CN104511011A - Daptomycin aseptic powder and preparation method thereof - Google Patents
Daptomycin aseptic powder and preparation method thereof Download PDFInfo
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- CN104511011A CN104511011A CN201310453014.4A CN201310453014A CN104511011A CN 104511011 A CN104511011 A CN 104511011A CN 201310453014 A CN201310453014 A CN 201310453014A CN 104511011 A CN104511011 A CN 104511011A
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- daptomycin
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Abstract
The invention belongs to the technical field of medicinal preparations, and concretely relates to a daptomycin aseptic powder and a preparation method thereof. The daptomycin aseptic powder only contains daptomycin and a pH adjusting agent. The technical scheme employs an aseptic split-charging technology for preparing the aseptic powder from daptomycin. Through a lot of experiments, the daptomycin aseptic powder with good stability is obtained by optimizing and improving the prescription and controlling the particle size of raw materials and auxiliary materials. At the same time, on the above basis, the air humidity for split charging is optimized, and thus finally the problems that the powder easily adsorbs moisture and is bad in stability are solved, and the daptomycin aseptic powder, which possesses uniform packing volume and good stability and is suitable for industrialized production, and the preparation method of the powder, are obtained.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of daptomycin sterilized powder and preparation method thereof.
Background technology
Daptomycin (Daptomycin) carrys out (Lilly) company original research by gift, the Cyclic lipopeptide antibiotic of Cubist drugmaker exploitation, the end of the year 2003, U.S. FDA is through the listing of quick examination and approval procedures approval injection daptomycin, must believe for trade name CUBICIN(gram), be used for the treatment of the concurrency skin and skin structure infection that are caused by some Gram-positive sensitive strains, as abscess, surgery cut infection and skin ulcer.Daptomycin mechanism of action is different from other antibiotic, and it by upsetting cell membrane to amino acid whose transhipment, thus hinders the biosynthesis of bacteria cell wall Peptidoglycan; In addition, it can also destroy bacterial cell membrane, makes its content leak and kill antibacterial, and therefore antibacterial is to the less generation drug resistance of daptomycin.
Chinese invention patent application prospectus CN1616083A discloses daptomycin freeze-dried dose of a kind of injection and preparation method thereof.In this technical scheme, daptomycin is added a certain amount of sodium hydroxide, pH adjusting agent, after being made into certain density solution with water for injection, lyophilization 30-60 hour obtained finished product is carried out in fill in control antibiotic cillin bottle.This patent application is identical with import prescription, and technique is also basically identical, but there are some inferior positions.First, daptomycin is slightly soluble in water, and unstable, easily degrades, and in freeze-dried powder production process, medicine needs first to be dissolved in water for injection and is made into certain density solution, in the process, drug degradation is very fast, and related substance increases, and brings certain security risk to medication.Secondly, freeze-drying process needs 30-60 hour, and the process such as to make up a prescription before adding, consuming time longer, freeze dryer power consumption is large, and cost of drugs rises, and adds the financial burden of patient, is unfavorable for the popularization of industrialization technology.
In view of all deficiencies of freeze-dried powder, technical staff often selects to adopt aseptic subpackaged technology that daptomycin is prepared into sterilized powder, but in aseptic subpackaged process, there is the daptomycin very easily moisture absorption, after the moisture absorption, viscosity becomes large, and mobility is deteriorated, and directly affects the subpackage uniformity of medicine, cause and can subpackage rate reduce, have no the relevant report of Tobramycin sterilized powder in prior art for this reason.
Summary of the invention
In order to overcome the defect of prior art, inventor providing a kind of stable daptomycin sterilized powder and being beneficial to the daptomycin sterilized powder preparation method of suitability for industrialized production.
One of the object of the invention discloses a kind of prescription of daptomycin sterilized powder.
Described daptomycin sterilized powder, is made up of the component of following weight portion:
Daptomycin 100-500mg
PH adjusting agent 10-50mg
Above-mentioned daptomycin raw material particle size is 50-150 μm.
The present invention carries out preferably described daptomycin raw material particle size, and preferably, above-mentioned daptomycin raw material particle size is 70-100 μm.
