CN101642440B - Adenine arabinoside monophosphate freeze-dried powder injection and preparation method thereof - Google Patents
Adenine arabinoside monophosphate freeze-dried powder injection and preparation method thereof Download PDFInfo
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- CN101642440B CN101642440B CN200910042356.0A CN200910042356A CN101642440B CN 101642440 B CN101642440 B CN 101642440B CN 200910042356 A CN200910042356 A CN 200910042356A CN 101642440 B CN101642440 B CN 101642440B
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Abstract
The present invention relates to a kind of adenine arabinoside monophosphate freeze-dried powder injection and preparation method thereof, this lyophilized injectable powder is formed by vidarabine phosphate drug solution lyophilizing, this vidarabine phosphate drug solution formula is: vidarabine phosphate 100g, mannitol 25g, disodium hydrogen phosphate 3g, sodium dihydrogen phosphate 0.3g, ethylenediamine tetraacetic two acid disodium 1g, water for injection adds to 2000mL.In the preparation method of this lyophilized injectable powder, lyophilizing technique includes pre-freeze, distil and heat up dry three processes.Lyophilized injectable powder of the present invention and preparation method thereof aqueous injection more commonly used in the prior art has has significant advantage at storage and transporter mask.
Description
Technical field
The present invention relates to a kind of medicine and preparation method thereof, particularly relate to a kind of vidarabine monophosphate for injection lyophilized powder
Injection and preparation method thereof.
Background technology
Vidarabine phosphate (Vidarabine Monophosphate, Ara-AMP) is the mono-phosphorylated of vidarabine
Compound, is the purine nucleoside compound by synthetic.Vidarabine phosphate can suppress the synthesis of viral DNA, specifically
For, after vidarabine phosphate enters cell, generate vidarabine diphosphonic acid (Ara-ADP), vidarabine through phosphorylation
Triphosphoric acid (Ara-ATP), its antiviral activity is mainly caused by arabinose vidarabine triphosphoric acid (Ara-ATP), vidarabine
(Ara-ATP) triphosphoric acid and deoxyadenosine triphosphate (dATP) are attached on viral DNA P with competing, thus inhibit the work of enzyme
Property and the synthesis of viral DNA.Suppressing the activity of viral nucleotide reductase simultaneously, and suppress the synthesis of viral DNA, it can also
The activity of suppression viral DNA end Deoxynucleotidyl transferase, makes vidarabine penetrate in the DNA of virus, and is connected to DNA
The end of 3 '-OH positions, thus inhibit the continuation of viral DNA to synthesize.So vidarabine phosphate is viral DNA polymerization
The inhibitor of enzymatic activity, is again the terminator of viral DNA synthesis, it is possible to the duplication of double inhibition virus, effectively reaches antiviral
Effect.
At present, the vidarabine phosphate dosage form of Clinical practice is mostly injection type, wherein, owing to aqueous injection has it
Effect is fast, it is easy to the feature of preparation, is therefore widely adopted, and such as Chinese patent CN200410021225.1, i.e. discloses a kind of single
Vidarabine phosphate agent and preparation method thereof, but compared to aqueous injection, lyophilized injectable powder not only has good curative effect, and
In transport, the aspect such as storage has more advantage, though and prior art has some for vidarabine phosphate lyophilizing technique and
The research of formula, but the formula of lyophilized injectable powder of the prior art and preparation method generally to there is the production cycle long, yield poorly,
Operating procedure is complicated, technology content requires the problems such as high.
Summary of the invention
In view of this, the technical problem to be solved is, overcomes the deficiencies in the prior art, it is provided that one
Kind of constant product quality is controlled and the simple adenine arabinoside monophosphate freeze-dried powder injection of operating procedure and preparation side thereof
Method.
In order to solve above-mentioned technical problem, on the one hand, the real-time mode of the present invention provides a kind of injection monophosphate
Vidarabine lyophilized injectable powder, it forms by vidarabine phosphate drug solution lyophilizing, and this vidarabine phosphate medicine is molten
Formula of liquid is as follows:
Vidarabine phosphate 100g
Mannitol 25g
Disodium hydrogen phosphate 3g
Sodium dihydrogen phosphate 0.3g
Ethylenediamine tetraacetic two acid disodium 1g
Water for injection adds to 2000mL
Vidarabine phosphate drug solution partition is dressed up 2mL/ bottle, and lyophilizing prepares injectable powder.
