CN107569454B - A kind of Olopatadine hydrochloride nasal spray and preparation method thereof - Google Patents
A kind of Olopatadine hydrochloride nasal spray and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to pharmaceutical technology field, a kind of Olopatadine hydrochloride nasal spray and preparation method thereof is provided, the nasal spray is made of Olopatadine hydrochloride, water soluble chitosan, chitosan quaternary ammonium salt, hydroxypropyl beta cyclodextrin, osmotic pressure regulator, buffer, pH adjusting agent and purified water.Olopatadine hydrochloride nasal spray provided by the invention extends holdup time of the Olopatadine hydrochloride in nasal cavity, improve the bioavilability of Olopatadine hydrochloride, in addition, also improve the stability of product and reduce product bitter taste, nose is bleeding, the incidence for the adverse reaction such as have sore throat, it is low to schneiderian membrane irritation, Small side effects, improve the security of nasal cavity applied medicine.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of Olopatadine hydrochloride nasal spray and preparation method thereof.
Background technology
Olopatadine is a kind of high selectivity dibenzo oxepane three developed and listed by consonance fermentation company of Japan
Alkene -2- acetic acid analogued histamines H1Acceptor inhibitor, can suppress tachykinin and other chemical mediators, such as histamine, arachidonic acid, blood
The release of bolt element, leukotriene etc., was waited available for treatment allergic rhinitis, nettle rash, eczema, dermatitis, pruigo, cutaneous pruritus
Quick property disease.Olopatadine is generally with hydrochloride form medication, and clinically common formulation is tablet, eye drops at present.
Nasal-cavity administration is convenient and easy, and patient can independently complete, smaller by environmental constraints, after medicine is by nasal absorption, no
By portal vein, body circulation is directly entered, avoids first pass effect, while can be metabolized to avoid gastrointestinal mucosal with medicine in stomach and intestine
Degraded in liquid, bioavilability is high, and small-molecule drug its bioavilability in part is easy suitable for intestines and stomach close to intravenous injection
The medicines such as the medicine of destruction and the influential medicine of liver first-pass effect, treatment respiratory tract and the disease for passing through respiratory tract infection
Administration.
103830219 A of Chinese patent application CN disclose a kind of olopatadine composition of stabilization, and said composition includes
Olopatadine hydrochloride 0.54~0.62% (w/v), glucose 1.9~2.9% (w/v), 0.005~0.02% (w/ of benzalkonium chloride
V), disodium hydrogen phosphate 0.3~0.6% (w/v), natrium adetate 0.005~0.02% (w/v), pH adjusting agent and water, pH are
3.4~3.9, the olopatadine composition can be used for preparing nasal spray, have very strong stability under light illumination.
2008, the Olopatadine hydrochloride nasal spray of Alcon companies of SwitzerlandFDA approval listings are obtained, should
Product is the olopatadine nose olopatadine product of currently the only listing, by the olopatadine equivalent to 0.6% olopatadine
Hydrochloride, 0.01% benzalkonium chloride and the disodium hydrogen phosphate for the amount of not expressing, sodium chloride, natrium adetate, the salt for adjusting pH
Acid or sodium hydroxide and pure water are made.
During pharmaceutical preparation research and development, the selection of auxiliary material is to the stability of main ingredient, the stability of pharmaceutical preparation
And the side effect of pharmaceutical preparation is respectively provided with very big influence.During the research and development of nasal pharmaceutical formulations, medicine or
The auxiliary materials such as additives, sorbefacient and preservative in preparation there may exist ciliary toxicity, and stimulation, limit are produced to schneiderian membrane
The research and application of nasal cavity administrated preparation are made.In addition, medicine residence time in nasal cavity is shorter, it is fine by mucous membrane quickly after administration
Hair is removed, and can influence the validity of nasal-cavity administration to a certain extent.
Existing olopatadine nasal spray, can be used for preparing nose as disclosed in 103830219 A of Chinese patent application CN
With spray olopatadine composition and the Olopatadine hydrochloride nasal spray of FDA approval listingsIn, auxiliary material group
Cheng Jun includes bacteriostatic agent benzalkonium chloride and chelating agent natrium adetate, and olopatadine and benzalkonium chloride are bitter substance, therefore,
Due to the scavenging action of nose cilium, after the administration of Olopatadine hydrochloride nasal spray, the adverse reactions such as bitter taste are easily produced；And study
Show, natrium adetate has significant impact to the stability of olopatadine.Paper " the new antiallergic that Xiao Xuecheng etc. is delivered
The study of pharmacy of Olopatadine hydrochloride nasal spray " is open, Olopatadine hydrochloride nasal sprayCommon (>1%)
Adverse reaction include bitter taste (12.8%), headache (4.4%), nose is bleeding (3.2%), have sore throat (2.2%), Postnasal drip
(1.5%) and cough (1.4%) etc., existing Olopatadine hydrochloride nasal spray mucous membrane irritation is larger, side effect is more, existing
Have and still lack that a kind of stability is strong, the Olopatadine hydrochloride nasal spray of few side effects in technology.