The purposes of pH adjusting agent regulates medicinal liquid pH value when being to redissolve, and promotes the rapid solution of active component daptomycin, and ensures its stability during use.So the present invention carries out preferably described pH adjusting agent, and preferably, above-mentioned pH adjusting agent is the one in sodium hydroxide, sodium bicarbonate.The present invention also carries out preferably the consumption of described pH adjusting agent, and preferably, the consumption of above-mentioned pH adjusting agent is 25-40mg.
The present invention's second object is the preparation method of openly a kind of daptomycin sterilized powder.
1) wash bottle: after cillin bottle manager bottle, enter wash bottle conveyer belt, inject inside and outside pure water, hairbrush and scrub, spray inside and outside water for injection, filtrated air blows back water, enters tunnel oven sterilizing; Air pressure 0.15Mpa, pure water, water for injection pressure 0.2Mpa; Pure water 0.45um metre filter, water for injection 0.22um metre filter;
2) bottle sterilizing: successively by electric heating self-controlling instrument, fan switch is opened, treats that temperature rises to: DEG C sterilizing section T2:300-320 DEG C, preheating section T1:250-300; DEG C cooling section T4:250-120 DEG C, soaking zone T3:320-350; Less than outlet temperature T5:40 DEG C; Bottle can be entered: enter bottle process and keep said temperature; 100 grades, baking oven bottle outlet local;
3) plug washing sterilizing: plug pours washing tank into, pure water rinsing 30 minutes under compressed air stirs, water for injection rinsing 15 minutes.Pull out and be contained in stainless steel disc and enter oven drying sterilizing; Baking temperature 121 DEG C, 0.5 hour drying time; Sterilising temp 121 DEG C, sterilization time 20 minutes; Pure water, water for injection are respectively through 0.45um, 0.22um metre filter;
4) mixed: in aseptic weighing area, the daptomycin of recipe quantity and pH adjusting agent to be crossed 80 ~ 100 mesh sieves, Homogeneous phase mixing;
5) subpackage: empty bottle, plug, after clarity test is qualified, start subpackage; Require more than subpackage air pressure 0.05Mpa, vacuum 600mmHg post, be filled under relative humidity is 15%-40% condition in cillin bottle, be filled with nitrogen; The medicine installed is divided to prop up the semi-finished product fastened through loading amount, plug;
6) gland: semi-finished product carry out rolling lid, lamp inspection, after waste product removing, packaging, labeling.
Homogeneous in order to ensure the filling effect of medicine and adjuvant, inventor optimizes the control of ambient humidity and daptomycin raw material particle size in preparation process.In addition, inventor utilizes the control of ambient humidity to solve daptomycin raw material and pH adjusting agent moisture absorption in preparation process, thus ensure that the qualified and stability of the moisture limit of final products.
The present invention carries out preferably damp condition in described filling process, and preferably, in above-mentioned filling process, environmental damp condition is relative humidity is 25%-35%.
The present invention carries out preferably described daptomycin raw material particle size, and preferably, above-mentioned filling daptomycin raw material particle size used is 50-150 μm; It is further preferred that above-mentioned daptomycin raw material particle size is 70-100 μm.
Inventor also finds to utilize the technology being filled with nitrogen, the contact effectively can isolating daptomycin and oxygen prevents its oxidative degradation, and product can be entered by the moisture limited to a certain extent in plug, ensure that in the long-time put procedure of product, water tariff collection is in lower level.
The present invention compared with prior art, has following outstanding advantage.
Technical solutions according to the invention adopt aseptic subpackaged technology that daptomycin is prepared into sterilized powder.Through great many of experiments, Optimal improvements of the present invention prescription also adopts the particle diameter controlling supplementary material, obtains the daptomycin sterilized powder had good stability.Meanwhile, on this basis, the present invention optimizes again air humidity during subpackage, finally solves the problem of easy moisture absorption poor stability, obtains the daptomycin sterilized powder that loading amount is even, have good stability.
