CN104434782B - Long-acting ribavirin medicine composition injection - Google Patents
Long-acting ribavirin medicine composition injection Download PDFInfo
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- CN104434782B CN104434782B CN201410628733.XA CN201410628733A CN104434782B CN 104434782 B CN104434782 B CN 104434782B CN 201410628733 A CN201410628733 A CN 201410628733A CN 104434782 B CN104434782 B CN 104434782B
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Abstract
The invention relates to a long-acting ribavirin medicine composition injection. A specification of the long-acting ribavirin medicine composition injection is 10ml:1g preferably, and ribavirin raw materials are refined products. The prepared ribavirin injection disclosed by the invention is long in plasma medicine elimination half-life, can be used for reducing the medication times of patients, is good in stability, and can be used for greatly improving the medication portability and safety.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to a kind of long-acting ribavirin medicine composition injection.
Background technology
Ribavirin：Chemical name：1- β-D-RIBOSE base -1H-1,2,4,-triazole -3- carboxylic acid amides, also known as virus
Azoles, ribavirin, Nice can be waited, and ribavirin is the ucleosides antiviral agents of synthesis.Cell culture invitro test shows, profit
Ba Weilin is to respiratory syncytial virus（RSV）There is selective inhibitory.Ribavirin is a kind of prodrug, when micro- life
Thing heredity carrier similar to purine RNA nucleotide when, it can replicate the metabolism of required RNA by viral interference.It is broad spectrum high-effect
Antiviral drugs, be now widely used for the preventing and treating of viral disease.Common formulations have injection, tablet, oral liquid, aerosol
Agent etc..
Ribavirin injection is the common formulations of ribavirin, because the elimination half-life of ribavirin is shorter, is
Reach therapeutic effect, clinically using needing to inject for multiple daily, be grown up 0.5g, and 2 times a day, children press body weight one
10～15mg/kg, point 2 administrations, the course for the treatment of 3～7 days.Ribavirin injection, as conventional antiviral drugs, improves medicine
Stability be also clinical urgent needss.For this problem, we obtain a kind of elimination half-life finally through numerous studies
Long extremely stable a kind of long-acting ribavirin medicine composition injection, improve ribavirin the elimination half-life and
Stability, substantially increases portability, the effectiveness and reliability of patient medication.
Content of the invention
Present invention aims to the problem that prior art exists, provide a kind of long-acting, stable ribavirin
Medicine composition injection and preparation method thereof.
The present invention provide technical scheme be：A kind of long-acting ribavirin medicine composition injection, by 100g～
250g ribavirin highly finished product, 5.0g sodium carboxymethyl cellulose, 9.0g betacyclodextrin, 2.0 g Povidone K 30, water for injection
Add to 2000ml to be prepared from.
The preparation method of described ribavirin medicine composition injection comprises the following steps：
1st, ribavirin raw material is refined：
1. by ribavirin raw material volume ratio by weight（g/ml）1:10 add 90%（v/v）In ethanol water, it is warming up to
75 DEG C, stirring and dissolving, obtain filtrate through 0.22 μm of membrane filtration；
2. under 120 revs/min of mixing speed, while stirring with 0.4 DEG C/min speed by step 1. in filtrate cooling
To 4 DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；By filter cake in 80 DEG C of dryings 7 hours, obtain final product ribavirin essence
Product；
2nd, press recipe quantity to add sodium carboxymethyl cellulose in 1600 ml waters for injection, stir to being completely dissolved, Ran Houyi
The secondary ribavirin highly finished product adding recipe quantity, betacyclodextrin, Povidone K 30 stir to being completely dissolved, and inject water to
2000ml, stirs；
3rd, add the activated carbon of 0.10g/100ml toward in step 2, stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure
Filtrate pH value, content, determine filling amount by specification, by filtrate subpackage to ampoule bottle, sealing by fusing, and 121 DEG C of moist heat sterilizations 15 minutes,
Obtain final product ribavirin medicine composition injection.
The ribavirin injection of the present invention can be prepared into different size by prescription loading amount, can be 1ml:100mg、
2ml:100mg、 2ml:200mg、 2ml:250mg、 5ml:250mg、5ml:500mg、10ml:1g, the preferred 10ml of the present invention:
1g.
