CN105061528A - Azithromycin compound and azithromycin soft capsule containing azithromycin compound - Google Patents
Azithromycin compound and azithromycin soft capsule containing azithromycin compound Download PDFInfo
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- CN105061528A CN105061528A CN201510473561.8A CN201510473561A CN105061528A CN 105061528 A CN105061528 A CN 105061528A CN 201510473561 A CN201510473561 A CN 201510473561A CN 105061528 A CN105061528 A CN 105061528A
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- azythromycin
- azithromycin
- gelatin
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Abstract
The invention belongs to the technical field of medicines and relates to an azithromycin compound and an azithromycin soft capsule containing the azithromycin compound. The azithromycin compound is a hydrate crystal and has a molecular formula of C38H72N2O12.3H2O. The azithromycin hydrate crystal is azithromycin trihydrate and is a novel crystal form azithromycin compound. Compared with the existing azithromycin monohydrate, the novel crystal form azithromycin compound has higher hygroscopicity the same to that of the existing azithromycin dihydrate and has higher dissolution rate and ratio.
Description
Technical field
The invention belongs to medical art, specifically, relate to a kind of Azythromycin compound and the soft capsule containing this compound.
Background technology
Azythromycin reaches anti-microbial effect by suppressing the matter synthesis of rrna 50s protein subunit.It has anti-microbial activity to multiple aerobic and anaerobic gram-positive bacterium, can suppress the Gram-negative bacteria of many important aerobic and anaerobism.The common pathogen chlamydia trachomatis be separated urogenital system and the urea bacteria of dissolved urea, Azythromycin all has activity, and also has bacteriostatic activity to atypical respiratory pathogenic bacterium Chlamydia pneumoniae, mycoplasma pneumoniae.The campylobacter jejuni of clinical separation to the susceptibility of Azythromycin higher than erythromycin, Clarithromycin.The helicobacter pylori of clinical separation is very responsive to Azythromycin.For some bacterial strains producing β-lactamase, all can effectively be suppressed as produced the Azythromycins such as enzyme streptococcus aureus, hemophilus influenzae, haemophilus parainfluenzae, Moraxella catarrhalis.
The oral preparations listings such as current domestic existing conventional tablet, capsule, dry suspensoid, in order to improve its bioavailability, cover the bitter taste of its exception, prior art conducts in-depth research the formulation of Azythromycin and preparation technology thereof.The experiment proved that, because Azythromycin itself is extremely bitter, is dissolved in oil and makes soft capsule, both effectively masked its bitter taste to there is again easy administration, rapid-action, stability high, be easy to be accepted by patient.
CN1857298A discloses a kind of soft capsule containing Azythromycin, comprising: content is the Azythromycin of 50-500mg; Content is the matrix of 25-1000mg; Content is the solubility promoter of 30-200mg, and said preparation can strengthen the beneficial effect of Azythromycin.Wherein said matrix is selected from poly(oxyethylene glycol) 400, Polyethylene Glycol-600 or its combination.
CN1593450A discloses and relates to Azithromycin soft capsules preparation and preparation method thereof, the polyoxyethylene glycol of the Azythromycin of 1 weight part and/or 0.5-3 weight part series and/or the solubility promoter of 0.1-1.0 weight part and/or the lipid acid mixed dissolution of 0.1-0.5 weight part are obtained colourless or light yellow transparent solution, pressed film method is adopted to prepare soft capsule, soft capsule through solidifying by cooling in wind, drying, with suitable solvent wash ball, eventually dryly obtain that there is novel appearance, be convenient to take, highly stable and oral after can steady absorbed soft capsule preparation.
CN101664396A discloses a kind of Azythromycin and preparation method thereof, the raw material of this soft capsule consists of: Azythromycin, poly(oxyethylene glycol) 400, Macrogol 200, water, acetic acid, 1, 2-propylene glycol etc., through stirring in preparation process, the steps such as compacting are prepared from, experiment shows that pharmaceutical composition of the present invention can make capsule contents liquid stable without separating out by the Azithromycin soft capsules preparation that employing preparation method of the present invention obtains, especially lactic acid conventional in prior art is replaced with acetic acid, other solubility promoters such as Citric Acid or lactobionic acid, and change common process in soft capsule process and add water preparing, this makes the soft capsule content prepared without precipitation, dissolve completely, good stability, ensure that the quality of capsule 's content.
In above-mentioned prior art, in the preparation process of Azithromycin soft capsules, all adopt polyoxyethylene glycol as soft capsule weighting agent, but due to the difference of molecular weight polyethylene glycol, it is also different that selected property absorb moisture in capsule shell, cause softgel shell to harden different, thus affect drug release rate.Further, low-molecular-weight polyoxyethylene glycol toxicity is maximum.
And, certain draw moist, and water-soluble bad because Azythromycin has, thus have impact on stability and the bioavailability of preparation.
In view of this, special proposition the present invention.
The multiple crystal formation of Azythromycin has been there is in prior art, in order to obtain the new crystal of the better Azythromycin of a kind of performance, contriver is through test repeatedly, continuous change crystallization means, crystallization path and crystallization condition, as the test conditions such as solvent, anti-solvent, finally obtain a kind of brand-new Azythromycin compound, its X-ray powder diffraction pattern shows, the solid interior molecule arranging structure of Azythromycin compound provided by the invention is different from Azythromycin of the prior art.
Further, in above-mentioned preparation method, step 1) described in the concentration of Azythromycin ethanolic soln be 1.2 ~ 2.6kg/L.
