CN103536445A - Vidarabine monophosphate for injection and method for producing vidarabine monophosphate - Google Patents

Abstract

The invention discloses vidarabine monophosphate for injection and a method for producing the vidarabine monophosphate. The vidarabine monophosphate for the injection comprises 100.0g of the vidarabine monophosphate, 50.0g of mannitol, 5.0g of medicinal carbon, and 2000ml of water for the injection. The method sequentially comprises the following steps: (1) washing, drying and disinfecting a bottle, (2) washing and disinfecting a plug, (3) conducting preparation, (4) conducting filling, (5) conducting freeze drying, (6) rolling a cover, (7) conducting light inspection, and (8) conducting lettering, packaging and storage. Compared with the prior art, the vidarabine monophosphate produced by the method is good in crystal form, simple in step and short in cycle, and the production efficiency is improved.

Description

A kind of vidarabine monophosphate for injection and production method thereof

Technical field

The present invention relates to a kind of vidarabine monophosphate for injection and production method thereof.

Background technology

Vidarabine phosphate (Vidarabine Monophosphate, Ara-AMP) is the monophosphate compound of vidarabine, is the purine nucleoside compound by synthetic.Vidarabine phosphate can suppress the synthetic of viral DNA, particularly, vidarabine phosphate enters after cell, through phosphorylation, generate vidarabine diphosphonic acid (Ara-ADP), vidarabine triphosphoric acid (Ara-ATP), its antiviral activity is mainly caused by arabinose vidarabine triphosphoric acid (Ara-ATP), be attached to viral DNA P to vidarabine (Ara-ATP) triphosphoric acid and deoxyadenosine triphosphate (dATP) competition upper, thereby suppressed the activity of enzyme and synthesizing of viral DNA.The activity that simultaneously suppresses viral nucleotide reductase, and suppress synthesizing of viral DNA, it can also suppress the activity of viral DNA terminal deoxyribotide transferase, vidarabine is infiltrated in viral DNA, and be connected to the end of DNA chain 3 '-OH position, thereby it is synthetic to have suppressed the continuation of viral DNA.So vidarabine phosphate is the inhibitor of viral dna polymerase activity, be again the synthetic terminator of viral DNA, can answering of double inhibition virus scrape, effectively reach antiviral effect.

At present, the vidarabine phosphate dosage form of clinical use is mostly injection type, wherein, because aqueous injection has its effect soon, be easy to the feature of preparation, therefore be widely adopted, as Chinese patent CN200410021225.1, a kind of vidarabine phosphate agent and preparation method thereof is disclosed, yet than aqueous injection, lyophilized injectable powder not only has good curative effect, and in transportation, the aspects such as storage have more advantage, though and prior art has some for the research of vidarabine phosphate freeze-dry process and formula, but of the prior art frozen in formula and the preparation method ubiquity production cycle of injectable powder long, yield poorly, operating procedure is complicated, technology content requires the problems such as high.

Chinese patent 2011103559447, and Chinese patent 2012104260761, all disclose the preparation method of adenine arabinoside monophosphate freeze-dried powder injection, it still exists the production cycle long, yields poorly, operating procedure is complicated, technology content requires the problems such as high.

Summary of the invention

The invention provides a kind of vidarabine monophosphate for injection and production method thereof.

Technical scheme of the present invention is: a kind of vidarabine monophosphate for injection and production method thereof, and raw material: vidarabine phosphate 100.0g, mannitol 50.0g, medicinal charcoal 5.0g, water for injection 2000ml, pass through following steps successively:

1) bottle of washing, dry, go out: the antibiotic bottle after reason in bottle washer, with water for injection, 45 ℃～55 ℃ of water temperatures, through ultrasonic waves for cleaning, again with water for injection and compressed air carry out three water, three air-blowings are washed, in tunnel oven, 340 ℃～360 ℃ sterilizings, should control conveyer belt frequency during sterilizing;

