CN110433161A - A kind of tablet and preparation method thereof for treating neurodegenerative disease - Google Patents
A kind of tablet and preparation method thereof for treating neurodegenerative disease Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2004—Excipients; Inactive ingredients
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The present invention relates to a kind of tablet and preparation method thereof, the conventional tablet contains nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride or nitric acid 2- (4- methylthiazol -5- base) ethyl ester maleate, filler, disintegrating agent, lubricant.Main ingredient in Tablets is that nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride or nitric acid 2- (4- methylthiazol -5- base) ethyl ester maleate, dosage account for 0.1%-50%.The present invention is excellent using nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride of direct powder compression preparation or the dissolution of nitric acid 2- (4- methylthiazol -5- base) ethyl ester maleate tablet, stability is good, and there is preferable bioavilability, production technology simplicity is easily-controllable, is suitble to produce in enormous quantities.The present invention is for preventing and/or treating cardiovascular and cerebrovascular disease and neurodegenerative disease.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride
Or nitric acid 2- (4- methylthiazol -5- base) ethyl ester maleate tablet and preparation method thereof.
Background technique
Known compound nitric acid 2- (4- methylthiazol -5- base) ethyl ester:
Its mechanism of action includes: the expression of inhibition inflammatory factor, especially TNF-α；Collaboration increase for example nmda receptor and
Activation of the amino acid neurals such as γ-aminobutyric acid A type (GABAA) receptor transmitting element to receptor；Increase the solubility of brain
Uridine acyl group cyclase (GCase)；Its itrate group is metabolized releasable NO in vivo, plays vasorelaxation action, increase the heart,
Cerebral blood flow (CBF) reduces blood pressure, and protects brain tissue.Therefore, this compound is suitable for the heart, brain and neuroprotection, realizes cognition enhancing.
Neurodegenerative disease is a kind of central nervous system based on progressive cognitive disorder and memory damage
Disease.Clinical manifestation is mainly memory (especially close memory) decline, cognitive function low, thought slowness and spatial orientation
Obstacle.Neurodegenerative disease be mainly shown as but be not limited to cranial vascular disease (such as acute and chronic cerebral apoplexy and vascular dementia,
Vascular dementia, VD), Alzheimer disease (Alzheimer ' s disease, AD) and both mixed type disease,
And diabetes mellitus encephalopathy.AD is a kind of central nervous system degenerative disease highly relevant with the age.Most feature is two big
Pathological change be fibre matting in the outer 4 amyloid deposition of brain tissue cell and neuron (neurofibrillary tangles,
NFT).The crowd that the disease mostly occurs at 60 years old or more.The illness rate of China over-65s old man is 4% or so.Cranial vascular disease,
It is the disease for causing the central nervous system sex dysfunction based on brain damage due to cerebrovascular trauma and generating, long term brain supplies
Blood deficiency is to lead to the major reason of vascular dementia.In China, diabetes morbidity is more than 10%, meta-analysis knot
Fruit shows that the disease incidence of diabetic's dementia is obviously increased compared with normal person, and especially the incidence probability of vascular dementia can increase
1 times or more.
Central nervous degenerative disease has the work that improves significantly to the existing pharmacodynamic study of this compound as the result is shown
With: its in acute cerebral ischemia and its more after treatment in, intraluminal middle cerebral artery occlusion in rats block can be obviously improved in (tMCAO) model it is big
The neurological deficit score of mouse reduces cerebral infarction volume, increases cerebral blood flow (CBF) and rear process model learning and memory in rats obstacle；In
In chronic cerebral ischemia (Bilateral Cervical, which always ligatures, causes vascular dementia) model, this compound, which can significantly improve rat model study, to be recognized
Know ability, inhibits the expression of inflammatory factor in brain tissue, the especially expression of TNF-α；In addition, compound is also effectively improved old age
The learning memory disorder of dull-witted transgenic models mouse (APP/PS1).The compound protects brain tissue in addition to protection, promotes cognition
Outside improving, also expansible peripheral blood vessel reduces blood pressure, effective protection systema cariovasculare functional.
China is going into the aging epoch, and dementia patients increase year by year.Nervous centralis degenerative disease patient not only this
People's pain, and very big burden is caused to family and society, but currently without preferable therapeutic agent, therefore find effective medicine
Object is to delay, the occurrence and development of control axis neurodegenerative disease are particularly important.
