CN101632646A

CN101632646A - Olopatadine hydrochloride tablet as well as preparation method and detecting method thereof

Info

Publication number: CN101632646A
Application number: CN200910085119A
Authority: CN
Inventors: 张建立; 曹相林; 陈婧; 蔡刚; 陈红燕; 李海冰
Original assignee: BEIJING SIHUANKEBAO PHARMACEUTICAL Co Ltd
Current assignee: Beijing Sihuan Kebao Pharmaceutical Co.,Ltd.
Priority date: 2009-05-31
Filing date: 2009-05-31
Publication date: 2010-01-27
Anticipated expiration: 2029-05-31
Also published as: CN101632646B

Abstract

The invention discloses an olopatadine hydrochloride tablet as well as a preparation method and a detecting method thereof. The olopatadine hydrochloride tablet comprises the raw materials based on parts by weight: 1-10 parts of olopatadine hydrochloride, 50-150 parts of lactose, 25-75 parts of microcrystalline cellulose, 30-50 parts of 2 percent of hydroxypropyl methyl cellulose and 0.15-2.2 parts of magnesium stearate. The olopatadine hydrochloride tablet has good dissolution performance and few selected auxiliary materials and can achieve good anti-allergic effect.

Description

A kind of Olopatadine hydrochloride sheet and preparation method thereof and detection method

Technical field

The present invention relates to a kind of Olopatadine hydrochloride sheet and preparation method thereof and detection method, Olopatadine hydrochloride sheet of particularly a kind of treatment of allergic rhinitis, chronic urticaria or anaphylaxis conjunctivitis and preparation method thereof and detection method.

Background technology

Studies show that olopatadine is better to allergic rhinitis, chronic urticaria, anaphylaxis conjunctivitis effect.Wherein, to seasonal autopath, olopatadine can obviously suppress histamine, the reaction of grass seed pollen cutaneous scarification, and effect obviously is better than terfenadine.To allergic rhinitis patient all the year round, the effectiveness of olopatadine and safety and oxatomide are suitable, and the therapeutic effect of nasal obstruction is better than similar medicine.Chronic urticaria patient takes olopatadine for a long time, and is evident in efficacy, compares with present clinical ketotifen commonly used, and the olopatadine effect obviously is better than ketotifen, and adverse reaction rate is low.

It is generally acknowledged that olopatadine is as a kind of novel high histamine H of relative selectivity ₁Receptor antagonist is to M ₁Seldom generation effect of receptor, invalid to alpha-2-adrenoceptor and serotonin receptor, so the side effect of central nervous system aspect must be lacked.The olopatadine of antiallergic dosage is to the nervus centralis of dog, mice, rat, Cavia porcellus, rabbit, cat, autonomic nerve, and peripheral nervous, cardiovascular system, the influence of digestion system and urinary system is very little.Estimate that in view of the above it will be the antiallergic drug of first choice of a new generation.

Because the present disclosed Olopatadine hydrochloride tablet of document stripping property is not good and preparation cost is high, the invention provides a kind of tablet that stripping property is good and preparation cost is low that has, the adjuvant of selecting for use is less, and can reach good antiallergic effect.

Summary of the invention

The object of the invention is to provide a kind of Olopatadine hydrochloride sheet; Another purpose of the present invention is to provide the preparation method of this Olopatadine hydrochloride sheet; Another purpose of the present invention is to provide the detection method of this Olopatadine hydrochloride sheet.

The present invention seeks to be achieved through the following technical solutions:

The raw material of Olopatadine hydrochloride sheet of the present invention is composed as follows:

Olopatadine hydrochloride 1-10 weight portion

Lactose 50-150 weight portion

Microcrystalline Cellulose 25-75 weight portion

2% hydroxypropyl methylcellulose 30-50 weight portion

Magnesium stearate 0.15-2.2 weight portion.

The raw material composition of Olopatadine hydrochloride sheet of the present invention is preferably as follows:

Olopatadine hydrochloride 2 weight portions

Lactose 145 weight portions

Microcrystalline Cellulose 30 weight portions

2% hydroxypropyl methylcellulose, 48 weight portions

Magnesium stearate 1.8 weight portions.

Olopatadine hydrochloride 9 weight portions

Lactose 55 weight portions

Microcrystalline Cellulose 70 weight portions

2% hydroxypropyl methylcellulose, 33 weight portions

Magnesium stearate 0.3 weight portion.

Olopatadine hydrochloride 5 weight portions

Lactose 90 weight portions

Microcrystalline Cellulose 45 weight portions

2% hydroxypropyl methylcellulose, 40 weight portions

Magnesium stearate 1.5 weight portions.

