CN103044426B - Ganciclovir crystal compound, new composition thereof and preparation method thereof - Google Patents
Ganciclovir crystal compound, new composition thereof and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines and particularly relates to a ganciclovir crystal compound, a new composition thereof and a preparation method thereof. The ganciclovir is a crystal. The X-ray powder, measured by Cu-Kalpha ray, of the ganciclovir crystal is diffracted to display characteristic peaks when 2 theta equals to 30 DEG, 35 DEG, 50 DEG, 60 DEG, 63 DEG or 74.5 DEG. The grain size of the ganciclovir crystal is 85 to 105 microns. The invention also relates to a ganciclovir medicinal composition. The medicinal composition is a ganciclovir freeze-dried preparation. The ganciclovir freeze-dried preparation comprises ganciclovir, sodium chloride and sodium hydroxide. In the preparation process, the freeze-drying process is controlled strictly. The prepared freeze-dried powder injection is stable, low in related substance and high in redissolving property.
Description
Technical field
The present invention relates to a kind of field of pharmaceutical preparations, more specifically to a kind of ganciclovir crystalline compounds, its pharmaceutical composition and preparation method thereof.
Background technology
Ganciclovir, its chemical name is: ganciclovir.Chemical structural formula:
Molecular formula: C
9h
13n
5o
4, molecular weight: 255.21
Ganciclovir is white crystalline powder; Odorless, tasteless; Have draw moist.Slightly soluble in water or Glacial acetic acid, almost insoluble in methyl alcohol, insoluble in trichloromethane; Slightly molten in hydrochloric acid soln or sodium hydroxide solution.Ganciclovir can suppress copying of simplexvirus in vivo, comprises hsv, varicella zoster virus, Epstein-Barr virus and cytomegalovirus etc., especially with remarkable to the effect of the resistance strain and cytomegalovirus that lack thymidine kinase; In addition, this product to hepatitis B virus, adenovirus and bleb VI virus also have and comparatively pretend use.Pharmacologically, this product kinase transformed one-tenth monophosphate of deoxy-guanine that infected induction produces in the cell of cmv infection, is then metabolized to ganciclovir triphosphate by guanylate kinase and phosphoglycerokinase.Its concentration in virus infected cell can higher than non-infected cell 100 times.Ganciclovir suppresses virus replication mainly through two kinds of modes: 1. its triphosphate (GTP) suppresses deoxyguanosine triphosphate to be combined with archaeal dna polymerase competitively, thus suppresses viral dna polymerase; 2. directly mix viral DNA, suppress DNA synthesis, stop the prolongation of viral DNA chain, and this effect is amplified by the accumulation of GTP in cmv infection cell.
The propagation of virus is the widest, and the disease caused by virus is one of communicable disease that sickness rate is the highest in the world at present.According to foreign statistic document announcement, the transmissible disease of nearly 3/4 is caused by virus, have 18 kinds to belong to Causative virus in 55 kinds of viruses that international virus taxis association (ICTV) in 1984 has been announced, different virus infectiones causes different illness, needs different antiviral treatments.Being applied in such clinical medicine nearly 2/3 is at present anti-herpesvirus.Simplexvirus is divided into herpes simplex, zoster, cytomegalovirus (CMV) and epstein-barr virus, and this viroid can form latent infection in human body, causes different tissues disease, under certain circumstances recurrent exerbation.In herpes simplex, have HSV-1 type and HSV-2 type, the further investigation carried out in recent years finds HSV-6 again, 7,8 types.Cytomegalovirus is a kind of simplexvirus, and parent can be caused geneogenous fetal anomaly by cmv infection; When human immunodeficiency virus (HIV) and cytomegalovirus polyinfection, the retinitis, encephalitis, locality pneumonia, hepatitis, stomach ulcer and skin injury can be produced, have a strong impact on HUMAN HEALTH.
CMV often can be checked through in patient's organ transplantation process, is that these patients produce complication and dead major reason.Clinical study shows: the infection rate of infection in lung transplantation of CMV is 39% ~ 40%, be 9% ~ 35% in heart transplantation, be 22% ~ 23% in pancreas and liver transplantation, be that the infection of 8% ~ 32%, CMV and morbidity cause the prolonged hospitalization of patient and medical treatment and nursing expense to increase in renal transplantation.Therefore in the urgent need to treating the medicine of anti-cytomegalovirus.