The volume ratio of described mixed solvent A, mixed solvent B and dehydrated alcohol is 5 ~ 10:10 ~ 30:1.
Step 3) described in stir speed be 50 ~ 60r/min; Step 4) described in the frequency of ultrasonic field be 3.5 ~ 6.5kHz, intensity is 0.6Wcm
-2~ 4Wcm
-2ultrasonic field; Step 3) described in the flow acceleration of mixed solvent A be 13 ~ 20L/min; Step 4) described in the flow acceleration of mixed solvent B be 6 ~ 12L/min.
Azythromycin crude product of the present invention can be commercially available azithromycin dihydrate bulk drug, also can be with reference to the obtained azithromycin dihydrate of the method for prior art.
For realizing the third object of the present invention, the present invention adopts following technical scheme:
A kind of Azithromycin soft capsules, wherein, described Azithromycin soft capsules contains Azythromycin compound of the present invention.
Azithromycin soft capsules of the present invention, wherein, every 1000 soft capsule contents are prepared from by following mass parts:
Azythromycin 125-150g
Soybean oil 375-475g;
Preferably, every 1000 soft capsule contents are prepared from by following mass parts:
Azythromycin 125g
Soybean oil 375g.
The gelatin solution formula of described Azithromycin soft capsules 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, and the consumption of titanium dioxide is 0.5 ~ 1.5wt% of gelatin;
Preferred gelatin: glycerine: water=1:0.4:1, the consumption of titanium dioxide is the 1.0wt% of gelatin.
The present invention also provides the preparation method of described Azithromycin soft capsules further, and the method comprises the steps:
1) gelatin solution preparation:
According to gelatin solution formula: gelatin: glycerine: the ratio of water=0.5 ~ 1.5:0.4 ~ 0.6:0.5 ~ 1.5, take gelatin, glycerine and purified water respectively, for subsequent use;
Adding purified water and glycerine, titanium dioxide to joining in glue tank, crossing colloidal mill, being heated to 60 DEG C of insulations, adding gelatin, open and stir, airtightly join glue tank, unlatching vacuum pump evacuation, purifies to the bubble in glue, till gelatin all dissolves, obtains gelatin solution;
2) content preparation:
Take Azythromycin and the soybean oil of described consumption, add in Agitation Tank, stir, obtain content liquid, for subsequent use;
3) soft capsule preparation
1. the preliminary adjustment of adhesive tape adjustment and loading amount:
By in the coating box of the gelatin solution of insulation press-in press molding machine, coating box temperature controls at 55 DEG C, regulates tape thickness between 0.7 ~ 0.9mm, regulates loading amount by blank soybean oil;
2. glue capsule:
Added by content in the materials-stored box of press molding machine, adjustment loading amount is also suppressed; The capsule suppressed is tentatively firmly solid to capsule skin through blowing, and preliminarily dried shrinks complete to capsule shell, softgel shell flexible, rinses with dehydrated alcohol, dry, obtains work in-process; Pack after passed examination and obtain described Azithromycin soft capsules.
Compared with prior art, tool of the present invention has the following advantages:
(1) Azythromycin compound of the present invention is almost moist without drawing;
(2) Azythromycin compound of the present invention has the dissolution rate and dissolution rate that significantly improve.
Summary of the invention
The first object of the present invention is the Azythromycin compound providing a kind of water absorbability and water-soluble improvement.
The second object of the present invention is to provide the preparation method of described Azythromycin compound.
The third object of the present invention is to provide a kind of containing Azythromycin compound of the present invention, to human non-toxic's property, use more comfortable, absorbs better Azithromycin soft capsules and preparation method thereof.
For realizing the first object of the present invention, the present invention adopts following technical scheme:
A kind of Azythromycin compound, wherein, described Azythromycin compound is hydrate crystal, and its molecular formula is: C
38h
72n
2o
123H
2o.
The X-ray powder diffractogram that described Azythromycin compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
Azythromycin is divided into anhydrous Azythromycin, a water Azythromycin, two water Azythromycins and non-two water Azythromycins etc., and wherein water absorbability that is anhydrous and a water Azythromycin makes it very unstable in the formulation, thus in clinical application, is subject to larger restriction.Two water Azythromycin no hygroscopicities, clinical application is wider.But because Azythromycin is almost insoluble in water, make it the same with other poorly water soluble drugs, the typical problem of Azythromycin in oral administration absorbs instability, causes bioavailability greatly to reduce.Therefore, raising medicine dissolution rate and solubleness become the key improving its bioavailability.The present invention is through a large amount of tests, obtain a kind of Azythromycin of brand-new crystal formation, studied by every physicochemical property, result show Azythromycin compound provided by the invention have low-down draw moist, and compared with the Azythromycin of prior art, there is the dissolution rate and dissolution rate that significantly improve.
For realizing the second object of the present invention, the present invention adopts following technical scheme:
A preparation method for Azythromycin compound of the present invention, wherein, described preparation method comprises the steps:
1) Azythromycin crude product is dissolved in dehydrated alcohol, obtains Azythromycin ethanolic soln;
2) to step 1) Azythromycin ethanolic soln in add gac, stir, suction filtration, gets filtrate;
3) under agitation to step 2) filtrate in stream add mixed solvent A, formed turbid solution, wherein said mixed solvent A is the mixed solvent that methyl alcohol and dimethyl formamide form with volume ratio 2 ~ 5:1;
4) by step 3) under the turbid solution of gained is placed in ultrasonic field, stream adds mixed solvent B wherein, finishes, and has crystal to separate out, and wherein said mixed solvent B is the mixed solvent that water and dioxane form with volume ratio 5 ~ 10:1;
5) close ultrasonic field, leave standstill growing the grain, filter, filter cake washes with water, and vacuum-drying obtains described Azythromycin compound.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffractogram of Azythromycin compound prepared by the embodiment of the present invention 1;
Fig. 2 is the thermogravimetric analysis figure of Azythromycin compound prepared by the embodiment of the present invention 1;
Fig. 3 is the In Vitro Dissolution curve of different Azythromycins;
Fig. 4 is that 18 health volunteer's oral azithromycin soft capsules are by the mean blood plasma concentration-time curve after test preparation and reference preparation 500mg.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is to further describe the present invention, instead of restriction the present invention.
