CN106279312B - A kind of azithromycin compound and combinations thereof - Google Patents
A kind of azithromycin compound and combinations thereof Download PDFInfo
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Abstract
The invention discloses a kind of azithromycin compounds, the X ray diffracting spectrum of the azithromycin compound is 7.5 ° ± 0.2 °, 8.1 ° ± 0.2 ° at 2 angles θ, 14.8 ° ± 0.2 °, 15.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.9 ° ± 0.2 °, 23.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 28.5 ° ± 0.2 ° of position shows characteristic diffraction peak.The invention also discloses a kind of compositions containing azithromycin compound.Azithromycin compound stability prepared by the present invention is good, and the dispersible tablet property containing azithromycin compound of preparation is stable, disintegration is rapid, dissolution rate is good, bioavilability is high, and in addition preparation method is easy to operate, easily-controllable, high production efficiency.
Description
Technical field
The invention belongs to field of medicine preparations, specifically, being related to a kind of azithromycin compound and combinations thereof.
Background technique
Azithromycin is 9 α insertion, one big ring of 15 member rings containing substituent methyl nitrogen-atoms in Erythromycin A lactonic ring
The novel spectrum antibiotic of propyl ester class nitrogen esters, chemical name are (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R) -13-
[(2,6- dideoxy -3-C- methyl -3-O- methyl-α-L- cores-pyranose) oxygen] -2- ethyl -3,4, trihydroxy -3 10-,
5,6,8,10,12,14- seven methyl-1 1- [[3,4,6- tri- deoxidation -3- (dimethylamino)-β-D- wood-pyranose] oxygen] -1-
Oxa- -6- azepine cyclopentadecane -15- ketone has structural formula shown in formula I.
As second generation macrolide antibiotics, antimicrobial spectrum is similar with erythromycin, but for treating suppurative hammer
Bacterium, sensitive bacterial, streptococcus pneumonia, haemophilus influenzae and mycoplasma pneumoniae, chlamydia trachomatis and non-a variety of drug resistance stranguria syndromes
Disease caused by Neisseria etc. has fabulous curative effect.In addition, because it has to sour stabilization, tissue permeability is good, blood plasma partly declines
The features such as phase grows (nearly 70h), clinical indication is wide, significant in efficacy, adverse reaction is few, patient compliance is good, has been widely used
In clinic.The kind dosage form of domestic listing includes ordinary tablet, dispersible tablet, capsule, granule, dry suspensoid agent etc. at present.
Due to azithromycin poorly water-soluble, ordinary tablet dissolution in vivo and absorption are greatly affected.Dispersible tablet is
In recent years a kind of novel quick-effective preparation rapidly developed, both can directly take, also can rapid dispersion drink afterwards in water, this dosage form
Appearance solve the problems such as solid pharmaceutical preparation disintegration is slow, and it is poor to dissolve out, and bioavilability is not high, particularly suitable for anti-infective, antipyretic
Analgesia etc. needs the drug of quick acting.The dosage form had specific definition in 2010 and requires, " dispersible tablet in version " Chinese Pharmacopoeia "
Meaning can be disintegrated rapidly and evenly dispersed tablet in water.Drug in dispersible tablet should be indissoluble.Dispersible tablet can add moisture
It is taken orally after dissipating, can also dispersible tablet be taken or be swallowed contained in sucking in mouth.