The content of the invention
To solve problems of the prior art, the present invention provides a kind of Olopatadine hydrochloride nasal spray.This hair
The Olopatadine hydrochloride nasal spray of bright offer, by the interaction of each component, not only increases active constituents of medicine hydrochloric acid
The stability of olopatadine, while also reduce the side effect of product.
Technical scheme will be further described in detail below reflect and description.
A kind of Olopatadine hydrochloride nasal spray, the component and its dosage of the nasal spray are：
Preferably, the osmotic pressure regulator is at least one of sodium chloride, glucose, sorbierite；It is highly preferred that institute
It is glucose to state osmotic pressure regulator.
Preferably, the pH adjusting agent is hydrochloric acid or sodium hydroxide.
Preferably, the component of the nasal spray and its dosage are：
Olopatadine hydrochloride nasal spray provided by the invention, is using Olopatadine hydrochloride as active constituents of medicine, with water
The auxiliary material group such as soluble chitosan, chitosan quaternary ammonium salt, hydroxypropyl-β-cyclodextrin, osmotic pressure regulator, pH adjusting agent, buffer
Lease making reasonable compatibility is made.
Water soluble chitosan of the present invention be the deacetylation that is prepared under homogeneous phase condition 50% or so can
It is dissolved in the low-molecular water-soluble chitosan of chitosan or relative molecular mass less than 10000 of water.
The removing function of Nasal mucociliary causes the time of contact of medicine and schneiderian membrane very short, and liquid is from when nasal cavity is removed
Between be about 20~30min, in order to extend holdup time of the Olopatadine hydrochloride in nasal cavity, inventor attempt add in the formulation
Water soluble chitosan, the positively charged amino group of water soluble chitosan itself can be with nasal cavities negatively charged on nasal membrane point
Secretion is combined, on the one hand, can be increased the time of contact of Olopatadine hydrochloride and nasal epithelia, be extended hydrochloric acid Ao Luota
It is scheduled on the holdup time of nasal cavity；On the other hand, absorption of the nasal epithelia to Olopatadine hydrochloride can be promoted, it is difficult to understand to improve hydrochloric acid
The bioavilability of Luo Tading.
But during experiment, inventor has found, after adding water soluble chitosan, preparation needs in preparation process
Long agitation just becomes clear, and Olopatadine hydrochloride photostability is poor, and mixing time, which extends to easily lead in preparation, to be had
Content of material is closed to improve；And find that product is also easy to produce precipitation, solution in storing process during long-term stable experiment investigation
Become cloudy.To solve the problems, such as this, inventor has carried out substantial amounts of experiment, during experiment, inventors be surprised to learn that, making
A small amount of hydroxypropyl-β-cyclodextrin (No. CAS is added in agent:After 128446-35-5), the content in relation to material reduces in preparation,
The stability of preparation improves.In addition, inventor also surprisingly has found, and after adding hydroxypropyl-β-cyclodextrin, obtained hydrochloric acid Austria Lip river
He determines nasal spray, and bitter taste, nose is bleeding, the adverse reaction rate such as have sore throat reduce.
Chitosan quaternary ammonium salt, its full name are hydroxypropyl-trimethyl ammonium chloride water soluble chitosan, are water soluble chitosan warps
Prepared by chemical modification water soluble chitosan higher derivative, substitution value is more than 90%.Chitosan quaternary ammonium salt is pleasantly sweet, water
Dissolubility and stability of solution are good, and have good antibiotic property, can not only substitute benzalkonium chloride as Olopatadine hydrochloride nose
The antiseptic of spray, has surprisingly been found that during experiment, using hydrochloric acid Ao Luota made from chitosan quaternary ammonium salt as antiseptic
Determine nasal spray, incidence of side effects reduces.
Correspondingly, the present invention also provides the preparation method of Olopatadine hydrochloride nasal spray of the present invention, including such as
Lower step：
S1：Hydroxypropyl-β-cyclodextrin is taken, adds purified water to be made saturated solution, adds Olopatadine hydrochloride, ultrasound under room temperature
30~60min, obtains solution I；
S2：Water-soluble chitosan, chitosan quaternary ammonium salt and osmotic pressure regulator, add appropriate purified water to be completely dissolved, obtain
Solution II；
S3：Solution II described in solution I described in step S1 and step S2 is stirred and evenly mixed, add purified water adjust liquor capacity be
The 80% of final solution volume, adds pH adjusting agent to adjust pH, adds buffer, then adds pH adjusting agent to adjust pH, finally adds purifying
Water adjusts liquor capacity to final solution volume, and, packing degerming using 0.22 μm of membrane filtration is filling, packs, to obtain the final product.
