CN105061528B - A kind of azithromycin compound and the Azithromycin soft capsules containing the compound - Google Patents
A kind of azithromycin compound and the Azithromycin soft capsules containing the compound Download PDFInfo
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- CN105061528B CN105061528B CN201510473561.8A CN201510473561A CN105061528B CN 105061528 B CN105061528 B CN 105061528B CN 201510473561 A CN201510473561 A CN 201510473561A CN 105061528 B CN105061528 B CN 105061528B
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Abstract
The invention belongs to pharmaceutical technology field, specifically, it is related to a kind of azithromycin compound and the soft capsule containing the compound.Azithromycin compound provided by the present invention is hydrate crystal, and its molecular formula is：C38H72N2O12·3H2O.Azithromycin hydrate crystal provided by the present invention is azithromycin trihydrate, it is a kind of crystal compound of azithromycin, the crystal compound has what is be obviously improved to draw moist compared with the azithromycin-hydrate of prior art, its draw the moist azithromycin dihydrate with prior art draw it is moist quite, and with the rate of dissolution and dissolution rate significantly improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically, it is related to a kind of azithromycin compound and containing the compound
Soft capsule.
Background technology
Azithromycin reaches antibacterial action by suppressing the synthesis of ribosomes 50s subunit proteins.It to it is a variety of it is aerobic and
Anaerobic gram-positive bacterium has antibacterial activity, can suppress the Gram-negative bacteria of many important aerobic and anaerobism.Uropoiesis is given birth to
The common pathogen chlamydia trachomatis of system separation and the urea bacteria of dissolved urea are grown, azithromycin is active, and to non-
Typical respiratory tract pathogenic bacteria CPN, mycoplasma pneumoniae also have bacteriostatic activity.The campylobacter jejuni being clinically separated is to Archie
The sensitiveness of mycin is higher than erythromycin, Clarithromycin.The helicobacter pylori being clinically separated is very sensitive to azithromycin.For
Produce some bacterial strains of beta-lactamase, such as producing enzyme staphylococcus aureus, haemophilus influenzae, haemophilus parainfluenzae, mucous membrane
The azithromycins such as scorching Moraxella can effectively be suppressed.
The oral formulations listings such as domestic at present existing conventional tablet, capsule, dry suspensoid agent, in order to improve its biological utilisation
Degree, covers its abnormal bitter taste, prior art is conducted in-depth research to the formulation and its preparation technology of azithromycin.Through reality
Checking is bright, because azithromycin is extremely bitter in itself, is dissolved in oil that soft capsule is made, both effectively masks its bitter taste, again
With it is convenient to take, rapid-action, stability is high the features such as, it is easy to be accepted by patients.
CN1857298A discloses a kind of soft capsule containing azithromycin, including：Content for 50-500mg Ah
Miramycin；Content is 25-1000mg matrix；Content is 30-200mg cosolvent, and said preparation can strengthen azithromycin
Beneficial effect.Wherein described matrix is selected from polyethylene glycol 400, Macrogol 600 or its combination.
CN1593450A, which is disclosed, is related to Azithromycin soft capsules preparation and preparation method thereof, by the Zitromax of 1 parts by weight
The cosolvent and/or 0.1-0.5 parts by weight of element and/or the polyethylene glycol of 0.5-3 parts by weight series and/or 0.1-1.0 parts by weight
Aliphatic acid mixed dissolution colourless or light yellow transparent solution is made, soft capsule is prepared using pressed film method, soft capsule is solid through cold wind
Change, dry, with appropriate solvent wash ball, eventually it is dry obtain with novel appearance, be easy to take, it is highly stable and oral after can put down
Steady absorbed soft capsule preparation.
CN101664396A discloses a kind of azithromycin and preparation method thereof, and the raw material composition of the soft capsule is：Archie
Mycin, polyethylene glycol 400, polyethylene glycol 200, water, acetic acid, 1,2-PD etc., by stirring, compacting etc. in preparation process
Step is prepared from, and experiment shows the Zitromax that pharmaceutical composition of the present invention is obtained by using preparation method of the present invention
Cellulose soft capsules preparation enables to capsule contents liquid stable without precipitation, especially replaces breast commonly used in the prior art with acetic acid
Other cosolvents such as acid, citric acid or lactobionic acid, and change common process during soft capsule is prepared and add water, this
So that the soft capsule content prepared is without precipitation, dissolving is complete, and stability is good, it is ensured that the quality of capsule 's content.
It is above-mentioned in the prior art, filled out in the preparation process of Azithromycin soft capsules as soft capsule using polyethylene glycol
Fill agent, but due to the difference of molecular weight polyethylene glycol, selected property absorbs in capsule shells that moisture is also different, causes softgel shell hardening not
Together, so as to influence drug release rate.Also, the polyethylene glycol toxicity of low molecule amount is maximum.
It is additionally, since azithromycin and draws moist with certain, and it is water-soluble bad, so as to have impact on the stability of preparation
And bioavilability.
In view of this, it is special to propose the present invention.
The content of the invention
The first object of the present invention is to provide a kind of hygroscopicity and water-soluble improved azithromycin compound.
The second object of the present invention is the preparation method of the azithromycin compound described in offer.
The third object of the present invention be to provide it is a kind of containing azithromycin compound of the present invention, it is nontoxic to human body
Property, use more comfortable, absorb more preferable Azithromycin soft capsules and preparation method thereof.
To realize the first object of the present invention, the present invention is adopted the following technical scheme that：
A kind of azithromycin compound, wherein, described azithromycin compound is hydrate crystal, and its molecular formula is：
C38H72N2O12·3H2O。
X-ray powder diffraction spectrogram such as Fig. 1 institutes that described azithromycin compound is obtained using Cu-K alpha ray measurements
Show.