Olopatadine hydrochloride piece preparation method of the present invention is as follows: with Olopatadine hydrochloride, lactose, microcrystalline Cellulose, sieves respectively, and standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the lactose mix homogeneously of the Olopatadine hydrochloride of recipe quantity and recipe quantity,,, make wet granular with above-mentioned 2% hydroxypropyl methylcellulose solution system soft material of recipe quantity again with the microcrystalline Cellulose mix homogeneously of recipe quantity; The wet granular airpillow-dry; Behind the granulate, add the magnesium stearate mix homogeneously of recipe quantity; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

Olopatadine hydrochloride piece preparation method of the present invention is preferably as follows: with Olopatadine hydrochloride, lactose, microcrystalline Cellulose, cross 120 mesh sieves respectively, and standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the Olopatadine hydrochloride and lactose mix homogeneously of recipe quantity, again with microcrystalline Cellulose mix homogeneously in the efficient wet mixer-granulator, the hydroxypropyl methylcellulose solution system soft material with above-mentioned 2%, high speed shear system wet granular; Wet granular is at airpillow-dry below 65 ℃; Behind the granulate, add the magnesium stearate mix homogeneously; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

Olopatadine hydrochloride piece preparation method of the present invention is preferably as follows: with Olopatadine hydrochloride, lactose, microcrystalline Cellulose, cross 200 mesh sieves respectively, and standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the Olopatadine hydrochloride and lactose mix homogeneously of recipe quantity, again with microcrystalline Cellulose mix homogeneously in the efficient wet mixer-granulator, the hydroxypropyl methylcellulose solution system soft material with above-mentioned 2%, high speed shear system wet granular; The wet granular airpillow-dry; Behind the granulate, add the magnesium stearate mix homogeneously; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

Olopatadine hydrochloride piece preparation method of the present invention is preferably as follows: with Olopatadine hydrochloride, lactose, microcrystalline Cellulose, cross 100 mesh sieves respectively, and standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the Olopatadine hydrochloride and lactose mix homogeneously of recipe quantity, again with microcrystalline Cellulose mix homogeneously in the efficient wet mixer-granulator, the hydroxypropyl methylcellulose solution system soft material with above-mentioned 2%, high speed shear system wet granular; Wet granular is at airpillow-dry below 65 ℃; Behind the granulate, add the magnesium stearate mix homogeneously; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

Detection method of the present invention comprises following discrimination method and/or determination of related substances method and/or content assaying method:

Discrimination method is: get the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 1-15mg, put in the 50-150ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 293-303nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of Olopatadine hydrochloride sheet of the present invention is muriatic identification.

Discrimination method is preferably: get the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 5mg, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 298nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of Olopatadine hydrochloride sheet of the present invention is muriatic identification.

Determination of related substances method in the detection method is:

Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 15-25cm; 20-60: the acetonitrile of 40-80 ratio: 10-30mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention that is equivalent to hydrochloric olopatadine 1-10mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 150-250 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 0.5-1.5ml, puts in the 50-150ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 1-3 of every 1ml μ g, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 150-250 μ g/ml is dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 0.5-1.5ml of isomer solution, puts in the 5-15ml measuring bottle, is made into mixed solution, sample introduction 10-30 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 10-30 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method in the detection method is:

High effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; 25-45: the acetonitrile of 55-75 ratio: the 10-30mmol/L potassium dihydrogen phosphate (contains 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) be mobile phase, the detection wavelength is 220-240nm, and column temperature: 15-35 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: take by weighing the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 1-10mg, put in the 50ml measuring bottle, add the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shake up, filter with filter membrane, discard filtrate just, measure subsequent filtrate 4.0-6.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 100-110 ℃ of Olopatadine hydrochloride reference substance that is dried to constant weight, dilute the solution of making hydrochloric olopatadine 10-30 μ g among every 1ml with mobile phase, precision is measured 10-30 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Determination of related substances method in the detection method is preferably:

Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 25: 75 ratios: 15mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention that is equivalent to hydrochloric olopatadine 9mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method in the detection method is preferably:

High effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 30: 70 ratios: 15mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of Olopatadine hydrochloride sheets of the present invention, the accurate title, decided porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 9mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 55: 45 ratios: 25mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention that is equivalent to hydrochloric olopatadine 2mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method in the detection method is preferably:

High effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 40: 60 ratios: 25mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: take by weighing the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 2mg, put in the 50ml measuring bottle, add the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shake up, filter with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 37: 63 ratios: 20mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention that is equivalent to hydrochloric olopatadine 5mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method in the detection method is preferably:

High effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 35: 65 ratios: 20mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of Olopatadine hydrochloride sheets of the present invention, the accurate title, decided porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 5mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Olopatadine hydrochloride sheet stripping property of the present invention is good, and selects less adjuvant for use, and can reach good antiallergic effect.

By following test and embodiment technical method of the present invention is further described, but not as limitation of the present invention.

The experiment of experimental example 1 prescription screening

(1) prescription adjuvant screening experiment 1

According to taking by weighing each supplementary material shown in the table 1, prepare tablet according to following method:

(1) raw material, adjuvant are handled: with crude drug, adjuvant 1, cross 100 mesh sieves respectively, and standby; Preparation adjuvant 2 solution, standby;

(2) technical process: get the crude drug and the adjuvant 1 of recipe quantity, mix homogeneously is with adjuvant 2 solution system soft materials, high speed shear system wet granular; Wet granular is at airpillow-dry below 65 ℃; Behind the granulate, add adjuvant 3 mix homogeneously.

