CN109730974A - One kind is for fragrant safe tablet and preparation method thereof - Google Patents
One kind is for fragrant safe tablet and preparation method thereof Download PDFInfo
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Abstract
The invention discloses one kind for fragrant safe tablet and preparation method thereof.It being made for fragrant safe tablet by the raw material of following parts by weight, crystal form replaces fragrant 280-320 parts of Thailand, and 180~250 parts of diluent, 20-30 parts of disintegrating agent, 7-12 parts of adhesive, 2.5-6 parts of lubricant；Preparation method for fragrant safe tablet includes the following steps, replaces fragrant Thailand to pulverize and sieve crystal form；Diluent and disintegrating agent are pre-processed, make its moisture content below 1.5%；Crystal form is uniformly mixed for fragrant safe, diluent and disintegrating agent, adhesive is added, wet granulation is dry；Addition mix lubricant is uniform, and tabletting to obtain the final product.Have the characteristics that anti-virus ability is strong, drug withdrawal does not rebound, has no toxic side effect to conscience kidney, patient compliance is high, does not generate drug resistance in the present invention for fragrant safe tablet, the preparation method in the present invention is simple, favorable reproducibility, obtained good for fragrant Thailand's tablet stability.
Description
Technical field
It is especially a kind of for fragrant safe tablet and preparation method thereof the present invention relates to anti-hbv drug technical field.
Background technique
The common drug for treating hepatitis B has Lamivudine, Entecavir, tenofovir, the anti-virus ability of Lamivudine
Difference cannot thoroughly remove hepatitis B, can not eradicate, and recurrence is easy after drug withdrawal, is easy to produce drug resistance；Entecavir is disease-resistant
Malicious ability is slightly strong, but its there are certain drug resistance and toxicity, exist simultaneously the low disadvantage of patient compliance；Tenofovir resists
Though virus capable is strong, its risk with kidney injury, especially for having basic kidney trouble, there are diabetes, hypertension to suffer from
Person will increase the risk of kidney injury, have the shortcomings that patient compliance is low.
Show there is apparent inhibiting effect to HBsAg and HBV-DNA for fragrant Thailand for fragrant safe In vitro antibacterial test, inhibits
Intensity has dose-effect relationship.It is proved for fragrant safe Lamivudine and entecavir resistant A64 test cell line, for fragrant Thailand to Lamivudine
Good anti-hepatitis B effect is shown with nucleoside medicines mdr cells such as Entecavirs.With the duck examination for doing DHBV infection for fragrant Thailand
It tests, has apparent anti-hepatitis virus effect for fragrant Thailand, have no rebound phenomenon after obvious be discontinued.By primary action Mechanism Study,
By the expression of pgRNA or the activity of archaeal dna polymerase is not inhibited to realize for the effect of fragrant safe anti-hepatitis virus, passes through suppression
The expression for making intracellular cccDNA is realized.In addition, have preferable protecting liver, lowering enzymes effect to different chemical damages for fragrant Thailand,
And it is better than nucleoside medicine.For the fragrant safe liver being suitable for alanine aminotransferase [ALT] raising and viral activity duplication
Functional compensation and to the nucleoside medicines such as Lamivudine, Entecavir it is drug resistant adult chronic hepatitis B patients treatment.
For fragrant safe { N- [N- benzoyl-O- (2- dimethylaminoethyl)-L- tyrosyl-]-L- phenylalaninol }, knot
Structure formula is as shown in Fig. 3, for the fragrant safe chemical skeleton with dipeptides, not with the chemical skeletons of the drugs such as nucleotide medicine and interferon
Together, with the activity of stronger anti-hepatitis virus.
To preclinical studies such as pharmacy, pharmacodynamics, pharmacokinetics and the toxicology carried out for fragrant Thailand the result shows that for sweet smell
There is Anti-HBV activity effect in safe inside and outside, reproducible, has good dose-effect relationship and time-effect relationship, and mechanism of action is clear, is discontinued
After be not easy to rebound, it is effective to nucleoside analogue drug-resistant Strain, be better than nucleoside analog, do not find to the big organ such as the heart, liver, kidney
Side effect, safety is good, sample stablize, it is quality controllable.