The preparation of embodiment 1, Azythromycin compound
1) by Azythromycin crude product 1kg, be dissolved in dehydrated alcohol 1.2L, obtain the Azythromycin ethanolic soln that concentration is 1.2kg/L;
2) to step 1) Azythromycin ethanolic soln in add gac, stir, suction filtration, gets filtrate;
3) in speed be 50r/min stirring under with the speed of 13L/min to step 2) filtrate in stream add organic solvent A 6L, form turbid solution, wherein said mixed solvent A is the mixed solvent that methyl alcohol and dimethyl formamide form with volume ratio 2:1;
4) by step 3) turbid solution of gained is placed in that frequency is 3.5kHz, intensity is 0.6Wcm
-2ultrasonic field under, with the speed of 6L/min wherein stream add mixed solvent B12L, finish, have crystal to separate out, wherein said mixed solvent B is the mixed solvent that water and dioxane form with volume ratio 5:1;
5) close ultrasonic field, leave standstill growing the grain, filter, filter cake washes with water, and vacuum-drying obtains described Azythromycin compound.
The Azythromycin compound of gained adopts U.S. Perkin-Elmer company PE2400 II elemental analyser, and ultimate analysis (%) calculated value is: C (56.86), H (9.73), N (3.49), O (29.92); Ultimate analysis (%) measured value: C (56.85), H (9.74), N (3.50), O (29.91).
The Azythromycin compound of gained is carried out cassette moisture determination, and result is 6.73%.
Powder X-ray diffraction assay method is used to measure the Azythromycin compound of gained, obtain X-ray powder diffractogram as shown in Figure 1, represent there is characteristic peak at 6.6 °, 7.9 °, 14.1 °, 15.7 °, 17.3 °, 20.0 °, 20.5 °, 24.8 °, 27.5 °, 29.5 °, 32.3 °, 35.4 °, 38.4 °, 40.0 ° and 44.1 ° of places with 2 θ angles in X-ray powder diffractogram, error is ± 0.2 °.
The thermogravimetric analysis figure adopting U.S. Perkin-Elmer company PEPyrisDiamondTG thermal analyzer to obtain the Azythromycin compound of gained as shown in Figure 2, thermogravimetric analysis experiment shows: Azythromycin compound prepared by this embodiment contains the moisture content of 6.741%, and this and the result containing 3 crystal water (theoretical value is 6.733%) are within limit of error.
The preparation of embodiment 2, Azythromycin compound
1) by Azythromycin crude product 1kg, be dissolved in dehydrated alcohol 2.6L, obtain the Azythromycin ethanolic soln that concentration is 2.6kg/L;
2) to step 1) Azythromycin ethanolic soln in add gac, stir, suction filtration, gets filtrate;
3) in speed be 60r/min stirring under with the speed of 20L/min to step 2) filtrate in stream add organic solvent A 6L, form turbid solution, wherein said mixed solvent A is the mixed solvent that methyl alcohol and dimethyl formamide form with volume ratio 5:1;
4) by step 3) turbid solution of gained is placed in that frequency is 6.5kHz, intensity is 4Wcm
-2ultrasonic field under, with the speed of 12L/min wherein stream add mixed solvent B12L, finish, have crystal to separate out, wherein said mixed solvent B is the mixed solvent that water and dioxane form with volume ratio 10:1;
5) close ultrasonic field, leave standstill growing the grain, filter, filter cake washes with water, and vacuum-drying obtains described Azythromycin compound.
The Azythromycin compound of gained is adopted U.S. Perkin-Elmer company PE2400 II elemental analyser, and ultimate analysis (%) calculated value is: C (56.86), H (9.73), N (3.49), O (29.92); Ultimate analysis (%) measured value: C (56.87), H (9.72), N (3.48), O (29.93).
The Azythromycin compound of gained is carried out cassette moisture determination, and result is 6.74%.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to obtained Azythromycin compound is similar to embodiment 1, and the thermogravimetric analysis figure adopting U.S. Perkin-Elmer company PEPyrisDiamondTG thermal analyzer to obtain is similar to embodiment 1.
The preparation of embodiment 3, Azythromycin compound
1) by Azythromycin crude product 1kg, be dissolved in dehydrated alcohol 2.0L, obtain the Azythromycin ethanolic soln that concentration is 2.0kg/L;
2) to step 1) Azythromycin ethanolic soln in add gac, stir, suction filtration, gets filtrate;
3) in speed be 55r/min stirring under with the speed of 16L/min to step 2) filtrate in stream add organic solvent A 6L, form turbid solution, wherein said mixed solvent A is the mixed solvent that methyl alcohol and dimethyl formamide form with volume ratio 3:1;
4) by step 3) turbid solution of gained is placed in that frequency is 5.0kHz, intensity is 2Wcm
-2ultrasonic field under, with the speed of 8L/min wherein stream add mixed solvent B12L, finish, have crystal to separate out, wherein said mixed solvent B is the mixed solvent that water and dioxane form with volume ratio 8:1;
5) close ultrasonic field, leave standstill growing the grain, filter, filter cake washes with water, and vacuum-drying obtains described Azythromycin compound.