The present invention adopts sodium carboxymethyl cellulose, betacyclodextrin as the adjuvant of ribavirin injection, this 2 adjuvants
Specific proportioning be used in combination to improve ribavirin injection the elimination half-life serve unexpected effect, below
Test is to this explanation：
The different prescription of table 1
| Prescription | 1 | 2 | 3 | 4 |
| Ribavirin highly finished product（g） | 200 | 200 | 200 | 200 |
| Sodium carboxymethyl cellulose（g） | — | 5 | — | 5 |
| Betacyclodextrin（g） | — | — | 9 | 9 |
| Water for injection | Add to 2000ml | Add to 2000ml | Add to 2000ml | Add to 2000ml |
Above prescription is prepared into 10ml by present invention process respectively:The ribavirin injection of 1g, by prescription 1～place
The ribavirin injection of the ribavirin injection of side 4 preparation and listing product carries out drug plasma and eliminates half-life test, will
Rabbit injects ribavirin injection with ribavirin 10mg/kg through auricular vein, and result of the test is shown in Table 2：
Table 2 drug plasma eliminates half-life result of the test
| Prescription | 1 | 2 | 3 | 4 | Listing product |
| Drug plasma eliminates the half-life（h） | 1.12 | 1.13 | 1.13 | 3.25 | 1.12 |
Above result of the test shows, the sodium carboxymethyl cellulose of specific proportioning, betacyclodextrin are used in combination can be obvious
The drug plasma improving ribavirin injection eliminates the half-life.It is prepared into the profit of other specifications by formulation and technology of the present invention
Eliminate half-life test through drug plasma under Ba Weilin injection the same terms and also achieve the result close with prescription 4.Need
To illustrate that the numerous studies through the applicant find that in the present invention, sodium carboxymethyl cellulose, the specific of betacyclodextrin are joined
The drug plasma elimination half-life comparing raising ribavirin injection is most important, the change of the even minimum amplitude of any amplitude
Change and all can produce significant impact to result, only enumerate low volume data below in order to illustrate（Sample specification, experimental condition and table 2
Identical）, it is shown in Table 3：
The impact to the half-life for table 3 different ratio
| Prescription | 1 | 2 | 3 | 4 | 5 |
| Ribavirin highly finished product（g） | 200 | 200 | 200 | 200 | 200 |
| Sodium carboxymethyl cellulose（g） | 4.0 | 4.5 | 4.5 | 5.0 | 5.5 |
| Betacyclodextrin（g） | 8.0 | 8.5 | 9.0 | 8.5 | 9.5 |
| Water for injection adds to | 2000ml | 2000ml | 2000ml | 2000ml | 2000ml |
| Drug plasma eliminates the half-life（h） | 1.13 | 1.12 | 1.14 | 1.10 | 1.11 |
Study further, it has been surprisingly found that the existing specific proportioning of ribavirin injection sodium carboxymethyl cellulose,
In the case of betacyclodextrin, continue to add the Povidone K 30 of specified quantitative, stablizing of ribavirin injection can be significantly improved
Property, add Povidone K 30 not affect the specific proportioning of sodium carboxymethyl cellulose, betacyclodextrin to raising profit bar through experimental study
Wei Lin drug plasma eliminates the effect of half-life, and the sodium carboxymethyl cellulose of specific proportioning, betacyclodextrin, polyvidone
Being used in combination of K30 serves unexpected effect to the stability improving ribavirin injection, and tests below is entered to this
Row explanation：
Table 4 adds the various prescriptions of Povidone K 30
It is 10ml that above prescription is all prepared into specification by present invention process:The ribavirin injection of 1g, above 8 kinds
Quadrat sampling product carry out influence factor's test, respectively in 60 DEG C, high light（4500lx±500lx）Place 20 days, took respectively at the 20th day
Sample is examined and determine, and result was compared with 0 day, and the stability result investigating sample is shown in Table 5：
The different prescription influence factor's result of the test of table 5
Be can be seen that by table 5 result of the test：The sodium carboxymethyl cellulose of specific proportioning, betacyclodextrin and Povidone K 30
As the adjuvant of ribavirin injection, the stability of note ribavirin injection can be significantly improved.
