CN102274197B - Ganciclovir composition for injection and preparation method thereof - Google Patents
Ganciclovir composition for injection and preparation method thereof Download PDFInfo
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- CN102274197B CN102274197B CN 201110202536 CN201110202536A CN102274197B CN 102274197 B CN102274197 B CN 102274197B CN 201110202536 CN201110202536 CN 201110202536 CN 201110202536 A CN201110202536 A CN 201110202536A CN 102274197 B CN102274197 B CN 102274197B
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Abstract
The invention relates to a ganciclovir composition for injection, which is freeze-dried powder composed of ganciclovir and sodium hydroxide, wherein the weight ratio of the ganciclovir to the sodium hydroxide is (6.6-7.0):1, the average particle size of the freeze-dried powder is 80-100nm, and the porosity is 94-98%. The preparation method comprises the following steps: 1) preparation: weighing ganciclovir and sodium hydroxide, putting the ganciclovir and sodium hydroxide into a preparation tank, adding water for injection, and stirring until the ganciclovir and sodium hydroxide are completely dissolved and evenly mixed; 2) sterile filtration and packaging; and 3) vacuum freeze drying. The invention has the advantages of simple formula, advanced technique, uniform quality and high stability, and has higher redissolution performance and clinical application safety.
Description
Technical field
What the present invention relates to is a kind of injection ganciclovir composition and method of making the same, and the injection ganciclovir compositions by the method preparation is used for the treatment of immunodeficiency and suffers from megaloblastic retinitis and bone marrow or organ transplantation receptor prevention cmv infection.
Background technology
The ganciclovir chemical name is 9-(1,3-dihydroxy-2-the third oxygen methyl)-guanine.
Its structural formula is:
Molecular formula: C
9H
13N
5O
4
Molecular weight: 255.23
Cytomegalovirus (Cytomegalovirus, CMV) can cause multiple different Infectious syndrome: can cause the CMV syndrome at neonate for the duplex DNA virus that herpesvirus β belongs to; Can cause that at normal healthy people monocytosis levies; The immunodeficiency patient, such as immaturity neonate, organ transplant recipients or acquired immune deficiency syndrome (AIDS) (AIDS) patient, CMV can cause serious disease syndrome.Can invade institute in a organized way and organ, and fall ill with the infected's age and immune functional state, perhaps be long-term latency, latent infection activates when immunity of organisms is low, causes the CMV disease, and its state of an illness is heavy, development soon, poor prognosis.
Immunologic function normal health adult, the IgG antibody positive rate of CMV reaches more than 40% in developed country in the blood, the area that falls behind in some economic development can reach more than 80%, but seldom pathogenic, heating, leukopenia, interstitial pneumonia, gastroenteritis, hepatitis, retinitis, polyradiculitis etc. just appear under immunologic hypofunction or other abnormal conditions.
Organ transplant recipients is because immunosuppressant therapy, be the high-risk group of cmv infection, have parenchymatous organ more than 50% to transplant the receptor cmv infection occurs that cmv infection occurs the patient of 30-90% behind the renal transplantation, no matter be infection reason or the cause of death, cmv infection all ranks first.
In liver-transplantation patients, its infection rate is up to 30%-65%, and wherein 18%-40% causes a disease or clinical symptoms occurs.CMV is the important pathogen body of patient's AIDS secondary infection, and it is very general that cmv infection occurs.Can cause pneumonia, enteritis, enterorrhagia, meningoencephalitis and retinitis etc., the incidence rate of its retinitis has 37% cytomegaloviral retinitis (CMVR) occurs approximately, untreated CMVR, 90% above having caused property of patient AIDS irreversibility is blind.
At present, cmv infection has become one of modal nosocomial infection, especially betides to connect to like liver, bone marrow transplantation or with the patient of immunosuppressant treatment.
Cmv infection can prolong patient's hospital stays, increases misery and hospitalization cost, and case fatality rate is raise, and is the large problem that the world of medicine pays close attention to.
The control of cmv infection, CMV is to vidarabine (adenine, arabinoside), cytosine arabinoside (Arabinosyl Cutosine), acyclovir (acyclovir, acycloguanosine) and the sensitivity of fluodeoxyuridine (fluodeoxyuridine) all very low, and these side effects of pharmaceutical drugs are larger, so should not be as the cause of disease treatment.
Ganciclovir (Ganciclovir) is called for short GCV.For the acycloguanosine analog, to herpes simplex virus, particularly CMV has powerful inhibitory action.Intravenously administrable is used for the treatment of immunodeficiency and suffers from megaloblastic retinitis and bone marrow or organ transplantation receptor prevention cmv infection, has good curative effect.This medicine is to downtrod patient's CMV of immunity treatment, and effective percentage is up to 80%, and relapse rate is about 20-30%, is first-selected at present anti-CMV medicine.