The Azythromycin compound of gained is adopted U.S. Perkin-Elmer company PE2400 II elemental analyser, and ultimate analysis (%) calculated value is: C (56.86), H (9.73), N (3.49), O (29.92); Ultimate analysis (%) measured value: C (56.89), H (9.72), N (3.48), O (29.91).
The Azythromycin compound of gained is carried out cassette moisture determination, and result is 6.72%.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to obtained Azythromycin compound is similar to embodiment 1, and the thermogravimetric analysis figure adopting U.S. Perkin-Elmer company PEPyrisDiamondTG thermal analyzer to obtain is similar to embodiment 1.
The preparation of embodiment 4, Azythromycin compound
1) by Azythromycin crude product 1kg, be dissolved in dehydrated alcohol 1.8L, obtain the Azythromycin ethanolic soln that concentration is 1.8kg/L;
2) to step 1) Azythromycin ethanolic soln in add gac, stir, suction filtration, gets filtrate;
3) in speed be 52r/min stirring under with the speed of 18L/min to step 2) filtrate in stream add organic solvent A 6L, form turbid solution, wherein said mixed solvent A is the mixed solvent that methyl alcohol and dimethyl formamide form with volume ratio 4:1;
4) by step 3) turbid solution of gained is placed in that frequency is 5.0kHz, intensity is 1.8Wcm
-2ultrasonic field under, with the speed of 10L/min wherein stream add mixed solvent B12L, finish, have crystal to separate out, wherein said mixed solvent B is the mixed solvent that water and dioxane form with volume ratio 7.5:1;
5) close ultrasonic field, leave standstill growing the grain, filter, filter cake washes with water, and vacuum-drying obtains described Azythromycin compound.
The Azythromycin compound of gained is adopted U.S. Perkin-Elmer company PE2400 II elemental analyser, and ultimate analysis (%) calculated value is: C (56.86), H (9.73), N (3.49), O (29.92); Ultimate analysis (%) measured value: C (56.84), H (9.71), N (3.51), O (29.94).
The Azythromycin compound of gained is carried out cassette moisture determination, and result is 6.73%.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to obtained Azythromycin compound is similar to embodiment 1, and the thermogravimetric analysis figure adopting U.S. Perkin-Elmer company PEPyrisDiamondTG thermal analyzer to obtain is similar to embodiment 1.
The preparation of embodiment 5, Azythromycin compound
1) by Azythromycin crude product 1kg, be dissolved in dehydrated alcohol 2.2L, obtain the Azythromycin ethanolic soln that concentration is 2.2kg/L;
2) to step 1) Azythromycin ethanolic soln in add gac, stir, suction filtration, gets filtrate;
3) in speed be 52r/min stirring under with the speed of 15L/min to step 2) filtrate in stream add organic solvent A 6L, form turbid solution, wherein said mixed solvent A is the mixed solvent that methyl alcohol and dimethyl formamide form with volume ratio 4.2:1;
4) by step 3) turbid solution of gained is placed in that frequency is 3.8kHz, intensity is 1.2Wcm
-2ultrasonic field under, with the speed of 8.5L/min wherein stream add mixed solvent B12L, finish, have crystal to separate out, wherein said mixed solvent B is the mixed solvent that water and dioxane form with volume ratio 8.5:1;
5) close ultrasonic field, leave standstill growing the grain, filter, filter cake washes with water, and vacuum-drying obtains described Azythromycin compound.The Azythromycin compound of gained is adopted U.S. Perkin-Elmer company PE2400 II elemental analyser, and ultimate analysis (%) calculated value is: C (56.86), H (9.73), N (3.49), O (29.92); Ultimate analysis (%) measured value: C (56.89), H (9.72), N (3.48), O (29.91).
The Azythromycin compound of gained is carried out cassette moisture determination, and result is 6.74%.
The X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain to obtained Azythromycin compound is similar to embodiment 1, and the thermogravimetric analysis figure adopting U.S. Perkin-Elmer company PEPyrisDiamondTG thermal analyzer to obtain is similar to embodiment 1.
The preparation of example of formulations 1, Azithromycin soft capsules
Prescription:
Preparation technology:
1) gelatin solution preparation:
According to gelatin solution formula: gelatin: glycerine: the ratio of water=1:0.4:1, take gelatin, glycerine and purified water respectively, for subsequent use;
Add purified water and glycerine, titanium dioxide to joining in glue tank, wherein the consumption of titanium dioxide is the 1.0wt% of gelatin; Cross colloidal mill, be heated to 60 DEG C of insulations, add gelatin, open and stir, airtightly join glue tank, open vacuum pump evacuation, purify to the bubble in glue, till gelatin all dissolves, obtain gelatin solution;
2) content preparation:
The Azythromycin trihydrate that the embodiment 1 taking described consumption obtains and soybean oil, add in Agitation Tank, stir, obtain content liquid, for subsequent use;
3) soft capsule preparation
1. the preliminary adjustment of adhesive tape adjustment and loading amount:
By in the coating box of the gelatin solution of insulation press-in press molding machine, coating box temperature controls at 55 DEG C, regulates tape thickness between 0.7 ~ 0.9mm, regulates loading amount by blank soybean oil;
2. glue capsule:
Added by content in the materials-stored box of press molding machine, adjustment loading amount is also suppressed; The capsule suppressed is tentatively firmly solid to capsule skin through blowing, and preliminarily dried shrinks complete to capsule shell, softgel shell flexible, rinses with dehydrated alcohol, dry, obtains work in-process; Pack after passed examination and obtain described Azithromycin soft capsules.