(3) measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

The screening of table 1 prescription adjuvant

The result shows that from compressibility, the compressibility of microcrystalline Cellulose, lactose, mannitol is good; From dissolution, contain the prescription of microcrystalline Cellulose, dissolution is good; Long-term 6 months outward appearance is investigated and is seen, contains the prescription good stability of microcrystalline Cellulose, lactose and mannitol; Take all factors into consideration, select microcrystalline Cellulose, lactose and mannitol to carry out next step screening.

(2) prescription adjuvant screening experiment 2

According to taking by weighing each supplementary material shown in the table 2, prepare tablet according to following method:

The screening of table 2 prescription adjuvant

The result shows, more than the prescription combination all can make the up-to-standard of tablet, but wherein lactose and microcrystalline Cellulose share the dissolution height that reaches.

(3) screening experiment of recipe quantity

Screen according to table 3 prescription and following preparation method, the result is as follows:

Preparation method:

(1) raw material, adjuvant are handled: with Olopatadine hydrochloride, lactose, microcrystalline Cellulose, cross 100 mesh sieves respectively, and standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby;

(2) technical process: after getting the Olopatadine hydrochloride and lactose mix homogeneously of recipe quantity, again with microcrystalline Cellulose mix homogeneously in the efficient wet mixer-granulator, the hydroxypropyl methylcellulose solution system soft material with above-mentioned 2%, high speed shear system wet granular; Wet granular is at airpillow-dry below 65 ℃; Behind the granulate, add the magnesium stearate mix homogeneously;

The screening of table 3 prescription ratio

Prescription	Prescription 11	Prescription 12	Prescription 13	Prescription 14
Prescription	Prescription 11	Prescription 12	Prescription 13	Prescription 14	Olopatadine hydrochloride	??5g	??5g	??5g	??5g
Lactose	??45g	??45g	??90g	??135g	Olopatadine hydrochloride	??5g	??5g	??5g	??5g
Lactose	??45g	??45g	??90g	??135g	Microcrystalline Cellulose	??90g	??45g	??45g	??45g
2% hydroxypropyl methylcellulose	??40g	??40g	??40g	??40g	Microcrystalline Cellulose	??90g	??45g	??45g	??45g
2% hydroxypropyl methylcellulose	??40g	??40g	??40g	??40g	Magnesium stearate	??1.5g	??1.5g	??1.5g	??1.5g
Dissolution during 30min (%)	??90.7	??97.2	??99.5	??94.2	Magnesium stearate	??1.5g	??1.5g	??1.5g	??1.5g

By table 3 as seen, the ratio of microcrystalline Cellulose and lactose is 1: dissolution height during 1-3, ratio are that 1: 2 o'clock dissolution is the highest, so optimizing prescriptions is that the ratio of microcrystalline Cellulose and lactose is 1: 2.

(4) Chu Fang screening experiment 3

1, test preparation 1:

Prescription (specification 5mg/ sheet)

Olopatadine hydrochloride 5g

Lactose 90g

Microcrystalline Cellulose 45g

2% hydroxypropyl methylcellulose 40g

Magnesium stearate 1.5g

Make 1000.

Preparation technology:

2, reference preparation

Commercially available olopatadine sheet, 5mg/ sheet, producer: Japanese Kyowa Hakkokogyo Co., Ltd

3, test preparation 2

Prescription (specification 5mg/ sheet)

Olopatadine hydrochloride 5g

Lactose 45g

Microcrystalline Cellulose 25g

Brazil wax 25g

Fatty acid glyceride 25g

2％HPMC?????????????40g

Magnesium stearate 1.5g

Light anhydrous silicic acid 1.5g

Titanium oxide 1g

Iron sesquioxide 1g

Ethyl cellulose 25g

Polyvinyl alcohol 40g

Make 1000

Preparation technology:

(1) raw material, adjuvant are handled: crude drug, lactose, microcrystalline Cellulose are crossed 80 mesh sieves respectively, in 80 ℃ dry 2-4 hour down, standby.

(2) technical process: the olopatadine of getting recipe quantity is with after lactose, microcrystalline Cellulose, Brazil wax, fatty acid glyceride mix by the equivalent incremental method, add 2%HPMC system soft material, the system wet granular, 60 ℃ of following air blast are to dry, behind the granulate, add magnesium stearate, light anhydrous silicic acid mixing.

(3) intermediate amounts detects: measure tabletting behind the dried granule drug content.

(4) coating: after titanium oxide, iron sesquioxide, ethyl cellulose, polyvinyl alcohol mix, coating, weightening finish 2%.