In conclusion common treating hepatitis B drug, it cannot have both that anti-virus ability is strong, is discontinued and does not rebound, to conscience kidney
It has no toxic side effect, patient compliance is high, does not generate the characteristics of drug resistance, and is had no in the prior art for fragrant safe for making hepatitis B
Therapeutic agent.
Summary of the invention
The purpose of the present invention is the provision of a kind of for fragrant safe tablet and preparation method thereof.Fragrant safe piece is replaced in the present invention
Agent is strong with anti-virus ability, is discontinued and does not rebound, has no toxic side effect to conscience kidney, patient compliance height, not generating drug resistance
Feature, the preparation method in the present invention is simple, and favorable reproducibility is obtained good for fragrant safe tablet stability.
Technical solution of the present invention: one kind is made, crystal form replaces sweet smell Thailand 250- for fragrant safe tablet by the raw material of following parts by weight
320 parts, 180~250 parts of diluent, 20-30 parts of disintegrating agent, 7-12 parts of adhesive, 2.5-6 parts of lubricant, the crystal form is for sweet smell
Safe XRPD map is 15.3 ± 0.2 °, 20.3 ± 0.2 °, 24.4 ± 0.2 °, 25.8 ± 0.2 °, 37.3 ± 0.2 °, 28.3 in 2 θ
±0.2°、28.7±0.2°、29.0±0.2°、29.6±0.2°、30.3±0.2°、31.2±0.2°、31.9±0.2°、32.4
±0.2°、33.0±0.2°、33.5±0.2°、34.2±0.2°、34.9±0.2°、35.9±0.2°、36.6±0.2°、37.2
±0.2°、38.3±0.2°、38.9±0.2°、39.5±0.2°、41.9±0.2°、42.3±0.2°、44.0±0.2°、46.8
There is diffraction maximum at ± 0.2 °, 47.4 ± 0.2 °, 51.3 ± 0.2 °, the crystal form is located at 175.8 for fragrant safe DSC characteristic peak~
176.9℃。
Above-mentioned to replace in fragrant safe tablet, the diluent is selected from one of Lactis Anhydrous, microcrystalline cellulose, maltodextrin
Or it is a variety of.
Above-mentioned to replace in fragrant safe tablet, the disintegrating agent is selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, crosslinking
One or more of sodium carboxymethylcellulose.
Above-mentioned to replace in fragrant safe tablet, described adhesive is selected from hydroxypropyl cellulose, polyvinylpyrrolidone, the poly- second of crosslinking
One or more of vinyl pyrrolidone.
Above-mentioned to replace in fragrant safe tablet, the lubricant is selected from magnesium stearate, talcum powder, sodium stearyl fumarate, micro mist
One or more of silica gel.
Above-mentioned to replace in fragrant safe tablet, the crystal form is as shown in Fig. 1 for the XRPD map of fragrant Thailand, and the crystal form is for fragrant safe
DSC figure it is as shown in Fig. 2.
It is above-mentioned that the crystal form is for fragrant safe preparation method in fragrant safe tablet,
It will be dissolved in ethyl alcohol for fragrant safe crude product, it is described for for fragrant safe content being 94% or more in fragrant safe crude product, until replacing
The proportion of fragrant Thailand's crude product and ethyl alcohol is 1:7-10g/ml；Under the conditions of 60-90 DEG C, petroleum ether is added dropwise, stops when until there is solid precipitation
Petroleum ether is only added dropwise；It stands to precipitation off-white powder；Off-white powder is filtered, it is crystalline substance that vacuum drying, which obtains white powder,
Type is for fragrant safe.
Above-mentioned to replace in fragrant safe tablet, the proportion for fragrant Thailand's crude product and ethyl alcohol is 1:6.7g/ml.
Preparation method above-mentioned for fragrant safe tablet, includes the following steps, replaces fragrant Thailand to crushed 150-250 mesh crystal form
Sieve；Diluent and disintegrating agent are pre-processed, make its moisture content below 1.5%；By crystal form for fragrant safe, diluent and disintegrating agent
It is uniformly mixed, adhesive is added, wet granulation is dry；Addition mix lubricant is uniform, and tabletting to obtain the final product.