U.S. Patent No. 6,310,052.It has been found that nitric acid 2- (4- methylthiazol -5- base) ethyl ester new solid forms can be with
It is prepared as maleate form.Referring to Chinese patent 201180041035.4.The patent describes two kinds in specification part
Using hydroxypropyl methyl cellulose K100M as the sustained release preparation prescription of slow-release material, but the dosage model of slow-release material is not limited
It encloses, the ratio of hydroxypropyl methyl cellulose K100M is respectively 35.75% and 25.75% in this two kinds of prescriptions.At this patent
Side is prepared for two kinds using hydroxypropyl methyl fibre element K100M as the sustained release preparation of slow-release material, according to version Chinese Pharmacopoeia four in 2015
The first method (basket method) in portion's " dissolution rate and drug release determination method " carries out drug release determination, the results showed that two kinds of sustained release preparations
The release in vitro percentage of the last one detection time point (12 hours) is below 90%, is unsatisfactory in Chinese Pharmacopoeia making sustained release
The requirement of agent vitro release.Specific data are shown in Figure of description 7.
The patent 201510275408.4 applied describes the sustained release tablets using hydroxypropyl methyl cellulose as slow-release material,
The release in vitro percentage of the last one detection time point (12 hours) is higher than 90%, meets in Chinese Pharmacopoeia to sustained release preparation body
The requirement of outer release, but it shows that blood concentration is lower, and AUC is smaller, biology in the intracorporal pharmacokinetics test of Beagle dog
Availability is lower.
The patent 201710268587.8 applied is described with Compritol 888 ATO or Compritol 888 ATO and hydroxypropyl
The mixture of methylcellulose is the sustained release tablets of main slow-release material, and the release in vitro of final optimization pass prescription is gentle and complete, most
The release in vitro percentage of the latter detection time point (12 hours) is higher than 90%, meets external to sustained release preparation in Chinese Pharmacopoeia
The requirement of release.And shown in the intracorporal pharmacokinetics test of Beagle dog, with the sustained release in patent 201510275408.4
Piece is compared, and blood concentration increases, and AUC increases, and bioavilability improves, and has apparent slow release effect.But it is steady in preparation
In the accelerated test of qualitative test, it is found that its is unstable, content decline is serious, and impurity increases significantly, is unable to meet production demand.
Tablet prepared by the present invention is ordinary preparation, and final optimization pass prescription disintegration time limited and dissolution rate meet Chinese Pharmacopoeia
It is required that showing in the intracorporal pharmacokinetics test of Beagle dog, blood concentration is high, and bioavilability is good.It is tried in preparation stability
It is shown in the accelerated test tested, content meets the requirements within 6 months, and dissolution rate meets the requirements.
Tablet prepared by the present invention improves the stability of drug, and simple production process is suitble to industrialized production.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride or nitric acid
2- (4- methylthiazol -5- base) ethyl ester maleate tablet and preparation method thereof.
To solve this technical problem, it adopts the following technical scheme that
A kind of tablet, which is characterized in that including main ingredient, filler, disintegrating agent, lubricant, wherein main ingredient is following formula chemical combination
One of object
Main ingredient dosage accounts for the 0.1%-50% of tablet, preferably 5%~50%, and further preferred 15%~50%.
The filler is selected from one or more of following auxiliary material combination: lactose, mannitol, pregelatinized starch, part
Pregelatinized corn starch, the filler loading account for 5%-80%, preferably 5%~70%, and further preferred 20%~70%.
When the filler is the mixture of lactose and mannitol, lactose dosage accounts for the 1%~70% of slice weight, preferably
5%~50%, further preferred 15%~40%, mannitol dosage accounts for the 0.1~70% of slice weight, preferably 15%~70%, into
One step preferably 15%~50%.
When the filler is the mixture of pregelatinized starch and mannitol, pregelatinized starch dosage accounts for the 1% of slice weight
~70%, preferably 5%~50%, further preferred 15%~40%, mannitol dosage accounts for the 0.1~70% of slice weight, preferably
15%~70%, further preferred 15%~50%.
When the filler is the mixture of part pregelatinized corn starch and mannitol, part pregelatinized corn starch
Dosage accounts for the 1%~70% of slice weight, preferably 5%~50%, and further preferred 15%~40%, mannitol dosage accounts for slice weight
0.1~70%, preferably 15%~70%, further preferred 15%~50%.
The disintegrating agent is selected from the combination of following auxiliary material one or more: dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl
Base cellulose, croscarmellose sodium, the disintegrating agent dosage account for 0.1%-40%, preferably 5%~40%, further excellent
Select 5%~30%.
The lubricant is selected from the combination of following auxiliary material one or more: stearic acid, calcium stearate, magnesium stearate, tristearin
Sour zinc, talcum powder, glycerin monostearate, glyceryl palmitostearate, Stepanol MG, polyethylene glycol, stearyl are rich
Horse acid sodium, the lubricant quantity account for 0.1%-5%, preferably 0.5%~5%, and further preferred 0.5%~3%.
