valid density of medicine in conjunctival sac; 3. reduce the zest of some drugs; 4. overcome low shortcoming of eye drop bioavailability and eye usefulness or the nasal cavity uppity shortcoming of gel dosage.
The macromolecular material poloxamer is the ABA block polymer that polyoxyethylene (PEO) and polyoxypropylene (PPO) are formed.Generating in solution with hydrophobicity PPO block is kernel, is wrapped in the globular micelle of hydrophilic PEO shell, and its gelation mechanism is considered to the result that tangles mutually and pile up along with between temperature rising micelle.Concentration is high more, and the volume fraction of the shared solution of polymer is just big more, micelle quantity and each other contact and the probability that tangles all increase, thereby phase transition temperature presents concentration dependent, and is lower than a certain concentration and then no longer forms gel.Therefore, in order to guarantee still to be formed gelling in conjunctival sac by after the tear dilution, it is 25% P407 solution that ophthalmic administration is given concentration usually.But the gelation temperature of 25% P407 solution is about 15 ℃, needs stored refrigerated, but low temperature produces the part tissue of eye of sensitivity and stimulates, cause to shed tears and winking reflex causes bioavailability to reduce, so, merge and use P188, regulate phase transition temperature.
Carbomer belongs to acrylic polymer, and it contains a large amount of carboxyls (being about 56%～68%), when pH value less than 4 the time, carboxyl dissociates hardly, polymer disperses in water and swelling, but does not dissolve, and shows very low stickiness.Inorganic base or organic base can make carboxyl dissociate, repulsive interaction between negative charge causes strand to expand, stretch, the carbomer of low concentration forms clear and bright solution, and when concentration was big, strand tangled mutually and forms and have certain intensity and elastic translucent gel.PH value is 6～12 o'clock, the gel viscosity maximum that carbomer forms.But because it is bigger to form the concentration of the required acid carbomer of stabilizing gel, be difficult for being neutralized and having zest,, eyes had zest so be unsuitable for being used alone as the substrate of situ-gel.So, merge and use HPMC, reduce the consumption of carbomer.
Summary of the invention
The purpose of this invention is to provide eye and use or the nasal cavity situ-gel with adaptation phase transition temperature and pH value,
The objective of the invention is to be achieved by the following scheme: 1. responsive to temperature type: medicine or the microgranule or the cyclodextrin clathrate that are loaded with medicine are dissolved in a small amount of sterile buffer or the pure water; taking by weighing an amount of poloxamer (Poloxamer 407) (being called for short F127) and poloxamer 188 (abbreviation F68) again joins in the above-mentioned solution under ice bath and stirring condition; deepfreeze is saved to the clarification uniform solution; add an amount of antiseptic, regulate pH and osmotic pressure.2. pH responsive type: medicine or the microgranule or the cyclodextrin clathrate that are loaded with medicine are dissolved in a small amount of sterile buffer or the pure water; taking by weighing an amount of carbomer 980 and HPMC again joins in the above-mentioned solution under ice bath and stirring condition; deepfreeze is saved to the clarification uniform solution, adds an amount of antiseptic.
(1) research of olopatadine thermosensitive in situ gel
1 poloxamer is to the influence of gelation temperature
1.1 the preparation of poloxamer solution
Adopt cold cut to prepare gel solution.Precision is measured required distilled water, place ice-water bath, slowly add the poloxamer of accurate weighing while stirring, make the poloxamer granule all by water-wet, in 4 ℃ refrigerator, preserve more than 24 hours, then until obtaining clarification, no agglomerate, finely dispersed solution.
1.2 the assay method of phase transition temperature
An amount of poloxamer solution is put into cillin bottle, put it in the ice bath.Punching and insertion precision are 0.1 ℃ precision thermometer in the middle of the rubber stopper of bottle, and the mercury ball of thermometer submerges in the poloxamer solution fully.Stir poloxamer solution with magnetic stir bar, make the solution internal temperature even, simultaneously slow rising bath temperature, programming rate is about 1 ℃/2min.Simultaneously, antibiotic bottle is constantly tilted 60 °, the temperature when not taking place to flow with solution is a phase transition temperature.