In preparation method above-mentioned for fragrant safe tablet, described adhesive is the aqueous solution that mass fraction is 6%-10%.
Compared with the prior art, the present invention replaces sweet smell Thailand for raw material with specific crystal formation, obtained to replace fragrant Thailand's tablet with anti-
Virus capable is strong, is discontinued and does not rebound, has no toxic side effect to conscience kidney, patient compliance height, not generating the characteristics of drug resistance, is second
Hepatopath's medication provides better choice.Specific crystal formation replaces fragrant safe material solution in 40 DEG C ± 2 DEG C of temperature, phase in the present invention
After placing 6 months under the conditions of being 75% ± 5% to humidity, clarity of solution does not decline；Substance in solution is not also bright
Aobvious variation, composition in solution with 0 month compared with almost without increase, in the present invention specific crystal formation for fragrant safe raw material with very
Good stability；For 18-30 times for fragrant safe content that fragrant safe comparatively safe dosage is in tablet, safety in the present invention
Height has drug resistance or renal toxicity or bone relative to hepatitis B clinical commonly used drug uncleosides as antiviral agents, interferon etc.
For marrow inhibits, for the fragrant safe side effect not found to the big organ such as the heart, liver, kidney, this is for fragrant safe maximum in safety
Advantage, a kind of this is again more for the hepatitis B patients of Long-term taking medicine, the especially patient of hepatitis B renal dysfunction clothes
Medicine selection；Good for the stability of fragrant safe tablet in the present invention, validity period was up to 24 months；Crystal form is in the present invention for fragrant safe preparation side
Method is simple, favorable reproducibility, and crystal form obtained is good for fragrant safe stability；It is simple for the preparation method of fragrant safe tablet in the present invention, weight
Existing property is good, easy to industrialized production.Therefore, anti-virus ability is strong, is discontinued and does not rebound, is right for having in the present invention for fragrant safe tablet
Conscience kidney has no toxic side effect, patient compliance is high, does not generate the characteristics of drug resistance, and the preparation method in the present invention is simple, reappears
Property it is good, it is obtained good for fragrant safe tablet stability.
Detailed description of the invention
Fig. 1 is for crystal form in fragrant safe tablet for fragrant safe X- powder diagram；
Fig. 2 is for crystal form in fragrant safe tablet for fragrant safe DSC figure；
Fig. 3 is for fragrant safe structural formula；
Fig. 4 is the relational graph of the dissolution time and the amount of dissolution for fragrant safe tablet in the phosphate buffer of pH6.8；
Fig. 5 is the relational graph of the dissolution time and the amount of dissolution for fragrant safe tablet in the phosphate buffer of pH4.5；
Fig. 6 is the relational graph of the dissolution time and the amount of dissolution for fragrant safe tablet in the hydrochloric acid solution of pH1.0；
Fig. 7 is the relational graph for fragrant safe tablet dissolution time in water and the amount of dissolution；
Fig. 8 is 01 batch for the fragrant safe dissolution time of tablet and the relational graph of the amount of dissolution；
Fig. 9 is 02 batch for the fragrant safe dissolution time of tablet and the relational graph of the amount of dissolution；
Figure 10 is 03 batch for the fragrant safe dissolution time of tablet and the relational graph of the amount of dissolution.
Specific embodiment
The present invention is further illustrated with reference to the accompanying drawings and examples, but be not intended as to the present invention limit according to
According to.
Embodiment 1.
Crystal form is for fragrant safe preparation
It will be dissolved in ethyl alcohol for fragrant safe crude product (for fragrant safe 94% or more content), the weight for fragrant safe crude product is
100g, the proportion of the ethyl alcohol are 750mL, and petroleum ether (60~90 DEG C) then are added dropwise, stop drop when discovery has solid precipitation
Add petroleum ether (60~90 DEG C), above-mentioned reaction solution is static to filter off-white powder to off-white powder is obtained, and is dried in vacuo
It is crystal form for fragrant safe (labeled as crystal form for fragrant safe No. 01 sample) 85.8g, yield 85.8% to white powder.