A kind of nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride or nitric acid 2- (4- methylthiazol -5- base) ethyl ester horse
Carry out the preparation method of hydrochlorate tablet: using the technique of direct powder compression, all auxiliary materials being sieved with 100 mesh sieve；Main ingredient is taken to be ground to
Powdered, general milling time is 1-30 minutes；Main ingredient, filler, the disintegrating agent for taking recipe quantity ground mix, add
Enter lubricant, mix, tabletting to obtain the final product.
Grinding steps are to improve the hardness of powder compressibility and tablet to crush medicine crystal in the present invention.Grinding
Time can be ground to until drug in until powdered determines according to actual conditions.For energy-saving consumption-reducing, when the present invention will be ground
Between be limited to 1-30 minutes.
A kind of nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride or nitric acid 2- (4- methylthiazol -5- base) ethyl ester horse
Carry out the application of hydrochlorate tablet: prevention or/and treatment cardiovascular and cerebrovascular disease and neurodegenerative disease.
The beneficial technical effect of the invention are as follows: it has been found that nitric acid 2- (4- methylthiazol -5- base) ethyl ester new solid forms can
To be prepared as maleate form.Referring to Chinese patent 201180041035.4.The patent describes two in specification part
Kind limits the dosage of slow-release material using hydroxypropyl methyl cellulose K100M as the sustained release preparation prescription of slow-release material
Range, the ratio of hydroxypropyl methyl cellulose K100M is respectively 35.75% and 25.75% in this two kinds of prescriptions.According to this patent
Prescription is prepared for two kinds using hydroxypropyl methyl fibre element K100M as the sustained release preparation of slow-release material, according to version Chinese Pharmacopoeia in 2015
The first method (basket method) in four " dissolution rate and drug release determination method " carries out drug release determination, the results showed that two kinds of sustained release preparations
The release in vitro percentage of the last one detection time point (12 hours) be below 90%, be unsatisfactory in Chinese Pharmacopoeia to sustained release
The requirement of agent in vitro release.Specific data are shown in Figure of description 7.
The patent 201510275408.4 applied describes the sustained release tablets using hydroxypropyl methyl cellulose as slow-release material,
The release in vitro percentage of the last one detection time point (12 hours) is higher than 90%, meets in Chinese Pharmacopoeia to sustained release preparation body
The requirement of outer release, but it shows that blood concentration is lower, and AUC is smaller, biology in the intracorporal pharmacokinetics test of Beagle dog
Availability is lower.
The patent 201710268587.8 applied is described with Compritol 888 ATO or Compritol 888 ATO and hydroxypropyl
The mixture of methylcellulose is the sustained release tablets of main slow-release material, and the release in vitro of final optimization pass prescription is gentle and complete, most
The release in vitro percentage of the latter detection time point (12 hours) is higher than 90%, meets external to sustained release preparation in Chinese Pharmacopoeia
The requirement of release.And shown in the intracorporal pharmacokinetics test of Beagle dog, with the sustained release in patent 201510275408.4
Piece is compared, and blood concentration increases, and AUC increases, and bioavilability improves, and has apparent slow release effect.But it is steady in preparation
In the accelerated test of qualitative test, it is found that its is unstable, content decline is serious, and impurity increases significantly, is unable to meet production demand.
Tablet prepared by the present invention is ordinary preparation, and final optimization pass prescription disintegration time limited and dissolution rate meet Chinese Pharmacopoeia
It is required that showing in the intracorporal pharmacokinetics test of Beagle dog, blood concentration is high, and bioavilability is good.It is tried in preparation stability
It is shown in the accelerated test tested, content meets the requirements within 6 months, and dissolution rate meets the requirements.
Detailed description of the invention
Fig. 1 illustrates the chromatogram of 1 high performance liquid chromatography assay of embodiment.
Fig. 2 illustrates the In Vitro Dissolution curve of 1,2,3 tablet of embodiment.
Fig. 3 illustrates the In Vitro Dissolution curve of 4,5,6 tablet of embodiment.
Fig. 4 illustrates the In Vitro Dissolution curve of 7,8,9 tablet of embodiment.
Fig. 5 illustrates the In Vitro Dissolution curve of 10,11,12 tablet of embodiment.
Fig. 6 illustrates the In Vitro Dissolution curve of embodiment 13,14 tablets.
Fig. 7 illustrates nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride piece of embodiment 1, embodiment 2, embodiment 3
Drug solubility figure in blood plasma after agent administration.