Azithromycin is divided into anhydrous azithromycin, a water azithromycin, two water azithromycins and non-two water azithromycin etc.,
Wherein anhydrous and a water azithromycin hygroscopicity makes it very unstable in the formulation, thus by compared with the day of one's doom in clinical practice
System.Two water azithromycin no hygroscopicities, clinical practice is wider.However, due to azithromycin in water it is almost insoluble, make it with it
His poorly water soluble drugs are the same, and typical problem of the azithromycin in oral administration is to absorb unstable, causes bioavilability
Substantially reduce.Therefore, improving medicine dissolution rate and solubility turns into the key for improving its bioavilability.The present invention is through excessive
The experiment of amount, has been made a kind of azithromycin of brand-new crystal formation, has been studied by every physicochemical property, as a result show offer of the present invention
Azithromycin compound have it is low-down draw moist, and compared with the azithromycin of prior art, with significantly improving
Rate of dissolution and dissolution rate.
To realize the second object of the present invention, the present invention is adopted the following technical scheme that：
A kind of preparation method of azithromycin compound of the present invention, wherein, described preparation method includes as follows
Step：
1) azithromycin crude product is dissolved in absolute ethyl alcohol, obtains azithromycin ethanol solution；
2) to step 1) azithromycin ethanol solution in add activated carbon, stir, suction filtration takes filtrate；
3) under agitation to step 2) filtrate in stream plus mixed solvent A, formed turbid solution, wherein described mixing is molten
Agent A is methanol and dimethylformamide with volume ratio 2~5：The mixed solvent of 1 composition；
4) by step 3) obtained by turbid solution be placed under ultrasonic field, thereto stream plus mixed solvent B, finish, there is crystal
Separate out, wherein described mixed solvent B is water and dioxane with volume ratio 5~10：The mixed solvent of 1 composition；
5) ultrasonic field is closed, growing the grain is stood, filtering, filter cake is washed with water, and vacuum drying obtains described azithromycin
Compound.
There are a variety of crystal formations of azithromycin in the prior art, in order to obtain a kind of more preferable azithromycin of performance
Novel crystal forms, inventor constantly changes crystallization means, crystallization path and crystallization condition by experiment repeatedly, such as solvent, anti-molten
The experimental conditions such as agent, have finally given a kind of brand-new azithromycin compound, and its X-ray powder diffraction pattern shows, this hair
The solid interior molecule arranging structure of the azithromycin compound of bright offer is different from azithromycin of the prior art.
Further, in above-mentioned preparation method, step 1) described in azithromycin ethanol solution concentration for 1.2~
2.6kg/L。
Described mixed solvent A, mixed solvent B and the volume ratio of absolute ethyl alcohol are 5~10：10~30：1.
Step 3) described in the speed that stirs be 50~60r/min；Step 4) described in ultrasonic field frequency for 3.5~
6.5kHz, intensity are 0.6Wcm-2~4Wcm-2Ultrasonic field；Step 3) described in mixed solvent A flow acceleration be 13
~20L/min；Step 4) described in mixed solvent B flow acceleration be 6~12L/min.
Azithromycin crude product of the present invention can be commercially available azithromycin dihydrate bulk drug or ginseng
According to azithromycin dihydrate made from the method for prior art.
To realize the third object of the present invention, the present invention is adopted the following technical scheme that：
A kind of Azithromycin soft capsules, wherein, described Azithromycin soft capsules contain azithromycin of the present invention
Compound.
Azithromycin soft capsules of the present invention, wherein, every 1000 soft capsule contents are prepared by following mass parts
Form：
Azithromycin 125-150g
Soybean oil 375-475g；
It is preferred that, every 1000 soft capsule contents are prepared from by following mass parts：
Azithromycin 125g
Soybean oil 375g.
The gelatin formula of liquid of the Azithromycin soft capsules is made up of gelatin, glycerine, water and titanium dioxide, wherein gelatin：It is sweet
Oil：Water=0.5~1.5：0.4~0.6：0.5~1.5, the consumption of titanium dioxide is 0.5~1.5wt% of gelatin；
It is preferred that gelatin：Glycerine：Water=1：0.4：1, the consumption of titanium dioxide is the 1.0wt% of gelatin.
The present invention furthermore provides the preparation method of described Azithromycin soft capsules, and this method comprises the following steps：
1) gelatin solution is prepared：
According to gelatin formula of liquid：Gelatin：Glycerine：Water=0.5~1.5：0.4~0.6：0.5~1.5 ratio, claims respectively
Gelatin, glycerine and purified water are taken, it is standby；
To with purified water and glycerine, titanium dioxide is added in glue tank, colloid mill is crossed, 60 DEG C of insulations is heated to, adds gelatin, open
Stirring is opened, it is closed to match somebody with somebody glue tank, open vavuum pump and vacuumize, the bubble into glue is purified, gelatin all untill dissolving, is produced bright
Glue；
2) content is prepared：
The azithromycin and soybean oil of the consumption are weighed, is added in Agitation Tank, is stirred, obtain content decoction, it is standby
With；
3) prepared by soft capsule
1. adhesive tape regulation and the preliminary regulation of loading amount：
In the coating box that the gelatin solution of insulation is pressed into molding press, coating box temperature control adjusts tape thickness at 55 DEG C
Between 0.7~0.9mm, loading amount is adjusted with blank soybean oil；
2. glue capsule：
In the material storing box that content is added to molding press, adjust loading amount and suppress；The capsule suppressed is through drying to capsule skin
Preliminary hard solid, preliminarily dried to capsule shells, which shrinks, to be finished, and softgel shell flexible is rinsed with absolute ethyl alcohol, is dried, is obtained semi-finished product；Inspection
Look into qualified rear packaging and produce described Azithromycin soft capsules.