Currently, Azithromycin dispersible tablet is in production generally using wet granulation technology production and direct powder compression work
Skill.A kind of azithromycin compound is disclosed application No. is the Chinese patent of CN201510473561.8 and containing the compound
Soft capsule provides a kind of azithromycin compound crystal that hygroscopicity is small.Application No. is 201210494115.1 China specially
Benefit discloses a kind of Azithromycin dispersible tablet and preparation method thereof, by weight percentage of each component azithromycin 56-75%, crystallite
Cellulose 9-12%, sodium carboxymethyl starch 8-12%, croscarmellose sodium 8-12%, silica 2-5%, stearic acid
Magnesium 1-2% composition.Application No. is 201310539019.9 Chinese patents to provide a kind of Azithromycin dispersible tablet and its preparation
Method, the Azithromycin dispersible tablet include azithromycin, filler, disintegrating agent, lubricant；In parts by weight, azithromycin is
45~58 parts, filler is 25~40 parts, and disintegrating agent is 10~16 parts, and lubricant is 0.3~1.5 part.The filler is sulphur
The mixture of one or both of sour calcium or calcium monohydrogen phosphate improves dispersion sheet hardness.But the above prior art still has surely
The not high problem of qualitative poor, dissolution rate.
Application No. is the Chinese patents of 201310442662.X to disclose a kind of Azithromycin dispersible tablet and preparation method thereof,
Said preparation is formed by medicine-containing particle and pharmaceutically acceptable auxiliary materials and mixing tabletting, the medicine-containing particle be by azithromycin and
Corn Ruan is dissolved in dehydrated alcohol, be added filler, rotary evaporation drying ethanol, sieving to get.But this technology not can guarantee
Zein more has an impact the package degree of azithromycin to disintegration rate.
In view of this present invention is specifically proposed.
Summary of the invention
The technical problem to be solved in the present invention is that overcome the deficiencies of the prior art and provide a kind of azithromycin compound and
Its composition.Azithromycin compound stability prepared by the present invention is good, the dispersible tablet containing azithromycin compound of preparation
Property is stable, disintegration is rapid, dissolution rate is good, bioavilability is high, and in addition preparation method is easy to operate, easily-controllable, high production efficiency.
The first object of the present invention is to provide a kind of azithromycin compound and preparation method thereof that stability is good.
The second object of the present invention is to provide a kind of composition containing the azithromycin compound, is Zitromax
Plain dispersible tablet.
The third object of the present invention is to provide a kind of preparation method of Azithromycin dispersible tablet.
The first purpose to realize the present invention, the present invention adopts the following technical scheme:
A kind of azithromycin compound, wherein the X ray diffracting spectrum of the azithromycin compound is at 2 angles θ
7.5 ° ± 0.2 °, 8.1 ° ± 0.2 °, 14.8 ° ± 0.2 °, 15.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.9 ° ± 0.2 °, 23.8 ° ±
0.2 °, 24.1 ° ± 0.2 °, 28.5 ° ± 0.2 ° of position shows characteristic diffraction peak.
The azithromycin compound the preparation method is as follows: by azithromycin crude product and dehydrated alcohol-methyl acetate-
The mixing of isopropanol solvent system, heating stirring dissolution after being cooled to 0-10 DEG C, are added 0-10 DEG C of water, place crystallization, cross and be filtered dry
It is dry to obtain the final product.
In the dehydrated alcohol-methyl acetate-isopropanol solvent system, the body of dehydrated alcohol, methyl acetate and isopropanol
Product ratio is 3-5:5-8:10, and the dosage of the dehydrated alcohol-methyl acetate-isopropanol solvent system is calculated as Zitromax with ml/g
The volume ratio of 10-30 times of plain crude product, the dehydrated alcohol-methyl acetate-isopropanol solvent system and water is 1:0.1-1.
Since solid kind drug is there are polymorphism, solid drugs of the same race unformed can both exist, can also be with
The polymorphic of different crystal structure forms exists, and the different crystal form of same drug may be in the side such as solubility, thermal stability
There are significant differences in face.Typical problem of the azithromycin in oral administration is that stability is poor, leads to bioavilability significantly
It reduces.The present invention has been made a kind of azithromycin of completely new crystal form, has been studied by every physicochemical property by a large amount of test,
The result shows that azithromycin compound stability provided by the invention is good.
The second purpose to realize the present invention, the present invention adopts the following technical scheme:
A kind of composition containing azithromycin compound of the present invention, the composition are azithromycin dispersion
Piece.
