CN109646418A - Azithromycin capsule and its dry-forming method - Google Patents
Azithromycin capsule and its dry-forming method Download PDFInfo
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- CN109646418A CN109646418A CN201811483566.9A CN201811483566A CN109646418A CN 109646418 A CN109646418 A CN 109646418A CN 201811483566 A CN201811483566 A CN 201811483566A CN 109646418 A CN109646418 A CN 109646418A
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- azithromycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
A kind of azithromycin capsule and its dry-forming method.It is made of capsule filling and capsule shells, and capsule filling is made of the raw material of following mass fraction: 145~250 parts of azithromycin dihydrate (with azithromycin), 27~33 parts of microcrystalline cellulose, 1.8~2.2 parts of lauryl sodium sulfate, 1.2~1.4 parts of magnesium stearate.The present invention is rolled into particle by dry granulation process using the crystallization water in material, after magnesium stearate total mix, improves the mobility of particle, is conducive to the filling capsule of continuous production.It has more excellent stability compared with wet processing, while improving production efficiency, facilitates large-scale production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, specifically, the present invention designs a kind of azithromycin capsule and its dry method system
Preparation Method.
Background technique
Azithromycin.Its chemical name is: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R) -13- [(2,6-
Dideoxy-3-C- methyl-3-O- methyl-α-L- core-pyranose) oxygen] trihydroxy-3,5,6,8-2- ethyl-3,4,10-,
Seven methyl-1 1- of 10,12,14- [[tri- deoxidation -3- (dimethylamino)-β-D- wood of 3,4,6--pyranose] oxygen] -1- oxa- -
- 15 ketone of 6- azepine cyclopentadecane, molecular formula are as follows: C38H72N2O12.Its chemical structural formula are as follows:
Azithromvcin is macrolide antibiotics, is suitable for acpuei pharyngitis, acute caused by treatment micrococcus scarlatinae
Fan peach body inflammation and sensitive thin caused acute bronchitis, acute exacerbation of chronic bronchitis, streptococcus pneumonia, Bacillus influenzae
And pneumonia caused by mycoplasma pneumoniae, suitable for treating urethritis caused by Chlamydia and nonspecific urethritis (uterine neck
It is scorching), skin soft-tissue infection caused by sensitive bacteria, pure genital infection (syphilis spiral shell caused by non-multidrug resistant gonococcus
Except rotation body concurrent infection) urogenital infections.Preparation method is the dry granulation pressure using dry granulation tabletting as principle
Piece refer to drug powder and necessary auxiliary material after mixing, with suitable equipment be pressed into solid (blocky, sheet or
It is granular), it is then ground into appropriately sized dry granular again, is finally pressed into tablet.Dry granulation technology be in medical industry using compared with
For extensive method, dry process reduces wet granulation and dry technique, simple process, work with respect to wet granulation technology
Skill step is few, high production efficiency, special standby suitable to wet, thermally labile drug.
Azithromycin can be produced in many different forms, and example is known, the commercial form of azithromycin is steady at present
The nonhygroscopic dihydrate of fixed crystallization-, referred to herein as A type are according to the side described in US6,268,489
Method preparation, then use water as granulation liquid by the way that dihydrate progress wet granulation is prepared into commercial tablets.
The azithromycin of the non-dihydrate object form of some crystallizations is also known, for example, US4,4174,768 are disclosed
A kind of azithromycin crystalline hydrate of moisture absorption, is referred to herein as Type B.Due to its water for being easy to adsorb different number
Property, this azithromycin form are difficult to be handled during preparation.
Wish the particle that the azithromycin of dihydrate form is prepared by dry granulation process.
Summary of the invention
The object of the present invention is to provide a kind of azithromycin capsule and its dry-forming methods, utilize the crystallization water in material
And the viscosity of auxiliary material, directly powder is rolled, is ground into particle, can be had with serialization industrial production than other granulating process
It is improved granule stability, increases granular pile density, improve mobility of particle, the advantages that dust is few, high yield rate, convenient big rule
Mould production.
Originally to achieve the above object, the following technical solution is employed by the present invention:
A kind of azithromycin capsule, it is made of capsule filling and capsule shells, and capsule filling is by following mass fraction
Raw material be made: 145~250 parts of azithromycin dihydrate (in terms of Afatinib), 27~33 parts of microcrystalline cellulose, 12
1.8~2.2 parts of sodium alkyl sulfate, 1.2~1.4 parts of magnesium stearate.