2) plug of washing, go out: plug in Full automatic rubber plug cleaning machine through slightly washing, sterilizing after rinsing, fine purifiation, 121 ℃ of sterilising temps, sterilization time 45 minutes;

3) preparation: measure appropriate water for injection in dilute preparing tank, water for injection is cooled to below 40 ℃, get water for injection, add mannitol, after dissolving completely, add medicinal charcoal, boil after 30 minutes and filter, filtrate is cooled to below 40 ℃, slowly add vidarabine phosphate, stir and circulate it is dissolved completely, with 10% sodium hydroxide solution adjust pH to 7.0～7.5, stir 10 minutes, standing 20 minutes, successively by 0.45 μ m and 0.22 μ m cartridge filter, filter;

4) fill: by the embedding of fill post operation rules, check at any time loading amount and the quality of partly jumping a queue, loading amount of selective examination in every 2 hours, partly jump a queue quality and visible foreign matters, content is 2.0ml ± 2%, partly jumps a queue that the degree of depth should be controlled at 3mm～4mm, visible foreign matters should be up to specification, from aseptic filtration, starts must not finish over 6 hours to fill;

5) lyophilization: products temperature is down to below-30 ℃, cold insulation more than 30 minutes, guarantees goods fully charge, when condenser is cooled to below-45 ℃, while being evacuated to 15pa left and right, opens electrical heating, and the conduction oil temperature of setting once distillation is below-5 ℃.When products temperature reaches 30 ℃, be incubated about 1.5 hours, goods crystal form is full evenly, when case internal pressure no longer obviously increases, at hydraulic pressure, is total head plug outlet under 6MPa state;

6) roll lid: require the edge of a knife level and smooth, three fingering handss are twisted the aluminium-plastic cap loosening phenomenon that do not have;

7) lamp inspection: press lamp inspection post operation rules operations, lamp inspection case illumination should be at 800～1000lx, clears out a gathering place by the rule of operation of clearing out a gathering place after lamp inspection finishes, Quality Inspector's passed examination after-discharge quality certification of clearing out a gathering place;

8) lettering, packing, warehouse-in.

Compared with prior art, the vidarabine phosphate crystal formation that the present invention produces is good, and step is simple, and the cycle is short, has improved production efficiency.

The specific embodiment

Below by specific embodiment, the present invention will be further described.

And a production method, raw material: vidarabine phosphate 100.0g, mannitol 50.0g, medicinal charcoal 5.0g, water for injection 2000ml, pass through following steps successively:

1) bottle of washing, dry, go out: the antibiotic bottle after reason in bottle washer, with water for injection, 45 ℃～55 ℃ of water temperatures, through ultrasonic waves for cleaning, again with water for injection and compressed air carry out three water, three air-blowings are washed, in tunnel oven, 340 ℃～360 ℃ sterilizings, should control conveyer belt frequency during sterilizing;

2) plug of washing, go out: plug in Full automatic rubber plug cleaning machine through slightly washing, sterilizing after rinsing, fine purifiation, 121 ℃ of sterilising temps, sterilization time 45 minutes;

3) preparation: measure appropriate water for injection in dilute preparing tank, water for injection is cooled to below 40 ℃, get water for injection, add mannitol, after dissolving completely, add medicinal charcoal, boil after 30 minutes and filter, filtrate is cooled to below 40 ℃, slowly add vidarabine phosphate, stir and circulate it is dissolved completely, with 10% sodium hydroxide solution adjust pH to 7.0～7.5, stir 10 minutes, standing 20 minutes, successively by 0.45 μ m and 0.22 μ m cartridge filter, filter;

4) fill: by the embedding of fill post operation rules, check at any time loading amount and the quality of partly jumping a queue, loading amount of selective examination in every 2 hours, partly jump a queue quality and visible foreign matters, content is 2.0ml ± 2%, partly jumps a queue that the degree of depth should be controlled at 3mm～4mm, visible foreign matters should be up to specification, from aseptic filtration, starts must not finish over 6 hours to fill;