First scheme, the composition containing azithromycin compound include: by weight
Further, the composition containing azithromycin compound includes: by weight
Alternative plan, the composition containing azithromycin compound include: by weight
The weight ratio of the azithromycin and glycine is 6:1~10:1, preferably 7:1~9:1.
Glycine is a kind of amino acid nonessential for human body, has acid and basic functionality simultaneously in the molecule,
It is strong electrolyte in aqueous solution, solubility is larger in intensive polar solvent, also can be used as buffer.It is a discovery of the invention that by sweet ammonia
Acid is added in Azithromycin dispersible tablet, due to the buffer function of glycine, improves the stability of azithromycin.Not only such as
This, glycine dispersion group value is small, and hydrophily is strong, and other disintegrating agents is cooperated to use, and plays the role of promoting disintegration, enhance
It is disintegrated effect, increases dissolution rate.
Third purpose to realize the present invention, the present invention adopts the following technical scheme:
A kind of preparation method of composition of the present invention containing azithromycin compound, the preparation method include
Following steps:
(1) prepared by supplementary material: azithromycin crosses that 40 meshes are spare, and it is spare that other auxiliary materials cross 60~100 meshes；
(2) preparation of adhesive: ethyl alcohol is configured to concentration and is 70% solution, and recipe quantity PVP K30 is added
Into ethanol solution, adhesive is made；
(3) it pelletizes: by the azithromycin of recipe quantity, microcrystalline cellulose, aspartame, croscarmellose sodium, carboxylic
Methyl starch sodium puts into wet granulator, is stirred, the adhesive prepared is added in mixed supplementary material, is made soft
Material continues to stir, particle finally is made in softwood；
(4) dry: it is dry that the particle pelletized is transferred to boiling drier；
(5) sieving whole grain；
(6) total mix: by the good dry particle of whole whole grains and load weighted additional auxiliary material sodium carboxymethyl starch, glycine,
Silica, magnesium stearate are put into Mixers with Multi-direction Movement, are uniformly mixed；
(7) tabletting, interior packet, storage.
Wherein, the supplementary material of step (3) is mixed with equivalent gradually-increased, and dosage is place in step (3) described carboxyrnethyl starch sodium
1/4 just measured, residue 3/4 is additional for step (6) total mix, and it is 65~80 DEG C that step (4), which controls drying temperature, dry to particle
Water content is 3~6%.
The composition containing azithromycin compound of alternative plan, in the preparation, by the glycine of recipe quantity 4/5 in step
Mixing is added in rapid 3 together with azithromycin, residue 1/5 is additional for step (6) total mix, and other preparation methods are identical.
After adopting the above technical scheme, compared with the prior art, the invention has the following beneficial effects:
(1) azithromycin compound stability prepared by the present invention is good；
(2) the composition property containing azithromycin compound of preparation is stable, disintegration is rapid, dissolution rate is good, biological benefit
Expenditure is high；
(3) preparation method of azithromycin compound and its composition is easy to operate, easily-controllable, high production efficiency.
A specific embodiment of the invention is described in further detail with reference to the accompanying drawing.
Detailed description of the invention
Fig. 1 is the X-ray powder diffraction spectrogram of azithromycin compound prepared by the embodiment of the present invention 1；
Fig. 2 is the blood concentration-time curve graph of test example 4 of the present invention.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
In attached drawing, the technical solution in embodiment is clearly and completely described, the following examples are intended to illustrate the invention, but
It is not intended to limit the scope of the invention.
The preparation of 1 azithromycin compound of embodiment
In 100g azithromycin crude product, 167mL dehydrated alcohol, 278mL methyl acetate, 555mL isopropanol solvent is added
System mixing, is heated to 45 DEG C, stirring and dissolving, then is cooled to 0-10 DEG C, and 10 DEG C of water 200mL is then added into solution, stirs
Uniformly mixed, standing crystallization 5h is mixed, is filtered, drying obtains azithromycin compound 96.2g, yield 96.2%, HPLC purity
99.74%.Elemental analysis (%) calculated value are as follows: C (58.09%), H (9.68%), O (28.54%), N (3.57%)；Element point
Analyse (%) measured value are as follows: C (58.12%), H (9.62%), O (28.51%), N (3.62%).