Specific embodiment：
The preparation of embodiment 1 ribavirin medicine composition injection（1ml:100mg）
1st, ribavirin raw material is refined：1. ribavirin raw material 300g is added the 90% of 3000ml（v/v）Ethanol is water-soluble
In liquid, it is warming up to 75 DEG C, stirring and dissolving, obtain filtrate through 0.22 μm of membrane filtration；2. under 120 revs/min of mixing speed, while stirring
Mix side, with 0.4 DEG C/min speed, the filtrate in 1. is cooled to 4 DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；
By filter cake in 80 DEG C of dryings 7 hours, obtain ribavirin highly finished product；2nd, 5.0g sodium carboxymethyl cellulose is added 1600 ml notes
Penetrate with water, stirring to being completely dissolved, then sequentially add 200g ribavirin highly finished product, 9.0g betacyclodextrin, 2.0g gather
Dimension ketone K30 stirs to being completely dissolved, and injects water to 2000ml, stirs；3rd, add the work of 0.10g/100ml toward in 2
Property charcoal, stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure filtrate pH value, content, by specification 1ml subpackage to ampoule bottle,
Sealing by fusing, 121 DEG C of moist heat sterilizations 15 minutes, obtain final product ribavirin medicine composition injection.Ribavirin manufactured in the present embodiment
Injection carries out drug plasma and eliminates half-life test, and rabbit is injected ribavirin with ribavirin 10mg/kg through auricular vein
Woods injection, records drug plasma and eliminates the half-life for 3.26h.
The preparation of embodiment 2 ribavirin medicine composition injection（2ml:200mg）
1st, ribavirin raw material is refined：1. ribavirin raw material 300g is added the 90% of 3000ml（v/v）Ethanol is water-soluble
In liquid, it is warming up to 75 DEG C, stirring and dissolving, obtain filtrate through 0.22 μm of membrane filtration；2. under 120 revs/min of mixing speed, while stirring
Mix side, with 0.4 DEG C/min speed, the filtrate in 1. is cooled to 4 DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；
By filter cake in 80 DEG C of dryings 7 hours, obtain ribavirin highly finished product；2nd, 5.0g sodium carboxymethyl cellulose is added 1600 ml notes
Penetrate with water, stirring to being completely dissolved, then sequentially add 200g ribavirin highly finished product, 9.0g betacyclodextrin, 2.0g gather
Dimension ketone K30 stirs to being completely dissolved, and injects water to 2000ml, stirs；3rd, add the work of 0.10g/100ml toward in 2
Property charcoal, stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure filtrate pH value, content, by specification 2ml subpackage to ampoule bottle,
Sealing by fusing, 121 DEG C of moist heat sterilizations 15 minutes, obtain final product ribavirin medicine composition injection.Ribavirin manufactured in the present embodiment
Injection carries out drug plasma and eliminates half-life test, and rabbit is injected ribavirin with ribavirin 10mg/kg through auricular vein
Woods injection, records drug plasma and eliminates the half-life for 3.25h.
The preparation of embodiment 3 ribavirin medicine composition injection（2ml:100mg）
1st, ribavirin raw material is refined：1. ribavirin raw material 200g is added the 90% of 2000ml（v/v）Ethanol is water-soluble
In liquid, it is warming up to 75 DEG C, stirring and dissolving, obtain filtrate through 0.22 μm of membrane filtration；2. under 120 revs/min of mixing speed, while stirring
Mix side, with 0.4 DEG C/min speed, the filtrate in 1. is cooled to 4 DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；
By filter cake in 80 DEG C of dryings 7 hours, obtain ribavirin highly finished product；2nd, 5.0g sodium carboxymethyl cellulose is added 1600 ml notes
Penetrate with water, stirring to being completely dissolved, then sequentially add 100g ribavirin highly finished product, 9.0g betacyclodextrin, 2.0g gather
Dimension ketone K30 stirs to being completely dissolved, and injects water to 2000ml, stirs；3rd, add the work of 0.10g/100ml toward in 2
Property charcoal, stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure filtrate pH value, content, by specification 2ml subpackage to ampoule bottle,
Sealing by fusing, 121 DEG C of moist heat sterilizations 15 minutes, obtain final product ribavirin medicine composition injection.Ribavirin manufactured in the present embodiment
Injection carries out drug plasma and eliminates half-life test, and rabbit is injected ribavirin with ribavirin 10mg/kg through auricular vein
Woods injection, records drug plasma and eliminates the half-life for 3.27h.
The preparation of embodiment 4 ribavirin medicine composition injection（2ml:250mg）
1st, ribavirin raw material is refined：1. ribavirin raw material 400g is added the 90% of 4000ml（v/v）Ethanol is water-soluble
In liquid, it is warming up to 75 DEG C, stirring and dissolving, obtain filtrate through 0.22 μm of membrane filtration；2. under 120 revs/min of mixing speed, while stirring
Mix side, with 0.4 DEG C/min speed, the filtrate in 1. is cooled to 4 DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；
By filter cake in 80 DEG C of dryings 7 hours, obtain ribavirin highly finished product；2nd, 5.0g sodium carboxymethyl cellulose is added 1600 ml notes
Penetrate with water, stirring to being completely dissolved, then sequentially add 250g ribavirin highly finished product, 9.0g betacyclodextrin, 2.0g gather
Dimension ketone K30 stirs to being completely dissolved, and injects water to 2000ml, stirs；3rd, add the work of 0.10g/100ml toward in 2
Property charcoal, stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure filtrate pH value, content, by specification 2ml subpackage to ampoule bottle,
Sealing by fusing, 121 DEG C of moist heat sterilizations 15 minutes, obtain final product ribavirin medicine composition injection.Ribavirin manufactured in the present embodiment
Injection carries out drug plasma and eliminates half-life test, and rabbit is injected ribavirin with ribavirin 10mg/kg through auricular vein
Woods injection, records drug plasma and eliminates the half-life for 3.26h.