1.3 the concentration of poloxamer 407 and the relation of phase transition temperature
Poloxamer is made 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% poloxamer aqueous solution according to " 1.1 " method, measure its phase transition temperature according to " 1.2 " method.
Fig. 1-1 phase transition temperature is with the F127 concentration curve
As Poloxamer 407 (be called for short 127) when concentration is lower than 15%, not gelling of solution; When F127 concentration was higher than 16%, solution was heated and reversibly forms the transparent and homogeneous gel, and its phase transition temperature reduces along with the increase of F127 concentration.
The change curve of the phase transition temperature of Fig. 1-2 F127 variable concentrations
The change curve of the phase transition temperature of Fig. 1-3 poloxamer 407 and poloxamer 188 compatibilities
By last figure as can be seen, along with the rising of temperature, the viscosity of poloxamer also increases gradually, and when reaching phase transition temperature, viscosity sharply increases.
Simple poloxamer 407 (be called for short F127) poloxamer 188 (being called for short F68) is different with the viscosity variation tendency of F127/F68 mixed solution: when simple F127 solution temperature reaches one regularly, its viscosity with temperature variation is not obvious; And F127/F68 mixed solution temperature reaches one regularly, and its viscosity still increases along with the rising of temperature.
1.4 poloxamer 188, PEG, PEO are to the influence of poloxamer 407 phase transition temperatures
With not commensurability poloxamer 407 respectively and not commensurability poloxamer 188 (F68), PEG4000, PEG6000, PEO join in the distilled water of amount of calculation, foundation " 1.1 " method is prepared into the solution of variable concentrations, measures its phase transition temperature according to " 1.2 " method.
Table 1F127 and F188 mixed solution gelation temperature (is solvent with water)
The gelation temperature of table 2F127 and variable concentrations PEG 6000 mixed liquors
The gelation temperature of table 3F127 and variable concentrations PEG 4000 mixed liquors
As can be seen from the table, a small amount of F68 can influence the gelation temperature of F127, and along with the increase of F68 addition, phase transition temperature rises gradually.
After 18%F127 and the PEG mixing intensification gelling, be unable to undergo the tear dilution.
PEO is very easily water-soluble, and a small amount of PEO is added in the distilled water, forms the agglomerate of a white " fish eyes " shape at once, can not uniform dissolution; Under stirring condition, PEO is added in the boiling water, PEO dissolving, along with the temperature solution gel that further raises, but that gel mixes is firmly opaque, and " draging silk " phenomenon is arranged.
To sum up, finishing screen selects for use poloxamer 188 to regulate the phase transition temperature of poloxamer 407
The dilution of 2 tears is to the influence of poloxamer solution
The volume averaging 40ul that the solution-type ophthalmic preparation is every, and the volume of tear is 7ul in the conjunctival sac.Poloxamer solution splashes into two kinds of extreme possibilities in back and the existence of tear mixed process in the conjunctival sac: best situation is just to have formed gel without the tear dilution, can guarantee that so the responsive gel preparation of body temperature obtains the comparatively ideal eye holdup time, the poorest situation is to mix with tear at first fully, and then forms gel.Situation after the body administration must fall between.So suitable prescription, room temperature should be liquid, and the artificial tears mixes by that with simulation, still can undergo phase transition 35 ℃ (temperature in the conjunctival sac).
2.4 the tear dilution is to the influence of the responsive gel viscosity of body temperature
The poloxamer solution of 21.4%F127/9.6%F68,16%F127/10%F68,20%F127/5%F68 is even by 40: 7 mixed with the simulation artificial tears, measure the variation of its dilution front and back viscosity with temperature by viscosity measurement.