X-ray powder diffraction collection such as Fig. 1 that azithromycin compound obtained is obtained using Cu-K alpha ray measurement
It is shown, it is 7.5 ° ± 0.2 °, 8.1 ° ± 0.2 °, 14.8 ° ± 0.2 °, 15.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.9 ° at 2 angles θ
± 0.2 °, 23.8 ° ± 0.2 °, 24.1 ° ± 0.2 °, 28.5 ° ± 0.2 ° of position shows characteristic diffraction peak.
It uses Karl_Fischer method measurement water content for 4.55%, shows to contain two in azithromycin compound of the present invention
A crystallization water (two hydrate theoretical water content of azithromycin is 4.58%).
The preparation of 2 azithromycin compound of embodiment
In 100g azithromycin crude product, 652mL dehydrated alcohol is added, 1048mL methyl acetate, 1300mL isopropanol is molten
The mixing of agent system, is heated to 45 DEG C, stirring and dissolving, then is cooled to 0 DEG C, and 0 DEG C of water 300mL, stirring are then added into solution
It is uniformly mixed, stands crystallization 8h, filter, it is dry, obtain azithromycin compound 98.4g, yield 98.4%, HPLC purity
99.81%.Elemental analysis (%) calculated value are as follows: C (58.09%), H (9.68%), O (28.54%), N (3.57%)；Element point
Analyse (%) measured value are as follows: C (58.25%), H (9.61%), O (28.58%), N (3.68%).
The X-ray powder diffraction collection and implementation that azithromycin compound obtained is obtained using Cu-K alpha ray measurement
Example 1 is similar, water content 4.63%.
The preparation of 3 azithromycin compound of embodiment
In 100g azithromycin crude product, 429mL dehydrated alcohol is added, 1141mL methyl acetate, 1430mL isopropanol is molten
The mixing of agent system, is heated to 45 DEG C, stirring and dissolving, then is cooled to 4 DEG C, and 4 DEG C of water 600mL, stirring are then added into solution
It is uniformly mixed, stands crystallization 6h, filter, it is dry, obtain azithromycin compound 97.5g, yield 97.5%, HPLC purity
99.85%.Elemental analysis (%) calculated value are as follows: C (58.09%), H (9.68%), O (28.54%), N (3.57%)；Element point
Analyse (%) measured value are as follows: C (58.19%), H (9.54%), O (28.61%), N (3.55%).
The X-ray powder diffraction collection and implementation that azithromycin compound obtained is obtained using Cu-K alpha ray measurement
Example 1 is similar, water content 4.68%.
The preparation of 4 azithromycin compound of embodiment
In 100g azithromycin crude product, 250mL dehydrated alcohol, 250mL methyl acetate, 500mL isopropanol solvent is added
System mixing, is heated to 45 DEG C, stirring and dissolving, then is cooled to 8 DEG C, and 8 DEG C of water 1000mL is then added into solution, and stirring is mixed
It closes uniformly, stands crystallization 3h, filter, it is dry, obtain azithromycin compound 95.2g, yield 95.2%, HPLC purity
99.64%.Elemental analysis (%) calculated value are as follows: C (58.09%), H (9.68%), O (28.54%), N (3.57%)；Element point
Analyse (%) measured value are as follows: C (58.12%), H (9.62%), O (28.51%), N (3.62%).
The X-ray powder diffraction collection and implementation that azithromycin compound obtained is obtained using Cu-K alpha ray measurement
Example 1 is similar, water content 4.52%.