Virus is one minimum in pathogenic micro-organism, and its structure is simply only containing a kind of nucleic acid (RNA (ribonucleic acid), or thymus nucleic acid DNA), and shell is protein, does not have a cellularstructure.Most of virus lacks enzyme system, can not carry out metabolism separately, and the enzyme system that must rely on host could survival and reproduction.Antiviral acts on the metabolic process of intracellular virus with must having high selectivity, and to host cell without obvious damage.The antiviral drug applied clinically at present mainly contains five classes:
(1) thymus nucleic acid C-type virus C (anti-DNA) is suppressed: acyclovir, ganciclovir, cytosine arabinoside, vidarabine etc.
(2) oxygen Yeast Nucleic Acid C-type virus C (anti-RNA) is suppressed: virazole (triazole) nucleosides.
(3) excite host cell to synthesize antiviral protein, suppress viral proliferation, infect.
(4) suppress surfaces of viral particles neuraminidase activity, stop virus release: isoquinoline class etc.
(5) stop virus to import host cell and shelling into, prevent host cell infected: amantadine etc.
China is the hotspot that human cytomegalic inclusion disease virus (human cytomegalovims, HCMV) infects, the Childhood that HCMV infecting multiple being born in.But HCMV is a kind of weak virulence factor, does not have obvious virulence to the normal healthy individuals of immunity, multiple escape host immune attack mechanism but can be induced.Therefore, HCMV, can long-term existence in vivo once invade body.Thus, there is HCMV to copy and always do not represent lysis, when HCMV infects physiological or pathologic immune suppresses individual, just easily cause disseminated disease or one organ infringement.Widely, the infected autopsy tissue pathological analysis shows that any organ can be infected to the biological cells and tissues preferendum of HCMV.But the tissue tropism of HCMV is obviously relevant with immune state to age.In the fetus an d neonate phase, neurocyte and sialisterium the most responsive to HCMV, reticuloendothelial system is also often got involved; Annual wool yield and adult, when immunity is normal, no matter former or send out infection again, virus is confined to sialisterium and kidney more, and minority primary symptomatic the infected can involve lymphocyte; And at immunosuppressed individuals, lung is the most often invaded, and often cause disseminated infection.In addition, due to the protective effect that blood brain barrier and blood-screen hinder, intraocular and encephalic HCMV infect and are mainly seen in intrauterine infection and immunosuppression person.Along with the universal of domestic viral diagnosis technology and anti-HCMV medicine ganciclovir localization with apply, the problem of preventing and treating of HCMV relative disease receives the concern of clinicist day by day.
Acyclovir is s-generation broad-spectrum antiviral medicament, by Britain Ge Lan element, welcon (GW) company researches and develops successfully, be the open nucleoside class medicine of first specificity anti-herpesvirus of Initial Public Offering in the world in 1981, this medicine can optionally copy by blocking virus in the cell of cmv infection.But the weak point of acyclovir is that may cause having given combination therapy treatment patient HIV produces compliance problem; When clinical treatment, acyclovir anti-cytomegalovirus weak effect, can cause renal glomerulus to block time heavy dose of.Disadvantage is that daily number of times exceedes conventional instructions about how to take medicine.
In recent years, the advantage of ganciclovir in anti-cytomegalovirus, bioavailability and longer action time etc. is proven, and has become the competing product of acyclovir.Ganciclovir is a guanosint glycoside derivates, similar with acyclovir, and it can not only suppress all herpes-like virus to the effective medicine of human cytomegalovirus to be first, and can block the lymphocytic pathology of normal band shape that Epstein-Barr virus causes.The approval listing of ganciclovir provides the methods for the treatment of of the cytomegalovirus disease progression rates that slows down, and particularly suffers from the CMV retinitis of HIV disease patient in late period, simultaneously concerning the patient that need carry out organ transplantation, is also a Gospel undoubtedly.