Viscosity changes before and after the poloxamer 407 of Fig. 2-1 figure olopatadine situ-gel 21.4% and the dilution of 9.6% poloxamer 188 compatibility tears
Viscosity changes before and after the dilution of Fig. 2-2 olopatadine situ-gel (20%F127/15%F68) tear
By last figure as can be seen, the viscosity of tear dilution can reduction poloxamer gel, but do not influence the trend that viscosity with temperature changes.
3 other compositions are to the influence of thermosensitive hydrogel phase transition temperature and viscosity
3.1 other compositions are to the influence of phase transition temperature
Olopatadine, benzalkonium bromide are added in the optimization poloxamer solution that has prepared, be prepared into the poloxamer solution that contains olopatadine; The poloxamer solution that contains 0.1 ‰ benzalkonium bromide is measured the phase transition temperature after the dilution of its phase transition temperature and tear.
3.2 other compositions are to the viscosity influence of poloxamer solution
Olopatadine, benzalkonium bromide are added in the optimization poloxamer solution that has prepared, be prepared into the poloxamer solution that contains olopatadine; Put into the mensuration container of viscometer, measure the variation of viscosity with temperature and the variation of the viscosity with temperature after artificial tears's dilution, other compositions are to the influence of the viscosity of gel in the investigation prescription.
The preparation technology of the responsive gel for eye use of 4 olopatadine body temperature
In the olopatadine of recipe quantity, isotonic phosphate buffer liquid that benzalkonium bromide is dissolved in pH7.4 earlier, the ice bath high speed stirs and adds poloxamer, and low tempertaure storage to poloxamer dissolves fully.Make the responsive gel for eye use of olopatadine body temperature.
5 pressure sterilizings are to the influence of thermosensitive hydrogel gelation temperature
The temperature sensitive responsive type gel of optimizing prescription is packed in the cillin bottle, seal, place in the pressure steam sterilizer,, after the cooling, measure the gelation temperature of thermosensitive hydrogel before and after the simulation artificial tears dilutes with 121 ℃ wet-hot steams sterilization 20min.
6 punctate opacity of the cornea design optimizations prescription
According to following table, the poloxamer solution of preparation variable concentrations is measured its phase transition temperature after the simulation artificial tears is by 40: 7 (V/V) dilution.
Table 4 factor level table
Model match and prediction
With gelation temperature as dependent variable, respectively each level of each factor (independent variable) is carried out multiple linear regression and binomial match, deletion degree of fitting not good (lack of fit) is each correlation coefficient of P＞0.05, carry out match again, try to achieve reduced equation, with this mathematical model is that three-dimensional dependent variable (response surface) is described on the basis, by F68 recipe quantity and itself the fixed dependent variable (temperature in the conjunctival sac) that the front is determined, determines the recipe quantity of F127.Prepare gel by best prescription, carry out forecast analysis.
Table 5 EXPERIMENTAL DESIGN and mensuration gelation temperature
The 3 d effect graph of the different P407/P188 ratios of Fig. 3 punctate opacity of the cornea design effect surface method olopatadine situ-gel
The quadratic polynomial match:
V3＝117.63-5.276V1-0.588V2+0.595V1
2-0.533*V1*V2-0.031V2
2
Simplify:
V3＝80.107-2.244V1+0.587V2-0.033V2
2(R＝0.9957)
With V2=9.6, in the V3=35 substitution simplified style, draw V1=21.4, promptly 21.4F127/9.6F68 is a best prescription.
According to optimum prescription preparation poloxamer solution, measure its gelation temperature before and after the simulation artificial tears dilutes, result such as figure below:
As can be seen from the above table, 21.4F127/9.6F68 and predictive value are very approaching, so determine that it is the final prescription of thermosensitive hydrogel.
(2) research of the responsive ocular in-situ gel of pH
The screening of 1Carbopol and HPMC consumption
Ideal responsive gel for eye use drug-supplying system (pH5.5,25 ℃) viscosity under non-physiological condition is little, can free-flow, be easy to splash into ophthalmic; And the bigger gel of formation intensity takes place to change mutually in (pH7.4,35 ℃) in conjunctival sac under physiological condition, delays drug release.Therefore be that evaluation index is the screening that index is carried out Carbopol and HPMC consumption with flow of solution, gel strength.