Fig. 8 is illustrated after nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride tablet for administration of embodiment 10 in blood plasma
Drug solubility figure.
Fig. 9 illustrates comparative example 1, the administration of nitric acid 2- (4- methylthiazol -5- base) the carbethoxy hydrochloride sustained release tablets of comparative example 2
Drug solubility figure in blood plasma afterwards.
Specific embodiment
Below with reference to embodiment, the present invention is described in further detail.Embodiment provides by way of example, not
It is construed as limiting the invention.
Embodiment 1: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 886.00g lactose, 1400.00g mannitol mix, and it is hard that 14.00g is added
Fatty acid magnesium mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets.According to 2015
The second method (paddle method) in version Chinese Pharmacopoeia four " dissolution rate and drug release determination method " carries out dissolution determination.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
High performance liquid chromatography assay
Chromatographic condition: chromatographic column: AlltimaTM5 μ column of C18,250 × 4.6mm；Column temperature: 40 DEG C；Detection wavelength:
247nm；Flow velocity: 0.8ml/min；Sample volume: 20 μ l；Mobile phase: 0.1% formic acid solution: methanol.Gradient elution.
20,1 sample of Example, accurately weighed, sufficiently finely ground, precision weighs appropriate (being approximately equivalent to bulk pharmaceutical chemicals 10mg),
It sets in 100ml volumetric flask, adds water about 80ml, ultrasonic 10 minutes and shaking frequently make it dissolve, be cooled to room temperature.It is diluted with water to
Scale shakes up, and primary filtrate 4-5 drop is filtered and discarded with 0.45 μm of filter membrane, takes subsequent filtrate as test solution, sample introduction, record
Chromatogram；Reference substance separately is taken, it is accurately weighed, add water quantitatively to dilute the solution being made in 1ml containing 0.1mg, is measured in the same method.By external standard
Method with calculated by peak area to get.
By 1 chromatogram of attached drawing it is found that main peak retention time is 22.080min, theoretical cam curve 143529, separating degree is
5.14, symmetrical factor 0.81.Wherein single largest impurity retention time is 23.251min, is 4- methyl 5- (2- chloroethyl)
Thiazole；The impurity that retention time is 8.515min is 4- methyl 5- (2- ethoxy) thiazole；Retention time is the miscellaneous of 19.557min
Matter is acetic acid 2- (4- methylthiazol -5- base) ethyl ester.
The related substance-measuring of high performance liquid chromatography
Chromatographic condition: chromatographic column: AlltimaTM5 μ column of C18,250 × 4.6mm；Column temperature: 40 DEG C；Detection wavelength:
247nm；Flow velocity: 0.8ml/min；Sample volume: 20 μ l；Mobile phase: 0.1% formic acid solution: methanol.Gradient elution.
1 sample of Example is appropriate, accurately weighed, adds water, is made containing about the solution of bulk pharmaceutical chemicals 1mg in every 1ml, as confession
Test sample solution；Test solution is diluted 100 times, is made containing about the solution of 10 μ g of bulk pharmaceutical chemicals in every 1ml, it is molten as reference substance
Liquid.Reference substance solution sample introduction adjusts detection sensitivity, and making the peak height of single largest impurity chromatographic peak is about the 10% of full scale,
Again by test solution and reference substance solution sample introduction, chromatogram is recorded to 4 times of principal component peak retention time.In test solution
Single largest impurity presses calculated by peak area, is not greater than reference substance solution main peak area (1%).
The test of Beagle dog Internal pharmacokinetics
Beagle dog 6 are taken, fasting 12 hours before being administered.Nitric acid 2- (the 4- methylthiazol-of the oral embodiment of the present invention 1
5- yl) carbethoxy hydrochloride sustained release tablets, dosage is 5mg/kg, and respectively after administration 1,3,5,10,20,30,60,90,120,180
With 240 minutes, acquisition whole blood 3ml, centrifugal separation plasma at forelimb cephalic vein were set -70 DEG C of refrigerators and are saved.Take 100 μ L blood plasma
10 μ L of blank methanol solution is added in sample, and internal standard (5 μ g/mL clormethiazole methanol solution) 20 μ L are added, and 500 μ L methanol are added,
14800rpm is centrifuged 5 minutes, using nitric acid 2- (4- methylthiazol -5- base) second in liquid-mass chromatography method measurement different time blood plasma
The concentration of ester hydrochloride draws blood concentration-time curve.
Pharmacokinetic data available is as follows:
Accelerated test
The sample for selecting embodiment 1, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 1 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 2: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 886.00g pregelatinized starch, 1400.00g mannitol mix, and are added
14.00g magnesium stearate mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets.Root
Dissolution determination is carried out according to the second method (paddle method) in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method ".