5) lyophilization: products temperature is down to below-30 ℃, cold insulation more than 30 minutes, guarantees goods fully charge, when condenser is cooled to below-45 ℃, while being evacuated to 15pa left and right, opens electrical heating, and the conduction oil temperature of setting once distillation is below-5 ℃.When products temperature reaches 30 ℃, be incubated about 1.5 hours, goods crystal form is full evenly, when case internal pressure no longer obviously increases, at hydraulic pressure, is total head plug outlet under 6MPa state;

6) roll lid: require the edge of a knife level and smooth, three fingering handss are twisted the aluminium-plastic cap loosening phenomenon that do not have;

7) lamp inspection: press lamp inspection post operation rules operations, lamp inspection case illumination should be at 800～1000lx, clears out a gathering place by the rule of operation of clearing out a gathering place after lamp inspection finishes, Quality Inspector's passed examination after-discharge quality certification of clearing out a gathering place;

8) lettering, packing, warehouse-in.

Claims (1)

1. vidarabine monophosphate for injection and a production method thereof, is characterized in that, it is characterized in that raw material: vidarabine phosphate 100.0g, mannitol 50.0g, medicinal charcoal 5.0g, water for injection 2000ml, pass through following steps successively:

1) bottle of washing, dry, go out: the antibiotic bottle after reason in bottle washer, with water for injection, 45 ℃～55 ℃ of water temperatures, through ultrasonic waves for cleaning, again with water for injection and compressed air carry out three water, three air-blowings are washed, in tunnel oven, 340 ℃～360 ℃ sterilizings, should control conveyer belt frequency during sterilizing;

2) plug of washing, go out: plug in Full automatic rubber plug cleaning machine through slightly washing, sterilizing after rinsing, fine purifiation, 121 ℃ of sterilising temps, sterilization time 45 minutes;

3) preparation: measure appropriate water for injection in dilute preparing tank, water for injection is cooled to below 40 ℃, get water for injection, add mannitol, after dissolving completely, add medicinal charcoal, boil after 30 minutes and filter, filtrate is cooled to below 40 ℃, slowly add vidarabine phosphate, stir and circulate it is dissolved completely, with 10% sodium hydroxide solution adjust pH to 7.0～7.5, stir 10 minutes, standing 20 minutes, successively by 0.45 μ m and 0.22 μ m cartridge filter, filter;

4) fill: by the embedding of fill post operation rules, check at any time loading amount and the quality of partly jumping a queue, loading amount of selective examination in every 2 hours, partly jump a queue quality and visible foreign matters, content is 2.0ml ± 2%, partly jumps a queue that the degree of depth should be controlled at 3mm～4mm, visible foreign matters should be up to specification, from aseptic filtration, starts must not finish over 6 hours to fill;

5) lyophilization: products temperature is down to below-30 ℃, cold insulation more than 30 minutes, guarantees goods fully charge, when condenser is cooled to below-45 ℃, while being evacuated to 15pa left and right, opens electrical heating, and the conduction oil temperature of setting once distillation is below-5 ℃.When products temperature reaches 30 ℃, be incubated about 1.5 hours, goods crystal form is full evenly, when case internal pressure no longer obviously increases, at hydraulic pressure, is total head plug outlet under 6MPa state;

6) roll lid: require the edge of a knife level and smooth, three fingering handss are twisted the aluminium-plastic cap loosening phenomenon that do not have;

7) lamp inspection: press lamp inspection post operation rules operations, lamp inspection case illumination should be at 800～1000lx, clears out a gathering place by the rule of operation of clearing out a gathering place after lamp inspection finishes, Quality Inspector's passed examination after-discharge quality certification of clearing out a gathering place;

8) lettering, packing, warehouse-in.