The preparation of embodiment 5 ribavirin medicine composition injection（5ml:250mg）
1st, ribavirin raw material is refined：1. ribavirin raw material 200g is added the 90% of 2000ml（v/v）Ethanol is water-soluble
In liquid, it is warming up to 75 DEG C, stirring and dissolving, obtain filtrate through 0.22 μm of membrane filtration；2. under 120 revs/min of mixing speed, while stirring
Mix side, with 0.4 DEG C/min speed, the filtrate in 1. is cooled to 4 DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；
By filter cake in 80 DEG C of dryings 7 hours, obtain ribavirin highly finished product；2nd, 5.0g sodium carboxymethyl cellulose is added 1600 ml notes
Penetrate with water, stirring to being completely dissolved, then sequentially add 100g ribavirin highly finished product, 9.0g betacyclodextrin, 2.0g gather
Dimension ketone K30 stirs to being completely dissolved, and injects water to 2000ml, stirs；3rd, add the work of 0.10g/100ml toward in 2
Property charcoal, stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure filtrate pH value, content, by specification 5ml subpackage to ampoule bottle,
Sealing by fusing, 121 DEG C of moist heat sterilizations 15 minutes, obtain final product ribavirin medicine composition injection.Ribavirin manufactured in the present embodiment
Injection carries out drug plasma and eliminates half-life test, and rabbit is injected ribavirin with ribavirin 10mg/kg through auricular vein
Woods injection, records drug plasma and eliminates the half-life for 3.24h.
The preparation of embodiment 6 ribavirin medicine composition injection（5ml:500mg）
1st, ribavirin raw material is refined：1. ribavirin raw material 300g is added the 90% of 3000ml（v/v）Ethanol is water-soluble
In liquid, it is warming up to 75 DEG C, stirring and dissolving, obtain filtrate through 0.22 μm of membrane filtration；2. under 120 revs/min of mixing speed, while stirring
Mix side, with 0.4 DEG C/min speed, the filtrate in 1. is cooled to 4 DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；
By filter cake in 80 DEG C of dryings 7 hours, obtain ribavirin highly finished product；2nd, 5.0g sodium carboxymethyl cellulose is added 1600 ml notes
Penetrate with water, stirring to being completely dissolved, then sequentially add 200g ribavirin highly finished product, 9.0g betacyclodextrin, 2.0g gather
Dimension ketone K30 stirs to being completely dissolved, and injects water to 2000ml, stirs；3rd, add the work of 0.10g/100ml toward in 2
Property charcoal, stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure filtrate pH value, content, by specification 5ml subpackage to ampoule bottle,
Sealing by fusing, 121 DEG C of moist heat sterilizations 15 minutes, obtain final product ribavirin medicine composition injection.Ribavirin manufactured in the present embodiment
Injection carries out drug plasma and eliminates half-life test, and rabbit is injected ribavirin with ribavirin 10mg/kg through auricular vein
Woods injection, records drug plasma and eliminates the half-life for 3.27h.
The preparation of embodiment 7 ribavirin medicine composition injection（10ml:1g）
1st, ribavirin raw material is refined：1. ribavirin raw material 300g is added the 90% of 3000ml（v/v）Ethanol is water-soluble
In liquid, it is warming up to 75 DEG C, stirring and dissolving, obtain filtrate through 0.22 μm of membrane filtration；2. under 120 revs/min of mixing speed, while stirring
Mix side, with 0.4 DEG C/min speed, the filtrate in 1. is cooled to 4 DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；
By filter cake in 80 DEG C of dryings 7 hours, obtain ribavirin highly finished product；2nd, 5.0g sodium carboxymethyl cellulose is added 1600 ml notes
Penetrate with water, stirring to being completely dissolved, then sequentially add 200g ribavirin highly finished product, 9.0g betacyclodextrin, 2.0g gather
Dimension ketone K30 stirs to being completely dissolved, and injects water to 2000ml, stirs；3rd, add the work of 0.10g/100ml toward in 2
Property charcoal, stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure filtrate pH value, content, by specification 10ml subpackage to ampoule bottle
In, sealing by fusing, 121 DEG C of moist heat sterilizations 15 minutes, obtain final product ribavirin medicine composition injection.Ribavirin manufactured in the present embodiment
Woods injection carries out drug plasma and eliminates half-life test, and rabbit is injected sharp bar with ribavirin 10mg/kg through auricular vein
Wei Lin injection, records drug plasma and eliminates the half-life for 3.25h.