Ganciclovir is the deoxyguanosine analogue that first Syntex drugmaker develops, its structure is similar to acyclovir (ACV), but there is than ACV the antivirus action of stronger more wide spectrum, after acyclovir, a kind of ucleosides broad-spectrum antiviral drug of exploitation is first medicine being used for the treatment of human body cytomegalovirus infection.Its first-line drug of infecting as the blinding cytomegalovirus of AIDS Complicated (CMV) of U.S. FDA official approval in 1989.
The sickness rate that Congenital CMV virus (cytomegalovirus, CMV) infects in all survival youngsters is about 1%, and its mortality ratio is up to 10% ~ 30%, and survivor more than 90% can leave over sequela in various degree.Antiviral therapy is the unique effective way controlling severe congenital cmv infection.Ganciclovir, as a kind of resisting DNA virus medicine of broad-spectrum high efficacy, has extremely strong antiviral activity to mankind CMV, can be used for treating cmv infection.
Ganciclovir is the viral inhibitors efficient, low toxicity, selectivity are strong, all has very strong inhibit activities to human body 6 kinds of herpesvirus infections.In June, 1988, ganciclovir tablet is first in Britain's approval listing, and subsequently, France, the U.S., Japan, West Germany, Italy and the state such as Canadian also ratify use in succession.Epidemic prevention defect patient, organ transplantation person's cytomegalovirus infection is used for more than 70 countries and regions in by the end of June, 1999 by.Within 2002, ganciclovir tablet obtains the approval of China SFDA, now goes on the market.Ganciclovir for injection is in the U.S. in listing (Roche company) in 1989, and the limit pharmacy of day Honda was gone on the market in nineteen ninety, and China started import in 2000, and 2003 Nian You domestic manufacturers produce listing.
CN102627643A discloses a kind of process for purification of ganciclovir, specifically adopt lower aliphatic aqueous acid heating for dissolving ganciclovir, filter out insolubles wherein, filtrate crystallisation by cooling, suction filtration, through inorganic alkali solution process, be then adjusted to neutrality, obtain the mode of solid with crystallization to reduce the content of guanine impurity in ganciclovir.
CN102643277A discloses a kind of process for purification of ganciclovir, and specifically adopt water and DMF mixing solutions heating for dissolving ganciclovir crude product, then carry out crystallisation by cooling in the mode of gradient cooling, filtering for crystallizing product obtains ganciclovir.
CN102210686A discloses a kind of pharmaceutical composition containing ganciclovir compound and preparation method thereof.This pharmaceutical composition is injection freeze-dried powder, is made up of ganciclovir, Polysorbate 80, sodium hydroxide and dextran.
CN102274197A discloses a kind of ganciclovir for injection composition and method of making the same.The lyophilized powder that described composition is made up of ganciclovir and sodium hydroxide, wherein, the part by weight of ganciclovir and sodium hydroxide is 6.6 ~ 7.0:1, and the average vertical footpath of described lyophilized powder is 80 ~ 110nm, and porosity is 94% ~ 98%.Its preparation method is: take ganciclovir and sodium hydroxide, puts in preparing tank, adds water for injection, stirs and makes it dissolve completely and mix, sterile filtration, packing, vacuum lyophilization, to obtain final product.
CN101711746A discloses a kind of ganciclovir for injection freeze-dried preparation and preparation method thereof.Comprise ganciclovir 50 ~ 250 parts, hydroxypropyl-beta-cyclodextrin 100 ~ 200 parts.Its preparation process, ganciclovir can be dissolved in solvent in pH value weakly acidic pH situation, and freezing dry process time shorten is extremely at 22 ~ 26 hours.
In above-mentioned prior art preparation method, ganciclovir crystallization crystal grain is relatively thicker, and again because the solvability of ganciclovir originally in water is poor, thus its dissolution time is long, uses inconvenience.
For better ganciclovir crystal can be found, the present inventor improves its technique, a kind of solvability, the better ganciclovir crystalline compounds of stability are prepared, and further this crystalline compounds is prepared into dried frozen aquatic products, its dried frozen aquatic products solubility is good, freeze the clarification of front solution appearance, the clarity of lyophilized injectable powder is good, good stability, quality controllable ganciclovir lyophilized injectable powder, thus completes the present invention.