The preparation of example of formulations 2, Azithromycin soft capsules
Prescription:
Preparation technology:
1) gelatin solution preparation:
According to gelatin solution formula: gelatin: glycerine: the ratio of water=0.5:0.4:1.5, take gelatin, glycerine and purified water respectively, for subsequent use;
Add purified water and glycerine, titanium dioxide to joining in glue tank, wherein the consumption of titanium dioxide is the 0.5wt% of gelatin; Cross colloidal mill, be heated to 60 DEG C of insulations, add gelatin, open and stir, airtightly join glue tank, open vacuum pump evacuation, purify to the bubble in glue, till gelatin all dissolves, obtain gelatin solution;
2) content preparation:
The Azythromycin trihydrate that the embodiment 2 taking described consumption obtains and soybean oil, add in Agitation Tank, stir, obtain content liquid, for subsequent use;
3) soft capsule preparation
1. the preliminary adjustment of adhesive tape adjustment and loading amount:
By in the coating box of the gelatin solution of insulation press-in press molding machine, coating box temperature controls at 55 DEG C, regulates tape thickness between 0.7 ~ 0.9mm, regulates loading amount by blank soybean oil;
2. glue capsule:
Added by content in the materials-stored box of press molding machine, adjustment loading amount is also suppressed; The capsule suppressed is tentatively firmly solid to capsule skin through blowing, and preliminarily dried shrinks complete to capsule shell, softgel shell flexible, rinses with dehydrated alcohol, dry, obtains work in-process; Pack after passed examination and obtain described Azithromycin soft capsules.
The preparation of example of formulations 3, Azithromycin soft capsules
Prescription:
Preparation technology:
1) gelatin solution preparation:
According to gelatin solution formula: gelatin: glycerine: the ratio of water=1.5:0.6:0.5, take gelatin, glycerine and purified water respectively, for subsequent use;
Add purified water and glycerine, titanium dioxide to joining in glue tank, wherein the consumption of titanium dioxide is the 1.5wt% of gelatin; Cross colloidal mill, be heated to 60 DEG C of insulations, add gelatin, open and stir, airtightly join glue tank, open vacuum pump evacuation, purify to the bubble in glue, till gelatin all dissolves, obtain gelatin solution;
2) content preparation:
The Azythromycin trihydrate that the embodiment 3 taking described consumption obtains and soybean oil, add in Agitation Tank, stir, obtain content liquid, for subsequent use;
3) soft capsule preparation
1. the preliminary adjustment of adhesive tape adjustment and loading amount:
By in the coating box of the gelatin solution of insulation press-in press molding machine, coating box temperature controls at 55 DEG C, regulates tape thickness between 0.7 ~ 0.9mm, regulates loading amount by blank soybean oil;
2. glue capsule:
Added by content in the materials-stored box of press molding machine, adjustment loading amount is also suppressed; The capsule suppressed is tentatively firmly solid to capsule skin through blowing, and preliminarily dried shrinks complete to capsule shell, softgel shell flexible, rinses with dehydrated alcohol, dry, obtains work in-process; Pack after passed examination and obtain described Azithromycin soft capsules.
The preparation of example of formulations 4, Azithromycin soft capsules
Prescription:
Preparation technology:
1) gelatin solution preparation:
According to gelatin solution formula: gelatin: glycerine: the ratio of water=1.0:0.5:1.0, take gelatin, glycerine and purified water respectively, for subsequent use;
Add purified water and glycerine, titanium dioxide to joining in glue tank, wherein the consumption of titanium dioxide is the 1.0wt% of gelatin; Cross colloidal mill, be heated to 60 DEG C of insulations, add gelatin, open and stir, airtightly join glue tank, open vacuum pump evacuation, purify to the bubble in glue, till gelatin all dissolves, obtain gelatin solution;
2) content preparation:
The Azythromycin trihydrate that the embodiment 4 taking described consumption obtains and soybean oil, add in Agitation Tank, stir, obtain content liquid, for subsequent use;
3) soft capsule preparation
1. the preliminary adjustment of adhesive tape adjustment and loading amount:
By in the coating box of the gelatin solution of insulation press-in press molding machine, coating box temperature controls at 55 DEG C, regulates tape thickness between 0.7 ~ 0.9mm, regulates loading amount by blank soybean oil;
2. glue capsule:
Added by content in the materials-stored box of press molding machine, adjustment loading amount is also suppressed; The capsule suppressed is tentatively firmly solid to capsule skin through blowing, and preliminarily dried shrinks complete to capsule shell, softgel shell flexible, rinses with dehydrated alcohol, dry, obtains work in-process; Pack after passed examination and obtain described Azithromycin soft capsules.