Ganciclovir is prepared into the stability that injection ganciclovir composite freeze-dried powder can significantly increase finished product, the transportation of also being more convenient for simultaneously.
But in the process of preparation injection ganciclovir compositions, because ganciclovir preparating liquid solid content is higher and be glassy state in freeze-drying process, be difficult to during reducing melting and shortening cryodesiccated week, average out, and the rising along with the flaggy temperature, skeleton must appear and the lyophilizing micro structure is subsided, these have all limited the raising of injection ganciclovir composition product quality and production efficiency, the most key is, because skeleton and lyophilizing micro structure are subsided, also directly had influence on injection ganciclovir compositions redissolution performance, cause particulate matter and clarity variation, even do not meet the pharmacopeia regulation, cause by the gross scrapping of medicine.Even if solubility injection ganciclovir compositions preferably when dispatching from the factory, because the existence that skeleton and lyophilizing micro structure are subsided, micro structure is subsided and continue to be extended in put procedure, causes whole lyophilizing pore structure further to destroy, so that redissolve gradually variation of performance.Both can significantly promote lyophilizing efficient in the urgent need to a kind of, and can effectively avoid again injection ganciclovir compositions skeleton and lyophilizing micro structure to subside, ensure the technical scheme of its redissolution performance.
CN200710062606.8 discloses a kind of medicine for external use for the treatment of condyloma acuminatum and genital herpes, mixed according to a certain percentage by Oleum Fructus Bruceae and Luo Wei class antiviral agents (acyclovir, ganciclovir etc.), be prepared into the exterior-applied formulations such as liniment, ointment by specific technique with pharmaceutically acceptable optional substrate, do not solve above-mentioned technological deficiency.
CN200780044300.8 disclose a kind of in water the Orally administered new solid pharmaceutical dosage formulation of valganciclovir hydrochlorate after the preparation, be used for the treatment of or control virally, such as herpes simplex virus or cytomegalovirus, do not solve above-mentioned technological deficiency.
CN200910260198.6 discloses a kind of injection ganciclovir lyophilized formulations, comprise 50～250 parts of ganciclovirs, 100～200 parts of HP-β-CD, the preparation method that also relates to this injection ganciclovir lyophilized formulations, but the freezing dry process time still needs 22～26 hours, do not have well to solve the problem that skeleton and lyophilizing micro structure are subsided, therefore do not solve above-mentioned technological deficiency.
CN200910249862.7 discloses a kind of fructose injection that contains ganciclovir, formed by ganciclovir, fructose and water, its weight ratio is 0.05～0.25: 5～25: 100～500, wherein the metabolism of fructose does not rely on the regulation and control of insulin, accretion rate is fast, make it when replenishing the diabetics energy i (in vivo), can effectively control the fluctuation of blood sugar concentration, therefore, be very suitable for diabetes patient and impaired glucose tolerance person's antiviral therapy, enlarge the scope of application of ganciclovir injection, do not solved above-mentioned technological deficiency.
CN02115931.9 discloses a kind of production method of ganciclovir injection: (1) adds 35 ℃～45 ℃ injection water dissolvings with the activated feedstock ganciclovir; (2), with the ganciclovir aqueous solution of pharmaceutical carrier isotonic agent and step (1), ganciclovir is thoroughly dissolved; (3), the pH value of rapid (2) solution of pacing is 7.0-8.0; (4), add to the full amount of water for injection; (5), with ultrafilter filtering pyrogen; (7), after the packing, autoclaving; (8), test package and get final product, do not solve above-mentioned technological deficiency.
CN03125422.5 discloses a kind of preparation method of ganciclovir injection, behind ganciclovir and alkali reaction salify, is dissolved in the water, thus the preparation injection: preparation water for injection; Pharmaceutical carrier is added 70～100 ℃ water for injection dissolving, be mixed with pharmaceutical carrier solution; Add 0.01wt%～10wt% adsorbent by amount of preparation, stir evenly, be heated to 90～100 ℃, adsorbed 5～60 minutes, filter; Be that 1: 0.1～1 ratio adds in the pharmaceutical carrier solution after filtering with activated feedstock ganciclovir and alkali in mole ratio, inject water to the concentration 0.01wt% of activated feedstock ganciclovir～1wt%, stirring and dissolving is prepared into drug solution; Add 0.01wt%～1wt% needle-use activated carbon, stir evenly, filter; The filtering with microporous membrane degerming; Packing, autoclaving namely get required ganciclovir injection, do not solve above-mentioned technological deficiency.