In view of this, special proposition the present invention.
Summary of the invention
The first object of the present invention is to provide a kind of solvability, stability better ganciclovir crystalline compounds.
The second object of the present invention is to provide a kind of novel compositions containing above-mentioned ganciclovir, said composition good forming ability, and dried frozen aquatic products solubility is good, and freeze the clarification of front solution appearance, clarity is good, has good stability, quality controllable.
The third object of the present invention is the preparation method providing above-mentioned ganciclovir composition.
For realizing above-mentioned first object, the present invention adopts following technical scheme:
A kind of ganciclovir crystalline compounds, the X-ray powder diffraction that described ganciclovir crystalline compounds uses the measurement of Cu-K alpha-ray to obtain is that 30 °, 35 °, 50 °, 60 °, 63 °, 74.5 ° places show characteristic peak at 2 θ.
According to foregoing ganciclovir crystalline compounds, the particle diameter of described ganciclovir crystalline compounds is 85 ~ 105 μm.
Ganciclovir X-ray powder diffraction provided by the present invention shows that its crystalline structure is different from the ganciclovir of prior art, the ganciclovir its related substances of new crystal provided by the invention is little, stability is better, and long-time storage ganciclovir content is little.Meanwhile, show that the dissolution time of the more existing ganciclovir of ganciclovir crystalline compounds of the present invention obviously shortens through dissolubility test, clinical using and operating of being more convenient for.
The preparation method of above-mentioned ganciclovir crystalline compounds provided by the invention comprises: get ganciclovir bulk drug, be dissolved in the aqueous sodium hydroxide solution of 5% ~ 20%, at room temperature stir 20 ~ 30 hours, be neutralized to neutrality with dilute hydrochloric acid solution, be cooled to 8 ~ 15 DEG C, leave standstill 1 ~ 3 hour, filtration obtains filter cake, by filter cake as recrystallization in water for injection, add 0.1 ~ 0.3% (g/ml) medicinal carbon, decolouring, filter, washing, dry, obtain white micro-crystals powder.
Same compound, the inner solid-state structure of different crystal formations is different, and cause its lattice energy different, lattice energy is more high more stable.The present invention with commercially available ganciclovir crude product for raw material, through experiment repeatedly, under finally comprising the crystallization conditions such as solvent species, consumption, temperature in change, prepared a kind of ganciclovir with new crystal formation, compared with prior art, ganciclovir crystal grain of the present invention is even, good dispersity, be convenient to packing, the crystalline structure of more existing ganciclovir is more stable, and dissolution time obviously shortens.
In above-mentioned preparation method, the aqueous sodium hydroxide solution of 5% ~ 20% refers to the aqueous sodium hydroxide solution that mass percent concentration is 5% ~ 20%.
In above-mentioned preparation method, after being neutralized to neutrality with dilute hydrochloric acid, be preferably cooled to 10 DEG C.
For improving quality further, the present invention also can be filtered into use ultrafiltration membrance filter preferably after decolouring.
The particle diameter of the ganciclovir crystalline compounds that the preparation method of above-mentioned ganciclovir obtains is 85 ~ 105 μm.
Present invention also offers a kind of novel compositions containing foregoing ganciclovir crystalline compounds.
According to foregoing composition, described composition is ganciclovir freeze-dried preparation.
According to foregoing ganciclovir preparation, comprise ganciclovir crystalline compounds, sodium hydroxide, sodium-chlor, by weight, described ganciclovir freeze-dried preparation comprises ganciclovir crystalline compounds 50 ~ 500 parts, 8 ~ 80 parts, sodium hydroxide, 0.003 ~ 0.1 part, sodium-chlor.
According to foregoing composition, by weight, described ganciclovir freeze-dried preparation comprises ganciclovir crystalline compounds 50 parts, 8 parts, sodium hydroxide, 0.008 part, sodium-chlor.
According to foregoing composition, by weight, described ganciclovir freeze-dried preparation comprises ganciclovir crystalline compounds 250 parts, 40 parts, sodium hydroxide, 0.05 part, sodium-chlor.