The preparation of example of formulations 5, Azithromycin soft capsules
Prescription:
Preparation technology:
1) gelatin solution preparation:
According to gelatin solution formula: gelatin: glycerine: the ratio of water=0.8:0.5:1.2, take gelatin, glycerine and purified water respectively, for subsequent use;
Add purified water and glycerine, titanium dioxide to joining in glue tank, wherein the consumption of titanium dioxide is the 0.8wt% of gelatin; Cross colloidal mill, be heated to 60 DEG C of insulations, add gelatin, open and stir, airtightly join glue tank, open vacuum pump evacuation, purify to the bubble in glue, till gelatin all dissolves, obtain gelatin solution;
2) content preparation:
The Azythromycin trihydrate that the embodiment 5 taking described consumption obtains and soybean oil, add in Agitation Tank, stir, obtain content liquid, for subsequent use;
3) soft capsule preparation
1. the preliminary adjustment of adhesive tape adjustment and loading amount:
By in the coating box of the gelatin solution of insulation press-in press molding machine, coating box temperature controls at 55 DEG C, regulates tape thickness between 0.7 ~ 0.9mm, regulates loading amount by blank soybean oil;
2. glue capsule:
Added by content in the materials-stored box of press molding machine, adjustment loading amount is also suppressed; The capsule suppressed is tentatively firmly solid to capsule skin through blowing, and preliminarily dried shrinks complete to capsule shell, softgel shell flexible, rinses with dehydrated alcohol, dry, obtains work in-process; Pack after passed examination and obtain described Azithromycin soft capsules.
Test example 1, draw moist test
Medicine draw the moist characteristic referring to that this material absorbing moisture is how many under certain temperature and humidity condition.
Sample:
Test sample: respectively according to the Azythromycin compound that the method for the embodiment of the present invention 1 to embodiment 5 is obtained;
Control sample 1: according to " synthesis of azithromycin dihydrate and crystallization processes improve " [Cao Wei, Wang Yunbin, Deng. the synthesis of azithromycin dihydrate and crystallization processes improve [J], fine-chemical intermediate, 2012,42 (3): 50-51] azithromycin dihydrate that method is obtained;
Control sample 2: according to the azithromycin-hydrate crystallization that the method for CN200810220584.8 embodiment 1 is obtained.
Draw moist test method: get test sample and control sample respectively appropriate, draw moist test direction principle according to " Chinese Pharmacopoeia " (version in 2005) two annex XIXJ medicines and tests.
Concrete measuring method is as follows:
1, get a certain amount of trial-product and put a precise weighing (m
1) tool plug glass weighing bottle (external diameter is 50mm, and height is 15mm) in, accurately weighed (m
2).
2, be placed in suitable 25 DEG C ± 1 DEG C thermostatic drier (ammonium chloride or ammonium sulfate saturated solution are placed in bottom) or growth cabinet (design temperature is 25 DEG C ± 1 DEG C) weighing bottleneck, relative humidity is in (80% ± 2%).
3, place 24 hours.
4, weighing bottle lid is built, precise weighing (m
3).
Percentage weight increase=(m
3-m
2)/(m
2-m
1) × 100%
5, draw moist feature description with draw wet increase weight define
Have draw moist: draw wet weightening finish and be not less than 15%.
Have draw moist: draw wet weightening finish and be less than 15% and be not less than 2%.
Slightly draw moist: draw wet weightening finish and be less than 2% and be not less than 0.2%.
Deliquescence: absorb enough water and divide formation liquid.
Test-results is in table 1:
Table 1, Azythromycin draw moist check 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 test-results shows, drawing that Azythromycin trihydrate crystal of the present invention tool compared with the Azithromycin monohydrate of prior art has clear improvement is moist, almost moist without drawing, and drawing of the azithromycin dihydrate of itself and prior art is quite moist.
Test example 2, In Vitro Dissolution are tested
This test example passes through dissolution rate and the dissolution rate of In Vitro Dissolution experiment investigation sample.
Azythromycin medicine:
Investigational agent: the Azythromycin trihydrate crystal that the embodiment of the present invention 1 is obtained;
Contrast medicine 1: according to " synthesis of azithromycin dihydrate and crystallization processes improve " [Cao Wei, Wang Yunbin, Deng. the synthesis of azithromycin dihydrate and crystallization processes improve [J], fine-chemical intermediate, 2012,42 (3): 50-51] azithromycin dihydrate that method is obtained;
Contrast medicine 2: according to the azithromycin-hydrate crystallization that the method for CN200810220584.8 embodiment 1 is obtained.
Dissolution in vitro test method: according to the dissolution method the 2nd method (paddle method) in " Chinese Pharmacopoeia " 2005 editions (2 editions), In Vitro Dissolution test is carried out to different Azythromycin samples.Using pH=7.4 phosphate buffered saline buffer as dissolution medium (must through degassed process before the deionized water of preparation dissolution medium), digestion instrument rotating speed of agitator and bath temperature be set as 100r/min and 37 ± 0.5 DEG C respectively.Respectively after input sample 2,5,10,15,30,45,60,90 and 120min sample 5mL, and with the membrane filtration of 0.45 μm; By gained filtrate through H
2sO
4after solution (75 → 100) colour developing, measure its ultraviolet absorptivity at 482nm place, calculate the amount of dissolved substance in dissolution medium according to the stripping typical curve measured in advance, and draw drug-eluting curve, drug characterization solubility property.
The In Vitro Dissolution test result of different Azythromycin samples as shown in Figure 3.As can be seen from Figure 3, the initial dissolution rate of azithromycin hydrate crystal of the present invention in buffered soln significantly improves, in throwing cup 10min, the dissolution rate of medicine can reach 60%, is about 2.6 times of same time reference substance 1 dissolution rate, 3 times of reference substance 2 dissolution rate; And reference substance 1, reference substance 2 will reach identical dissolution rate needs about 40min.This fully shows that azithromycin hydrate crystal of the present invention can significantly improve dissolution rate and dissolution rate.
Also carried out above-mentioned test to the Azythromycin trihydrate crystal prepared by other embodiment of the present invention, its result obtained is similar.