Olopatadine hydrochloride nasal spray provided by the invention, by the interaction of each component, extends hydrochloric acid Austria Lip river
He is scheduled on the holdup time of nasal cavity, improves the bioavilability of Olopatadine hydrochloride, in addition, also improving the stability of product
And reduce product bitter taste, nose is bleeding, the incidence for the adverse reaction such as have sore throat, side effect low to schneiderian membrane irritation
It is small, improve the security of nasal cavity applied medicine.
Embodiment
Below by specific embodiment, the present invention is described in further detail.
Material used in the embodiment of the present invention, is the material commercially obtained unless otherwise specified.
The preparation of embodiment 1~3,1~2 Olopatadine hydrochloride nasal spray of comparative example
Formula：
Preparation method：
S1：Hydroxypropyl-β-cyclodextrin is taken, adds purified water to be made saturated solution, adds Olopatadine hydrochloride, ultrasound under room temperature
30min, obtains solution I；
S2：Water-soluble chitosan, chitosan quaternary ammonium salt and osmotic pressure regulator, add appropriate purified water to be completely dissolved, obtain
Solution II；
S3：Solution II described in solution I described in step S1 and step S2 is stirred and evenly mixed, add purified water adjust liquor capacity be
The 80% of final solution volume, adds 6mol/L hydrochloric acid solutions or 1mol/L sodium hydroxide solutions to adjust pH, adds buffer, then add
6mol/L hydrochloric acid solutions or 1mol/L sodium hydroxide solutions adjust pH, and finally plus solution is settled to 100mL by purified water, is used
0.22 μm of membrane filtration is degerming, packing, filling, packaging, to obtain the final product.
3 Olopatadine hydrochloride nasal spray of comparative example
Compared with Example 3, comparative example 3 Olopatadine hydrochloride nasal spray differs only in：By chitosan quaternary ammonium salt
Replace with benzalkonium chloride.
4 Olopatadine hydrochloride nasal spray of comparative example
Compared with Example 3, comparative example 4 Olopatadine hydrochloride nasal spray differs only in：By citric acid-citric acid
Sodium buffer solution replaces with disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution.
Test example one, stability test
1st, test specimen：By the hydrochloric acid Ao Luota before being dispensed as made from embodiment 1~3,1~4 scheme of comparative example
Determine nasal spray liquid, take 30mL filling into Clear glass bottles and jars, each filling 30 bottles of embodiment sample, and gland, seal, make
For test specimen.Positive controls sample is commercially available Olopatadine hydrochloride nasal sprayTake 30mL liquids filling
Into Clear glass bottles and jars, filling 30 bottles, and gland, sealing, as test specimen.
2nd, test method：Temperature be 30 ± 2 DEG C, relative humidity 65% ± 5%, the bar that illuminance is 4500 ± 500LX
Investigated under part, the Olopatadine hydrochloride content of sample, related content of material, solution appearance character are measured after 10 days
And observation.Wherein, Olopatadine hydrochloride content, the assay method in relation to content of material are high performance liquid chromatography (with reference to China
Four 0512 high performance liquid chromatographies of general rule of pharmacopeia version in 2015).
3rd, result of the test：It is shown in Table 1.
1 stability test result of table
By 1 results showed that of table compared with positive controls, Olopatadine hydrochloride nasal spray provided by the invention,
The stability of Olopatadine hydrochloride significantly improves.Individually added by the results showed that of embodiment 3, comparative example 1, comparative example 2
Chitosan or hydroxypropyl-β-cyclodextrin, are unfavorable for the stability of preparation, comparative example 1, the spray of 2 Olopatadine hydrochloride nose of comparative example
Mist agent liquid, after being placed 10 days under conditions of illuminance is 4500 ± 500LX, under the content of Olopatadine hydrochloride is notable
Drop, related content of material dramatically increase.1 Olopatadine hydrochloride nasal spray liquid of comparative example needs for a long time in preparation process
Stirring just becomes clear, and related content of material improves in preparation, and after placing 10 days, if dry particl occurs in liquid, preparation is steady
Qualitative difference.
Test example two, pharmacodynamics test
1st, test specimen：Olopatadine hydrochloride nasal spray made from embodiment 3, comparative example 2~4, fills after liquid packing
It is fitted into nasal spray device and nasal spray is made, dosage is 100 μ L/ sprays.