The preparation of embodiment 5-10 Azithromycin dispersible tablet
Prescription is shown in Table 1
The prescription (80,000, each ingredient units kg) of 1 embodiment 5-10 of table
| Ingredient | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 | Embodiment 10 |
| Azithromycin | 20 | 18 | 23 | 18 | 23 | 20 |
| Glycine | - | - | - | 1.5 | 3.5 | 3 |
| Microcrystalline cellulose | 12.8 | 10 | 15 | 10 | 15 | 12.8 |
| Croscarmellose sodium | 0.8 | 0.5 | 1.3 | 0.5 | 1.3 | 0.8 |
| Aspartame | 2.4 | 2.0 | 2.9 | 2.0 | 2.9 | 2.4 |
| PVP K30 | 0.12 | 0.09 | 0.15 | 0.09 | 0.15 | 0.12 |
| Sodium carboxymethyl starch | 3.2 | 2.8 | 3.5 | 2.8 | 3.5 | 3.2 |
| Magnesium stearate | 1.04 | 0.7 | 1.2 | 0.7 | 1.2 | 1.04 |
| Silica | 1.44 | 1.1 | 1.8 | 1.1 | 1.8 | 1.44 |
| 95% ethyl alcohol | 7.35 | 5.6 | 6.9 | 5.6 | 6.9 | 7.35 |
| Purified water | 3.15 | 2.4 | 2.9 | 2.4 | 2.9 | 3.15 |
Preparation method:
(1) prepared by supplementary material: it is spare that azithromycin and other auxiliary materials cross 60-100 mesh；
(2) preparation of adhesive: ethyl alcohol is configured to concentration and is 70% solution, and recipe quantity PVP K30 is added
Into ethanol solution, adhesive is made；
(3) it pelletizes: by the azithromycin of recipe quantity, microcrystalline cellulose, aspartame, croscarmellose sodium, 4/5
The sodium carboxymethyl starch of the glycine (embodiment 1-3 is not added) of recipe quantity, 1/4 recipe quantity puts into wet process using equivalent gradually-increased
In granulator, it is stirred 5min, the adhesive that step (2) prepares is added in mixed supplementary material, softwood is made, continues to stir
It mixes, particle finally is made with 16 mesh of oscillating granulator in softwood；
(4) dry: the particle pelletized is transferred to boiling drier drying, and control drying temperature is 65~80 DEG C, and drying is extremely
Particle water content is 3~6%；
(5) sieving whole grain；
(6) total mix: by the carboxymethyl starch of the good dry particle of whole whole grains and load weighted additional 3/4 recipe quantity of auxiliary material
Silica, the magnesium stearate of sodium, the glycine (embodiment 1-3 is not added) of 1/5 recipe quantity and recipe quantity put into Multidirectional motion
In mixing machine, it is uniformly mixed；
(7) tabletting, interior packet, storage.Azithromycin dispersible tablet finished product hardness is 30~50N.
It should be noted that the additive amount of the aspartame in preparation method step (3) pelletization of embodiment 6 is prescription
The 2/3 of amount, the additive amount of aspartame is the 1/3 of recipe quantity in step (6).
The test of 1 azithromycin compound stability of test example
Azithromycin compound sample prepared by Example 1~4, at 40 ± 2 DEG C of temperature, relative humidity 75% ± 5%
Under conditions of place, measure in 0 month, 1 month, 2 months, 3 months, 6 months related substance situations of change.
Control sample 1: according to " synthesis of azithromycin dihydrate and crystallization processes improve ", [Cao Wei, Wang Yunbin wait
The synthesis of azithromycin dihydrate and crystallization processes improve [J], fine-chemical intermediate, 2012,42 (3): 50-51] side
Azithromycin dihydrate made from method；
Control sample 2: azithromycin dihydrate knot made from the method according to CN201510371898.8 embodiment 1
It is brilliant.The results are shown in Table 2.
The Detection of Stability result of 2 azithromycin compound of table
As shown in Table 2, compared with control sample 1 and 2, azithromycin compound prepared by the present invention during storage,
Related content of material is stablized, with good stability without significant change.