The present invention provides tests below and comparing result：
The embodiment of the present invention 1, ribavirin injection prepared by embodiment 7 and commercially available ribavirin injection are carried out
Accelerated stability is investigated（40 DEG C ± 2 DEG C, RH 75% ± 5%）12 months, the results are shown in Table 6.
Table 6 ribavirin injection speed result of the test
Compared surely by the ribavirin pharmaceutical composition injection prior art that the result of table 6 can be seen that present invention preparation
Qualitative significantly improve.The ribavirin medicine composition injection of other embodiments of the invention preparation has been also carried out identical test
, obtained similar result.
Claims (3)
1. a kind of long-acting ribavirin medicine composition injection it is characterised in that：Refined by 100g～250g ribavirin
Product, 5.0g sodium carboxymethyl cellulose, 9.0g betacyclodextrin, 2.0g Povidone K 30, water for injection add to 2000ml preparation and
Become.
2. long-acting ribavirin medicine composition injection according to claim 1 it is characterised in that：Described injection
Specification be 10ml:1g.
3. the preparation method of the long-acting ribavirin medicine composition injection described in claim 1, comprises the following steps：
(1) ribavirin raw material is refined：
1. ribavirin raw material is added in 90% (v/v) ethanol water, be warming up to 75 DEG C, stirring and dissolving, filter through 0.22 μm
Membrane filtration obtains filtrate；The amount ratio of ribavirin raw material and 90% (v/v) ethanol water is 1g:10ml；
2. under 120 revs/min of mixing speed, while stirring with 0.4 DEG C/min speed by step 1. in filtrate be cooled to 4
DEG C, stop stirring, standing growing the grain 6 hours, filter, obtain filter cake；By filter cake in 80 DEG C of dryings 7 hours, obtain final product ribavirin and refine
Product；
(2) press recipe quantity to add sodium carboxymethyl cellulose in 1600ml water for injection, stir to being completely dissolved, then add successively
Enter the ribavirin highly finished product of recipe quantity, betacyclodextrin, Povidone K 30 stir to being completely dissolved, inject water to
2000ml, stirs；
(3) add the activated carbon of 0.10g/100ml toward in step (2), stir 25 minutes, 0.22 μm of membrane filtration is degerming, measure
Filtrate pH value, content, determine filling amount by specification, by filtrate subpackage to ampoule bottle, sealing by fusing, and 121 DEG C of moist heat sterilizations 15 minutes,
Obtain final product ribavirin medicine composition injection.
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| CN102366401A (en) * | 2011-09-28 | 2012-03-07 | 河南辅仁怀庆堂制药有限公司 | Ribavirin injection and preparation process thereof |
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| CN102366401A (en) * | 2011-09-28 | 2012-03-07 | 河南辅仁怀庆堂制药有限公司 | Ribavirin injection and preparation process thereof |
Non-Patent Citations (2)
| Title |
|---|
| 利巴韦林的研究应用及展望;余文英;《亚太传统医药》;20101130;第6卷(第11期);第175-177页 * |
| 氟苯尼考长效混悬注射液的研制及其质量控制;刘晓强，等;《西北农林科技大学学报》;20100630;第38卷(第6期);第42-46页 * |
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Effective date of registration: 20171208 Address after: 432800 Xiaogan City, Hubei Province town of Chengguan Dawu County Han market No. 102 Patentee after: Hubei Taixin medicine science and Technology Co Ltd Address before: 430014, Zhenghe Plaza, 707 Zhongshan Avenue, Jiang'an District, Hubei, Wuhan, 1506 Patentee before: Hubei Merryclin Pharmaceutical Co., Ltd. |
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Effective date of registration: 20181108 Address after: 432500 Yunmeng County Economic Development Zone, Xiaogan, Hubei Patentee after: Hubei Merryclin Pharmaceutical Co., Ltd. Address before: 432800 102, Han Da market, Chengguan Town, Dawu County, Xiaogan, Hubei Patentee before: Hubei Taixin medicine science and Technology Co Ltd |