1.1Carbopol the screening compound concentration of consumption is a series of Carbopol solution of 0.1%～0.7% (w/v).With above-mentioned solution with the 1mol/L sodium hydroxide solution respectively adjust pH to pH5.5 ± 0.1, pH7.4 ± 0.1, the flowability of perusal solution and gelling ability.Select the consumption of Carbopol.
1.2HPMC the screening compound concentration of consumption is 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5% aqueous solution, and the consumption of the Carbopol that brings Selection In respectively stir until dissolving fully.With above-mentioned solution with the 1mol/L sodium hydroxide solution respectively tone pitch to pH5.5 ± 0.1, pH7.4 ± 0.1, perusal flow of solution and gelling ability.Select the consumption of HPMC.
1.3Carbopol and the optimization of HPMC consumption preparation Carbopol to be investigated and the consumption of HPMC, with the 1mol/L sodium hydroxide solution respectively tone pitch to pH5.5 ± 0.1, pH7.4 ± 0.1, the relatively flowability and the gelling ability of its solution are finally determined prescription.
2 other compositions are to the influence of the responsive gel viscosity of pH
Olopatadine, mannitol, benzalkonium bromide are added in the optimization Carbopol/HPMC mixed solution that has prepared, be prepared into the Carbopol/HPMC solution that contains olopatadine; The Carbopol/HPMC solution that contains 5% mannitol; Contain the Carbopol/HPMC solution of 0.1 ‰ benzalkonium bromide, measure its viscosity under pH5.5 ± 0.1, pH7.4 ± 0.1 condition.
The preparation technology of the responsive gel for eye use of 3 olopatadine pH
With the Carbopol/HPMC of recipe quantity in being sprinkling upon under the stirring condition on the distilled water liquid level, placement is spent the night, make its abundant aquation swelling, after olopatadine, mannitol, the benzalkonium bromide of recipe quantity slowly joined under stirring condition make dissolving fully in the Carbopol/HPMC solution, NaOH regulates pH, makes the responsive gel for eye use of olopatadine pH.
4 pressure sterilizings are to the influence of the responsive gel viscosity of pH
The pH responsive type gel of optimizing prescription is packed in the cillin bottle, seal, place in the pressure steam sterilizer, the wet-hot steams sterilization 20min with 121 ℃ after the cooling, measures the viscosity of pH responsive type gel under pH5.5 ± 0.1, pH7.4 ± 0.1 condition.
So the prescription of the olopatadine situ-gel of the present invention that obtains and the key point of method for making are as follows:
1. the olopatadine situ-gel is characterized in that: for liquid, gel takes place to be transformed into mutually after the administration under this situ-gel room temperature condition and the non-physiological condition.The olopatadine situ-gel comprises temperature-sensitive situ-gel and pH sensitive in-situ gel.Wherein the concentration of olopatadine is 0.1-0.3%.
2. Fa Ming olopatadine temperature-sensitive situ-gel is characterized in that: contain poloxamer 407 about 16-25%, preferred 20-22%; Contain poloxamer 188 about 5-15%, preferred 9-10%, the said preparation phase transition temperature is adjusted to 35 ± 2 ℃;
3. Fa Ming olopatadine temperature-sensitive situ-gel is characterized in that: it is about 21.4% to contain poloxamer 407, and it is about 9.6% to contain poloxamer 188, and the said preparation phase transition temperature is adjusted to 35 ± 2 ℃;
4. Fa Ming olopatadine pH sensitive in-situ gel, it is characterized in that: carbomer 980 accounts for 0.1-0.5%, hypromellose HPMC accounts for 0.5%-5.0%, the viscosity＜1100mpa.s of said preparation when non-physiological condition pH5.0, the viscosity＞2500mpa.s. when physiological condition pH7.4
5. invention olopatadine pH sensitive in-situ gel, it is characterized in that: carbomer 980 accounts for 0.2%, hypromellose HPMC accounts for 1.0%, the viscosity＜1100mpa.s of said preparation when non-physiological condition pH5.0, the viscosity＞2500mpa.s. when physiological condition pH7.4
6. Fa Ming olopatadine temperature and pH sensitive in-situ gel is characterized in that: can add olopatadine, the microparticle dispersion that is loaded with olopatadine and cyclodextrin clathrate in the preparation.