CN200410012638.3 discloses a kind of ganciclovir injection and production method thereof: (1) is with an amount of water for injection lytic activity raw material ganciclovir; (2) with pharmaceutic adjuvant and step (1) gained ganciclovir aqueous solution, and ganciclovir is thoroughly dissolved; (3) pH value of regulating step (2) gained solution is 7.0～10.0, adds to the full amount of water for injection; (4) conform with the ganciclovir injection of drug standard by the requirement production of Good Manufacturing Practice and Quality Control of Drug, do not solve above-mentioned technological deficiency.
CN200510005177.1 discloses a kind of ganciclovir injection its preparation method, does not solve above-mentioned technological deficiency.
CN200510019163.5 discloses a kind of Ganciclovir lactated ringer solution, every liter of injection contains 0.1-1.5 gram ganciclovir, ganciclovir derivant or its pharmaceutical salts (in ganciclovir), 3.1 gram sodium lactate, 6.0 gram sodium chloride, 0.3 gram potassium chloride, 0.2 the water for injection of gram calcium chloride and surplus does not solve above-mentioned technological deficiency.
Existing known technology is all less than the suggestion that above defective is proposed improve.
Summary of the invention
The objective of the invention is provides injection ganciclovir composition and method of making the same for above weak point, to this medicine that needs lyophilizing but exist skeleton and lyophilizing micro structure to subside at freeze-drying process of ganciclovir, the present invention can significantly promote lyophilizing efficient, and effectively avoided injection ganciclovir compositions skeleton and lyophilizing micro structure to subside, thereby fundamentally ensure its redissolution performance, the safety of clinical application is more guaranteed.
The present inventor finds by research experiment, because ganciclovir preparating liquid solid content is higher, be difficult to form complete vapor channel, be unfavorable for the distillation of steam in the goods, be glassy state in the freeze-drying process simultaneously, melting very easily occurs, melting phenomenon is more remarkable when programming rate is very fast, for avoiding melting, often have to significantly prolong the cryodesiccated cycle.In addition, this product is along with the rising of flaggy temperature, when carrying out lyophilizing by prior art skeleton must appear and the lyophilizing micro structure is subsided, with regard to these defectives, the lyophilization cycle length also only be the raising that has limited injection ganciclovir composition production efficient, the skeleton that occurs when carrying out lyophilizing by prior art and lyophilizing micro structure are subsided and then are directly connected to the quality of final products, this be because, skeleton and lyophilizing micro structure are subsided and have directly been had influence on injection ganciclovir compositions redissolution performance, must cause particulate matter and clarity variation, even do not meet the pharmacopeia regulation, cause by the gross scrapping of medicine.Even if solubility injection ganciclovir compositions preferably when dispatching from the factory, because the existence that skeleton and lyophilizing micro structure are subsided, micro structure is subsided and continue to be extended in put procedure, causes whole lyophilizing pore structure further to destroy, so that redissolve gradually variation of performance.
Part by weight by ganciclovir and sodium hydroxide in the adjustment injection ganciclovir compositions, when the part by weight of ganciclovir and sodium hydroxide is 6.6～7.0: in the time of 1, both can guarantee that ganciclovir fully dissolved, and can avoid to greatest extent again injection ganciclovir compositions visible foreign matters and clarity to increase variation along with adding alkali number.Preferred, the part by weight of ganciclovir and sodium hydroxide is 6.8: 1.
In addition, find through a large amount of experimental studies, on the basis of above-mentioned composition proportion of composing, in conjunction with unique advanced vacuum freeze-drying technique, both can significantly promote lyophilizing efficient, can effectively avoid again injection ganciclovir compositions skeleton and lyophilizing micro structure to subside, prepare a kind of mean diameter and the porosity injection ganciclovir compositions significantly different from the product of prior art preparation, this injection ganciclovir compositions has the lyophilizing structure of remarkable excellence, mean diameter and porosity, redissolution performance that can Effective Raise injection ganciclovir compositions also ensures that this performance is in the stable and concordance of its preparation in effect duration.
This vacuum freeze-drying technique at first will divide the ganciclovir medicinal liquid that installs to put in the freeze dryer, reduce rapidly products temperature, when products temperature is lower than-45 ℃, continue to make in freezing 60 minutes ganciclovir medicinal liquid fully charge, this pre-freeze process can guarantee to obtain relatively to be easy to the frozen state that distils on the one hand, reduced to a certain extent simultaneously vitrification, abandon on the other hand known technology pre-freeze insulating process fully, continued freezing 60 minutes, this process is except making ganciclovir medicinal liquid fully charge, also can so that the temperature of goods is low as much as possible before the final distillation that heats up, for heating up, the follow-up rapid greatly amplitude that surmounts routine techniques create the larger safe rising space of products temperature.