The crystal form in fragrant safe X-ray powder diffraction figure, 2 θ of angle of reflection be 15.3 °, 20.3 °, 24.4,25.8 °,
37.3°、28.3°、28.7°、29.0°、29.6°、30.3°、31.2°、31.9±0.2°、32.4°、33.0°、33.5°、34.2°、
34.9°、35.9±0.2°、36.6±0.2°、37.2±0.2°、38.3°、38.9°、39.5°、41.9°、42.3°、44.0°、
There is diffraction maximum at 46.8 °, 47.4 °, 51.3 °, DSC characteristic peak is located at 175.8~176.9 DEG C to XPRD map as shown in Figure 1:,
Its DSC figure is as shown in Figure 2.
Embodiment 2.
Crystal form is for fragrant safe preparation
It will be dissolved in ethyl alcohol for fragrant safe crude product (for fragrant safe 94% or more content), the weight for fragrant safe crude product is
100g, the proportion of the ethyl alcohol are 900mL, and petroleum ether (60~90 DEG C) then are added dropwise, stop drop when discovery has solid precipitation
Add petroleum ether (60~90 DEG C), above-mentioned reaction solution is static to filter off-white powder to off-white powder is obtained, and is dried in vacuo
It is crystal form for sweet smell Thailand 84.7g (labeled as crystal form for fragrant safe No. 02 sample), yield 84.4% to white powder.
The crystal form in fragrant safe X-ray powder diffraction figure, 2 θ of angle of reflection be 15.3 °, 20.3 °, 24.4,25.8 °,
37.3°、28.3°、28.7°、29.0°、29.6°、30.3°、31.2°、31.9±0.2°、32.4°、33.0°、33.5°、34.2°、
34.9°、35.9±0.2°、36.6±0.2°、37.2±0.2°、38.3°、38.9°、39.5°、41.9°、42.3°、44.0°、
There is diffraction maximum at 46.8 °, 47.4 °, 51.3 °, DSC characteristic peak is located at 175.8~176.9 DEG C to XPRD map as shown in Figure 1:,
Its DSC figure is as shown in Figure 2.
Embodiment 3.
Crystal form is for fragrant safe preparation
It will be dissolved in ethyl alcohol for fragrant safe crude product (for fragrant safe 94% or more content), the weight for fragrant safe crude product is
100g, the proportion of the ethyl alcohol are 950mL, and petroleum ether (60~90 DEG C) then are added dropwise, stop drop when discovery has solid precipitation
Add petroleum ether (60~90 DEG C), above-mentioned reaction solution is static to filter off-white powder to off-white powder is obtained, and is dried in vacuo
It is crystal form for sweet smell Thailand 85.7g (labeled as crystal form for fragrant safe No. 03 sample), yield 85.6% to white powder.
The crystal form in fragrant safe X-ray powder diffraction figure, 2 θ of angle of reflection be 15.3 °, 20.3 °, 24.4,25.8 °,
37.3°、28.3°、28.7°、29.0°、29.6°、30.3°、31.2°、31.9±0.2°、32.4°、33.0°、33.5°、34.2°、
34.9°、35.9±0.2°、36.6±0.2°、37.2±0.2°、38.3°、38.9°、39.5°、41.9°、42.3°、44.0°、
There is diffraction maximum at 46.8 °, 47.4 °, 51.3 °, DSC characteristic peak is located at 175.8~176.9 DEG C to XPRD map as shown in Figure 1:,
Its DSC figure is as shown in Figure 2.
Embodiment 4.
For fragrant safe tablet
For fragrant safe tablet, 1500 tablets are made by the raw material of 1 prescription of table:
Table 1 is for fragrant safe tablet formulation 1
For the preparation method of fragrant safe tablet
For the preparation method of fragrant safe tablet, comprising the following steps: replace fragrant Thailand to crushed 150 meshes crystal form；By diluent
It is pre-processed with disintegrating agent, makes its moisture content below 1.5%；Crystal form is uniformly mixed for fragrant safe, diluent and disintegrating agent, is added
Enter adhesive, wet granulation is dry；It is uniform that mix lubricant is added, tabletting is up to (labeled as 01 batch, tablet).