Table 4 comparing result

(5) adjuvant interference screening test

The adjuvant of selecting for use in the final prescription of table 4 is mixed, press spectrophotography (2000 editions two appendix IV A of Chinese Pharmacopoeia) down method detect, the result shows that selected adjuvant is noiseless to the principal agent detection.

Experimental example 2 stability experiments

1, influence factor's test

According to the Chinese Pharmacopoeia relevant requirements, the Olopatadine hydrochloride sheet sample that embodiment 6 is made carries out influence factor's test, and the result shows that temperature is bigger to this product stability influence, and humidity and illumination are not obvious to this product influence, and result of the test is as follows:

Table 6 influence factor result of the test

2, technology stability test

According to embodiment 6 technologies, manufacture experimently three batches of Olopatadine hydrochloride sheets continuously, 1000 every batch, favorable reproducibility between testing result shows batch, process stabilizing, three batch sample testing results are as follows:

Table 5 technology stability result of the test

The sample lot number	Appearance character	Tablet weight variation	Friability (%)	Dissolution (%)	Uniformity of dosage units
The sample lot number	Appearance character	Tablet weight variation	Friability (%)	Dissolution (%)	Uniformity of dosage units	??040616	The off-white color sheet	Qualified	??0.1	??90.5	Qualified
??040618	The off-white color sheet	Qualified	??0.1	??89.7	Qualified	??040616	The off-white color sheet	Qualified	??0.1	??90.5	Qualified
??040618	The off-white color sheet	Qualified	??0.1	??89.7	Qualified	??040620	The off-white color sheet	Qualified	??0.1	??92.0	Qualified

Experimental example 3 pharmacological experiments

The Olopatadine hydrochloride sheet of embodiment 6 preparations is relative selectivity histamine H1 receptor blocker and mastocyte membrane stabilizer.The essence of I allergic reaction type be the mastocyte of sensitization with after basophil contacts allergen once more, discharge biological active agents and cause clinical super quick symptom.The Olopatadine hydrochloride sheet of embodiment 6 preparation can be stablized mast cell membrane, can suppress IL-6 after oral, and IL-8 generates, oozes out, migration, suppress eosinophilic granulocyte's migration, suppress mast cell degranulation, can block histamine H1-receptor again simultaneously, play the effect of antagonism histamine.Internal and external test shows that all the Olopatadine hydrochloride sheet of embodiment 6 preparations is effective to suppressing the I allergic reaction type, behind the oral administration, can be effective to treat asthma, seasonal allergic rhinitis, urticaria and skin pruritus etc.

The mechanism of action of the Olopatadine hydrochloride sheet of embodiment 6 preparation is by to the antagonism of histamine receptor H1, anti-allergic effects is played in the generation of various inflammatory cell chemical mediators and the inhibition of release.Remove in addition, the Olopatadine hydrochloride sheet of embodiment 6 preparations is to the not significantly influence of other system of human body.Preclinical study shows: after the administration, Olopatadine hydrochloride is to laboratory animal central nervous system's influence fainter (the results are shown in Table 7); To the basic not influence (seeing Table 8) of nerve-skeletal muscle reflection; Influence smaller (seeing Table 9) to breathing, blood circulation.

Table 7 Olopatadine hydrochloride is to laboratory animal central nervous system's influence

	Laboratory animal	Administering mode	Experimental result
	Laboratory animal	Administering mode	Experimental result	SMA	Mice	??PO	The 300mg/kg SMA reduces
The harmony motion	Mice	??PO	There is not influence	SMA	Mice	??PO	The 300mg/kg SMA reduces
The harmony motion	Mice	??PO	There is not influence	Anesthetic action	Mice	??PO	There is not influence
The effect of spasm spasmolytic	Mice	??PO	There is not influence	Anesthetic action	Mice	??PO	There is not influence
The effect of spasm spasmolytic	Mice	??PO	There is not influence	The pain sensation	Mice	??PO	There is not influence
Body temperature	Rat	??PO	300mg/kg group degree of taking a favourable turn body temperature descends	The pain sensation	Mice	??PO	There is not influence
Body temperature	Rat	??PO		Electroencephalogram	Rabbit	??i.v	There is not influence
Awake reaction	Rabbit	??i.v	There is not influence	Electroencephalogram	Rabbit	??i.v	There is not influence
Awake reaction	Rabbit	??i.v	There is not influence	Spinal reflex	Cat	??i.v	There is not influence
The eyelid reflection	Mice	??PO	There is not influence	Spinal reflex	Cat	??i.v	There is not influence
The eyelid reflection	Mice	??PO	There is not influence	The physostigmine lethal response	Mice	??PO	1 of 300mg/kg group survival
Pupillary reaction	Mice	??PO	100mg/kg, the 300mg/kg group is slight to be enlarged	The physostigmine lethal response	Mice	??PO	1 of 300mg/kg group survival
Pupillary reaction	Mice	??PO	100mg/kg, the 300mg/kg group is slight to be enlarged	The instant embrane reflection	Cat	??PO	There is not influence