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
The test of Beagle dog Internal pharmacokinetics
Beagle dog 6 are taken, fasting 12 hours before being administered.Nitric acid 2- (the 4- methylthiazol-of the oral embodiment of the present invention 2
5- yl) carbethoxy hydrochloride sustained release tablets, dosage is 5mg/kg, and respectively after administration 1,3,5,10,20,30,60,90,120,180
With 240 minutes, acquisition whole blood 3ml, centrifugal separation plasma at forelimb cephalic vein were set -70 DEG C of refrigerators and are saved.Take 100 μ L blood plasma
10 μ L of blank methanol solution is added in sample, and internal standard (5 μ g/mL clormethiazole methanol solution) 20 μ L are added, and 500 μ L methanol are added,
14800rpm is centrifuged 5 minutes, using nitric acid 2- (4- methylthiazol -5- base) second in liquid-mass chromatography method measurement different time blood plasma
The concentration of ester hydrochloride draws blood concentration-time curve.
Pharmacokinetic data available is as follows:
| Parameter name | Unit | Data |
| t1/2z | min | 70.72 |
| Tmax | min | 17.50 |
| Cmax | ng/mL | 212.34 |
| AUC(0-t) | ng/mL*min | 5264.24 |
| AUC(0-∞) | ng/mL*min | 5470.30 |
| MRT(0-t) | min | 37.05 |
| MRT(0-∞) | min | 51.95 |
Accelerated test
The sample for selecting embodiment 2, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 2 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 3: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, the part 886.00g pregelatinized corn starch, 1400.00g mannitol mix
It is even, 14.00g magnesium stearate is added, mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride
Tablet.Dissolution rate is carried out according to the second method (paddle method) in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Measurement.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
The test of Beagle dog Internal pharmacokinetics
Beagle dog 6 are taken, fasting 12 hours before being administered.Nitric acid 2- (the 4- methylthiazol-of the oral embodiment of the present invention 3
5- yl) carbethoxy hydrochloride sustained release tablets, dosage is 5mg/kg, and respectively after administration 1,3,5,10,20,30,60,90,120,180
With 240 minutes, acquisition whole blood 3ml, centrifugal separation plasma at forelimb cephalic vein were set -70 DEG C of refrigerators and are saved.Take 100 μ L blood plasma
10 μ L of blank methanol solution is added in sample, and internal standard (5 μ g/mL clormethiazole methanol solution) 20 μ L are added, and 500 μ L methanol are added,
14800rpm is centrifuged 5 minutes, using nitric acid 2- (4- methylthiazol -5- base) second in liquid-mass chromatography method measurement different time blood plasma
The concentration of ester hydrochloride draws blood concentration-time curve.
Pharmacokinetic data available is as follows:
| Parameter name | Unit | Data |
| t1/2z | min | 44.15 |
| Tmax | min | 24.00 |
| Cmax | ng/mL | 62.31 |
| AUC(0-t) | ng/mL*min | 2327.59 |
| AUC(0-∞) | ng/mL*min | 2536.61 |
| MRT(0-t) | min | 36.86 |
| MRT(0-∞) | min | 58.98 |
Accelerated test
The sample for selecting embodiment 3, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 3 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 4: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 2006.00g lactose, 280.00g hydroxypropyl cellulose mix, and are added
14.00g magnesium stearate mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets.Root
Dissolution determination is carried out according to the second method (paddle method) in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method ".