Embodiment 5.
For fragrant safe tablet, 1500 tablets are made by the raw material of 2 prescription of table:
Table 2 is for fragrant safe tablet formulation 2
For the preparation method of fragrant safe tablet
For the preparation method of fragrant safe tablet, comprising the following steps: replace fragrant Thailand to crushed 200 meshes crystal form；By diluent
It is pre-processed with disintegrating agent, makes its moisture content below 1.5%；Crystal form is uniformly mixed for fragrant safe, diluent and disintegrating agent, is added
Enter adhesive, wet granulation is dry；It is uniform that mix lubricant is added, tabletting is up to (labeled as 02 batch, tablet).
Embodiment 6.
For fragrant safe tablet, 1500 tablets are made by the raw material of 3 prescription of table:
Table 3 is for fragrant safe tablet formulation 3
For the preparation method of fragrant safe tablet
For the preparation method of fragrant safe tablet, comprising the following steps: replace fragrant Thailand to crushed 250 meshes crystal form；By diluent
It is pre-processed with disintegrating agent, makes its moisture content below 1.5%；Crystal form is uniformly mixed for fragrant safe, diluent and disintegrating agent, is added
Enter adhesive, wet granulation is dry；It is uniform that mix lubricant is added, tabletting is up to (labeled as 03 batch, tablet).
Test example 1.
Crystal form is for fragrant safe stability test
Fragrant Thailand is replaced to carry out crystal form in the present invention according to (four general rules 9001 of Chinese Pharmacopoeia version in 2015) relevant regulations
Accelerated test.It is placed 6 months under the conditions of 40 DEG C ± 2 DEG C of temperature, relative humidity are 75% ± 5%, respectively at the 0th, 1,2,3,6
A the end of month is separately sampled, and the situation of change in relation to substance the results are shown in Table 4:
4 crystal form of table is for fragrant safe stability test result
The above result shows that the crystal form in the present invention is 75% ± 5% in 40 DEG C ± 2 DEG C of temperature, relative humidity for fragrant Thailand
Under the conditions of place 6 months after, related substance does not have significant change, does not increase substantially, illustrates the crystalline substance in tablet of the present invention
Type is for fragrant safe with extraordinary stability.
Test example 2.
By 01 batch of -03 batch of tablet respectively the phosphate buffer of 900mlpH6.8, pH4.5 phosphate buffer,
Dissolution rate is measured in 0.1mol/L hydrochloric acid solution, water (Chinese Pharmacopoeia 2015 editions), using 2015 editions four dissolution rates of Chinese Pharmacopoeia
The second method of measuring method (paddle method) measurement, revolving speed are set as 50rpm, and temperature is set as 37 DEG C, measure the dissolution rate of 10min respectively.
Testing result is as shown in table 5, and the relationship of dissolution time and the amount of dissolution is shown in Fig. 4-Fig. 7:
Dissolution time and the amount of dissolution relational graph of the table 5 by 01 batch of -03 batch of tablet in respective media
01 batch of -03 batch of tablet is done into the test of dissolution rate full inspection, full inspection result summarizes as shown in table 6: three batches of test sample piece matter
Measure uniform, the relationship of dissolution time and the amount of dissolution is shown in Fig. 8-Figure 10.
6 01 batches of -03 batch of Dissolution of Tablet full inspection test results of table
The applicant to the enlarged experiments of three batches of test samples experiments have shown that, the prescription and technique reproducibility of this research establishment are good
Good, the dissolution curve of different batches tablet is consistent, and also completely the same three batches of test sample tablet qualities are uniform for other indexs.
In conclusion applicant thinks that the prescription of this preparation is reasonable, simple process, reliable in quality is good clinical use
Medicine selection.