The dissolution in vitro of 2 Azithromycin dispersible tablet of test example is tested
2.1 drug
Test specimen: Azithromycin dispersible tablet made from the embodiment of the present invention 5 and embodiment 8；
Control sample: taking the azithromycin compound of the control sample 1 and 2 prepared in test example 1, referring to embodiment 5-10
Preparation method, Azithromycin dispersible tablet is prepared into, as control sample A and control sample B.
2.2 measuring methods and result
According to the 2nd method (paddle method) of dissolution method of Chinese Pharmacopoeia version in 2010, to different azithromycin samples into
The test of row In Vitro Dissolution.Using pH=7.4 phosphate buffer as dissolution medium (prepare dissolution medium deionized water before palpus
Degassed processing), digestion instrument rotating speed of agitator and bath temperature are respectively set as 100r/min and 37 ± 0.5 DEG C.It is throwing respectively
Enter 1 after sample, 3,5,10min sampling 5mL, and with 0.45 μm of membrane filtration；By gained filtrate through H2SO4Solution (75 → 100)
After colour developing, its ultraviolet absorptivity is measured at 482nm, is calculated in dissolution medium and is dissolved according to the dissolution standard curve measured in advance
The amount of drug, and drug-eluting curve is drawn, characterize drug solubility energy.
The In Vitro Dissolution test result of different samples is as shown in table 3.From table 3 it can be seen that azithromycin of the invention point
Initial dissolution rate of the discrete piece in buffer solution significantly improves, and is throwing in cup 3min, the dissolution rate of drug is up to 97.5%, greatly
It is approximately 1.2 times of reference substance A, 1.1 times of reference substance B.This sufficiently shows that azithromycin compound of the invention is remarkably improved
The rate of dissolution and dissolution rate of Azithromycin dispersible tablet.
It has been confirmed by experiments that the rate of dissolution of the Azithromycin dispersible tablet of embodiment 6-7 and embodiment 9-10 and dissolution rate with
This result is similar.
The dissolution in vitro test result of 3 Azithromycin dispersible tablet of table
The stability test of 3 Azithromycin dispersible tablet of test example
Test specimen: the Azithromycin dispersible tablet of Example 5-10 preparation is as test specimen.
Control sample: taking the azithromycin compound of the control sample 1 and 2 prepared in test example 1, referring to embodiment 5-10
Preparation method, Azithromycin dispersible tablet is prepared into, as control sample A and control sample B.
Accelerated test
Azithromycin dispersible tablet is taken, by commercially available back, at 40 DEG C ± 2 DEG C of temperature, under conditions of relative humidity 75% ± 5%
It places 6 months, is sampled respectively at 1,2,3,6 the end of month, it is spare.Following index is detected, the results are shown in Table 4:
(1) dissolution rate: this item test measures potency of azithromycin using high-efficient liquid phase color law popularization, investigates azithromycin dispersion
The dissolving out capability of piece, specific method use Chinese Pharmacopoeia version in 2010.
(2) disintegration time limited and dispersing uniformity: azithromycin of the present invention is measured by " Chinese Pharmacopoeia " 2010 editions correlation techniques
The disintegration time limited of dispersible tablet and dispersing uniformity.
(3) in relation to substance: measuring Azithromycin dispersible tablet and Archie of the present invention by " Chinese Pharmacopoeia " 2010 editions correlation techniques
Related content of material in mycin raw material, including largest single impurity and total miscellaneous.
The stability test result of 4 Azithromycin dispersible tablet of table
As shown in Table 4, compared with control sample A and B, the Azithromycin dispersible tablet of 5-10 of embodiment of the present invention preparation is being stored up
During depositing, related content of material is stablized, without significant change, meanwhile, the azithromycin of 5-10 of embodiment of the present invention preparation is molten
Out-degree is apparently higher than control sample A and B, and disintegration time limited is also obviously shortened.This explanation contains azithromycin chemical combination of the present invention
The Azithromycin dispersible tablet stability of object significantly improves, and dissolution rate and disintegration rate also increase.