On the other hand, the real-time mode of the present invention additionally provides a kind of vidarabine monophosphate for injection freeze-dried powder
The preparation method of agent, comprises the following steps:
1. weigh required component according to formula in claim 1, aseptically dissolve and stir；
2. adjusting pH value range is 7.0～7.5, constant volume；
3. aseptic filtration 2～3 times, collect filtrate；
4. fill, lyophilizing；
Wherein, described freeze-drying process includes successively:
Pre-freeze, puts into product the lyophilizing cabinet pre-freeze of pre-freeze extremely-40 DEG C, makes product freeze reality, 4 hours pre-freeze time；
Distillation, after pre-freeze completes and condenser temperature reaches-60 DEG C, Qidong vacuum equipment, make system vacuum reach
10Pa, and maintain 1 hour.Then start heater, control temperature of charge and be-20 DEG C.It is not higher than 20Pa condition in vacuum
Under, slowly distillation 10 hours；
Heating up and be dried, treat that product distillation is complete, product is rarefaction, and maintaining temperature of charge is 40 DEG C, vacuum 10Pa
Condition heat preservation and dryness 4-6 hour, terminates lyophilizing.
Owing to pre-freezing temperature is controlled below vidarabine phosphate solution eutectic point 10 DEG C～20 DEG C by the present invention, keep
4 hours, make medicine freeze real after heat up again, and due in the present invention heating load during sublimation drying control preferably, suitably put
Slow programming rate, controls temperature less than eutectic point, thus preferably prevents spray bottle.If additionally, drying time is long,
Will also result in product appearance defective, therefore use the lyophilizing technique used by the present invention, products obtained therefrom quality is loosened, fast after adding water
Instant solution, quickly recovers the primary characteristic of medicinal liquid.If cooling rate is fast when starting to freeze, goods are made to form fine crystallization, close
Degree is big, distils relatively big by resistance, and moisture is difficult to evaporate, and goods gradually can cause volume contraction to cause profile insatiable hunger by deliquescence
Expire or form bulk.If freezing speed is the slowest, ice crystal growth time is longer, the most easily concentrates, and causes medicine to divide with solvent
Uneven from, finished product structure.The present invention, through repeated tests, has formulated the optimal freeze-drying curve of this product, obtained product
Having enough intensity, be not broken into powder, full appearance, not atrophy, uniform color, water content is low, and porous is good, energy after adding water
Redissolve rapidly.Therefore, the product dosage obtained by preparation method involved in the present invention is accurate, good appearance.
In this formula, owing to adding appropriate adjuvant mannitol, disodium hydrogen phosphate, sodium dihydrogen phosphate and second two
Amine four or two acid disodium, it is possible to improve the face shaping of the freeze-drying prods using preparation method involved in the present invention to prepare further
And sedimentation, and make the surface of product more smooth.Pharmaceutical properties is the most stable simultaneously, it is simple to the preservation of medicine and fortune
Defeated.
Described aseptic filtration includes 0.45 μm aseptic filtration and at least one times 0.22 μm aseptic filtration at least one times.Preferably
For, successively through a 0.45 μm aseptic filtration and a 0.22 μm aseptic filtration, cross rate through twice aseptic filtration, according to this
Lyophilized injectable powder prepared by inventive method meets the injection pharmaceutical standards of 100 grades.
The preparation method of adenine arabinoside monophosphate freeze-dried powder injection the most involved in the present invention, its operating procedure
Simply, technology is less demanding, the production cycle is relatively short, and obtained constant product quality is controlled, is conducive to long-term storage
Deposit.
Detailed description of the invention
Hereinafter embodiments of the invention are described in more detail, but the present invention is not limited only to the present embodiment.
Embodiment
1. prescription:
Prescription:
Vidarabine phosphate 100g
Mannitol 25g
Disodium hydrogen phosphate 3g
Sodium dihydrogen phosphate 0.3g
Ethylenediamine tetraacetic two acid disodium 1g
Water for injection adds to 2000mL
It is distributed into 1000 bottles
2. preparation method:
(1) weigh.Required component is weighed according to prescription, indoor in the preparation of the cleanliness factors of 10000 grades, former by weigh up
Material adds in material-compound tank, dissolves each said components with water for injection
(2) pour buffer solution into, start stirring, regulate between PH7.0～7.5 with the sodium hydroxide of 2.5M, then with injecting
Use water constant volume, after stirring, sample to inspection center, measure content inspection and do tiny electrolytic cell.
(3) 10000 grades join in filter chamber, the medicinal liquid peristaltic pump prepared is delivered to oneself mounted aperture is
0.45 μm and the nuclepore membrane filter of 0.22 μm, carry out aseptic filtration.The oil strain started is vertical to be back in original liquid box, treats clear and bright
After degree passed examination, medicinal liquid receives with the most autoclaved serum bottle.After degerming, medicinal liquid moves into fill room.