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Accelerated test
The sample for selecting embodiment 4, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 4 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 5: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 2006.00g pregelatinized starch, 280.00g hydroxypropyl cellulose mix,
14.00g magnesium stearate is added, mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride piece
Agent.Dissolution rate survey is carried out according to the second method (paddle method) in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
It is fixed.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Accelerated test
The sample for selecting embodiment 5, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 5 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 6: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, the part 2006.00g pregelatinized corn starch, 280.00g hydroxy propyl cellulose
Element mixes, and 14.00g magnesium stearate is added, and mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt
Hydrochlorate tablet.It is carried out according to the second method (paddle method) in 2015 version Chinese Pharmacopoeia four " dissolution rate and drug release determination method " molten
Out-degree measurement.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Accelerated test
The sample for selecting embodiment 6, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 6 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 7: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 1446.00g lactose, 560.00g mannitol, 280.00g hydroxy propyl cellulose
Element mixes, and 14.00g magnesium stearate is added, and mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt
Hydrochlorate tablet.It is carried out according to the second method (paddle method) in 2015 version Chinese Pharmacopoeia four " dissolution rate and drug release determination method " molten
Out-degree measurement.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Accelerated test
The sample for selecting embodiment 7, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 7 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 8: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 1446.00g pregelatinized starch, 560.00g mannitol, 280.00g hydroxypropyl
Base cellulose mixes, and 14.00g magnesium stearate is added, and mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base)
Ethyl ester salt tablets.According to the second method (paddle method) in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Carry out dissolution determination.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Accelerated test
The sample for selecting embodiment 8, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 8 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 9: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.500.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, the part 1446.00g pregelatinized corn starch, 560.00g mannitol,
280.00g hydroxypropyl cellulose mixes, and 14.00g magnesium stearate is added, and mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- first
Base thiazole -5- base) ethyl ester salt tablets.According in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Second method (paddle method) carries out dissolution determination.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Accelerated test
The sample for selecting embodiment 9, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 9 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 10: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.250.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 443.00g lactose, 700.00g mannitol mix, and it is stearic that 7.00g is added
Sour magnesium mixes, 7 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets.According to version in 2015
The second method (paddle method) in Chinese Pharmacopoeia four " dissolution rate and drug release determination method " carries out dissolution determination.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
The test of Beagle dog Internal pharmacokinetics
Beagle dog 6 are taken, fasting 12 hours before being administered.Nitric acid 2- (the 4- methylthiazol-of the oral embodiment of the present invention 10
5- yl) carbethoxy hydrochloride sustained release tablets, dosage is 2.5mg/kg, and respectively after administration 1,3,5,10,20,30,60,90,120,
180 and 240 minutes, whole blood 3ml is acquired at forelimb cephalic vein, centrifugal separation plasma is set -70 DEG C of refrigerators and saved.Take 100 μ L blood
10 μ L of blank methanol solution is added in slurry samples, and internal standard (5 μ g/mL clormethiazole methanol solution) 20 μ L are added, and 500 μ L first are added
Alcohol, 14800rpm are centrifuged 5 minutes, using nitric acid 2- (4- methylthiazol -5- base) in liquid-mass chromatography method measurement different time blood plasma
The concentration of carbethoxy hydrochloride draws blood concentration-time curve.
Pharmacokinetic data available is as follows:
| Parameter name | Unit | Data |
| t1/2z | min | 107.94 |
| Tmax | min | 1.33 |
| Cmax | ng/mL | 38.82 |
| AUC(0-t) | ng/mL*min | 2199.28 |
| AUC(0-∞) | ng/mL*min | 4693.63 |
| MRT(0-t) | min | 48.77 |
| MRT(0-∞) | min | 155.83 |
Accelerated test
The sample for selecting embodiment 10, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tried
Test guideline " carry out accelerated test.Aluminum-plastic packaged sample set 30 ± 2 DEG C, 65 ± 5% condition of RH place, respectively at 1,2,3,
It is measured by sampling within 6 months.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement；Dissolution in vitro is according to the second method (paddle in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method "
Method), using the fresh purified water of degassing as dissolution medium, dissolution medium 900ml, revolving speed 75r/min are measured, 37 DEG C of temperature, is sampled
Time is 30min.As a result it see the table below.
The above test results show that indices become without obvious after 10 sample accelerated test condition of embodiment is placed 6 months
Change.
Embodiment 11: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.250.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 443.00g pregelatinized starch, 700.00g mannitol mix, and are added
7.00g magnesium stearate mixes, 7 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets.According to
The second method (paddle method) in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method " carries out dissolution determination.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Embodiment 12: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.250.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, the part 443.00g pregelatinized corn starch, 700.00g mannitol mix,
7.00g magnesium stearate is added, mixes, 7 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets.
Dissolution determination is carried out according to the second method (paddle method) in version Chinese Pharmacopoeia four in 2015 " dissolution rate and drug release determination method ".
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Embodiment 13: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.1000.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 386.00g lactose, 1400.00g mannitol mix, and it is hard that 14.00g is added
Fatty acid magnesium mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets.According to 2015
The second method (paddle method) in version Chinese Pharmacopoeia four " dissolution rate and drug release determination method " carries out dissolution determination.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Embodiment 14: the prescription of nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets is as follows:
Ingredient acts on dosage:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt tablets, all excipient difference
It crushes, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.1000.00g nitre is weighed respectively according to the composition in embodiment 1
Sour 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 946.00g lactose, 560.00g mannitol, 280.00g hydroxy propyl cellulose
Element mixes, and 14.00g magnesium stearate is added, and mixes, 9 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base) ethyl ester salt
Hydrochlorate tablet.It is carried out according to the second method (paddle method) in 2015 version Chinese Pharmacopoeia four " dissolution rate and drug release determination method " molten
Out-degree measurement.