Meanwhile compared with embodiment 5-7, the Azithromycin dispersible tablet of embodiment 8-10 preparation is added to glycine, is adding
Related substances significantly reduce in speed test, and content does not have significant change, and disintegration time limited is also obviously shortened, and illustrates adding for glycine
Add, increases the stability of Azithromycin dispersible tablet, also increase disintegration rate.
4 pharmacokinetic trial of test example
4.1 test drug
By test preparation: Azithromycin dispersible tablet made from the embodiment of the present invention 5 and embodiment 8, specification: every 0.25g (with
Azithromycin)；
Reference reagent: Azithromycin dispersible tablet made from the prescription and method according to invention formulation embodiment 5, institute are different
, the azithromycin used is commercially available azithromycin dihydrate bulk pharmaceutical chemicals, and specification: every 0.25g is (with azithromycin
Meter).
The selection of 4.2 subjects
Selecting 30 male volunteers is subject, year at age (25.54 ± 1.1), weight (68.25 ± 5.37) kg, body
High (173.9 ± 6.21).Whole subjects are normal, no tobacco and wine through inspections such as electrocardiogram, Liver and kidney functions through inquiring medical history
Hobby, other unused any drugs during testing first 14 days and testing.Illustrate that test objective, drug are special to subject before test
Property, clinical application range and the adverse drug reaction being likely to occur.By signed informed consent form.Testing program is entrusted through ethics
Member executes after ratifying.
4.3 medications and blood specimen collection
Using 2 period dual crossing experimental designs.
30 subjects are randomly divided into totally three groups of test group 1, test group 2 and control group, every group of 10 people.Test group 1 is taken
Embodiment 5 prepare by test preparation；Test group 2 take embodiment 8 preparation by test preparation；Control group takes reference preparation.By
After examination person's fasting 12h, empty stomach oral administration is tested respectively and reference preparation 500mg is taken with warm water 250mL by Yu Qingchen 7:00, and in
4h is into standard meal after medication.
In medication before and administration after 0.5,1.0,1.5,2.0,3.0,4.0,6.0,8.0,12.0,24.0,48.0,
72.0,96.0,120.0,144.0h take upper arm venous blood 4.0mL, anticoagulant heparin, centrifugation, separated plasma, in -40 DEG C of refrigerators
It saves to be measured；Strenuous exercise should be avoided after subject's medication, must not also lie in bed for a long time.
During test, researcher records blood sampling time and adverse drug reaction in detail.Whole process is by training through GCP
Clinician and nurse observe and handle in time.
4.4 data processing and inversion
Referring to " relative bioavailability of azithromycin dispersible tablets in healthy volunteers and medicine dynamics ", [Liu Xin, Ji Jingjuan wait Archie
Mycin dispersible tablet Bioavailability of Human Body and medicine dynamics [J], theory of medicine and practice, 2006,19 (2): 229-231]
Method measure blood concentration-time data of 30 subject's oral azithromycins after by test preparation and reference preparation 500mg,
Mean blood plasma concentration-time graph is drawn, as shown in Figure 2.
From mean blood plasma concentration-time graph of azithromycin can be seen that embodiment 5 and embodiment 8 prepare it is tested
The Cmax of preparation be better than reference preparation, AUC is calculated using trapezoidal method, the results showed that by test preparation AUC also superior to reference system
Agent.
It can also be seen that, the Cmax by test preparation for being added to the preparation of embodiment 8 of glycine will slightly be better than reference system simultaneously
Agent calculates AUC using trapezoidal method, the results showed that prepared by embodiment 8 is also slightly better than prepared by embodiment 5 by test preparation AUC
By test preparation.
The above is only presently preferred embodiments of the present invention, is not intended to limit the present invention in any form, though
So the present invention has been disclosed as a preferred embodiment, and however, it is not intended to limit the invention, any technology people for being familiar with this patent
Member without departing from the scope of the present invention, when the technology contents using above-mentioned prompt make it is a little change or be modified to
The equivalent embodiment of equivalent variations, but anything that does not depart from the technical scheme of the invention content, it is right according to the technical essence of the invention
Any simple modification, equivalent change and modification made by above embodiments, in the range of still falling within the present invention program.