Secondly, in the rear cabinet refrigeration stage, utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃, carry out the cold deposit for the follow-up rapidly very big amplitude that surmounts routine techniques heats up.
Again, in vacuumizing phase, guarantee front case vacuum is evacuated to below the 10Pa, carry out the vacuum preparation for the follow-up rapidly very big amplitude that surmounts routine techniques heats up.
Next, at the high speed drying stage, disposablely rapidly the conduction oil temperature is risen to 50 ℃ at the utmost point in the short time, high for this class solid content of injection ganciclovir compositions, vitrification is melting and the product that subsides with skeleton and lyophilizing micro structure very easily, this is inconceivable at existing known technology, yet, owing to carried out the safe rising space of said products temperature, the preparation of the aspects such as cold deposit and vacuum, this high-speed heating sublimation drying process can be able to smooth security implementation, its direct preparation effect is exactly, a large amount of heat supplies so that in the goods moisture innerly fallen by a large amount of distillations in the extremely short time (being generally 4～6 hours), products temperature also can rise rapidly therebetween, but because the time is short, initial products temperature is low, not yet reach the temperature that skeleton and lyophilizing micro structure are subsided, therefore can possess splendid lyophilizing skeleton and micro structure.
At last, after high-speed dry dryness accumulated in the stomach and intestine bundle, namely when products temperature reaches-13 ℃, rapidly the conduction oil temperature is down to 20 ℃, enter at the uniform velocity drying stage, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and close before valve the case vacuum without significant change after, tamponade, outlet is used the aluminium-plastic combined cover tying, packing namely gets injection ganciclovir compositions after quality inspection is qualified.Find by a large amount of development tests, when products temperature reaches-13 ℃, rapidly the conduction oil temperature is down to 20 ℃, can prevent effectively that products temperature from further raising rapidly, and then avoid goods before bone dry, to level off to the temperature that skeleton and lyophilizing micro structure subside, guaranteed also the situation that lyophilizing skeleton and micro structure are subsided can not occur at drying stage at the uniform velocity.Because high speed drying stage moisture drying amount is larger, even if adopted the existing lower baking temperature of known technology at drying stage at the uniform velocity, also can thoroughly remove residual moisture, so that the requirement of final products moisture conformance with standard.Because the existing known technology of final baking temperature is low, the probability to lyophilizing skeleton and Microstructure Fracture in the dry run is also less simultaneously.
Find that by detecting the product of the existing known technology preparation of the injection ganciclovir compositions of the inventive method preparation has lyophilizing structure, mean diameter and the porosity of remarkable excellence.
Find by a large amount of further experimental studies, the mean diameter of the injection ganciclovir compositions of the inventive method preparation is 80～110nm, when porosity was 94%～98%, redissolution performance that can Effective Raise injection ganciclovir compositions also ensured that this performance is in the stable and concordance of its preparation in effect duration.
Injection ganciclovir compositions provided by the invention, specific as follows:
A kind of injection ganciclovir compositions, by the lyophilized powder that ganciclovir and sodium hydroxide form, wherein, the part by weight of ganciclovir and sodium hydroxide is 6.6～7.0: 1, and mean diameter is 80～110nm, and porosity is 94%～98%.
One states in the injection ganciclovir compositions, and the part by weight of ganciclovir and sodium hydroxide is preferably 6.8: 1.
A kind of injection ganciclovir compositions is prepared as follows:
1) preparation: take by weighing ganciclovir and sodium hydroxide at 6.6～7.0: 1 by weight, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
2) aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, be sub-packed in the cillin bottle, partly jump a queue;
3) vacuum lyophilization:
A, pre-freeze: will go on foot poly-2) divide the ganciclovir medicinal liquid that installs to put in the freeze dryer, reduce rapidly products temperature, when products temperature is lower than-45 ℃, continue to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: open vacuum pump, front case vacuum is evacuated to below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, beginning high-speed heating sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-13 ℃, rapidly the conduction oil temperature is down to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet, use the aluminium-plastic combined cover tying, packing after quality inspection is qualified, and get final product.