Table 8 Olopatadine hydrochloride is to the influence of laboratory animal skeletal muscle-smooth muscle

Table 9 Olopatadine hydrochloride is to the influence of breathing, blood circulation

	Laboratory animal	Administering mode	Experimental result
	Laboratory animal	Administering mode	Experimental result	Breathe blood pressure, pulse, blood flow, electrocardiogram (anesthesia)	Dog	??i.v	Breathe during 5mg/kg, pulse increases, and mean blood pressure slightly descends, and electrocardiogram is not had influence
Electrocardiogram, heart rate, blood pressure (non-narcotic)	Dog	??PO	QTc prolongs during 100mg/kg, and heart rate increases		Dog	??i.v
	Dog	??PO	QTc prolongs during 100mg/kg, and heart rate increases	Femoral artery blood flow	Dog	??i.v	0.3mg/kg reduce, 1.5mg/kg increases
The renal artery blood flow amount	Dog	??i.v	There is not influence	Femoral artery blood flow	Dog	??i.v	0.3mg/kg reduce, 1.5mg/kg increases
The renal artery blood flow amount	Dog	??i.v	There is not influence	Blood pressure response	Dog	??i.v	There is not influence
The defeated charcoal experiment of intestinal	Mice	??PO	There is not influence	Blood pressure response	Dog	??i.v	There is not influence
The defeated charcoal experiment of intestinal	Mice	??PO	There is not influence	Salivation	Mice	??PO	Suppress during 300mg/kg
The urine amount	Mice	??PO	The urine amount has the tendency of increasing during 30mg/kg	Salivation	Mice	??PO	Suppress during 300mg/kg
The urine amount	Mice	??PO		Electrolyte	Mice	??PO	Row's potassium amount increases during 300mg/kg
Blood coagulation	Rabbit	??In?vitro	There is not influence	Electrolyte	Mice	??PO	Row's potassium amount increases during 300mg/kg
Blood coagulation	Rabbit	??In?vitro	There is not influence	Hemolytic	Human blood	??In?vitro	??10 ⁴The above haemolysis of g/ml

Experimental example 4 toxicological experiments

The studies on acute toxicity result of single-dose: the LD50 of mice oral administration: male is 1150mg/kg, and female is 1830mg/kg.The LD50 of rat oral administration: male is 3000-5000mg/kg, and female is 3870mg/kg; The LD50 of quiet notes administration: male is 127.5mg/kg, and female is 144.1mg/kg.The LD50 of dog oral administration: male＞5000mg/kg, the LD50 of quiet notes administration: male is 300mg/kg.

The long term toxicity test result in 52 weeks of administration: the non-toxic of the long-term oral this product of rat is 10mg/kg.The non-toxic of the long-term oral this product of dog mouth is 5mg/kg.

Ames test, the test of Chinese hamster cultured cell chromosome, Mus micronucleus test, the result all is shown as feminine gender.

In genotoxicity research, reach the gestation initial stage before the gestation, more than the rat dosage 50mg/kg mydriasis appears, degradation under the testis; Abnormal breathing appears in the 400mg/kg group, weight increase is descended by inhibition, food ration minimizing, pregnancy rate, and corpus luteum number, implantation number, implantation rate reduce low; The mating rate no abnormality seen, tire Mus no abnormality seen.The period of organogenesis dosage does not see that until 600mg/kg the tire Mus is unusual and lopsided.When perinatal stage and age of sucking, dosage 200mg/kg was above, the parent food ration reduced, and 600mg/kg group weight increase suppresses.The following dosage of filial mice: 4mg/kg weight increase occurs and suppresses.Do not see that secondary generation reproductive performance is unusual.

In this product 103 all carcinogenic toxicity researchs, each dosage group does not see that pathological changes increases.

Following embodiment all can realize the effect of above-mentioned experimental example.

The specific embodiment

Embodiment 1: the Olopatadine hydrochloride sheet

Olopatadine hydrochloride 2g

Lactose 145g

Microcrystalline Cellulose 30g

2% hydroxypropyl methylcellulose 48g

Magnesium stearate 1.8g

Above raw material is made the Olopatadine hydrochloride sheet according to common process.

Embodiment 2: the Olopatadine hydrochloride sheet

Olopatadine hydrochloride 9g

Lactose 55g

Microcrystalline Cellulose 70g

2% hydroxypropyl methylcellulose 33g

Magnesium stearate 0.3g

Embodiment 3: the Olopatadine hydrochloride sheet

Olopatadine hydrochloride 5g

Lactose 90g

Microcrystalline Cellulose 45g

2% hydroxypropyl methylcellulose 40g

Magnesium stearate 1.5g

Embodiment 4: the Olopatadine hydrochloride sheet

Olopatadine hydrochloride 2g

Lactose 145g

Microcrystalline Cellulose 30g

2% hydroxypropyl methylcellulose 50g

Magnesium stearate 1.8g

With Olopatadine hydrochloride, lactose, microcrystalline Cellulose, cross 120 mesh sieves respectively, standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the Olopatadine hydrochloride and lactose mix homogeneously of recipe quantity, again with microcrystalline Cellulose mix homogeneously in the efficient wet mixer-granulator, the hydroxypropyl methylcellulose solution system soft material with above-mentioned 2%, high speed shear system wet granular; Wet granular is at airpillow-dry below 65 ℃; Behind the granulate, add the magnesium stearate mix homogeneously; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