Compared with prior art, the invention has the advantages that：
(1) azithromycin compound of the invention is moist almost without drawing；
(2) azithromycin compound of the invention has the rate of dissolution and dissolution rate significantly improved.
Brief description of the drawings
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 thermogravimetric analysis figure of azithromycin compound prepared by the embodiment of the present invention 1；
Fig. 3 is the In Vitro Dissolution curve of different azithromycins；
Fig. 4 is 18 health volunteer's oral azithromycin soft capsules by being averaged after test preparation and reference preparation 500mg
Blood concentration-time curve.
Embodiment
Be below the embodiment of the present invention, described embodiment be in order to further describe the present invention, rather than
The limitation present invention.
The preparation of embodiment 1, azithromycin compound
1) by azithromycin crude product 1kg, it is dissolved in absolute ethyl alcohol 1.2L, obtains the azithromycin second that concentration is 1.2kg/L
Alcoholic solution；
2) to step 1) azithromycin ethanol solution in add activated carbon, stir, suction filtration takes filtrate；
3) under speed is 50r/min stirring with 13L/min speed to step 2) filtrate in stream plus organic solvent
A6L, forms turbid solution, wherein described mixed solvent A is methanol and dimethylformamide with volume ratio 2：The mixing of 1 composition
Solvent；
4) by step 3) obtained by turbid solution to be placed in frequency be that 3.5kHz, intensity are 0.6Wcm-2Ultrasonic field under, with
6L/min speed flows plus mixed solvent B12L thereto, finishes, there is crystal precipitation, wherein described mixed solvent B be water and
Dioxane is with volume ratio 5：The mixed solvent of 1 composition；
5) ultrasonic field is closed, growing the grain is stood, filtering, filter cake is washed with water, and vacuum drying obtains described azithromycin
Compound.
The azithromycin compound of gained uses the elemental analysers of Perkin-Elmer companies of U.S. PE 2,400 II, element
Analyzing (%) calculated value is：C(56.86)、H(9.73)、N(3.49)、O(29.92)；Elementary analysis (%) measured value：C
(56.85)、H(9.74)、N(3.50)、O(29.91)。
The azithromycin compound of gained is subjected to cassette determination of moisture, is as a result 6.73%.
The azithromycin compound of gained is determined using powder X-ray diffraction determination method, obtains as shown in Figure 1
In X-ray powder diffraction spectrogram, X-ray powder diffraction spectrogram with 2 θ angles represent 6.6 °, 7.9 °, 14.1 °, 15.7 °,
There is characteristic peak at 17.3 °, 20.0 °, 20.5 °, 24.8 °, 27.5 °, 29.5 °, 32.3 °, 35.4 °, 38.4 °, 40.0 ° and 44.1 °,
Error is ± 0.2 °.
By the azithromycin compound of gained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG heat point
The thermogravimetric analysis figure that analyzer is obtained is as shown in Fig. 2 thermogravimetric analysis experiment shows：Azithromycin compound prepared by the embodiment contains
6.741% moisture content, this is with the result containing 3 crystallizations water (theoretical value 6.733%) within error range.
The preparation of embodiment 2, azithromycin compound
1) by azithromycin crude product 1kg, it is dissolved in absolute ethyl alcohol 2.6L, obtains the azithromycin second that concentration is 2.6kg/L
Alcoholic solution；
2) to step 1) azithromycin ethanol solution in add activated carbon, stir, suction filtration takes filtrate；
3) under speed is 60r/min stirring with 20L/min speed to step 2) filtrate in stream plus organic solvent
A6L, forms turbid solution, wherein described mixed solvent A is methanol and dimethylformamide with volume ratio 5：The mixing of 1 composition
Solvent；
4) by step 3) obtained by turbid solution to be placed in frequency be that 6.5kHz, intensity are 4Wcm-2Ultrasonic field under, with
12L/min speed flows plus mixed solvent B12L thereto, finishes, there is crystal precipitation, wherein described mixed solvent B be water and
Dioxane is with volume ratio 10：The mixed solvent of 1 composition；
5) ultrasonic field is closed, growing the grain is stood, filtering, filter cake is washed with water, and vacuum drying obtains described azithromycin
Compound.
The azithromycin compound of gained is used into the elemental analysers of Perkin-Elmer companies of U.S. PE 2,400 II, member
Element analyzes (%) calculated value：C(56.86)、H(9.73)、N(3.49)、O(29.92)；Elementary analysis (%) measured value：C
(56.87)、H(9.72)、N(3.48)、O(29.93)。
The azithromycin compound of gained is subjected to cassette determination of moisture, is as a result 6.74%.
The X-ray powder diffraction spectrogram and reality obtained to obtained azithromycin compound using Cu-K alpha ray measurements
Apply the thermogravimetric analysis figure that example 1 is similar, is obtained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermal analyzers
It is similar to Example 1.
The preparation of embodiment 3, azithromycin compound
1) by azithromycin crude product 1kg, it is dissolved in absolute ethyl alcohol 2.0L, obtains the azithromycin second that concentration is 2.0kg/L
Alcoholic solution；
2) to step 1) azithromycin ethanol solution in add activated carbon, stir, suction filtration takes filtrate；
3) under speed is 55r/min stirring with 16L/min speed to step 2) filtrate in stream plus organic solvent
A6L, forms turbid solution, wherein described mixed solvent A is methanol and dimethylformamide with volume ratio 3：The mixing of 1 composition
Solvent；
4) by step 3) obtained by turbid solution to be placed in frequency be that 5.0kHz, intensity are 2Wcm-2Ultrasonic field under, with
8L/min speed flows plus mixed solvent B12L thereto, finishes, there is crystal precipitation, wherein described mixed solvent B be water and
Dioxane is with volume ratio 8：The mixed solvent of 1 composition；
5) ultrasonic field is closed, growing the grain is stood, filtering, filter cake is washed with water, and vacuum drying obtains described azithromycin
Compound.