Claims (11)
1. a kind of azithromycin compound, which is characterized in that the X ray diffracting spectrum of the azithromycin compound, at 2 angles θ
It is 7.5 ° ± 0.2 °, 8.1 ° ± 0.2 °, 14.8 ° ± 0.2 °, 15.3 ° ± 0.2 °, 21.1 ° ± 0.2 °, 21.9 ° ± 0.2 °, 23.8 °
± 0.2 °, 24.1 ° ± 0.2 °, 28.5 ° ± 0.2 ° of position shows characteristic diffraction peak.
2. a kind of preparation method of azithromycin compound described in claim 1, which is characterized in that the preparation method is such as
Under: azithromycin crude product is mixed with dehydrated alcohol-methyl acetate-isopropanol solvent system, heating stirring dissolution is cooled to 0-
After 10 DEG C, 0-10 DEG C of water is added, places crystallization, filtration drying to obtain the final product.
3. the preparation method of azithromycin compound according to claim 2, which is characterized in that the dehydrated alcohol-second
In sour methyl esters-isopropanol solvent system, the volume ratio of dehydrated alcohol, methyl acetate and isopropanol is 3-5:5-8:10, the nothing
Water-ethanol-methyl acetate-isopropanol solvent system dosage, 10-30 times for being calculated as azithromycin crude product with ml/g are described anhydrous
Ethanol-Acetic Acid methyl esters-isopropanol solvent system and the volume ratio of water are 1:0.1-1.
4. a kind of composition containing azithromycin compound described in having the right to want 1, which is characterized in that the composition be Ah
Miramycin dispersible tablet.
5. the composition according to claim 4 containing azithromycin compound, which is characterized in that include: by weight
6. the composition according to claim 4 containing azithromycin compound, which is characterized in that include: by weight
7. the composition according to claim 4 containing azithromycin compound, which is characterized in that include: by weight
8. the composition according to claim 7 containing azithromycin compound, which is characterized in that the azithromycin with
The weight ratio of glycine is 6:1~10:1.
9. the composition according to claim 8 containing azithromycin compound, which is characterized in that the azithromycin with
The weight ratio of glycine is 7:1~9:1.
10. a kind of preparation method of the composition containing azithromycin compound described in claim 7-9 any one, special
Sign is, it is described the preparation method is as follows:
(1) prepared by supplementary material: it is spare that azithromycin and other auxiliary materials cross 60~100 meshes；
(2) preparation of adhesive: ethyl alcohol is configured to concentration and is 70% solution, and recipe quantity PVP K30 is added to second
In alcoholic solution, adhesive is made；
(3) it pelletizes: by the azithromycin of recipe quantity, microcrystalline cellulose, aspartame, croscarmellose sodium, carboxymethyl
Sodium starch is stirred, the adhesive prepared is added in mixed supplementary material, is made soft using in investment wet granulator
Material continues to stir, particle finally is made in softwood；
(4) dry: it is dry that the particle pelletized is transferred to boiling drier；
(5) sieving whole grain；
(6) total mix: by the good dry particle of whole whole grains and load weighted additional auxiliary material sodium carboxymethyl starch, glycine, dioxy
SiClx, magnesium stearate are put into Mixers with Multi-direction Movement, are uniformly mixed；
(7) tabletting, interior packet, storage.
11. the preparation method of the composition according to claim 10 containing azithromycin compound, which is characterized in that step
Suddenly the supplementary material of (3) is mixed with equivalent gradually-increased, and dosage is the 1/4 of recipe quantity, residue 3/ in step (3) described carboxyrnethyl starch sodium
4 is additional for total mix, and it is 65~80 DEG C that step (4), which controls drying temperature, and drying to particle water content is 3~6%.
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