External drug dissolution test
Using the fresh purified water of degassing as dissolution medium, measure dissolution medium 900ml, revolving speed 75r/min, 37 DEG C of temperature,
It is filtered in 5,10,15,30,45,60 minutes absorption 5ml solution, and 5ml dissolution medium is replenished in time, subsequent filtrate is taken to be used as examination
Product solution.Absorbance is measured at 247nm using ultraviolet spectrophotometry, calculates the every dissolution rate in different time.
Dissolution data is as follows:
Comparative example 1: according to nitric acid 2- described in Chinese patent 201710268587.8 (4- methylthiazol -5- base) ethyl ester
The tablet formulation of hydrochloride sustained release tablet recipe preparation is as follows:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride sustained release preparations, all excipient
It crushes respectively, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.499.5g is weighed respectively according to the composition in embodiment 3
Nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 120.0g Compritol 888 ATO, 300.0g hydroxypropyl methyl cellulose
K15M, 685.5g microcrystalline cellulose PH101 are mixed, with 4% povidone ethanol solution softwood, the granulation of 18 meshes, 50 DEG C of bakings
Dry, 15.0g magnesium stearate is added in 20 mesh sieves, mixes, 7 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base)
Carbethoxy hydrochloride sustained release preparation.
The test of Beagle dog Internal pharmacokinetics
Beagle dog 6 are taken, fasting 12 hours before being administered.Nitric acid 2- (the 4- methylthiazol-of oral comparative example 1 of the present invention
5- yl) carbethoxy hydrochloride sustained release tablets, dosage is 50mg, and respectively after administration 5,10,20,30,60,90,120,180,240,
360,480,600 and 720 minutes, whole blood 3ml is acquired at forelimb cephalic vein, centrifugal separation plasma is set -70 DEG C of refrigerators and saved.
100 μ L plasma samples are taken, 10 μ L of blank methanol solution is added, internal standard (5 μ g/mL clormethiazole methanol solution) 20 μ L are added, add
Enter 500 μ L methanol, 14800rpm is centrifuged 5 minutes, using nitric acid 2- (4- methyl in liquid-mass chromatography method measurement different time blood plasma
Thiazole -5- base) carbethoxy hydrochloride concentration, draw blood concentration-time curve.
Pharmacokinetic data available is as follows:
| Parameter name | Unit | Data |
| t1/2z | min | 264.85 |
| Tmax | min | 30 |
| Cmax | ng/mL | 55.56 |
| AUC(0-t) | ng/mL*min | 12208.98 |
| AUC(0-∞) | ng/mL*min | 14922.64 |
| MRT(0-t) | min | 265.97 |
| MRT(0-∞) | min | 433.94 |
Accelerated test
The sample for selecting comparative example 1, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement.As a result it see the table below.
The above test results show that content decline is significant, related after 1 sample accelerated test condition of comparative example is placed 6 months
Substance dramatically increases.
Comparative example 2: according to nitric acid 2- described in Chinese patent 201710268587.8 (4- methylthiazol -5- base) ethyl ester
The tablet formulation of hydrochloride sustained release tablet recipe preparation is as follows:
For preparing 10000 nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride sustained release preparations, all excipient
It crushes respectively, crosses 100 mesh nylon mesh.Main ingredient is taken to be ground to powdery.499.5g is weighed respectively according to the composition in embodiment 6
Nitric acid 2- (4- methylthiazol -5- base) carbethoxy hydrochloride, 300.0g Compritol 888 ATO, 450.0g hydroxypropyl methyl cellulose
K15M, 235.5g microcrystalline cellulose PH101 are mixed, with 4% povidone ethanol solution softwood, the granulation of 18 meshes, 50 DEG C of bakings
Dry, 15.0g magnesium stearate is added in 20 mesh sieves, mixes, 7 formed punch tabletting of φ.Up to nitric acid 2- (4- methylthiazol -5- base)
Carbethoxy hydrochloride sustained release preparation.
The test of Beagle dog Internal pharmacokinetics
Beagle dog 6 are taken, fasting 12 hours before being administered.Nitric acid 2- (the 4- methylthiazol-of oral comparative example 2 of the present invention
5- yl) carbethoxy hydrochloride sustained release tablets, dosage is 50mg, and respectively after administration 5,10,20,30,60,90,120,180,240,
360,480,600 and 720 minutes, whole blood 3ml is acquired at forelimb cephalic vein, centrifugal separation plasma is set -70 DEG C of refrigerators and saved.