(4) canned.Carrying out canned in the fill indoor of the 100 grades of cleanliness factors in local, medicinal liquid is delivered to by quantitative peristaltic pump
In filling machine, the glass tube vial after sterilizing also synchronizes to deliver to the rotating disk of filling machine, peristaltic pump by quantitative liquid medicine filling to glass tube vial
In, by the linkage of half tamponade, plug is built, be sent in lyophilizing box.
(5) lyophilization
Lyophilization in turn includes the following steps:
One, pre-freeze, puts into product the lyophilizing cabinet pre-freeze of pre-freeze extremely-40 DEG C, makes product freeze reality, and the pre-freeze time 4 is little
Time；
Two, distillation, after pre-freeze completes and condenser temperature reaches-60 DEG C, Qidong vacuum equipment, make system vacuum reach
10Pa, and maintain 1 hour.Then start heater, control temperature of charge and be-20 DEG C.It is not higher than 20Pa condition in vacuum
Under, slowly distillation 10 hours；
Three, intensification is dried, and treats that product distillation is complete, and product is rarefaction, and maintaining temperature of charge is 40 DEG C, vacuum
10Pa condition heat preservation and dryness 4-6 hour, terminates lyophilizing.
Four, tamponade, after lyophilizing terminates, starts oil gear, is pressed in bottle by plug, then passes to pure air, recover
Normal pressure, wait is offerd for sale.
(6) lid, visual inspection, labeling and packaging are rolled.
In above-mentioned prescription, medicinal liquid is divided into 1000 parts, implements in preparation process, can be according to the use of effective ingredient
Amount, adjusts the medicament contg in every bottle of lyophilized injectable powder, the typically medicine liquid volume by loading in adjusting every bottle and i.e. can produce
Go out the medicine of different size, it is, of course, also possible to by adjusting the concentration of each component in prescription, be scaling up or reduce each group
The consumption divided, it is also possible to prepare the adenine arabinoside monophosphate freeze-dried powder injection pharmaceutical product of different size.
[sample quality inspection]
By above prescription 2 and technique, this product carried out three batches of little trial productions (preparing 500 bottles for every batch), three batch sample quality
The most qualified, assay is shown in Table 2.
The assay of table 2 sample
| Sample lot number | 1 | 2 | 3 |
| Character | White loose block | White loose block | White loose block |
| Differentiate | In positive reaction | In positive reaction | In positive reaction |
| Acidity | 7.3 | 7.2 | 7.4 |
| Moisture (%) | 1.2 | 1.2 | 1.2 |
| Content uniformity | Meet regulation | Meet regulation | Meet regulation |
| Clarity | Meet regulation | Meet regulation | Meet regulation |
| Endotoxin | Meet regulation | Meet regulation | Meet regulation |
| Aseptic | Meet regulation | Meet regulation | Meet regulation |
| Active ingredient/(with the percentage ratio of labelled amount) | 98.7 | 99.1 | 98.9 |
Wherein, active ingredient vidarabine phosphate should be the 90.0～115.0% of labelled amount.
As can be seen here, the quality of three batches of products all meets Chinese Pharmacopoeia regulation (hereinafter referred to as meeting regulation), and this product is described
Prescription and technique be feasible.
Correspondingly, injectable powder is prepared according to prescription 1 and prescription 3, it is also possible in this test, draw similar result of the test,
Visible, the quality of three kinds of prescription products all meets Chinese Pharmacopoeia regulation (hereinafter referred to as meeting regulation), illustrate the prescription of this product with
Technique is feasible.
[influence factor's test]
Take test sample 1 batch, carry out influence factor's test, respectively at illumination (4500Lx), high temperature (60 DEG C), high humidity
(RH92.5%) place 10 days under the conditions of, and respectively at 5 days, 10 days sampling every Testing index of investigation, and the detection knot with 0 day
Fruit is compared, and checks appearance luster, acidity, moisture, the clarity of solution, protein, other material, measures content, the results are shown in Table
3。
Table 3 influence factor's result of the test
Above-mentioned result of the test shows, this product is equal under the conditions of illumination (4500Lx), high temperature (60 DEG C), high humidity (RH92.5%)
More stable.This result illustrates the feasibility of this product technique.
It addition, for other batches and the product prepared according to other prescriptions, carry out what above-mentioned test all can obtain being similar to
Result of the test.
[raw material, adjuvant source and quality standard]
The quality control of pharmaceutical raw material is most important to the quality of finished product, vidarabine phosphate involved in the present invention,
By pharmaceutical factory of Guangdong Prov. Inst. of Materia Medica bio feedstocks Workshop Production, and it is largely used to produce Vidarabine monophosphate injection.