The azithromycin compound of gained is used into the elemental analysers of Perkin-Elmer companies of U.S. PE 2,400 II, member
Element analyzes (%) calculated value：C(56.86)、H(9.73)、N(3.49)、O(29.92)；Elementary analysis (%) measured value：C
(56.89)、H(9.72)、N(3.48)、O(29.91)。
The azithromycin compound of gained is subjected to cassette determination of moisture, is as a result 6.72%.
The X-ray powder diffraction spectrogram and reality obtained to obtained azithromycin compound using Cu-K alpha ray measurements
Apply the thermogravimetric analysis figure that example 1 is similar, is obtained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermal analyzers
It is similar to Example 1.
The preparation of embodiment 4, azithromycin compound
1) by azithromycin crude product 1kg, it is dissolved in absolute ethyl alcohol 1.8L, obtains the azithromycin second that concentration is 1.8kg/L
Alcoholic solution；
2) to step 1) azithromycin ethanol solution in add activated carbon, stir, suction filtration takes filtrate；
3) under speed is 52r/min stirring with 18L/min speed to step 2) filtrate in stream plus organic solvent
A6L, forms turbid solution, wherein described mixed solvent A is methanol and dimethylformamide with volume ratio 4：The mixing of 1 composition
Solvent；
4) by step 3) obtained by turbid solution to be placed in frequency be that 5.0kHz, intensity are 1.8Wcm-2Ultrasonic field under, with
10L/min speed flows plus mixed solvent B12L thereto, finishes, there is crystal precipitation, wherein described mixed solvent B be water and
Dioxane is with volume ratio 7.5：The mixed solvent of 1 composition；
5) ultrasonic field is closed, growing the grain is stood, filtering, filter cake is washed with water, and vacuum drying obtains described azithromycin
Compound.
The azithromycin compound of gained is used into the elemental analysers of Perkin-Elmer companies of U.S. PE 2,400 II, member
Element analyzes (%) calculated value：C(56.86)、H(9.73)、N(3.49)、O(29.92)；Elementary analysis (%) measured value：C
(56.84)、H(9.71)、N(3.51)、O(29.94)。
The azithromycin compound of gained is subjected to cassette determination of moisture, is as a result 6.73%.
The X-ray powder diffraction spectrogram and reality obtained to obtained azithromycin compound using Cu-K alpha ray measurements
Apply the thermogravimetric analysis figure that example 1 is similar, is obtained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermal analyzers
It is similar to Example 1.
The preparation of embodiment 5, azithromycin compound
1) by azithromycin crude product 1kg, it is dissolved in absolute ethyl alcohol 2.2L, obtains the azithromycin second that concentration is 2.2kg/L
Alcoholic solution；
2) to step 1) azithromycin ethanol solution in add activated carbon, stir, suction filtration takes filtrate；
3) under speed is 52r/min stirring with 15L/min speed to step 2) filtrate in stream plus organic solvent
A6L, forms turbid solution, wherein described mixed solvent A is methanol and dimethylformamide with volume ratio 4.2：1 composition it is mixed
Bonding solvent；
4) by step 3) obtained by turbid solution to be placed in frequency be that 3.8kHz, intensity are 1.2Wcm-2Ultrasonic field under, with
8.5L/min speed flows plus mixed solvent B12L thereto, finishes, there is crystal precipitation, wherein described mixed solvent B is water
With dioxane with volume ratio 8.5：The mixed solvent of 1 composition；
5) ultrasonic field is closed, growing the grain is stood, filtering, filter cake is washed with water, and vacuum drying obtains described azithromycin
Compound.The azithromycin compound of gained is used into the elemental analysers of Perkin-Elmer companies of U.S. PE 2,400 II, element point
Analysing (%) calculated value is：C(56.86)、H(9.73)、N(3.49)、O(29.92)；Elementary analysis (%) measured value：C(56.89)、
H(9.72)、N(3.48)、O(29.91)。
The azithromycin compound of gained is subjected to cassette determination of moisture, is as a result 6.74%.
The X-ray powder diffraction spectrogram and reality obtained to obtained azithromycin compound using Cu-K alpha ray measurements
Apply the thermogravimetric analysis figure that example 1 is similar, is obtained using Perkin-Elmer companies of U.S. PE Pyris Diamond TG thermal analyzers
It is similar to Example 1.
The preparation of example of formulations 1, Azithromycin soft capsules
Prescription：
Preparation technology：
1) gelatin solution is prepared：
According to gelatin formula of liquid：Gelatin：Glycerine：Water=1：0.4：1 ratio, weighs gelatin, glycerine and purified water respectively,
It is standby；
To with purified water and glycerine, titanium dioxide is added in glue tank, the wherein consumption of titanium dioxide is the 1.0wt% of gelatin；Cross
Colloid mill, is heated to 60 DEG C of insulations, adds gelatin, opens stirring, closed to match somebody with somebody glue tank, opens vavuum pump and vacuumizes, into glue
Bubble purify, gelatin all dissolving untill, produce gelatin solution；
2) content is prepared：
Azithromycin trihydrate and soybean oil made from the embodiment 1 of the consumption are weighed, is added in Agitation Tank, stirring
Uniformly, content decoction is obtained, it is standby；
3) prepared by soft capsule
1. adhesive tape regulation and the preliminary regulation of loading amount：
In the coating box that the gelatin solution of insulation is pressed into molding press, coating box temperature control adjusts tape thickness at 55 DEG C
Between 0.7~0.9mm, loading amount is adjusted with blank soybean oil；
2. glue capsule：
In the material storing box that content is added to molding press, adjust loading amount and suppress；The capsule suppressed is through drying to capsule skin
Preliminary hard solid, preliminarily dried to capsule shells, which shrinks, to be finished, and softgel shell flexible is rinsed with absolute ethyl alcohol, is dried, is obtained semi-finished product；Inspection
Look into qualified rear packaging and produce described Azithromycin soft capsules.