One of advantage of the present invention is without processes such as dissolving, filtration, lyophilizing, medicine does not contact with water in whole production process, subpackage directly can be mixed homogeneously with pH adjusting agent, avoid the hydrolysis of medicine, improve drug quality, namely the medicine prepared by the present invention, daptomycin medicine is almost without degraded, related substance is starkly lower than commercially available dried frozen aquatic products, long-time stability are also better than commercially available product, drug safety risk reduces, and effectively overcomes the deficiency existing for solution type injection agent and freeze-dried powder.
Another advantage of the present invention is that production technology is simple; do not need the processes such as freeze dryer lyophilizing, degerming membrane filtration; make up a prescription consuming time short; not only the production time by 3-4 days/batch significantly foreshortening to 1 day/batch, and reduce energy consumption, production cost also reduces greatly; alleviate the financial burden of patient, be beneficial to large-scale production and reduce drug price.
Detailed description of the invention
Further illustrate the present invention by the following examples, but these embodiments do not limit the present invention in any way.
Embodiment 1
Prescription:
Daptomycin 100mg
Sodium hydroxide 10mg
Preparation method is as follows:
1) wash bottle: after cillin bottle manager bottle, enter wash bottle conveyer belt, inject inside and outside pure water, hairbrush and scrub, spray inside and outside water for injection, filtrated air blows back water, enters tunnel oven sterilizing; Air pressure 0.15Mpa, pure water, water for injection pressure 0.2Mpa; Pure water 0.45um metre filter, water for injection 0.22um metre filter;
2) bottle sterilizing: successively by electric heating self-controlling instrument, fan switch is opened, treats that temperature rises to: DEG C sterilizing section T2:300-320 DEG C, preheating section T1:250-300; DEG C cooling section T4:250-120 DEG C, soaking zone T3:320-350; Less than outlet temperature T5:40 DEG C; Bottle can be entered: enter bottle process and keep said temperature; 100 grades, baking oven bottle outlet local;
3) plug washing sterilizing: plug pours washing tank into, pure water rinsing 30 minutes under compressed air stirs, water for injection rinsing 15 minutes.Pull out and be contained in stainless steel disc and enter oven drying sterilizing; Baking temperature 121 DEG C, 0.5 hour drying time; Sterilising temp 121 DEG C, sterilization time 20 minutes; Pure water, water for injection are respectively through 0.45um, 0.22um metre filter;
4) mixed: in aseptic weighing area, the daptomycin of recipe quantity and sodium hydroxide to be crossed 80 ~ 100 mesh sieves, daptomycin size controlling at 50-70 μm, Homogeneous phase mixing;
5) subpackage: empty bottle, plug, after clarity test is qualified, start subpackage; Require more than subpackage air pressure 0.05Mpa, vacuum 600mmHg post, be filled under relative humidity is 40% condition in cillin bottle, be filled with nitrogen; The medicine installed is divided to prop up the semi-finished product fastened through loading amount, plug;
6) gland: semi-finished product carry out rolling lid, lamp inspection, after waste product removing, packaging, labeling.
Embodiment 2
Prescription:
Daptomycin 300mg
Sodium hydroxide 35mg
Preparation method:
Other steps are with embodiment 1, and wherein the daptomycin size controlling of step 4) is at 70-100 μm, and pH adjusting agent is sodium hydroxide, the relative humidity 25% of step 5).
Embodiment 3
Prescription:
Daptomycin 300mg
Sodium bicarbonate 50mg
Preparation method:
Other steps are with embodiment 1, and wherein the daptomycin size controlling of step 4) is at 70-100 μm, and pH adjusting agent is sodium bicarbonate, the relative humidity 35% of step 5).
Embodiment 4
Prescription:
Daptomycin 500mg
Sodium hydroxide 50mg
Preparation method:
Other steps are with embodiment 1, and wherein the daptomycin size controlling of step 4) is at 60-90 μm, and pH adjusting agent is sodium hydroxide, the relative humidity 30% of step 5).
Embodiment 5
Prescription:
Daptomycin 200mg
Sodium bicarbonate 35mg
Preparation method:
Other steps are with embodiment 1, and wherein the daptomycin size controlling of step 4) is at 120-150 μm, and pH adjusting agent is sodium bicarbonate, the relative humidity 15% of step 5).