7. Fa Ming olopatadine temperature and pH sensitive in-situ gel, it is characterized in that: related medicine can be olopatadine and salt (comprising hydrochloric acid, hydrobromate etc.) thereof in the preparation.
8. Fa Ming olopatadine temperature and pH sensitive in-situ gel, it is characterized in that: the said preparation nasal cavity applied medicine can be used for seasonal allergic rhinitis, and eye is local to drip with being applicable to the treatment anaphylaxis conjunctivitis.
The invention has the advantages that: utilize the temperature sensitivity of poloxamer and the pH sensitivity of carbomer, the eye that has prepared temperature and pH sensitivity is used or the nasal cavity situ-gel, its under non-physiological state to change gel into after the liquid condition administration, prolonged the holdup time of medicine greatly at medicine-feeding part, improve bioavailability, improved curative effect.
Description of drawings
Fig. 1-1 phase transition temperature is with the F127 concentration curve
The change curve of the phase transition temperature of Fig. 1-2 F127 variable concentrations
The change curve of the phase transition temperature of Fig. 1-3 poloxamer 407 and poloxamer 188 compatibilities
Viscosity changes before and after the poloxamer 407 of Fig. 2-1 olopatadine situ-gel 21.4% and the dilution of 9.6% poloxamer 188 compatibility tears
Viscosity changes before and after the dilution of Fig. 2-2 olopatadine situ-gel (20%F127/15%F68) tear
The 3 d effect graph of the different P407/P188 ratios of Fig. 3 punctate opacity of the cornea design effect surface method olopatadine situ-gel
The specific embodiment
The preparation of (or nasal cavity is used) gel of the temperature sensitive eye of embodiment 1 olopatadine
[prescription] olopatadine 0.15g
Bromo geramine (benzalkonium bromide) 0.02g
F127 21.4g
F68 9.6g
Add isotonic phosphate buffer liquid (pH7.4) to full dose 100g
[method for making] gets olopatadine, and bromo geramine slowly adds the F127 and the F68 of recipe quantity down with recipe quantity 60% sterile isotonic phosphate buffer (pH7.4) dissolving, stirring condition, add isotonic phosphate buffer liquid to capacity, deepfreeze is preserved, and makes abundant swelling, until forming clear and bright uniform solution.
The preparation of (or nasal cavity is used) gel of the temperature sensitive eye of embodiment 2 olopatadines
[prescription] olopatadine 0.1g
Bromo geramine (benzalkonium bromide) 0.02g
F127 21.4g
F68 9.6g
NaCl 0.9g
Adding distil water is to full dose 100g
[method for making] gets olopatadine, bromo geramine, and NaCl slowly adds the F127 and the F68 of recipe quantity down with recipe quantity 60% dissolved in distilled water, stirring condition, and adding distil water is to capacity, and deepfreeze is preserved, and makes abundant swelling, until forming clear and bright uniform solution.
The preparation of (or nasal cavity is used) gel of the temperature sensitive eye of embodiment 3 olopatadines
[prescription] olopatadine 0.3g
Bromo geramine (benzalkonium bromide) 0.02g
F127 21.4g
F68 9.6g
Mannitol 5g
Adding distil water is to full dose 100g
[method for making] gets olopatadine, bromo geramine, and mannitol slowly adds the F127 and the F68 of recipe quantity down with recipe quantity 60% dissolved in distilled water, stirring condition, and adding distil water is to capacity, and deepfreeze is preserved, and makes abundant swelling, until forming clear and bright uniform solution.