100 μ L plasma samples are taken, 10 μ L of blank methanol solution is added, internal standard (5 μ g/mL clormethiazole methanol solution) 20 μ L are added, add
Enter 500 μ L methanol, 14800rpm is centrifuged 5 minutes, using nitric acid 2- (4- methyl in liquid-mass chromatography method measurement different time blood plasma
Thiazole -5- base) carbethoxy hydrochloride concentration, draw blood concentration-time curve.
Pharmacokinetic data available is as follows:
| Parameter name | Unit | Data |
| t1/2z | min | 149.51 |
| Tmax | min | 20 |
| Cmax | ng/mL | 33.51 |
| AUC(0-t) | ng/mL*min | 5332.44 |
| AUC(0-∞) | ng/mL*min | 5598.71 |
| MRT(0-t) | min | 274.58 |
| MRT(0-∞) | min | 306.02 |
Accelerated test
The sample for selecting comparative example 2, according to " Chinese Pharmacopoeia " version four in 2015, " material medicine and preparation stability are tested
Guideline " carries out accelerated test.Aluminum-plastic packaged sample sets 30 ± 2 DEG C, the placement of 65 ± 5% condition of RH, respectively at 1,2,3,6
It is measured by sampling within a month.Assay uses external standard method；Related substance is according to content assaying method, using 1% own control
Method measurement.As a result it see the table below.
The above test results show that content decline is significant, related after 2 sample accelerated test condition of comparative example is placed 6 months
Substance dramatically increases.
Bibliography
1, SGC Pharmacy stock Co., Ltd salt compound: China, 201180041035 [P] .2013-10-02.
2、Queen's University at Kingston(Kingston,CA).Nitrate esters and
their use for neurological conditions:CA,6,310,052[P].2001-10-30.
Claims (8)
1. a kind of tablet, which is characterized in that including main ingredient, filler, disintegrating agent, lubricant, wherein main ingredient is two kinds of following formula changes
One of object is closed,
2. a kind of tablet according to claim 1, which is characterized in that the main ingredient dosage accounts for 0.1%-50%.
3. a kind of tablet according to claim 1, which is characterized in that the filler be selected from one of following auxiliary material or
Several combinations: lactose, mannitol, pregelatinized starch, part pregelatinized corn starch, the filler loading account for 5%-80%.
4. a kind of tablet according to claim 1, which is characterized in that it is one or more of that the disintegrating agent is selected from following auxiliary material
Combination: dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, the disintegrating agent are used
Amount accounts for 0.1%-40%.
5. a kind of tablet according to claim 1, which is characterized in that it is one or more of that the lubricant is selected from following auxiliary material
Combination: stearic acid, calcium stearate, magnesium stearate, zinc stearate, talcum powder, glycerin monostearate, palm stearin acid glycerol
Ester, Stepanol MG, polyethylene glycol, stearyl fumarate, the lubricant quantity account for 0.1%-5%.
6. according to claim 1 to the preparation method of any one of 5 tablets, which is characterized in that using following steps system
It is standby: all auxiliary materials are sieved with 100 mesh sieve, take main ingredient to be ground to powdered, main ingredient, filler, the disintegrating agent for taking recipe quantity ground,
Mix, be added lubricant, mix, tabletting to get.
7. preventing and treating cardiovascular and cerebrovascular disease and nervus retrogression in preparation to any one of 5 tablets according to claim 1
Application in disease medicament.
8. application according to claim 7, the tablet is by mitigating individual nerve degeneration, realizing neuroprotection and/or reality
Now cognition enhancing, for preventing and/or treating cardiovascular and cerebrovascular disease and neurodegenerative disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810412768 | 2018-05-03 | ||
| CN2018104127688 | 2018-05-03 |
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| CN110433161A true CN110433161A (en) | 2019-11-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201811635823.6A Pending CN110433161A (en) | 2018-05-03 | 2018-12-29 | A kind of tablet and preparation method thereof for treating neurodegenerative disease |
Country Status (1)
| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103339127A (en) * | 2010-08-24 | 2013-10-02 | Sgc制药股份有限公司 | Salt compound |
| CN106166142A (en) * | 2015-05-20 | 2016-11-30 | 中国医学科学院药物研究所 | A kind of slow releasing preparation treating Alzheimer and preparation method thereof |
-
2018
- 2018-12-29 CN CN201811635823.6A patent/CN110433161A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103339127A (en) * | 2010-08-24 | 2013-10-02 | Sgc制药股份有限公司 | Salt compound |
| CN106166142A (en) * | 2015-05-20 | 2016-11-30 | 中国医学科学院药物研究所 | A kind of slow releasing preparation treating Alzheimer and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 张奕华等: "一氧化氮供体型新药研究", 《药学学报》 * |
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