According to foregoing composition, by weight, described ganciclovir freeze-dried preparation comprises ganciclovir crystalline compounds 300 parts, 48 parts, sodium hydroxide, 0.06 part, sodium-chlor.
According to foregoing composition, by weight, described ganciclovir freeze-dried preparation comprises ganciclovir crystalline compounds 500 parts, 80 parts, sodium hydroxide, 0.1 part, sodium-chlor.
Preferably, described ganciclovir crystalline compounds and sodium hydroxide mol ratio are 1:1.
The present inventor has done the stability experiment of a series of composition containing foregoing ganciclovir crystalline compounds, result shows, the good stability of the ganciclovir crystalline compounds in composition, it is low that said composition places its related substances for a long time, be convenient to store transport, substantially increase the drug safety of patient.
Present invention also offers the preparation method of above-mentioned ganciclovir novel compositions, described preparation method comprises the following steps:
1) ganciclovir, sodium-chlor and sodium hydroxide is taken by described consumption; First use 20% water for injection dissolved hydrogen sodium oxide of full dose, for subsequent use; Again 60% water for injection of full dose is added in Agitation Tank, then add above-mentioned sodium hydroxide solution for subsequent use, add load weighted ganciclovir while stirring, continue stirring and make it dissolve, regulate liquid pH value 11.0 ~ 11.5, add water for injection to full dose;
2) adding medicinal carbon, whip attachment, circulates in Tuo Tan limit, limit, and after intermediate detection is qualified, Sterile Filtration, obtains filtrate;
3) by step 2) be filled in injection cillin bottle filtrate dividing of gained, partly jump a queue, put into Freeze Drying Equipment and carry out lyophilize, after freeze-drying terminates, total head plug, outlet.
Above-mentioned steps 1) in solution temperature when adding ganciclovir in Agitation Tank control between 5 ~ 20 DEG C.
Step 2) for adding medicinal carbon whip attachment after 30 minutes, with 3 μm of titanium filter stick circulation decarbonization filterings; Intermediate detects qualified rear use 0.22 μm of filtering with microporous membrane.
The present invention is studied the consumption of gac and using method, adopts the method for Tuo Tan limit, limit circulation, makes its Sterile Filtration effect reach splendid state.The method of Tuo Tan limit, limit circulation has the following advantages: 1. gac is attached on filter stick and makes the adsorptive power of gac obtain reinforcement; 2. ensure once, secondary 0.2 μm of degerming not blocking of filter membrane and successfully complete filtering liquid medicine; 3. after improve the clarity of filtering liquid medicine, freeze-drying, solvability is better.
In above-mentioned preparation method, described lyophilize is divided into pre-freeze, primary drying and redrying three phases.
Pre-freeze: shelf temperature is down to about-35 ~-50 DEG C, reaches after eutectic point until sample temperature for after product inlet about 1.5 hours, keep 3 ~ 5 hours, cold hydrazine temperature is down to-55 DEG C ± 5 DEG C, is evacuated to vacuum tightness in case and reaches 10Pa ± 5Pa; Primary drying: shelf slowly heats up, makes products temperature below product eutectic point, carry out low-temperature distillation to the completely dissolve of product ice crystal, then keeps 5 ~ 8 hours; Redrying: shelf temperature rises to 45 DEG C ± 5 DEG C, is incubated 4 ~ 6 hours, then is down to 35 DEG C ± 5 DEG C insulations 2 ~ 3 hours.Freeze-drying terminates, total head plug, outlet.
Processing condition in the inventive method are to ensureing that the quality of product plays vital effect.The control of the temperature and time particularly when pre-freeze, distillation, effectively improves the crystalline state of bulk drug and the air permeability of finished product.Also enable water vapour appear smoothly simultaneously, make the full appearance not atrophy of product, and color and luster is homogeneous, drying fully, and maintains medicine satisfactory stability and porousness.State before freeze-drying can be recovered rapidly after finished product add water.Freeze-drying process, adopts distinctive low-temperature quick-freezing, and heat up sublimation drying stage by stage, the freeze drying process of parsing-desiccation under lesser temps, and gained ganciclovir freeze-dried preparation is shaped good, and nondiscoloration, water content is low.In a word, the ganciclovir freeze-dried preparation that the present invention obtains has higher stability, and its related substances is low, and quality is homogeneous controlled, stores and transport convenient.Preparation technology of the present invention is simple, facilitate feasible, reproducible, scrap rate (variable color) is low, and lamp inspection inspection rejects difficulty is low, saves manpower, shorter production cycle, lower scrap rate and lower human cost, production cost is significantly reduced, considerable economic and social benefit can be produced, industrialization can be realized and produce.