The preparation of (or nasal cavity is used) gel of the temperature sensitive eye of embodiment 4 olopatadines
[prescription] Olopatadine hydrochloride 0.15g
Bromo geramine (benzalkonium bromide) 0.02g
F127 21.4g
F68 9.6g
Add isotonic phosphate buffer liquid (pH7.4) to full dose 100g
[method for making] gets the F127 and the F68 of recipe quantity, add recipe quantity 80% sterile isotonic phosphate buffer (pH7.4), deepfreeze is preserved, make abundant swelling, until forming clear and bright solution, stirring condition slowly adds olopatadine, bromo geramine down, add isotonic phosphate buffer liquid to capacity, stir until forming uniform solution.
The preparation of (or nasal cavity is used) gel of the temperature sensitive eye of embodiment 5 olopatadines
[prescription] Olopatadine hydrochloride 0.1g
Bromo geramine (benzalkonium bromide) 0.02g
F127 21.4g
F68 9.6g
NaCl 0.9g
Adding distil water is to full dose 100g
[method for making] gets the F127 and the F68 of recipe quantity, adds recipe quantity 80% distilled water, and deepfreeze is preserved, and makes abundant swelling, until forming clear and bright solution, stirring condition slowly adds olopatadine, bromo geramine down, NaCl, adding distil water stir until forming uniform solution to capacity.
The preparation of (or nasal cavity is used) gel of the temperature sensitive eye of embodiment 6 olopatadines
[prescription] olopatadine 0.3g
Bromo geramine (benzalkonium bromide) 0.02g
F127 21.4g
F68 9.6g
Mannitol 5g
Adding distil water is to full dose 100g
[method for making] gets the F127 and the F68 of recipe quantity, adds recipe quantity 80% distilled water to full dose, and deepfreeze is preserved, and makes abundant swelling, until forming clear and bright solution, stirring condition slowly adds olopatadine, bromo geramine down, mannitol, adding distil water stir until forming uniform solution to capacity.
The preparation of (or nasal cavity is used) gel of the quick eye of embodiment 7 olopatadine pH
[prescription] olopatadine 0.15g
Carbopol(980NF) 0.2g
HPMC(4000) 0.5g
Bromo geramine (benzalkonium bromide) 0.02g
NaCl 0.9g
Add water to full dose 100g
[method for making] with Carbopol, the HPMC of recipe quantity in stirring condition slowly add down in recipe quantity 80% distilled water, placement is spent the night and is made abundant swelling, adding olopatadine, bromo geramine, NaCl make the equal solution of dissolving formation fully down in stirring condition again, regulate pH to 5.5 with NaOH, add water to capacity, stir.
The preparation of (or nasal cavity is used) gel of the quick eye of embodiment 8 olopatadine pH
[prescription] olopatadine 0.1g
Carbopol(980NF) 0.2g
HPMC(4000) 0.5g
Bromo geramine (benzalkonium bromide) 0.02g
NaCl 0.9g
Add water to full dose 100g
[method for making] with Carbopol, the HPMC of recipe quantity in stirring condition slowly add down in recipe quantity 50% distilled water, placing spends the night makes abundant swelling get solution 1; With olopatadine, BKC, the NaCl of recipe quantity under stirring condition, join in 40% distilled water solution 2; Merge solution 1 and 2, stir uniform solution, regulate pH to 5.5 with NaOH, add water to capacity, stir.
The preparation of (or nasal cavity is used) gel of the quick eye of embodiment 9 olopatadine pH
[prescription] olopatadine 0.3g
Carbopol(980NF) 0.2g
HPMC(4000) 0.5g
Bromo geramine (benzalkonium bromide) 0.02g
Mannitol 5g
Add water to full dose 100g
[method for making] with Carbopol, the HPMC of recipe quantity in stirring condition slowly add down in recipe quantity 80% distilled water, placement is spent the night and is made abundant swelling, adding olopatadine, bromo geramine, mannitol make dissolving formation uniform solution fully down in stirring condition again, regulate pH to 5.5 with NaOH, add water to capacity, stir.