A kind of preparation method of injection ganciclovir compositions is:
1) preparation: take by weighing ganciclovir and sodium hydroxide at 6.6～7.0: 1 by weight, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
2) aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, be sub-packed in the cillin bottle, partly jump a queue;
3) vacuum lyophilization:
A, pre-freeze: will go on foot poly-2) divide the ganciclovir medicinal liquid that installs to put in the freeze dryer, reduce rapidly products temperature, when products temperature is lower than-45 ℃, continue to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: open vacuum pump, front case vacuum is evacuated to below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, beginning high-speed heating sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-13 ℃, rapidly the conduction oil temperature is down to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet, use the aluminium-plastic combined cover tying, packing after quality inspection is qualified, and get final product.
In the preparation method of above-mentioned injection ganciclovir compositions, the part by weight of ganciclovir and sodium hydroxide is 6.8: 1.
In the product of lyophilizing, only contain ganciclovir and sodium hydroxide, in the finished product in component and the raw material ratio do not have substantial variation.
Injection ganciclovir composition and method of making the same of the present invention, solved the very easily melting of such medicine, lyophilization cycle is long, skeleton and the lyophilizing micro structure problem such as subside, rational prescription proportioning and unique advanced preparation technology have been adopted, significantly promoted lyophilizing efficient, and effectively avoided injection ganciclovir compositions skeleton and lyophilizing micro structure to subside, prepare a kind of mean diameter and the porosity injection ganciclovir compositions significantly different from the product of prior art preparation, this injection ganciclovir compositions has the lyophilizing structure of remarkable excellence, mean diameter and porosity, redissolution performance that can Effective Raise injection ganciclovir compositions also ensures that this performance is in the stable and concordance of its preparation in effect duration, its quality stable homogeneous, content is evenly accurate, moisture drying is thorough, stability in transportation and storage process is better, and clinical use has better safety.Preparation technology of the present invention is simple, and is convenient feasible, good reproducibility, and production cost is lower, is easy to realize industrialized great production, thereby can produce considerable economic and social benefit.
The specific embodiment
Further specify the present invention below by embodiment.Should correct understanding be: embodiments of the invention are only used for the present invention is described and provide, rather than limitation of the present invention, so, under method prerequisite of the present invention, simple modifications of the present invention is all belonged to the scope of protection of present invention.
Be guarantee test result's concordance, reference examples of the present invention, embodiment and test example have been used identical raw material, adjuvant, cillin bottle and plug.
Reference examples 1:
Prescription:
Ganciclovir 2.5Kg
Sodium hydroxide 368g
Water for injection adds to 25Kg
Preparation: take by weighing ganciclovir and sodium hydroxide, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
Aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, the loading amount of propping up by 2.5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
Vacuum lyophilization:
A, pre-freeze: will divide the ganciclovir medicinal liquid that installs to put in the freeze dryer, be cooled to-45 ℃ in 3 hours, and in-45 ℃ of insulations 6 hours;
B, intensification sublimation drying: utilize compressor that the rear cabinet cold-trap is freezed, after the pre-freeze insulation finishes, open vacuum pump, front case vacuum is evacuated to below the 20Pa, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 3 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 6 hours, when products temperature and flaggy temperature again near the time finish lyophilizing, tamponade, outlet is used the aluminium-plastic combined cover tying, packing after quality inspection is qualified, and get final product.Prepared injection ganciclovir compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method its mean diameter of measure and calculation and porosity.
Whole freeze-drying time reaches 33 hours.
Reference examples 2:
Prescription:
Ganciclovir 2.5Kg
Sodium hydroxide 368g
Water for injection adds to 30Kg
Preparation: take by weighing ganciclovir and sodium hydroxide, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
Aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, the loading amount of propping up by 3ml/ is sub-packed in the cillin bottle, partly jumps a queue;
Vacuum lyophilization:
A, pre-freeze: will divide the ganciclovir medicinal liquid that installs to put in the freeze dryer, be cooled to-45 ℃ in 3 hours, and in-45 ℃ of insulations 6 hours;
B, intensification sublimation drying: utilize compressor that the rear cabinet cold-trap is freezed, after the pre-freeze insulation finishes, open vacuum pump, front case vacuum is evacuated to below the 20Pa, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 3 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 6 hours, when products temperature and flaggy temperature again near the time finish lyophilizing, tamponade, outlet is used the aluminium-plastic combined cover tying, packing after quality inspection is qualified, and get final product.Prepared injection ganciclovir compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method its mean diameter of measure and calculation and porosity.
Whole freeze-drying time reaches 33 hours.