Embodiment 5: the Olopatadine hydrochloride sheet

Olopatadine hydrochloride 9g

Lactose 55g

Microcrystalline Cellulose 70g

2% hydroxypropyl methylcellulose 30g

Magnesium stearate 0.3g

With Olopatadine hydrochloride, lactose, microcrystalline Cellulose, cross 200 mesh sieves respectively, standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the Olopatadine hydrochloride and lactose mix homogeneously of recipe quantity, again with microcrystalline Cellulose mix homogeneously in the efficient wet mixer-granulator, the hydroxypropyl methylcellulose solution system soft material with above-mentioned 2%, high speed shear system wet granular; The wet granular airpillow-dry; Behind the granulate, add the magnesium stearate mix homogeneously; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

Embodiment 6: the Olopatadine hydrochloride sheet

Olopatadine hydrochloride 5g

Lactose 90g

Microcrystalline Cellulose 45g

2% hydroxypropyl methylcellulose 40g

Magnesium stearate 1.5g

With Olopatadine hydrochloride, lactose, microcrystalline Cellulose, cross 100 mesh sieves respectively, standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the Olopatadine hydrochloride and lactose mix homogeneously of recipe quantity, again with microcrystalline Cellulose mix homogeneously in the efficient wet mixer-granulator, the hydroxypropyl methylcellulose solution system soft material with above-mentioned 2%, high speed shear system wet granular; Wet granular is at airpillow-dry below 65 ℃; Behind the granulate, add the magnesium stearate mix homogeneously; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

Embodiment 7: discrimination method

Get the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 1 preparation that is equivalent to Olopatadine hydrochloride 2mg, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 298nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of the Olopatadine hydrochloride sheet of the present invention of embodiment 1 preparation is muriatic identification.

Embodiment 8: discrimination method

Get the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 2 preparation that is equivalent to Olopatadine hydrochloride 9mg, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 298nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of the Olopatadine hydrochloride sheet of the present invention of embodiment 2 preparations is muriatic identification.

Embodiment 9: discrimination method

Get the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 3 preparation that is equivalent to Olopatadine hydrochloride 5mg, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 298nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of the Olopatadine hydrochloride sheet of the present invention of embodiment 3 preparations is muriatic identification.

Embodiment 10: the determination of related substances method

Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 25: 75 ratios: 15mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention of embodiment 1 preparation that is equivalent to hydrochloric olopatadine 9mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%.

Embodiment 11: content assaying method

High effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 30: 70 ratios: 15mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of the Olopatadine hydrochloride sheets of the present invention of embodiment 2 preparation, accurate claim fixed, porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 2 preparations that are equivalent to Olopatadine hydrochloride 9mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Embodiment 12: assay method

The determination of related substances method is: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 25: 75 ratios: 15mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention of embodiment 3 preparations that are equivalent to hydrochloric olopatadine 9mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method is: high effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 30: 70 ratios: 15mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of the Olopatadine hydrochloride sheets of the present invention of embodiment 3 preparation, accurate claim fixed, porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 3 preparations that are equivalent to Olopatadine hydrochloride 9mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Embodiment 13: the determination of related substances method

Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 55: 45 ratios: 25mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention of embodiment 4 preparations that are equivalent to hydrochloric olopatadine 2mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%.

Embodiment 14: content assaying method

High effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 40: 60 ratios: 25mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of the Olopatadine hydrochloride sheets of the present invention of embodiment 5 preparation, accurate claim fixed, porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 5 preparations that are equivalent to Olopatadine hydrochloride 2mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Embodiment 15: assay method

The determination of related substances method is: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 55: 45 ratios: 25mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention of embodiment 6 preparations that are equivalent to hydrochloric olopatadine 2mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method is: high effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 40: 60 ratios: 25mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of the Olopatadine hydrochloride sheets of the present invention of embodiment 6 preparation, accurate claim fixed, porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 6 preparations that are equivalent to Olopatadine hydrochloride 2mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Embodiment 16: detection method

Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 37: 63 ratios: 20mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention of embodiment 3 preparations that are equivalent to hydrochloric olopatadine 5mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Embodiment 17: detection method

High effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 35: 65 ratios: 20mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of the Olopatadine hydrochloride sheets of the present invention of embodiment 3 preparation, accurate claim fixed, porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 3 preparations that are equivalent to Olopatadine hydrochloride 5mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Embodiment 18: assay method