The preparation of (or nasal cavity is used) gel of the quick eye of embodiment 10 olopatadine pH
[prescription] olopatadine 0.3g
Carbopol(980NF) 0.2g
HPMC(4000) 0.5g
Bromo geramine (benzalkonium bromide) 0.02g
Mannitol 5g
Add water to full dose 100g
[method for making] with Carbopol, the HPMC of recipe quantity in stirring condition slowly add down in recipe quantity 50% distilled water, placing spends the night makes abundant swelling get solution 1; With olopatadine, bromo geramine, the mannitol of recipe quantity under stirring condition, join in 40% distilled water solution 2; Merge solution 1 and 2, stir uniform solution, regulate pH to 5.5 with NaOH, add water to capacity, stir.
The preparation of gel of quick eye usefulness of embodiment 11 olopatadine pH or nasal cavity
[prescription] olopatadine 0.3g
Carbopol(980NF) 0.2g
HPMC(4000) 0.5g
Bromo geramine (benzalkonium bromide) 0.02g
NaCl 0.9g
Add water to full dose 100g
[method for making] adds the Carbopol of recipe quantity makes abundant swelling get solution 1 in an amount of distilled water; The HPMC of recipe quantity added make abundant swelling get solution 2 in an amount of distilled water; With olopatadine, bromo geramine, the NaCl of recipe quantity add stir in an amount of distilled water make dissolve solution 3; Merge solution 1,2,3, stir uniform solution, regulate pH to 5.5 with NaOH, add water to capacity, stir.
The preparation of gel of quick eye usefulness of embodiment 12 olopatadine pH or nasal cavity
[prescription] olopatadine 0.3g
Carbopol(980NF) 0.2g
HPMC(4000) 0.5g
Bromo geramine (benzalkonium bromide) 0.02g
Mannitol 5g
Add water to full dose 100g
[method for making] adds the Carbopol of recipe quantity makes abundant swelling get solution 1 in an amount of distilled water; The HPMC of recipe quantity added make abundant swelling get solution 2 in an amount of distilled water; With olopatadine, bromo geramine, the mannitol of recipe quantity add stir in an amount of distilled water make dissolve solution 3; Merge solution 1,2,3, stir uniform solution, regulate pH to 5.5 with NaOH, add water to capacity, stir.
Claims (8)
1. the olopatadine situ-gel is characterized in that: for liquid, gel takes place to be transformed into mutually after the administration under this situ-gel room temperature condition and the non-physiological condition.The olopatadine situ-gel comprises temperature-sensitive situ-gel and pH sensitive in-situ gel.Wherein the concentration of olopatadine is 0.1-0.3%.
2. the described olopatadine temperature-sensitive situ-gel of claim 1 is characterized in that: contain poloxamer 407 about 16-25%, preferred 20-22%; Contain poloxamer 188 about 5-15%, preferred 9-10%, the said preparation phase transition temperature is adjusted to 35 ± 2 ℃.
3. the described olopatadine temperature-sensitive situ-gel of claim 1 is characterized in that: it is about 21.4% to contain poloxamer 407, and it is about 9.6% to contain poloxamer 188, and the said preparation phase transition temperature is adjusted to 35 ± 2 ℃.
4. the described olopatadine pH of claim 1 sensitive in-situ gel, it is characterized in that: carbomer 980 accounts for 0.1-0.5%, hypromellose HPMC accounts for 0.5%-5.0%, viscosity＜the 1100mpa.s of said preparation when non-physiological condition pH5.0, the viscosity＞2500mpa.s when physiological condition pH7.4.
5. the described olopatadine pH of claim 1 sensitive in-situ gel, it is characterized in that: carbomer 980 accounts for 0.2%, hypromellose HPMC accounts for 1.0%, the viscosity＜1100mpa.s of said preparation when non-physiological condition pH5.0, the viscosity＞2500mpa.s when physiological condition pH7.4.