Preferably, the azithromycin granularity, which controls, requires are as follows: D50:100~400 μm；D90:200~600 μm.
Preferably, the capsule is No. 1 capsule of gelatin.
The present invention also provides a kind of azithromycin capsule preparation methods, include the next steps:
Each supplementary material is accurately taken according to mass fraction, now mixes azithromycin dihydrate and microcrystalline cellulose, is used
Dry granulating machine is pelletized, and lauryl sodium sulfate, magnesium stearate mixing is added after obtaining particle, carries out No. 1 capsule of gelatin
It is filling, control loading amount 308mg.
The present invention prepares azithromycin capsule using dry granulation process, using in material the crystallization water and material it is viscous
Property, particle directly is made in powder, which all has relative to wet granulation suitable for wet, thermally labile drug
Dry powder is directly carried out roll-in, molding, crushing, sieving by feature, and dry granulating machine is electromechanical integration equipment, can be connected
Continuous metaplasia produces, and has than other granulating process and improves granule stability, increases granular pile density, improves mobility of particle, dust
Less, the advantages that high yield rate, facilitate large-scale production.
Detailed description of the invention
Fig. 1 is the embodiment of the present invention experimental result picture.
Specific embodiment
In order to which the present invention is apparent to understand, the present invention is further described combined with specific embodiments below, to help reason
Solve the contents of the present invention.
Embodiment one:
Setting about 105 DEG C of oven temperature, dry microcrystalline cellulose about 2h, be dried to its moisture meet the requirements (LOD≤
3.0%), then microcrystalline cellulose 150.2g, Azithromycin Raw Material 1315.1g are weighed, bores mixing machine mixing 10min with single；With dry
Method granulator is pelletized, and sets feeding frequency: 10~25Hz, tabletting frequency: 10~30Hz, carries out roll-in particle, setting system
Grain frequency: 20~30Hz, lower screen cloth aperture: 1.2mm carries out particle crushing, crosses the subdivision dry granulation again of 80 meshes；It weighs
Lauryl sodium sulfate 10.2g, magnesium stearate 65.2g and above-mentioned particle mix 10min, and the preparation of capsule content is completed, particle
Good fluidity, progress No. 1 capsule of gelatin is filling, controls loading amount 305mg.
| Title | Prescription 1 (g) | Prescription 2 (g) |
| Azithromycin | 1315.1 | 1315.3 |
| Microcrystalline cellulose | 150.2 | 148.2 |
| Lauryl sodium sulfate | 10.2 | 10.4 |
| Magnesium stearate | 65.2 | 66.1 |
| It summarizes | 1540.7 | 1540.0 |
Embodiment two:
About 105 DEG C of oven temperature of setting dries microcrystalline cellulose about 2h, is dried to its moisture and meets the requirements, and LOD is (LOD
≤ 3.0%), then microcrystalline cellulose 148.2g, Azithromycin Raw Material 1315.3g are weighed, bores mixing machine mixing 10min with single；With
Dry granulating machine is pelletized, and sets feeding frequency: 10~25Hz, tabletting frequency, and: 10~30Hz carries out roll-in particle, setting
Pelletize frequency: 20~30Hz, lower screen cloth aperture: 1.2mm carries out particle crushing, crosses the subdivision dry granulation again of 80 meshes；Claim
Lauryl sodium sulfate 10.4g is taken, magnesium stearate 66.1g and above-mentioned particle mix 10min, and the preparation of capsule content is completed,
Grain good fluidity, progress No. 1 capsule of gelatin is filling, controls loading amount 308mg.
The azithromycin granularity requirements granularity, which controls, to be required are as follows: D50:100~400 μm；D90:200~600 μm.
According to Noves-Whitney formula: dm/dt=A × D/d × (Cs-Cb), it is known that, the dissolution release of solid pharmaceutical preparation and drug
Specific surface area is directly proportional, i.e., square is inversely proportional with granularity.The present invention passes through the range of control API granularity, to control drug
Dissolution release, keep In Vitro Dissolution consistent with reference preparation, and then reach equivalent with reference preparation in vivo.Secondly dodecane
Base ammonium sulfate is surfactant, by improving the diffusion coefficient of dissolution medium, plays the role of promoting drug release.FDA
Announce its IIG research on maximum utilized quantity be 25.8mg, the present invention preferably 1.8~2.2mg/.The magnesium stearate is main in tablet manufacturing
It to be used as lubricant, it has been generally acknowledged that oral, non-toxic, dosage is generally 0.25%~5.0%, and magnesium stearate is in hydrophobicity, and energy
Blocking medicine is dissolved out from solid dosage forms, therefore, as far as possible using minimum in prescription while ensureing mobility of particle
Concentration, when closing with solid pharmaceutical preparation auxiliary material, the mixed coefficient of variation increases, and dissolution rate reduces, and incorporation time increases, tablet
Dissolution rate and degree of fragmentation reduce, and magnesium stearate may also increase the friability of tablet, therefore the incorporation time of magnesium stearate is answered
Cautious control.