Other raw materials include vidarabine phosphate, mannitol, disodium hydrogen phosphate, sodium dihydrogen phosphate, ethylenediamine tetraacetic two acid disodium and note
Penetrate with water all according to the control standard processed of Chinese Pharmacopoeia 2005 editions.
Last institute is it should be noted that, the present invention is only protected by above example in order to technical scheme to be described
Protecting the restriction of scope, although being explained in detail the present invention with reference to preferred embodiment, those of ordinary skill in the art should
Understand, technical scheme can be modified or equivalent, without deviating from the essence of technical solution of the present invention
And scope.
Claims (2)
1. an adenine arabinoside monophosphate freeze-dried powder injection, it forms by vidarabine phosphate drug solution lyophilizing,
This vidarabine phosphate drug solution formula is as follows:
The distribution of vidarabine phosphate drug solution is dressed up 2ml/ bottle, and lyophilizing prepares injectable powder.
2. the preparation method of an adenine arabinoside monophosphate freeze-dried powder injection, it is characterised in that this preparation method include with
Lower step:
1. weigh required component according to formula in claim 1, aseptically dissolve and stir；
2. adjusting pH value range is 7.0～7.5, constant volume；
3. aseptic filtration 2～3 times, collect filtrate；
4. fill, lyophilizing；
Wherein, described freeze-drying process includes successively:
Pre-freeze, puts into product the lyophilizing cabinet pre-freeze of pre-freeze extremely-40 DEG C, makes product freeze reality, 4 hours pre-freeze time；
Distillation, after pre-freeze completes and condenser temperature reaches-60 DEG C, starts vacuum equipment, makes system vacuum reach 10Pa, and
Maintain 1 hour；Then start heater, control temperature of charge and be-20 DEG C；Under the conditions of vacuum is not higher than 20Pa, slowly
Distil 10 hours；
Heating up and be dried, treat that product distillation is complete, product is rarefaction, and maintaining temperature of charge is 40 DEG C, vacuum 10Pa condition
Heat preservation and dryness 4-6 hour, terminates lyophilizing；
Described aseptic filtration is successively through a 0.45 μm aseptic filtration and a 0.22 μm aseptic filtration.
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| CN200910042356.0A CN101642440B (en) | 2009-09-01 | 2009-09-01 | Adenine arabinoside monophosphate freeze-dried powder injection and preparation method thereof |
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| CN200910042356.0A CN101642440B (en) | 2009-09-01 | 2009-09-01 | Adenine arabinoside monophosphate freeze-dried powder injection and preparation method thereof |
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| CN2011103559447A Division CN102389403B (en) | 2009-09-01 | 2009-09-01 | Freeze dried monophosphate adenine arabinoside powder injection for injection and preparation method thereof |
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| CN102379853B (en) * | 2011-11-16 | 2013-01-16 | 海南锦瑞制药股份有限公司 | Vidarabine monophosphate freeze-dried powder injection and preparation method thereof |
| CN103599080B (en) * | 2013-11-26 | 2015-08-19 | 广东隆赋药业有限公司 | A kind of Pharmaceutical composition of vidarabine monophosphate for injection |
| CN104543584A (en) * | 2015-01-23 | 2015-04-29 | 湖北龙王恨渔具集团有限公司 | Application of freeze-dried blood worm prototype in bait |
| CN107890459A (en) * | 2017-11-24 | 2018-04-10 | 海南通用康力制药有限公司 | Adenine arabinoside monophosphate freeze-dried powder injection and preparation method thereof |
| CN113171347B (en) * | 2021-04-06 | 2022-11-29 | 海南锦瑞制药有限公司 | Preparation method of vidarabine monophosphate freeze-dried powder injection for injection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562068A (en) * | 2004-04-05 | 2005-01-12 | 孟繁浩 | Vidarabine monophosphate injection and its preparing method |
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| CN102389403B (en) * | 2009-09-01 | 2012-11-28 | 广东隆赋药业有限公司 | Freeze dried monophosphate adenine arabinoside powder injection for injection and preparation method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562068A (en) * | 2004-04-05 | 2005-01-12 | 孟繁浩 | Vidarabine monophosphate injection and its preparing method |
Non-Patent Citations (2)
| Title |
|---|
| M.S.L.KWEE etal.Formulation of a stable vidarabine phosphate injection.《Pharmaceutish Weekblad Scientific Edition》.1984,第6卷第101-104页. * |
| 陈卫波等.注射用单磷酸阿糖腺苷的冻干工艺研究.《中国热带医学》.2007,第7卷(第4期),第654-655页. * |
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