Embodiment 1:
Prescription:
Ganciclovir 2.5Kg
Sodium hydroxide 368g
Water for injection adds to 25Kg
Preparation: take by weighing ganciclovir and sodium hydroxide, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
Aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, the loading amount of propping up by 2.5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
Vacuum lyophilization:
A, pre-freeze: will divide the ganciclovir medicinal liquid that installs to put in the freeze dryer, and reduce rapidly products temperature, and when products temperature is lower than-45 ℃, continue to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: open vacuum pump, front case vacuum is evacuated to below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, beginning high-speed heating sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-13 ℃, rapidly the conduction oil temperature is down to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet, use the aluminium-plastic combined cover tying, packing after quality inspection is qualified, and get final product.Prepared injection ganciclovir compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method its mean diameter of measure and calculation and porosity.
Whole freeze-drying time is 17 hours.
Embodiment 2:
Prescription:
Ganciclovir 2.5Kg
Sodium hydroxide 357g
Water for injection adds to 25Kg
Preparation: take by weighing ganciclovir and sodium hydroxide, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
Aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, the loading amount of propping up by 2.5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
Vacuum lyophilization:
A, pre-freeze: will divide the ganciclovir medicinal liquid that installs to put in the freeze dryer, and reduce rapidly products temperature, and when products temperature is lower than-45 ℃, continue to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: open vacuum pump, front case vacuum is evacuated to below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, beginning high-speed heating sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-13 ℃, rapidly the conduction oil temperature is down to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet, use the aluminium-plastic combined cover tying, packing after quality inspection is qualified, and get final product.Prepared injection ganciclovir compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method its mean diameter of measure and calculation and porosity.
Whole freeze-drying time is 17 hours.
Embodiment 3:
Prescription:
Ganciclovir 2.5Kg
Sodium hydroxide 379g
Water for injection adds to 25Kg
Preparation: take by weighing ganciclovir and sodium hydroxide, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
Aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, the loading amount of propping up by 2.5ml/ is sub-packed in the cillin bottle, partly jumps a queue;
Vacuum lyophilization:
A, pre-freeze: will divide the ganciclovir medicinal liquid that installs to put in the freeze dryer, and reduce rapidly products temperature, and when products temperature is lower than-45 ℃, continue to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C, evacuation: open vacuum pump, front case vacuum is evacuated to below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, beginning high-speed heating sublimation drying;
E, at the uniform velocity dry: when products temperature reaches-13 ℃, rapidly the conduction oil temperature is down to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet, use the aluminium-plastic combined cover tying, packing after quality inspection is qualified, and get final product.Prepared injection ganciclovir compositions is put in the F-Sorb 3400-porosimeter, adopts nitrogen absorption continuous flow method its mean diameter of measure and calculation and porosity.
Whole freeze-drying time is 17 hours.
The present invention also further provides following test example, so that effect of the present invention is further described:
Test example 1:
This test is pressed embodiment 1 preparating liquid, is filtered and packing, puts in the freeze dryer, investigates different vacuum freeze-drying techniques to the impact of final freeze-drying prods, and it the results are shown in Table 1.
Table 1 injection ganciclovir compositions vacuum freeze-drying technique is investigated
Annotate: it is as follows that numbering described in the table 1 represents concrete technology:
A1---pre-freeze: slowly reduce products temperature, products temperature was down to-45 ℃ in 3 hours, products temperature-45 ℃ kept 6 hours, made ganciclovir medicinal liquid fully charge;
A2---pre-freeze: reduce rapidly products temperature, products temperature was down to-45 ℃ in 1 hour, products temperature-45 ℃ kept 6 hours, made ganciclovir medicinal liquid fully charge;
A3---pre-freeze: slowly reduce products temperature, products temperature was down to-45 ℃ in 3 hours, continue to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
A4---pre-freeze: reduce rapidly products temperature, products temperature was down to-45 ℃ in 1 hour, continue to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
B1---rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-45 ℃;
B2---rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-50 ℃;
B3---rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-60 ℃;
B4---rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make the rear cabinet condenser temperature be lower than-70 ℃;
C1---evacuation: open vacuum pump, front case vacuum is evacuated to below the 50Pa;
C2---evacuation: open vacuum pump, front case vacuum is evacuated to below the 20Pa;
C3---evacuation: open vacuum pump, front case vacuum is evacuated to below the 10Pa;
D1---common drying: in first hour conduction oil is risen to-10 ℃, later conduction oil heats up with 5 ℃/hour speed, when the temperature of conduction oil rises to 38 ℃, keep the temperature-resistant of conduction oil, when treating that products temperature reaches 28 ℃～32 ℃, be incubated 4 hours, tamponade, outlet;
D2---common drying: in first hour conduction oil is risen to-10 ℃, later conduction oil heats up with 3 ℃/hour speed, when the temperature of conduction oil rises to 38 ℃, keep the temperature-resistant of conduction oil, when treating that products temperature reaches 28 ℃～32 ℃, be incubated 4 hours, tamponade, outlet;
D3---common drying: the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 3 hours, when products temperature and flaggy temperature near the time, continue rising flaggy temperature to 30 ℃ and be incubated 6 hours, when products temperature and flaggy temperature again near the time finish lyophilizing, tamponade, outlet;
D4---fully at a high speed dry: rapidly the conduction oil temperature is risen to 50 ℃, beginning high-speed heating sublimation drying, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet;
D5---dry, at the uniform velocity dry at a high speed: as rapidly the conduction oil temperature to be risen to 50 ℃, beginning high-speed heating sublimation drying, when products temperature reaches-13 ℃, rapidly the conduction oil temperature is down to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet.