Comparative example 6
Prescription:
Daptomycin 200mg
Sodium dihydrogen phosphate 35mg
Preparation method:
Other steps are with embodiment 1, and wherein the daptomycin size controlling of step 4) is at 70-100 μm, and pH adjusting agent is sodium dihydrogen phosphate, the relative humidity 25% of step 5).
Comparative example 7:
Prescription:
Daptomycin 200mg
Sodium bicarbonate 35mg
Preparation method:
Other steps are with embodiment 1, and wherein the daptomycin size controlling of step 4) is at 70-100 μm, and pH adjusting agent is sodium bicarbonate, the relative humidity 50% of step 5).
Comparative example 8
Prescription:
Daptomycin 200mg
Sodium bicarbonate 35mg
Preparation method:
Other steps are with embodiment 1, and wherein the daptomycin size controlling of step 4) is at 170-200 μm, and pH adjusting agent is sodium bicarbonate, the relative humidity 25% of step 5).
Test example 9. product quality is investigated
Under embodiment 1-5 products obtained therefrom and comparative example 6-8, commercially available injection daptomycin are placed in the same terms, (25 DEG C, RH60%) carry out quality versus, the results are shown in Table 1.
Table 1. quality versus
By table 1, can find out the subpackage uniformity RSD<2.0% of product of the present invention, homogeneity is better; Content and the related substance of product of the present invention are all better than commercially available product, illustrate that product quality of the present invention is outstanding.The pH adjusting agent of embodiment 6 has selected sodium dihydrogen phosphate, can not promote the rapid solution of daptomycin, and have impact on its stability related substance increases obviously; High humidity time prepared by embodiment 7, when causing subpackage, relative humidity is higher, the product moisture absorption, and final subpackage uniformity RSD becomes large; Embodiment 8 due to raw material particle size comparatively large, subpackage uniformity reduces, and related substance also obviously increases because of the moisture absorption.
Test example 10. product long-time stability are investigated
Under embodiment 1-5 products obtained therefrom and comparative example 6-8, commercially available injection daptomycin are placed in the same terms (25 DEG C, RH60%) long-term placement carries out long-time stability investigation in 24 months, detect in sampling in the 3rd, 6,12,24 month, test item is clarity and color, content and related substance, relatively its stability, the results are shown in Table 2.
Table 2. long-time stability investigate result
Can be found out by table 2 long-term stable experiment, clear, colorless after daptomycin sterilized powder product prepared by the present invention dissolves, product drug content and related substance change, all much smaller than comparative example 6-8 and commercially available product, show that product stability of the present invention is good.
Test example 11. product accelerated stability is investigated
Under embodiment 1-5 products obtained therefrom and comparative example 6-8, commercially available injection daptomycin are placed in the same terms (50 DEG C, RH85%) January is carried out accelerated stability investigation in placement, detect in sampling in the 10th, 20,30 day, test item is clarity and color, content and related substance, relatively its stability, the results are shown in Table 3.
Table 3. accelerated stability investigates result
Can be found out by table 3 accelerated stability test, clear, colorless after daptomycin sterilized powder product prepared by the present invention dissolves, the change of drug content and related substance, all much smaller than comparative example 6-8 and commercially available product, shows that product stability of the present invention is good.
Claims (6)
1. a daptomycin sterilized powder, is characterized in that: be made up of the component of following weight portion:
Daptomycin 100-500mg
PH adjusting agent 10-50mg
Wherein, the particle diameter of described daptomycin is 50-150 μm.
2. daptomycin sterilized powder according to claim 1, is characterized in that daptomycin particle diameter being 70-100 μm.
3. daptomycin sterilized powder according to claim 1, is characterized in that described pH adjusting agent is the one in sodium hydroxide, sodium bicarbonate.