Certainly, the present invention can also have other various embodiments, without deviating from the spirit and substance of the present invention, ripe
It knows those skilled in the art and makes various corresponding changes and modifications, but these corresponding changes and change in accordance with the present invention
Shape all should fall within the scope of protection of the appended claims of the present invention.
Claims (10)
1. one kind is for fragrant safe tablet, it is characterised in that: be made by the raw material of following parts by weight, crystal form replaces fragrant 250-320 parts of Thailand, dilute
180~250 parts of agent are released, 20-30 parts of disintegrating agent, 7-12 parts of adhesive, 2.5-6 parts of lubricant, the crystal form is for fragrant safe XRPD
Map 2 θ be 15.3 ± 0.2 °, 20.3 ± 0.2 °, 24.4 ± 0.2 °, 25.8 ± 0.2 °, 37.3 ± 0.2 °, 28.3 ± 0.2 °,
28.7±0.2°、29.0±0.2°、29.6±0.2°、30.3±0.2°、31.2±0.2°、31.9±0.2°、32.4±0.2°、
33.0±0.2°、33.5±0.2°、34.2±0.2°、34.9±0.2°、35.9±0.2°、36.6±0.2°、37.2±0.2°、
38.3±0.2°、38.9±0.2°、39.5±0.2°、41.9±0.2°、42.3±0.2°、44.0±0.2°、46.8±0.2°、
There is diffraction maximum, the crystal form is located at 175.8~176.9 for fragrant safe DSC characteristic peak at 47.4 ± 0.2 °, 51.3 ± 0.2 °
℃。
2. according to claim 1 for fragrant safe tablet, it is characterised in that: it is fine that the diluent is selected from Lactis Anhydrous, crystallite
One of dimension element, maltodextrin are a variety of.
3. according to claim 1 for fragrant safe tablet, it is characterised in that: the disintegrating agent is selected from low substituted hydroxy-propyl fiber
One or more of element, sodium carboxymethyl starch, croscarmellose sodium.
4. according to claim 1 for fragrant safe tablet, it is characterised in that: described adhesive is selected from hydroxypropyl cellulose, gathers
One or more of vinylpyrrolidone, cross-linking polyethylene pyrrolidone.
5. according to claim 1 for fragrant safe tablet, it is characterised in that: the lubricant be selected from magnesium stearate, talcum powder,
One or more of sodium stearyl fumarate, superfine silica gel powder.
6. according to claim 1 for fragrant safe tablet, it is characterised in that: the crystal form is for fragrant safe XRPD map such as attached drawing
Shown in 1, the crystal form is as shown in Fig. 2 for fragrant safe DSC figure.
7. according to any claim from 1 to 6 replace fragrant safe tablet, it is characterised in that: the crystal form is for fragrant Thailand
Preparation method is,
It will be dissolved in ethyl alcohol for fragrant safe crude product, it is described for for fragrant safe content being 94% or more in fragrant safe crude product, to for fragrant Thailand
The proportion of crude product and ethyl alcohol is 1:7-10g/ml；Under the conditions of 60-90 DEG C, petroleum ether is added dropwise, until stopping drop when having solid precipitation
Add petroleum ether；It stands to precipitation off-white powder；Off-white powder is filtered, it is that crystal form replaces that vacuum drying, which obtains white powder,
Fen Tai.
8. according to claim 7 for fragrant safe tablet, it is characterised in that: the proportion for fragrant safe crude product and ethyl alcohol is 1:
6.7g/ml。
9. according to claim 1 for the preparation method of fragrant safe tablet described in -8 any claims, it is characterised in that: including with
Crystal form is replaced fragrant Thailand to crushed 150-250 mesh by lower step；Diluent and disintegrating agent are pre-processed, its moisture content is made to exist
1.5% or less；Crystal form is uniformly mixed for fragrant safe, diluent and disintegrating agent, adhesive is added, wet granulation is dry；Profit is added
Lubrication prescription is uniformly mixed, and tabletting to obtain the final product.
10. the preparation method according to claim 9 for fragrant safe tablet, it is characterised in that: described adhesive is quality point
Number is the aqueous solution of 6%-10%.
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