As can be seen from Table 1, adopt A4, B4, C3, D5 group technology, the preparation effect of lyophilizing is best, and freeze-drying time also can significantly shorten.
Test example 2:
Ganciclovir 2.5Kg is got respectively in this test, finally be mixed with the 25Kg medicinal liquid, after the loading amount packing of propping up by 2.5ml/ after the aseptic filtration, put in the freeze dryer and carry out lyophilizing according to the A4 in the test example 1, B4, C3, D5 group technology, investigate the part by weight of different ganciclovirs and sodium hydroxide to the impact of injection ganciclovir visible foreign matters and clarity, it the results are shown in Table 2.
Table 2 injection ganciclovir visible foreign matters and clarity are investigated
Annotate: " part by weight " described in the table 2 refers to " part by weight of ganciclovir and sodium hydroxide ".
As can be seen from Table 2, the part by weight of ganciclovir and sodium hydroxide is 6.6～7.0: 1 o'clock, both can guarantee fast fully dissolving of ganciclovir, and can avoid to greatest extent again injection ganciclovir compositions visible foreign matters and clarity to increase variation along with adding alkali number.When the part by weight of ganciclovir and sodium hydroxide is 6.8: 1, its preparation better effects if.
Test example 3:
Respectively prepare respectively injection ganciclovir compositions by reference examples 1～2 and embodiment 1～3, check respectively mean diameter, porosity, solubility, visible foreign matters, clarity and particulate matter again, it the results are shown in Table 3.
Table 3 injection ganciclovir compositions check result
As can be seen from Table 3, technical scheme of the present invention (embodiment 1～3) compares with prior art (reference examples 1～2), have better mean diameter and porosity, significantly improved the redissolution performance of ganciclovir compositions, quality control level at particulate matter has clear superiority, the drug risks such as capillary embolism that cause because of particulate matter in the time of can significantly reducing clinical use simultaneously.
Test example 4:
Respectively prepare respectively injection ganciclovir compositions by reference examples 1～2 and embodiment 1～3, put under the room temperature lucifuge condition and carry out study on the stability, check to check respectively mean diameter, porosity, clarity and particulate matter, it the results are shown in Table 4, table 5, table 6 again.
Table 4 injection ganciclovir compositions mean diameter, porosity study on the stability result
Table 5 injection ganciclovir compositions clarity study on the stability result
Table 6 injection ganciclovir compositions particulate matter study on the stability result
Technical scheme of the present invention (embodiment 1～3) compares with prior art (reference examples 1～2), has better stability at aspects such as mean diameter, porosity, clarity and particulate matters, and quality-advantage is obvious.
In addition, respectively according to the injection ganciclovir compositions of each embodiment preparation of Chinese patent CN200910260198.6 etc., by F-Sorb 3400-porosimeter nitrogen absorption continuous flow method its mean diameter of measure and calculation and porosity, carrying out simultaneously solubility and long-term shelf-stability investigates, the product that the result shows the preparation of above-mentioned known technology is with the skeleton of varying degree and the lyophilizing structure is little subsides, its mean diameter is product of the present invention head and shoulders above also, porosity is low than product of the present invention, the redissolution poor-performing, study on the stability shows, along with the prolongation of standing time, defects is more obvious, is further improved.
The present invention has also carried out similar test to other embodiment and test example, has obtained result, conclusion and the trend similar with above embodiment and test example, because length is limit, the inventor enumerates no longer one by one.