The preparation of example of formulations 2, Azithromycin soft capsules
Prescription：
Preparation technology：
1) gelatin solution is prepared：
According to gelatin formula of liquid：Gelatin：Glycerine：Water=0.5：0.4：1.5 ratio, weighs gelatin, glycerine and pure respectively
Change water, it is standby；
To with purified water and glycerine, titanium dioxide is added in glue tank, the wherein consumption of titanium dioxide is the 0.5wt% of gelatin；Cross
Colloid mill, is heated to 60 DEG C of insulations, adds gelatin, opens stirring, closed to match somebody with somebody glue tank, opens vavuum pump and vacuumizes, into glue
Bubble purify, gelatin all dissolving untill, produce gelatin solution；
2) content is prepared：
Azithromycin trihydrate and soybean oil made from the embodiment 2 of the consumption are weighed, is added in Agitation Tank, stirring
Uniformly, content decoction is obtained, it is standby；
3) prepared by soft capsule
1. adhesive tape regulation and the preliminary regulation of loading amount：
In the coating box that the gelatin solution of insulation is pressed into molding press, coating box temperature control adjusts tape thickness at 55 DEG C
Between 0.7~0.9mm, loading amount is adjusted with blank soybean oil；
2. glue capsule：
In the material storing box that content is added to molding press, adjust loading amount and suppress；The capsule suppressed is through drying to capsule skin
Preliminary hard solid, preliminarily dried to capsule shells, which shrinks, to be finished, and softgel shell flexible is rinsed with absolute ethyl alcohol, is dried, is obtained semi-finished product；Inspection
Look into qualified rear packaging and produce described Azithromycin soft capsules.
The preparation of example of formulations 3, Azithromycin soft capsules
Prescription：
Preparation technology：
1) gelatin solution is prepared：
According to gelatin formula of liquid：Gelatin：Glycerine：Water=1.5：0.6：0.5 ratio, weighs gelatin, glycerine and pure respectively
Change water, it is standby；
To with purified water and glycerine, titanium dioxide is added in glue tank, the wherein consumption of titanium dioxide is the 1.5wt% of gelatin；Cross
Colloid mill, is heated to 60 DEG C of insulations, adds gelatin, opens stirring, closed to match somebody with somebody glue tank, opens vavuum pump and vacuumizes, into glue
Bubble purify, gelatin all dissolving untill, produce gelatin solution；
2) content is prepared：
Azithromycin trihydrate and soybean oil made from the embodiment 3 of the consumption are weighed, is added in Agitation Tank, stirring
Uniformly, content decoction is obtained, it is standby；
3) prepared by soft capsule
1. adhesive tape regulation and the preliminary regulation of loading amount：
In the coating box that the gelatin solution of insulation is pressed into molding press, coating box temperature control adjusts tape thickness at 55 DEG C
Between 0.7~0.9mm, loading amount is adjusted with blank soybean oil；
2. glue capsule：
In the material storing box that content is added to molding press, adjust loading amount and suppress；The capsule suppressed is through drying to capsule skin
Preliminary hard solid, preliminarily dried to capsule shells, which shrinks, to be finished, and softgel shell flexible is rinsed with absolute ethyl alcohol, is dried, is obtained semi-finished product；Inspection
Look into qualified rear packaging and produce described Azithromycin soft capsules.
The preparation of example of formulations 4, Azithromycin soft capsules
Prescription：
Preparation technology：
1) gelatin solution is prepared：
According to gelatin formula of liquid：Gelatin：Glycerine：Water=1.0：0.5：1.0 ratio, weighs gelatin, glycerine and pure respectively
Change water, it is standby；
To with purified water and glycerine, titanium dioxide is added in glue tank, the wherein consumption of titanium dioxide is the 1.0wt% of gelatin；Cross
Colloid mill, is heated to 60 DEG C of insulations, adds gelatin, opens stirring, closed to match somebody with somebody glue tank, opens vavuum pump and vacuumizes, into glue
Bubble purify, gelatin all dissolving untill, produce gelatin solution；
2) content is prepared：
Azithromycin trihydrate and soybean oil made from the embodiment 4 of the consumption are weighed, is added in Agitation Tank, stirring
Uniformly, content decoction is obtained, it is standby；
3) prepared by soft capsule
1. adhesive tape regulation and the preliminary regulation of loading amount：
In the coating box that the gelatin solution of insulation is pressed into molding press, coating box temperature control adjusts tape thickness at 55 DEG C
Between 0.7~0.9mm, loading amount is adjusted with blank soybean oil；
2. glue capsule：
In the material storing box that content is added to molding press, adjust loading amount and suppress；The capsule suppressed is through drying to capsule skin
Preliminary hard solid, preliminarily dried to capsule shells, which shrinks, to be finished, and softgel shell flexible is rinsed with absolute ethyl alcohol, is dried, is obtained semi-finished product；Inspection
Look into qualified rear packaging and produce described Azithromycin soft capsules.