The determination of related substances method is: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 37: 63 ratios: 20mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention of embodiment 6 preparations that are equivalent to hydrochloric olopatadine 5mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method is: high effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 35: 65 ratios: 20mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of the Olopatadine hydrochloride sheets of the present invention of embodiment 6 preparation, accurate claim fixed, porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 6 preparations that are equivalent to Olopatadine hydrochloride 5mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Embodiment 19: detection method

Discrimination method is: get the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 2 preparation that is equivalent to Olopatadine hydrochloride 2mg, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 298nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of the Olopatadine hydrochloride sheet of the present invention of embodiment 2 preparations is muriatic identification;

The determination of related substances method is: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 25: 75 ratios: 15mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention of embodiment 2 preparations that are equivalent to hydrochloric olopatadine 9mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method is: high effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 30: 70 ratios: 15mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of the Olopatadine hydrochloride sheets of the present invention of embodiment 2 preparation, accurate claim fixed, porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 2 preparations that are equivalent to Olopatadine hydrochloride 9mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Embodiment 20: detection method

Discrimination method is: get the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 4 preparation that is equivalent to Olopatadine hydrochloride 9mg, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 298nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of the Olopatadine hydrochloride sheet of the present invention of embodiment 4 preparations is muriatic identification;

The determination of related substances method is: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 55: 45 ratios: 25mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention of embodiment 4 preparations that are equivalent to hydrochloric olopatadine 2mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

Content assaying method is: high effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 40: 60 ratios: 25mmol/L potassium dihydrogen phosphate (contain 0.4% sodium heptanesulfonate, the phosphoric acid adjust pH is 3.0) is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: get 20 of the Olopatadine hydrochloride sheets of the present invention of embodiment 4 preparation, accurate claim fixed, porphyrize, precision takes by weighing the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 4 preparations that are equivalent to Olopatadine hydrochloride 2mg, puts in the 50ml measuring bottle, adds the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shakes up, and filters with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

Embodiment 21: detection method

Discrimination method is: get the Olopatadine hydrochloride sheet fine powder of the present invention of embodiment 6 preparation that is equivalent to Olopatadine hydrochloride 5mg, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 298nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of the Olopatadine hydrochloride sheet of the present invention of embodiment 6 preparations is muriatic identification;

Claims

1, a kind of Olopatadine hydrochloride sheet is characterized in that this tablet is to be made by following raw material:

Olopatadine hydrochloride 1-10 weight portion

Lactose 50-150 weight portion

Microcrystalline Cellulose 25-75 weight portion

2% hydroxypropyl methylcellulose 30-50 weight portion

Magnesium stearate 0.15-2.2 weight portion.

2, Olopatadine hydrochloride sheet as claimed in claim 1 is characterized in that this tablet is to be made by following raw material:

Olopatadine hydrochloride 2 weight portions

Lactose 145 weight portions

Microcrystalline Cellulose 30 weight portions

2% hydroxypropyl methylcellulose, 48 weight portions

Magnesium stearate 1.8 weight portions.

3, Olopatadine hydrochloride sheet as claimed in claim 1 is characterized in that this tablet is to be made by following raw material:

Olopatadine hydrochloride 9 weight portions

Lactose 55 weight portions

Microcrystalline Cellulose 70 weight portions

2% hydroxypropyl methylcellulose, 33 weight portions

Magnesium stearate 0.3 weight portion.

4, Olopatadine hydrochloride sheet as claimed in claim 1 is characterized in that this tablet is to be made by following raw material:

Olopatadine hydrochloride 5 weight portions

Lactose 90 weight portions

Microcrystalline Cellulose 45 weight portions

2% hydroxypropyl methylcellulose, 40 weight portions

Magnesium stearate 1.5 weight portions.

5,, it is characterized in that this method is as the preparation method of the arbitrary described a kind of Olopatadine hydrochloride sheet of claim 1-4: with Olopatadine hydrochloride, lactose, microcrystalline Cellulose, sieve respectively, standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the lactose mix homogeneously of the Olopatadine hydrochloride of recipe quantity and recipe quantity,,, make wet granular with above-mentioned 2% hydroxypropyl methylcellulose solution system soft material of recipe quantity again with the microcrystalline Cellulose mix homogeneously of recipe quantity; The wet granular airpillow-dry; Behind the granulate, add the magnesium stearate mix homogeneously of recipe quantity; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

6, the preparation method of Olopatadine hydrochloride sheet as claimed in claim 5 is characterized in that this method is: with Olopatadine hydrochloride, lactose, microcrystalline Cellulose, cross 100 mesh sieves respectively, and standby; The hydroxypropyl methylcellulose solution of preparation 2%, standby; After getting the Olopatadine hydrochloride and lactose mix homogeneously of recipe quantity, again with microcrystalline Cellulose mix homogeneously in the efficient wet mixer-granulator, the hydroxypropyl methylcellulose solution system soft material with above-mentioned 2%, high speed shear system wet granular; Wet granular is at airpillow-dry below 65 ℃; Behind the granulate, add the magnesium stearate mix homogeneously; Measure dried granule drug content, determine that sheet is heavy, tabletting; Detect packing.