Claims (4)
1. injection ganciclovir compositions, it is characterized in that the lyophilized powder that described compositions is comprised of ganciclovir and sodium hydroxide, wherein, the part by weight of ganciclovir and sodium hydroxide is 6.6～7.0:1, the mean diameter of described lyophilized powder is 80～110nm, and porosity is 94%～98%; Described compositions is prepared as follows:
1) preparation: take by weighing ganciclovir and sodium hydroxide by weight 6.6～7.0:1, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
2) aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, be sub-packed in the cillin bottle, partly jump a queue;
3) vacuum lyophilization:
A, pre-freeze: will go on foot poly-2) the ganciclovir medicinal liquid that minute installs puts in the freeze dryer, reduces rapidly products temperature, when products temperature hangs down in 45 ℃ of –, continues to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make 70 ℃ of rear cabinet condenser temperature Di Yu –;
C, evacuation: open vacuum pump, front case vacuum is evacuated to below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, beginning high-speed heating sublimation drying;
E, at the uniform velocity dry: as products temperature Da during Dao 13 ℃ of –, rapidly the conduction oil temperature is down to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet, use the aluminium-plastic combined cover tying, packing namely gets product after quality inspection is qualified.
2. injection ganciclovir compositions according to claim 1, the part by weight that it is characterized in that described ganciclovir and sodium hydroxide is 6.8:1.
3. the preparation method of an injection ganciclovir compositions claimed in claim 1 is characterized in that preparation method is:
1) preparation: take by weighing ganciclovir and sodium hydroxide by weight 6.6～7.0:1, put in the preparing tank, add water for injection, stir and make it to dissolve fully also mix homogeneously;
2) aseptic filtration, packing: with the microfilter of 0.22 μ m with medical filtration to sterilizing room, be sub-packed in the cillin bottle, partly jump a queue;
3) vacuum lyophilization:
A, pre-freeze: will go on foot poly-2) the ganciclovir medicinal liquid that minute installs puts in the freeze dryer, reduces rapidly products temperature, when products temperature hangs down in 45 ℃ of –, continues to make in freezing 60 minutes ganciclovir medicinal liquid fully charge;
B, rear cabinet refrigeration: utilize compressor to rear cabinet cold-trap refrigeration, make 70 ℃ of rear cabinet condenser temperature Di Yu –;
C, evacuation: open vacuum pump, front case vacuum is evacuated to below the 10Pa;
D, dry at a high speed: rapidly the conduction oil temperature is risen to 50 ℃, beginning high-speed heating sublimation drying;
E, at the uniform velocity dry: as products temperature Da during Dao 13 ℃ of –, rapidly the conduction oil temperature is down to 20 ℃, and keep this temperature sublimation drying that at the uniform velocity heats up, when products temperature reaches 15 ℃, and in closing before valve the case vacuum without significant change after, tamponade, outlet, use the aluminium-plastic combined cover tying, packing namely gets product after quality inspection is qualified.
4. the preparation method of injection ganciclovir compositions according to claim 3 is characterized in that, wherein the part by weight of ganciclovir and sodium hydroxide is 6.8:1.
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| CN103044426B (en) * | 2012-12-27 | 2015-05-20 | 海南锦瑞制药有限公司 | Ganciclovir crystal compound, new composition thereof and preparation method thereof |
| CN103054819B (en) * | 2013-01-31 | 2014-07-16 | 南京正宽医药科技有限公司 | Ganciclovir for injection and preparation method thereof |
| CN103330687B (en) * | 2013-07-16 | 2015-03-18 | 成都天台山制药有限公司 | Stable ganciclovir freeze-dried powder injection |
| CN110559266A (en) * | 2019-09-19 | 2019-12-13 | 湖北科益药业股份有限公司 | Freeze-drying process of ganciclovir for injection |
| CN110585141A (en) * | 2019-09-19 | 2019-12-20 | 湖北科益药业股份有限公司 | Stable ganciclovir freeze-dried powder injection |
| CN111973564A (en) * | 2020-09-02 | 2020-11-24 | 海南倍特药业有限公司 | Ganciclovir composition for injection and freeze-drying process thereof |
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| CN1383827A (en) * | 2002-05-14 | 2002-12-11 | 刘万忠 | Prepn of antiviral N-9 substituted guanine medicine powder for injection |
| CN1403084A (en) * | 2002-06-06 | 2003-03-19 | 武汉华龙生物制药有限公司 | Ganciclovir injection and its production process |
| CN1524530A (en) * | 2003-09-16 | 2004-09-01 | 湖北丽益医药科技有限公司 | Method for preparing ganciclovir intravenous fluid |
| CN1679580A (en) * | 2005-02-01 | 2005-10-12 | 山东鲁抗辰欣药业有限公司 | Ganciclovir injection and preparation thereof |
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Address after: 211112 Kejian Road, Jiangning Science Park, Nanjing City, Jiangsu Province, 699 Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd. Address before: 211112 Kejian Road, Jiangning Science Park, Nanjing City, Jiangsu Province, 699 Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd. |