The preparation of example of formulations 5, Azithromycin soft capsules
Prescription：
Preparation technology：
1) gelatin solution is prepared：
According to gelatin formula of liquid：Gelatin：Glycerine：Water=0.8：0.5：1.2 ratio, weighs gelatin, glycerine and pure respectively
Change water, it is standby；
To with purified water and glycerine, titanium dioxide is added in glue tank, the wherein consumption of titanium dioxide is the 0.8wt% of gelatin；Cross
Colloid mill, is heated to 60 DEG C of insulations, adds gelatin, opens stirring, closed to match somebody with somebody glue tank, opens vavuum pump and vacuumizes, into glue
Bubble purify, gelatin all dissolving untill, produce gelatin solution；
2) content is prepared：
Azithromycin trihydrate and soybean oil made from the embodiment 5 of the consumption are weighed, is added in Agitation Tank, stirring
Uniformly, content decoction is obtained, it is standby；
3) prepared by soft capsule
1. adhesive tape regulation and the preliminary regulation of loading amount：
In the coating box that the gelatin solution of insulation is pressed into molding press, coating box temperature control adjusts tape thickness at 55 DEG C
Between 0.7~0.9mm, loading amount is adjusted with blank soybean oil；
2. glue capsule：
In the material storing box that content is added to molding press, adjust loading amount and suppress；The capsule suppressed is through drying to capsule skin
Preliminary hard solid, preliminarily dried to capsule shells, which shrinks, to be finished, and softgel shell flexible is rinsed with absolute ethyl alcohol, is dried, is obtained semi-finished product；Inspection
Look into qualified rear packaging and produce described Azithromycin soft capsules.
Test example 1, draws moist test
Drawing for medicine moist refers to the how many characteristic of the material absorbing moisture under certain temperature and damp condition.
Sample：
Test specimen：Respectively according to azithromycin compound made from the embodiment of the present invention 1 to the method for embodiment 5；
Control sample 1：According to " synthesis of azithromycin dihydrate and crystallization processes are improved "【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：According to azithromycin-hydrate knot made from the method for CN200810220584.8 embodiments 1
It is brilliant.
Draws moist test method：Test specimen and appropriate control sample are taken respectively, are shone《Chinese Pharmacopoeia》(version in 2005) two
Portion's annex XIX J medicine draws moist test guidelines are tested.
Specific assay method is as follows：
1st, a certain amount of test sample is taken to put a precise weighing (m1) tool plug glass measuring cup (external diameter is 50mm, a height of
In 15mm), accurately weighed (m2)。
2nd, weighing bottleneck is placed in ± 1 DEG C of thermostatic drier of suitable 25 DEG C and (places ammonium chloride or ammonium sulfate saturation in bottom
Solution) or growth cabinet (design temperature is 25 DEG C ± 1 DEG C), relative humidity is in (80% ± 2%).
3rd, place 24 hours.
4th, measuring cup lid, precise weighing (m are covered3)。
Percentage weight increase=(m3-m2)/(m2-m1) × 100%
5th, moist feature description is drawn with drawing defining for wet weightening
It is great to draw moist：Draw wet weightening and be not less than 15%.
Have and draw moist：Draw wet weightening less than 15% and not less than 2%.
Slightly draw moist：Draw wet weightening less than 2% and not less than 0.2%.
Deliquescence：Absorb enough moisture formation liquid.
Result of the test is shown in Table 1：
Table 1, azithromycin draw moist inspection result
| Sample | Draw moist (%) |
| Embodiment 1 | 0.08 |
| Embodiment 2 | 0.07 |
| Embodiment 3 | 0.06 |
| Embodiment 4 | 0.07 |
| Embodiment 5 | 0.06 |
| Control sample 1 | 0.08 |
| Control sample 2 | 1.97 |
Above-mentioned result of the test shows, azithromycin trihydrate crystal of the invention and the water of azithromycin one of prior art
Compound is compared draws moist with what is be obviously improved, and moist almost without drawing, it draws with the azithromycin dihydrate of prior art
It is moist suitable.
Test example 2, In Vitro Dissolution experiment
Rate of dissolution and dissolution rate that this test example passes through In Vitro Dissolution experiment investigation sample.
Azithromycin medicine：
Investigational agent：Azithromycin trihydrate crystal made from the embodiment of the present invention 1；
Comparison medicine 1：According to " synthesis of azithromycin dihydrate and crystallization processes are improved "【Cao Wei, Wang Yunbin, wait Ah
The synthesis of miramycin dihydrate and crystallization processes improve [J], fine-chemical intermediate, 2012,42 (3)：50-51】Method
Obtained azithromycin dihydrate；
Comparison medicine 2：According to azithromycin-hydrate crystallization made from the method for CN200810220584.8 embodiments 1.
Dissolution in vitro test method：According to《Chinese Pharmacopoeia》Method (the oar of dissolution method the 2nd in 2005 editions (2 editions)
Method), In Vitro Dissolution experiment is carried out to different azithromycin samples.(matched somebody with somebody as dissolution medium using pH=7.4 phosphate buffers
The degassed processing of palpus before the deionized water of dissolution medium processed), digestion instrument rotating speed of agitator and bath temperature are respectively set as
100r/min and 37 ± 0.5 DEG C.2,5,10,15,30,45,60, the 90 and 120min samplings 5mL after input sample, is used in combination respectively
0.45 μm of membrane filtration；By gained filtrate through H2SO4After solution (75 → 100) colour developing, its ultraviolet light absorption is determined at 482nm
Degree, the amount that medicine is dissolved in dissolution medium is calculated according to the dissolution standard curve determined in advance, and draw drug-eluting curve, table
Levy drug solubility energy.
The In Vitro Dissolution test result of different azithromycin samples is as shown in Figure 3.From figure 3, it can be seen that the present invention
Initial dissolution rate of the azithromycin hydrate crystal in cushioning liquid is significantly improved, and is being thrown in cup 10min, the dissolution of medicine
Degree is up to 60%, 2.6 times, 3 times of the dissolution rate of reference substance 2 of the about same dissolution rate of time comparison product 1；And reference substance 1, control
Product 2 will reach that identical dissolution rate needs 40min or so.This fully shows that the azithromycin hydrate crystal of the present invention can be carried significantly
High rate of dissolution and dissolution rate.