6. described olopatadine temperature of claim 1 and pH sensitive in-situ gel is characterized in that: can add olopatadine, the microparticle dispersion that is loaded with olopatadine and cyclodextrin clathrate in the preparation.
7. described olopatadine temperature of claim 1 and pH sensitive in-situ gel, it is characterized in that: related medicine can be olopatadine and salt (comprising hydrochloric acid, hydrobromate etc.) thereof in the preparation.
8. described olopatadine temperature of claim 1 and pH sensitive in-situ gel, it is characterized in that: the said preparation nasal cavity applied medicine can be used for seasonal allergic rhinitis, and eye is local to drip with being applicable to the treatment anaphylaxis conjunctivitis.
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| CN2009101609923A CN101966144A (en) | 2009-07-28 | 2009-07-28 | Preparation and application of olopatadine in-situ gel |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103202833A (en) * | 2012-12-25 | 2013-07-17 | 常州市亚邦医药研究所有限公司 | Pharmaceutical composition of olopatadine or salts of olopatadine, and preparation method thereof |
| CN106256351A (en) * | 2015-06-18 | 2016-12-28 | 江苏吉贝尔药业股份有限公司 | Olopatadine hydrochloride gel eyedrop and preparation method thereof |
| CN106309354A (en) * | 2015-06-24 | 2017-01-11 | 复旦大学 | Nasal-delivery temperature-sensitive in-situ gel sustained-release preparation comprising ketorolac tromethamine |
| CN110433133A (en) * | 2019-08-19 | 2019-11-12 | 中国人民解放军军事科学院军事医学研究院 | The cannabidiol nasal formulations for treating posttraumatic stress disorder |
| CN115737547A (en) * | 2022-11-21 | 2023-03-07 | 山东诺明康药物研究院有限公司 | Loteprednol etabonate temperature-sensitive in-situ gel eye drops and preparation method thereof |
| CN115887367A (en) * | 2022-11-21 | 2023-04-04 | 山东诺明康药物研究院有限公司 | Olopatadine hydrochloride in-situ gel eye drops and preparation method and application thereof |
| CN120241701A (en) * | 2025-06-06 | 2025-07-04 | 北京爱力佳医药科技有限公司 | Olopatadine hydrochloride-containing oral medicine composition and preparation method thereof |
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2009
- 2009-07-28 CN CN2009101609923A patent/CN101966144A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103202833A (en) * | 2012-12-25 | 2013-07-17 | 常州市亚邦医药研究所有限公司 | Pharmaceutical composition of olopatadine or salts of olopatadine, and preparation method thereof |
| CN106256351A (en) * | 2015-06-18 | 2016-12-28 | 江苏吉贝尔药业股份有限公司 | Olopatadine hydrochloride gel eyedrop and preparation method thereof |
| CN106309354A (en) * | 2015-06-24 | 2017-01-11 | 复旦大学 | Nasal-delivery temperature-sensitive in-situ gel sustained-release preparation comprising ketorolac tromethamine |
| CN110433133A (en) * | 2019-08-19 | 2019-11-12 | 中国人民解放军军事科学院军事医学研究院 | The cannabidiol nasal formulations for treating posttraumatic stress disorder |
| CN115737547A (en) * | 2022-11-21 | 2023-03-07 | 山东诺明康药物研究院有限公司 | Loteprednol etabonate temperature-sensitive in-situ gel eye drops and preparation method thereof |
| CN115887367A (en) * | 2022-11-21 | 2023-04-04 | 山东诺明康药物研究院有限公司 | Olopatadine hydrochloride in-situ gel eye drops and preparation method and application thereof |
| CN120241701A (en) * | 2025-06-06 | 2025-07-04 | 北京爱力佳医药科技有限公司 | Olopatadine hydrochloride-containing oral medicine composition and preparation method thereof |
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