Test example 3,
1, prescription screening
Select conventional oral soybean oil to be soft capsule matrix, carried out the prescription screening of according to the form below 2 by the dissolving situation of main ingredient Azythromycin in soybean oil.
Table 2, prescription screening are tested
2, the stability of solution
Suspendible solid precipitation and homogeneity thereof before the stability of content liquid directly affects encapsulated, in encapsulated process and after encapsulated, and affect the accurate of divided dose.The present invention observes its suspension ability, in table 3 with sedimentation volume assay method.
The settling ratio test-results of table 3, liquid
Test-results shows, this product is disperseed relatively more even in oil, good stability.
3, distributed test again
By the suspension after above-mentioned placement for some time, rotate with the speed of 20r/min, through the rotation of certain hour, whether the sediment observed bottom graduated cylinder disperses again, and test-results shows, this product good dispersion again in vegetables oil.
4, the selection of soft capsule size
By above-mentioned test, the ratio selecting medicine and matrix is 125:375, and in actual production process, the loading amount of machine has the error of bound, for guaranteeing to produce capsule that is attractive in appearance, high-quality, is defined as No. 8 moulds.
5, the selection of tinting material and consumption thereof
Because this product content liquid is oil-based suspension, consider the specious of capsule, in capsule shell, use appropriate covering agent.The present invention selects titanium dioxide as covering agent.Stability of drug products test-results shows, titanium dioxide (1.0% of gelatin consumption) to the content influence of soft capsule content without considerable change, disintegration slightly extends, but conform with the regulations, therefore select titanium dioxide (1.0% of gelatin consumption) as the covering agent of Azithromycin soft capsules.
6, the principal element test of soft capsule quality and the basis for selecting of wrapping material is affected
Get the Azithromycin soft capsules that invention formulation embodiment 1 is obtained, removing outer packaging, places, in 0,5,10 day sampling analysis respectively under the drastic conditions such as high temperature 60 DEG C, illumination 4500 ± 500Lux, high humidity RH92.5%.Investigate outward appearance, content and related substance.The results are shown in Table 4 ~ table 6.
Table 4, the Azithromycin soft capsules influence factor test-results under 60 DEG C of hot conditionss
Table 5, the Azithromycin soft capsules influence factor test-results under 4500Lx rayed condition
Table 6, the Azithromycin soft capsules influence factor test-results under air exposure condition
This product is placed under high humidity RH92.5% condition, because softgel shell is adhered, so cannot measure.
Through influence factor tests such as illumination, high temperature, high humidity, result shows: this soft capsule should not be placed under high humidity, hot conditions, should adopt protection against the tide, pack.
Test example 4, pharmacokinetic trial
1, medicine
By test preparation: the Azithromycin soft capsules that invention formulation embodiment 1 is obtained, specification: every 125mg (with azithromycin); Reference preparation: the Azithromycin soft capsules obtained according to prescription and the method for invention formulation embodiment 1, difference is adopted Azythromycin is commercially available azithromycin dihydrate bulk drug, specification: every 125mg (with azithromycin).
2, the selection of experimenter
18 routine healthy male subjects, year at age (21.34 ± 1.12), body weight (67.89 ± 7.24) kg.Whole experimenter, through inquiry medical history, is normal through electrocardiogram(ECG, Liver and kidney function etc. inspections, without habits of smoking and alcohol drinking, test first 14 days and duration of test not with other any medicines.In the adverse drug reaction that test forward direction experimenter illustrates test objective, medicinal property, clinical application range and may occur.By signed Informed Consent Form.Testing program performs after Ethics Committee's approval.
3, medication and blood specimen collection
Adopt 2 cycle dual crossing test design.
18 healthy volunteers are divided into test group and control group 2 groups at random, often organize 9 people.Test group is taken by test preparation; Control group takes reference preparation.After experimenter's fasting 12h, in early morning 7:00 respectively on an empty stomach oral test and reference preparation 500mg warm water 250mL take, and 4h enters standard meal after taking medicine.
Before taking medicine and after administration 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, get upper arm venous blood 4.0mL, anticoagulant heparin, centrifugal, separated plasma, preserves to be measured in-40 DEG C of refrigerators.
Duration of test, researchist records blood sampling time and adverse drug reaction in detail.Whole process carries out observation by the clinician trained through GCP and nurse and process in time.
4, with reference to " Azithromycin soft capsules is at the pharmacokinetics of healthy volunteer and relative bioavailability " [Wu Huizhe, Wei Minjie, Deng. Azithromycin soft capsules at the pharmacokinetics of healthy volunteer and relative bioavailability [J], the Chinese Journal of Clinical Pharmacology, 2007,23 (6): 442-445] method measures 18 health volunteer's oral azithromycins by the blood concentration-time data after test preparation and reference preparation 500mg, draw mean blood plasma concentration-time curve, as shown in Figure 4.
As can be seen from the mean blood plasma concentration-time curve of Azythromycin, the Cmax by test preparation is better than reference preparation, adopts trapezoidal method to calculate AUC, and result shows also to be better than reference preparation by the AUC of test preparation.
Claims (10)
1. an Azythromycin compound, is characterized in that, described Azythromycin compound is hydrate crystal, and its molecular formula is: C
38h
72n
2o
123H
2o.