The dissolution release data of the capsule of embodiment one
| Detection time | Dissolve out release |
| 5 | 38.6% |
| 10 | 72.1% |
| 15 | 77.6% |
| 30 | 85.7% |
| 45 | 90.6% |
The capsule of embodiment one 45min dissolution rate in pH6.0 phosphoric acid salt medium is not less than 75%.
The influence factor experimental data of the capsule of embodiment one
The supplementary material weight ratio of azithromycin of the present invention is tested by a large amount of optimizations, and technique is tested
It demonstrate,proves, just obtains, can be directly obtained not by preparation teaching material or other references, through being sieved after stability study
Choosing test, process certification, stability study confirm that supplementary material ratio of the present invention is reasonable, and stable preparation process, finished product preparation is stablized,
Meet the preparation guideline requirement of galenic pharmacy and State Food and Drug Administration for capsule.
Claims (6)
1. a kind of azithromycin capsule, it is characterised in that: it is made of capsule filling and capsule shells, and capsule filling is by following
The supplementary material of mass fraction is made: 145~250 parts of azithromycin dihydrate (in terms of Afatinib), microcrystalline cellulose 27~
33 parts, 1.8~2.2 parts of lauryl sodium sulfate, 1.2~1.4 parts of magnesium stearate.
2. capsule according to claim 1, it is characterised in that: the azithromycin granularity control requires are as follows:
D50: 100~400 μm；D90: 200~600 μm.
3. capsule according to claim 1, it is characterised in that: the moisture requirement of the microcrystalline cellulose are as follows: LOD≤3%.
4. capsule according to claim 1, it is characterised in that: the capsule-core grain graininess is within the scope of 20~80 mesh.
5. capsule according to claim 1, it is characterised in that: the capsule is No. 1 capsule of gelatin.
6. a kind of azithromycin capsule dry-forming method: first by microcrystalline cellulose be dried to moisture meet the requirements (LOD≤
3.0%) it, then by it with azithromycin dihydrate mixes, is then pelletized using dry method machine, be added 12 after obtaining particle
Sodium alkyl sulfate and magnesium stearate mix, and progress No. 1 capsule of gelatin is filling, control loading amount 308mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811483566.9A CN109646418A (en) | 2018-11-30 | 2018-11-30 | Azithromycin capsule and its dry-forming method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811483566.9A CN109646418A (en) | 2018-11-30 | 2018-11-30 | Azithromycin capsule and its dry-forming method |
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| Publication Number | Publication Date |
|---|---|
| CN109646418A true CN109646418A (en) | 2019-04-19 |
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ID=66111934
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811483566.9A Pending CN109646418A (en) | 2018-11-30 | 2018-11-30 | Azithromycin capsule and its dry-forming method |
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| Country | Link |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110292567A (en) * | 2019-05-17 | 2019-10-01 | 北京悦康科创医药科技股份有限公司 | A kind of preparation method of azithromycin capsule |
| CN111467362A (en) * | 2020-05-09 | 2020-07-31 | 北京四环制药有限公司 | Azithromycin medicinal composition, preparation method and application thereof |
| CN112999185A (en) * | 2019-12-19 | 2021-06-22 | 康普药业股份有限公司 | Cefradine capsule preparation |
-
2018
- 2018-11-30 CN CN201811483566.9A patent/CN109646418A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110292567A (en) * | 2019-05-17 | 2019-10-01 | 北京悦康科创医药科技股份有限公司 | A kind of preparation method of azithromycin capsule |
| CN112999185A (en) * | 2019-12-19 | 2021-06-22 | 康普药业股份有限公司 | Cefradine capsule preparation |
| CN111467362A (en) * | 2020-05-09 | 2020-07-31 | 北京四环制药有限公司 | Azithromycin medicinal composition, preparation method and application thereof |
| CN111467362B (en) * | 2020-05-09 | 2021-07-06 | 北京四环制药有限公司 | Azithromycin medicinal composition, preparation method and application thereof |
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20190419 |
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| WD01 | Invention patent application deemed withdrawn after publication |