Compared with prior art, tool of the present invention has the following advantages:
(1) ganciclovir crystalline compounds of the present invention is compared compared with prior art and is had more excellent stability, and dissolution time obviously shortens;
(2) ganciclovir composition stability of the present invention is better;
(3) preparation method's simple possible of ganciclovir crystalline compounds provided by the present invention and composition, can realize industrialized production.
Accompanying drawing explanation
Fig. 1 is the X-RD collection of illustrative plates of ganciclovir crystal prepared by embodiment 1.
Embodiment
The specific embodiment of the present invention is only limitted to further explain and the present invention is described, does not limit Composition of contents of the present invention.
Embodiment 1
The preparation of ganciclovir crystalline compounds: ganciclovir bulk drug 30g, is dissolved in the aqueous sodium hydroxide solution of 475ml5%, at room temperature stirs 20 hours, be neutralized to neutrality with dilute hydrochloric acid solution, be cooled to 10 DEG C, leave standstill 1 hour, filtration obtains filter cake, by filter cake as recrystallization in water for injection, adds 0.1% (g/ml) medicinal carbon, decolouring, filters, washing, drying, obtains ganciclovir crystal, and particle diameter is 85 μm, yield 82%, HPLC content 99.1%.The X-ray powder diffraction that the ganciclovir crystal obtained uses the measurement of Cu-K alpha-ray to obtain is that 30 °, 35 °, 50 °, 60 °, 63 °, 74.5 ° places show characteristic peak at 2 θ.
Embodiment 2
The preparation of ganciclovir crystalline compounds: ganciclovir bulk drug 63.2g, is dissolved in the aqueous sodium hydroxide solution of 667ml10%, at room temperature stirs 25 hours, be neutralized to neutrality with dilute hydrochloric acid solution, be cooled to 8 DEG C, leave standstill 2 hours, filtration obtains filter cake, by filter cake as recrystallization in water for injection, adds 0.2% (g/ml) medicinal carbon, decolouring, washing, filters, drying, obtains ganciclovir crystal, and particle diameter is 105 μm, yield 83%, HPLC content 97.8%.The ganciclovir crystal obtained has identical parameter with the X-ray powder diffraction of embodiment 1 product.
Embodiment 3
The preparation of ganciclovir crystalline compounds: ganciclovir bulk drug 100g, is dissolved in the aqueous sodium hydroxide solution of 1800ml20%, at room temperature stirs 30 hours, be neutralized to neutrality with dilute hydrochloric acid solution, be cooled to 15 DEG C, leave standstill 3 hours, filtration obtains filter cake, by filter cake as recrystallization in water for injection, adds 0.3% (g/ml) medicinal carbon, decolouring, filters, washing, drying, obtains ganciclovir crystal, and particle diameter is 90 μm, yield 83%, HPLC content 99.5%.The ganciclovir crystal obtained has identical parameter with the X-ray powder diffraction of embodiment 1 product.