4. a preparation method for daptomycin sterilized powder, is characterized in that:
1) wash bottle: after cillin bottle manager bottle, enter wash bottle conveyer belt, inject inside and outside pure water, hairbrush and scrub, spray inside and outside water for injection, filtrated air blows back water, enters tunnel oven sterilizing; Air pressure 0.15Mpa, pure water, water for injection pressure 0.2Mpa; Pure water 0.45um metre filter, water for injection 0.22um metre filter;
2) bottle sterilizing: successively by electric heating self-controlling instrument, fan switch is opened, treats that temperature rises to: DEG C sterilizing section T2:300-320 DEG C, preheating section T1:250-300; DEG C cooling section T4:250-120 DEG C, soaking zone T3:320-350; Less than outlet temperature T5:40 DEG C; Bottle can be entered: enter bottle process and keep said temperature; 100 grades, baking oven bottle outlet local;
3) plug washing sterilizing: plug pours washing tank into, pure water rinsing 30 minutes under compressed air stirs, water for injection rinsing 15 minutes.Pull out and be contained in stainless steel disc and enter oven drying sterilizing; Baking temperature 121 DEG C, 0.5 hour drying time; Sterilising temp 121 DEG C, sterilization time 20 minutes; Pure water, water for injection are respectively through 0.45um, 0.22um metre filter;
4) mixed: in aseptic weighing area, the daptomycin of recipe quantity and pH adjusting agent to be crossed 80 ~ 100 mesh sieves, Homogeneous phase mixing;
5) subpackage: empty bottle, plug, after clarity test is qualified, start subpackage; Require more than subpackage air pressure 0.05Mpa, vacuum 600mmHg post, be filled under relative humidity is 15%-40% condition in cillin bottle, be filled with nitrogen; The medicine installed is divided to prop up the semi-finished product fastened through loading amount, plug;
6) gland: semi-finished product carry out rolling lid, lamp inspection, after waste product removing, packaging, labeling.
5. daptomycin sterilized powder preparation method according to claim 4, is characterized in that daptomycin particle diameter being 70-100 μm.
6. daptomycin sterilized powder preparation method according to claim 4, is characterized in that described damp condition is 25%-35%.
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| CN201310453014.4A CN104511011A (en) | 2013-09-29 | 2013-09-29 | Daptomycin aseptic powder and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106943587A (en) * | 2016-01-06 | 2017-07-14 | 山东新时代药业有限公司 | A kind of daptomycin freeze-dried powder pin of injection and its preparation technology |
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| CN1616083A (en) * | 2004-09-01 | 2005-05-18 | 魏雪纹 | Daptomycin freeze-dried preparation for injection and preparing method |
| CN101830970A (en) * | 2009-03-12 | 2010-09-15 | 成都雅途生物技术有限公司 | Purification and preparation method of high-purity Daptomycin |
| WO2011062676A1 (en) * | 2009-11-23 | 2011-05-26 | Eagle Pharmaceuticals, Inc. | Formulations of daptomycin |
| CN102712677A (en) * | 2009-11-23 | 2012-10-03 | 丘比斯特药物股份有限公司 | Lipopeptide compositions and related methods |
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2013
- 2013-09-29 CN CN201310453014.4A patent/CN104511011A/en active Pending
Patent Citations (6)
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| CN1054537A (en) * | 1989-03-06 | 1991-09-18 | 伊莱利利公司 | Improved diluent formulation for daptomycin |
| CN1404487A (en) * | 2000-01-20 | 2003-03-19 | 卡比斯特制药公司 | High purity lipopeptides, lipopeptide micelles, process for preparing same |
| CN1616083A (en) * | 2004-09-01 | 2005-05-18 | 魏雪纹 | Daptomycin freeze-dried preparation for injection and preparing method |
| CN101830970A (en) * | 2009-03-12 | 2010-09-15 | 成都雅途生物技术有限公司 | Purification and preparation method of high-purity Daptomycin |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106943587A (en) * | 2016-01-06 | 2017-07-14 | 山东新时代药业有限公司 | A kind of daptomycin freeze-dried powder pin of injection and its preparation technology |
| CN106943587B (en) * | 2016-01-06 | 2021-06-22 | 山东新时代药业有限公司 | Daptomycin freeze-dried powder injection for injection and preparation process thereof |
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