2nd, test method：The trial volunteer with seasonal allergic rhinitis of 200 18 years old ages and the above is invited,
4 groups are randomly divided into, respectively 3 groups of embodiment, 2~4 groups of comparative example, every group of 50 people, respectively using corresponding Olopatadine hydrochloride
Nasal spray carries out the validity of 2 weeks and safety testing by a definite date.During experiment, according to the feedback record bitter taste of subject,
Nose is bleeding, have sore throat, Postnasal drip, a situation arises for the adverse reaction such as cough, calculate the hair of adverse reaction after the test
Raw rate and the effective percentage for the treatment of, criterion of therapeutical effect is with " symptom disappears, and sign substantially mitigates, nasal secretion smear after the test
Experiment is shown in that eosinophil count is judged as " treatment is effective " less than 5% ".
3rd, result of the test：It is shown in Table 2.
2 Olopatadine hydrochloride nasal spray results of pharmacodynamic test of table
It is high, bad anti-by the results showed that of table 2 Olopatadine hydrochloride aerosol therapy validity provided by the invention
Answer incidence low, only there is the adverse reaction that bitter taste or cough occur for 1 patient feedback in therapeutic process respectively, adverse reaction is more right
2~4 groups of reductions of ratio.
Above content is that a further detailed description of the present invention in conjunction with specific preferred embodiments, it is impossible to is assert
The specific implementation of the present invention is confined to these explanations.For general technical staff of the technical field of the invention,
On the premise of not departing from present inventive concept, some simple deduction or replace can also be made, should all be considered as belonging to the present invention's
Protection domain.
Claims (6)
1. a kind of Olopatadine hydrochloride nasal spray, it is characterised in that the component and its dosage of the nasal spray be：
2. Olopatadine hydrochloride nasal spray as claimed in claim 1, it is characterised in that the osmotic pressure regulator is chlorination
At least one of sodium, glucose, sorbierite.
3. Olopatadine hydrochloride nasal spray as claimed in claim 2, it is characterised in that the osmotic pressure regulator is grape
Sugar.
4. Olopatadine hydrochloride nasal spray as claimed in claim 1, it is characterised in that the pH adjusting agent is hydrochloric acid or hydrogen
Sodium oxide molybdena.
5. Olopatadine hydrochloride nasal spray as claimed in claim 1, it is characterised in that the component of the nasal spray and its
Dosage is：
The glucose is osmotic pressure regulator.
6. the preparation method of the Olopatadine hydrochloride nasal spray as described in Claims 1 to 5 is any, it is characterised in that described
Preparation method includes the following steps：
S1：Hydroxypropyl-β-cyclodextrin is taken, adds purified water to be made saturated solution, adds Olopatadine hydrochloride, ultrasound 30 under room temperature~
60min, obtains solution I；
S2：Water-soluble chitosan, chitosan quaternary ammonium salt and osmotic pressure regulator, add appropriate purified water to be completely dissolved, obtain solution
II；
S3：Solution II described in solution I described in step S1 and step S2 is stirred and evenly mixed, it is final to add purified water to adjust liquor capacity
The 80% of liquor capacity, adds pH adjusting agent to adjust pH, adds citric acid-sodium citrate buffer, then adds pH adjusting agent to adjust pH,
Finally plus purified water adjusts liquor capacity to final solution volume, packing degerming using 0.22 μm of membrane filtration, filling, packaging,
To obtain the final product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710909766.5A CN107569454B (en) | 2017-09-29 | 2017-09-29 | A kind of Olopatadine hydrochloride nasal spray and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710909766.5A CN107569454B (en) | 2017-09-29 | 2017-09-29 | A kind of Olopatadine hydrochloride nasal spray and preparation method thereof |
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| CN107569454B true CN107569454B (en) | 2018-05-04 |
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| CN109806224B (en) * | 2019-03-15 | 2021-05-28 | 江苏长泰药业有限公司 | Olopatadine composition and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI1814538T1 (en) * | 2004-11-24 | 2010-01-29 | Alcon Inc | Method of delivering nasal spray |
| BR112012001169A2 (en) * | 2009-07-17 | 2016-03-01 | Alcon Res Ltd | olopatadine nasal spray system for children |
| CN103127147A (en) * | 2011-11-30 | 2013-06-05 | 天津金耀集团有限公司 | Medicine composition containing budesonide and nitric oxide synthase (NOS) inhibitor and for treating nose inflammation |
| ES2658972T3 (en) * | 2012-06-20 | 2018-03-13 | University Of Waterloo | Mucoadhesive nanoparticle administration system |
| CN103830219A (en) * | 2012-11-20 | 2014-06-04 | 深圳大佛药业有限公司 | Stable olopatadine composition |
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