Embodiment 4
Prescription:
Table 1
Preparation method:
(1) ganciclovir, sodium-chlor and sodium hydroxide is taken by recipe quantity; First use 20% water for injection dissolved hydrogen sodium oxide of full dose, for subsequent use; Use 60% water for injection of full dose again, add above-mentioned sodium hydroxide solution for subsequent use, add load weighted ganciclovir while stirring, continue stirring and make it dissolve, regulate liquid pH value 11.0 ~ 11.5, add water for injection to full dose;
(2) adding medicinal carbon, whip attachment, circulates in Tuo Tan limit, limit, and after intermediate detection is qualified, Sterile Filtration, obtains filtrate;
(3) filtrate of step (2) gained is filtered, dividing is filled in injection cillin bottle, partly jump a queue, put into Freeze Drying Equipment and carry out lyophilize, described lyophilize is divided into pre-freeze, primary drying and redrying three phases, and wherein pre-freeze is: shelf temperature was down to about-35 ~-50 DEG C in after product inlet about 1.5 hours, reach after eutectic point until sample temperature, keep 3 ~ 5 hours, cold hydrazine temperature is down to-55 DEG C ± 5 DEG C, is evacuated to vacuum tightness in case and reaches 10Pa ± 5Pa; Primary drying is: shelf slowly heats up, and makes products temperature below product eutectic point, carry out low-temperature distillation to the completely dissolve of product ice crystal, then keeps 5 ~ 8 hours; Redrying is: shelf temperature rises to 45 DEG C ± 5 DEG C, is incubated 4 ~ 6 hours, then is down to 35 DEG C ± 5 DEG C insulations 2 ~ 3 hours.Freeze-drying terminates, total head plug, outlet.
Embodiment 5
Prescription:
Table 2
Preparation method:
(1) ganciclovir, sodium-chlor and sodium hydroxide is taken by recipe quantity; First use 20% water for injection dissolved hydrogen sodium oxide of full dose, for subsequent use; Add in Agitation Tank with 60% water for injection of full dose again, add above-mentioned sodium hydroxide solution for subsequent use, control the temperature of Agitation Tank between 5 ~ 20 DEG C, add load weighted ganciclovir while stirring, continuing stirring makes it dissolve, regulate liquid pH value 11.0 ~ 11.5, add water for injection to full dose;
(2) medicinal carbon whip attachment is added after 30 minutes, with 3 μm of titanium filter stick circulation decarbonization filterings; Intermediate detects qualified rear use 0.22 μm of filtering with microporous membrane;
(3) filtrate the dividing of step (2) gained is filled in injection cillin bottle, partly jump a queue, put into Freeze Drying Equipment and carry out lyophilize, described lyophilize is divided into pre-freeze, primary drying and redrying three phases, wherein pre-freeze is: within after product inlet about 1.5 hours, shelf temperature is down to about-40 DEG C, reaches after eutectic point until sample temperature, keep 4 hours, cold hydrazine temperature is down to-55 DEG C, is evacuated to vacuum tightness in case and reaches 10Pa; Primary drying is: shelf slowly heats up, and makes products temperature below product eutectic point, carry out low-temperature distillation to the completely dissolve of product ice crystal, then keeps 7 hours; Redrying is: shelf temperature rises to 45 DEG C, is incubated 5 hours, then is down to 35 DEG C of insulations 2.5 hours.Freeze-drying terminates, total head plug, outlet.
Experimental example 1
This test example detects related substance in the ganciclovir composition prepared by embodiment 4, this test is carried out according to Chinese Pharmacopoeia 2010 editions second annex VIII P residual solvent assay method, annex XIX F medicine impurity analysis governing principle, and it the results are shown in Table 2:
The assay of table 2, related substance
| Preparation | Sodium hydroxide | Hydrochloric acid | Other related substance |
| First group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Second group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 3rd group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 4th group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 5th group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 6th group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 7th group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 8th group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| 9th group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
| Tenth group | Conform with the regulations | Conform with the regulations | Conform with the regulations |
Experimental example 2
This experimental example has investigated the solvability of the ganciclovir of ganciclovir crystalline compounds provided by the invention and prior art.
Sample:
Sample 1: the ganciclovir crystalline compounds that the embodiment of the present invention 1 is obtained;
Sample 2: the ganciclovir crystalline compounds that the embodiment of the present invention 2 is obtained;
Sample 3: the ganciclovir crystalline compounds that the embodiment of the present invention 3 is obtained;
Sample 4: with reference to the ganciclovir that the method for CN102643277A embodiment 1 is obtained;
Sample 5: with reference to the ganciclovir that the method for CN102627643A embodiment 1 is obtained.