Above-mentioned experiment is also carried out to the azithromycin trihydrate crystal prepared by other embodiments of the present invention, it is obtained
Result it is similar.
Test example 3,
1st, prescription screening
It is soft capsule matrix from conventional oral soybean oil, passes through dissolving situation of the main ingredient azithromycin in soybean oil
The prescription screening of according to the form below 2 is carried out.
Table 2, prescription screening experiment
2nd, the stability of solution
The stability of content decoction is directly affected before encapsulated, suspension solid precipitation and its uniform during encapsulated and after encapsulated
Property, and influence the accurate of divided dose.The present invention observes its suspension ability with sedimentation volumn determination method, is shown in Table 3.
The settling ratio result of the test of table 3, decoction
Result of the test shows that this product dispersion ratio in oil is more uniform, and stability is good.
3rd, distributed test again
By the suspension after above-mentioned placement a period of time, rotated with 20r/min speed, by the rotation of certain time,
Whether the precipitum of observation graduated cylinder bottom disperses again, and result of the test shows, this product is again well dispersed in vegetable oil.
4th, the selection of soft capsule size
By above-mentioned experiment, the ratio of selection medicine and matrix is 125：375, in actual production process, the loading amount of machine
There is the error of bound, to ensure to produce attractive in appearance, high-quality capsule, be defined as No. 8 moulds.
5th, the selection of colouring agent and its consumption
Because this product content liquid be oil-based suspension, it is considered to capsule it is specious, in capsule shells use appropriate screening
Lid agent.Present invention selection titanium dioxide is used as covering agent.Stability of drug products result of the test shows that titanium dioxide be (gelatin consumption
1.0%) content on soft capsule content is influenceed without significant change, and disintegration time limited slightly has extension, but meets regulation, therefore selects
Titanium dioxide (the 1.0% of gelatin consumption) is used as the covering agent of Azithromycin soft capsules.
6th, the principal element experiment of influence soft capsule quality and the basis for selecting of packaging material
Azithromycin soft capsules made from invention formulation embodiment 1 are taken, outer packing are removed, respectively in 60 DEG C of high temperature, light
Placed according under the drastic conditions such as 4500 ± 500Lux, high humility RH92.5%, in 0,5,10 days sampling analyses.Investigate outward appearance, contain
Amount and relevant material.It the results are shown in Table 4~table 6.
The influence factor result of the test of table 4, Azithromycin soft capsules under 60 DEG C of hot conditions
The influence factor result of the test of table 5, Azithromycin soft capsules under the conditions of 4500Lx light irradiations
The influence factor result of the test of table 6, Azithromycin soft capsules under the conditions of air exposure
This product is placed under the conditions of high humility RH92.5%, because softgel shell is adhered, so can not determine.
Test, as a result show through influence factors such as illumination, high temperature, high humility：The soft capsule should not be in high humidity, hot conditions
It is lower to place, protection against the tide should be used, packed.
Test example 4, pharmacokinetic trial
1st, medicine
By test preparation：Azithromycin soft capsules made from invention formulation embodiment 1, specification：Every 125mg is (with Archie
Mycin meter)；Reference preparation：According to Azithromycin soft capsules made from the prescription and method of invention formulation embodiment 1, institute is different
Be used azithromycin be commercially available azithromycin dihydrate bulk drug, specification：Every 125mg is (with azithromycin
Meter).
2nd, the selection of subject
18 healthy male subjects, year at age (21.34 ± 1.12), body weight (67.89 ± 7.24) kg.Whole subjects
Through inquiring medical history, check to be normal, no habits of smoking and alcohol drinking through electrocardiogram, Liver and kidney function etc., during first 14 days of experiment and experiment not
With other any medicines.In illustrating test objective, medicinal property, clinical application range to subject before experiment and be likely to occur
Adverse drug reaction.By signed informed consent form.Testing program is performed after ratifying through Ethics Committee.
3rd, medication and blood specimen collection
Using 2 cycle dual crossing experimental designs.
18 healthy volunteers are randomly divided into 2 groups of test group and control group, every group of 9 people.Test group is taken by test preparation；It is right
Reference preparation is taken according to group.After subject's fasting 12h, in early morning 7:00 difference empty stomach oral test and reference preparation 500mg are used
Warm water 250mL takes, and enters standard meal in 4h 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,
72.0th, 96.0,120.0,144.0h, takes upper arm venous blood 4.0mL, anticoagulant heparin, centrifugation, separated plasma, in -40 DEG C of refrigerators
Preserve to be measured.
During experiment, researcher records blood sampling time and adverse drug reaction in detail.Whole process is by training through GCP
Clinician and nurse are observed and handled in time.
4th, with reference to " pharmacokinetics and relative bioavailability of the Azithromycin soft capsules in healthy volunteer "【Wu Hui
Wise man, Wei Minjie waits Azithromycin soft capsules in the pharmacokinetics and relative bioavailability [J] of healthy volunteer, China faces
Bed pharmacology magazine, 2007,23 (6)：442-445】Method determine 18 health volunteer's oral azithromycins by test preparation
With the blood concentration-time data after reference preparation 500mg, mean blood plasma concentration-time graph is drawn, as shown in Figure 4.
It can be seen that from mean blood plasma concentration-time graph of azithromycin and be better than reference preparation by the Cmax of test preparation,
AUC is calculated using trapezoidal method, as a result shows the AUC by test preparation also superior to reference preparation.