2. Azythromycin compound according to claim 1, is characterized in that, the X-ray powder diffractogram that described Azythromycin compound uses the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
3. a preparation method for the Azythromycin compound described in claim 1 or 2, is characterized in that, described preparation method comprises the steps:
1) Azythromycin crude product is dissolved in dehydrated alcohol, obtains Azythromycin ethanolic soln;
2) to step 1) Azythromycin ethanolic soln in add gac, stir, suction filtration, gets filtrate;
3) under agitation to step 2) filtrate in stream add mixed solvent A, formed turbid solution, wherein said mixed solvent A is the mixed solvent that methyl alcohol and dimethyl formamide form with volume ratio 2 ~ 5:1;
4) by step 3) under the turbid solution of gained is placed in ultrasonic field, stream adds mixed solvent B wherein, finishes, and has crystal to separate out, and wherein said mixed solvent B is the mixed solvent that water and dioxane form with volume ratio 5 ~ 10:1;
5) close ultrasonic field, leave standstill growing the grain, filter, filter cake washes with water, and vacuum-drying obtains described Azythromycin compound.
4. preparation method according to claim 3, is characterized in that, step 1) described in the concentration of Azythromycin ethanolic soln be 1.2 ~ 2.6kg/L.
5. preparation method according to claim 3, is characterized in that, the volume ratio of described mixed solvent A, mixed solvent B and dehydrated alcohol is 5 ~ 10:10 ~ 30:1.
6. preparation method according to claim 3, is characterized in that, step 3) described in stir speed be 50 ~ 60r/min; Step 4) described in the frequency of ultrasonic field be 3.5 ~ 6.5kHz, intensity is 0.6Wcm
-2~ 4Wcm
-2ultrasonic field; Step 3) described in the flow acceleration of mixed solvent A be 13 ~ 20L/min; Step 4) described in the flow acceleration of mixed solvent B be 6 ~ 12L/min.
7. an Azithromycin soft capsules, is characterized in that, described Azithromycin soft capsules contains the Azythromycin compound described in claim 1 or 2.
8. Azithromycin soft capsules according to claim 7, is characterized in that, every 1000 soft capsule contents are prepared from by following mass parts:
Azythromycin 125-150g
Soybean oil 375-475g;
Preferably, every 1000 soft capsule contents are prepared from by following mass parts:
Azythromycin 125g
Soybean oil 375g.
9. Azithromycin soft capsules according to claim 8, it is characterized in that, the gelatin solution formula of described Azithromycin soft capsules 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;
Preferred gelatin: glycerine: water=1:0.4:1, the consumption of titanium dioxide is the 1.0wt% of gelatin.
10. a preparation method for the Azithromycin soft capsules described in claim 8 or 9, is characterized in that, described preparation method comprises the steps:
1) gelatin solution preparation:
According to gelatin solution formula: gelatin: glycerine: the ratio of water=0.5 ~ 1.5:0.4 ~ 0.6:0.5 ~ 1.5, take gelatin, glycerine and purified water respectively, for subsequent use;
Adding purified water and glycerine, titanium dioxide to joining in glue tank, crossing colloidal mill, being heated to 60 DEG C of insulations, adding gelatin, open and stir, airtightly join glue tank, unlatching vacuum pump evacuation, purifies to the bubble in glue, till gelatin all dissolves, obtains gelatin solution;
2) content preparation:
Take Azythromycin and the soybean oil of described consumption, add in Agitation Tank, stir, obtain content liquid, for subsequent use;
3) soft capsule preparation
1. the preliminary adjustment of adhesive tape adjustment and loading amount:
By in the coating box of the gelatin solution of insulation press-in press molding machine, coating box temperature controls at 55 DEG C, regulates tape thickness between 0.7 ~ 0.9mm, regulates loading amount by blank soybean oil;
2. glue capsule:
Added by content in the materials-stored box of press molding machine, adjustment loading amount is also suppressed; The capsule suppressed is tentatively firmly solid to capsule skin through blowing, and preliminarily dried shrinks complete to capsule shell, softgel shell flexible, rinses with dehydrated alcohol, dry, obtains work in-process; Pack after passed examination and obtain described Azithromycin soft capsules.
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| US4517359A (en) * | 1981-03-06 | 1985-05-14 | Sour Pliva Farmaceutska, Kemijska Prehrambena I Kozmeticka Industrija, N.Sol.O. | 11-Methyl-11-aza-4-0-cladinosyl-6-0-desosaminyl-15-ethyl-7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyl-oxacyclopentadecane-2-one 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 |
| CN1505629A (en) * | 2001-04-25 | 2004-06-16 | ����ҩƷ��ҵ��ʽ���� | Clathrate of azithromycin hydrate with 1,2-propyleneglycol, method for the manufacture thereof and pharmaceutical composition comprising same |
| CN1780847A (en) * | 2001-05-22 | 2006-05-31 | 辉瑞产品公司 | Crystal forms of azithromycin |
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2015
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US4517359A (en) * | 1981-03-06 | 1985-05-14 | Sour Pliva Farmaceutska, Kemijska Prehrambena I Kozmeticka Industrija, N.Sol.O. | 11-Methyl-11-aza-4-0-cladinosyl-6-0-desosaminyl-15-ethyl-7,13,14-trihydroxy-3,5,7,9,12,14-hexamethyl-oxacyclopentadecane-2-one 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 |
| CN1505629A (en) * | 2001-04-25 | 2004-06-16 | ����ҩƷ��ҵ��ʽ���� | Clathrate of azithromycin hydrate with 1,2-propyleneglycol, method for the manufacture thereof and pharmaceutical composition comprising same |
| CN1780847A (en) * | 2001-05-22 | 2006-05-31 | 辉瑞产品公司 | Crystal forms of azithromycin |
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