7,, it is characterized in that this method comprises following discriminating and/or determination of related substances and/or content assaying method as the detection method of the arbitrary described Olopatadine hydrochloride sheet of claim 1-4:

The A discrimination method is: get the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 1-15mg, put in the 50-150ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 293-303nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of Olopatadine hydrochloride sheet of the present invention is muriatic identification;

B determination of related substances method is: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 15-25cm; 20-60: the acetonitrile of 40-80 ratio: the 10-30mmol/L potassium dihydrogen phosphate is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention that is equivalent to hydrochloric olopatadine 1-10mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 150-250 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 0.5-1.5ml, puts in the measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 1-3 of every 1ml μ g, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 150-250 μ g/ml is dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 0.5-1.5ml of isomer solution, puts in the measuring bottle, is made into mixed solution, sample introduction 10-30 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 10-30 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

The C content assaying method is: high effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; 25-45: the acetonitrile of 55-75 ratio: the 10-30mmol/L potassium dihydrogen phosphate is a mobile phase, and the detection wavelength is 220-240nm, and column temperature: 15-35 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: take by weighing the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 1-10mg, put in the measuring bottle, add the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shake up, filter with filter membrane, discard filtrate just, measure subsequent filtrate 4.0-6.0ml and put in the measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 100-110 ℃ of Olopatadine hydrochloride reference substance that is dried to constant weight, dilute the solution of making hydrochloric olopatadine 10-30 μ g among every 1ml with mobile phase, precision is measured 10-30 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.

8, the detection method of Olopatadine hydrochloride sheet as claimed in claim 7 is characterized in that this method is:

The A discrimination method: get the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 5mg, put in the 100ml measuring bottle, be dissolved in water and be diluted to scale, filter, according to spectrophotometry, there is absorption maximum at the place at the 298nm wavelength; In the chromatogram under the assay item, the retention time of the main peak of need testing solution should be consistent with the retention time of reference substance; The aqueous solution of Olopatadine hydrochloride sheet of the present invention is muriatic identification;

B determination of related substances: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, column length 25cm; The acetonitrile of 37: 63 ratios: the 20mmol/L potassium dihydrogen phosphate is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃; Number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; The Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Get the powder of the Olopatadine hydrochloride sheet porphyrize of the present invention that is equivalent to hydrochloric olopatadine 5mg, the accurate title, decide, and adds the solution that mobile phase is mixed with hydrochloric olopatadine 200 μ g among the 1ml, filters, and gets subsequent filtrate as need testing solution; Precision is measured above-mentioned need testing solution 1.0ml, puts in the 100ml measuring bottle, adds mobile phase to scale, is made into the solution of the hydrochloric olopatadine 2 μ g of every 1ml, in contrast solution; Other takes by weighing (E)-configuration reference substance, adds the isomer solution that 200 μ g/ml are dissolved and be diluted to mobile phase; Precision is measured need testing solution and each 1.0ml of isomer solution, puts in the 10ml measuring bottle, is made into mixed solution, sample introduction 20 μ l, the Olopatadine hydrochloride peak with (E)-separating degree at configuration peak should be greater than 2.0; Precision is measured contrast solution 20 μ l and is injected chromatograph of liquid, regulates instrumental sensitivity, and making the main peak peak height is 15～25% of full scale; Precision is measured above-mentioned need testing solution and isomer solution sample introduction again, the record chromatogram if any impurity peaks, is measured the summation of each impurity peak area to 5 times of main constituent peak retention time in the need testing solution chromatogram, must not be greater than 1.5 times of the main peak peak area of contrast solution, promptly 1.5%; Wherein, if any chromatographic peak, its peak area must not be greater than half of contrast solution main peak peak area at (E)-configuration peak position place, and promptly 0.5%;

The C content assaying method is: high effective liquid chromatography for measuring: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; The acetonitrile of 35: 65 ratios: the 20mmol/L potassium dihydrogen phosphate is a mobile phase, and the detection wavelength is 230nm, column temperature: 25 ℃, number of theoretical plate calculates by the Olopatadine hydrochloride peak should be not less than 3000; Algoscopy: take by weighing the Olopatadine hydrochloride sheet fine powder of the present invention that is equivalent to Olopatadine hydrochloride 5mg, put in the 50ml measuring bottle, add the mobile phase dissolving, jolting, reuse mobile phase is diluted to scale, shake up, filter with filter membrane, discard filtrate just, measure subsequent filtrate 5.0ml and put in the 25ml measuring bottle, be diluted to scale with mobile phase, as need testing solution; It is an amount of that other is taken at 105 ℃ of Olopatadine hydrochloride reference substances that are dried to constant weight, dilute the solution of making hydrochloric olopatadine 20 μ g among every 1ml with mobile phase, precision is measured 20 μ l injection high performance liquid chromatograph, record peak area respectively, calculate percentage composition by external standard method, promptly.