Claims (11)
1. a kind of azithromycin compound crystal, it is characterised in that described azithromycin compound crystal is hydrate crystal,
Its molecular formula is：C38H72N2O12·3H2O；The X-ray powder that described azithromycin compound is obtained using Cu-K alpha ray measurements
Last diffraction spectrogram is as shown in Figure 1.
2. a kind of preparation method of the azithromycin compound crystal described in claim 1, it is characterised in that described preparation side
Method comprises the following steps：
1) azithromycin crude product is dissolved in absolute ethyl alcohol, obtains azithromycin ethanol solution；
2) to step 1) azithromycin ethanol solution in add activated carbon, stir, suction filtration takes filtrate；
3) under agitation to step 2) filtrate in stream plus mixed solvent A, formed turbid solution, wherein described mixed solvent A
It is methanol and dimethylformamide with volume ratio 2~5：The mixed solvent of 1 composition；
4) by step 3) obtained by turbid solution be placed under ultrasonic field, thereto stream plus mixed solvent B, finish, there is crystal precipitation,
Wherein described mixed solvent B is water and dioxane with volume ratio 5~10：The mixed solvent of 1 composition；
5) ultrasonic field is closed, growing the grain is stood, filtering, filter cake is washed with water, and vacuum drying obtains described azithromycin compound
Crystal.
3. preparation method according to claim 2, it is characterised in that step 1) described in azithromycin ethanol solution
Concentration is 1.2~2.6kg/L.
4. preparation method according to claim 2, it is characterised in that described mixed solvent A, mixed solvent B and anhydrous
The volume ratio of ethanol is 5~10：10~30：1.
5. preparation method according to claim 2, it is characterised in that step 3) described in the speed that stirs be 50~60r/
min；Step 4) described in the frequency of ultrasonic field be that 3.5~6.5kHz, intensity are 0.6Wcm-2~4Wcm-2Ultrasonic field；
Step 3) described in mixed solvent A flow acceleration be 13~20L/min；Step 4) described in mixed solvent B flow acceleration
For 6~12L/min.
6. a kind of Azithromycin soft capsules, it is characterised in that described Azithromycin soft capsules contain the Ah described in claim 1
Miramycin compound crystal.
7. Azithromycin soft capsules according to claim 6, it is characterised in that every 1000 soft capsule contents are by following
Mass parts are prepared from：
Azithromycin 125-150g
Soybean oil 375-475g.
8. Azithromycin soft capsules according to claim 7, it is characterised in that every 1000 soft capsule contents are by following
Mass parts are prepared from：
Azithromycin 125g
Soybean oil 375g.
9. Azithromycin soft capsules according to claim 8, it is characterised in that the gelatin solution of the Azithromycin soft capsules
Formula is made up of gelatin, glycerine, water and titanium dioxide, wherein gelatin：Glycerine：Water=0.5~1.5：0.4~0.6：0.5~1.5,
The consumption of titanium dioxide is 0.5~1.5wt% of gelatin.
10. Azithromycin soft capsules according to claim 9, it is characterised in that gelatin：Glycerine：Water=1：0.4：1, titanium
The consumption of white powder is the 1.0wt% of gelatin.
11. the preparation method of the Azithromycin soft capsules described in a kind of claim 7 or 8 or 9 or 10, it is characterised in that described
Preparation method comprise the following steps：
1) gelatin solution is prepared：
According to gelatin formula of liquid：Gelatin：Glycerine：Water=0.5~1.5：0.4~0.6：0.5~1.5 ratio, is weighed bright respectively
Glue, glycerine and purified water, it is standby；
To with purified water and glycerine, titanium dioxide is added in glue tank, colloid mill is crossed, 60 DEG C of insulations is heated to, adds gelatin, unlatching is stirred
Mix, it is closed to match somebody with somebody glue tank, open vavuum pump and vacuumize, the bubble into glue is purified, gelatin all untill dissolving, produces gelatin
Liquid；
2) content is prepared：
The azithromycin and soybean oil of the consumption are weighed, is added in Agitation Tank, is stirred, obtain content decoction, it is standby；
3) prepared by soft capsule
1. adhesive tape regulation and the preliminary regulation of loading amount：
In the coating box that the gelatin solution of insulation is pressed into molding press, coating box temperature control is at 55 DEG C, and regulation tape thickness is 0.7
Between~0.9mm, loading amount is adjusted with blank soybean oil；
2. glue capsule：
In the material storing box that content is added to molding press, adjust loading amount and suppress；The capsule suppressed is preliminary to capsule skin through drying
Hard solid, preliminarily dried to capsule shells, which shrinks, to be finished, and softgel shell flexible is rinsed with absolute ethyl alcohol, is dried, is obtained semi-finished product；Check and close
Packaging produces described Azithromycin soft capsules after lattice.
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| SI8110592A8 (en) * | 1981-03-06 | 1996-06-30 | Pliva Pharm & Chem Works | Process for preparing of n-methyl-11-aza-10-deoxo-10-dihydroerythromycine a and derivatives thereof |
| CN1093370A (en) * | 1993-12-10 | 1994-10-12 | 北京市集才药物研究所 | A kind of new azido erythromycin crystal and preparation method thereof |
| CN1161971A (en) * | 1997-01-03 | 1997-10-15 | 石家庄制药集团有限公司 | Azimycin crystal and preparation method thereof |
| KR100431431B1 (en) * | 2001-04-25 | 2004-05-14 | 한미약품 주식회사 | Clathrate of azithromycin hydrate with 1,2-propyleneglycol, methods for the manufacture thereof, and pharmaceutical compositions thereof |
| UA74887C2 (en) * | 2001-05-22 | 2006-02-15 | Pfizer Prod Inc | A crystalline form of azythromycin |
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