Experimental technique: get 1 gram of above-mentioned ganciclovir sample and add 0.04 gram of sodium hydroxide and be dissolved in the water for injection of 10ml and do dissolution experiment, measure the time needed for dissolving, acquired results is as shown in table 3 below:
Table 3, dissolution experiment data
| Sample | Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 |
| Dissolution time (second) | 67 | 68 | 65 | 272 | 275 |
Visible, the ganciclovir crystalline compounds that the present invention obtains obviously shortens compared with the dissolution time of the ganciclovir of prior art.
Experimental example 3
This test example has investigated the stability of ganciclovir crystalline compounds provided by the invention.
This test is carried out according to Chinese Pharmacopoeia 2005 editions second annex XIX C medicine stability test governing principle, and measure the content of ganciclovir, result is as follows:
Table 4, accelerated test result
| Sample | 0 month | 1 month | 2 months | 3 months |
| 1 | 99.5％ | 99.6％ | 99.4％ | 99.3％ |
| 2 | 100.0％ | 99.6％ | 99.8％ | 99.5％ |
| 3 | 99.9％ | 99.8％ | 99.8％ | 99.6％ |
| 4 | 100.1％ | 99.1％ | 98.8％ | 97.9％ |
| 5 | 100.1％ | 100.0％ | 98.9％ | 99.1％ |
Wherein sample 1 is the product that the embodiment of the present invention 1 obtains, and sample 2 is the product that the embodiment of the present invention 2 obtains, and sample 3 is the product that the embodiment of the present invention 3 obtains;
Sample 4 is with reference to the obtained ganciclovir of the method for CN102643277A embodiment 1;
Sample 5 is with reference to the obtained ganciclovir of the method for CN102627643A embodiment 1.
This experimental example illustrates, ganciclovir crystal stability provided by the invention is good, and accelerated test ganciclovir purity content is little, and the common ganciclovir crystal stability of prior art is poor, and accelerated test ganciclovir content is large.
Experimental example 4
This test example has investigated the stability of ganciclovir composition provided by the invention.
This test is carried out according to Chinese Pharmacopoeia 2005 editions second annex XIX C medicine stability test governing principle, and result is as follows:
Table 5, accelerated test result
Table 6, long-term test results
Wherein sample 6 is the product of in embodiment 4 first group, and sample 7 is the product of in embodiment 4 second group, and sample 8 is the product of in embodiment 4 the 3rd group; Sample 9 is the ganciclovir composition prepared according to the method for CN102210686A embodiment 1; Sample 10 is the ganciclovir composition prepared according to the method for CN102274197A embodiment 1.
This experimental example high spot reviews ganciclovir the composition content of ganciclovir and changing conditions of its related substances in Acceleration study and long-term experiment, the explanation of investigation result, relative to the ganciclovir composition of prior art, in ganciclovir composition provided by the invention, ganciclovir content is little, stability is better, the content of related substance is few, it is little to change, and substantially increases the drug safety of patient.
Experimental example 5
This experimental example has investigated the change of particulate matter after the ganciclovir of ganciclovir for injection of the present invention and prior art and 5% Dextrose and Sodium Chloride Inj. compatibility.
1, laboratory sample and reagent, experiment condition
Sample: 1. contrast medicine A: with reference to the ganciclovir for injection composition that the method for CN102274197A embodiment 1 is obtained;
2. medicine B is contrasted: with reference to the ganciclovir for injection that the method for CN102210686A embodiment 1 is obtained;
3. investigational agent A: the ganciclovir for injection that the 3rd group of prescription of the embodiment of the present invention 4 and method obtain;
4. investigational agent B: the ganciclovir for injection that the 8th group of prescription of the embodiment of the present invention 5 and method obtain;
Compatibility injection liquid: 5% Dextrose and Sodium Chloride Inj.
Need testing solution: get above-mentioned three kinds of ganciclovir for injection samples, makes the solution one bottle of 1g/250ml respectively with above-mentioned various compatibility injection liquid.
Experiment condition: carry out under room temperature condition (20 DEG C) daylight.
Investigation project: with the particulate matter of the 0th, 1,2,3,4 hour after infusion.
2, method and result
Prepare need testing solution according to the method described above, according to " Chinese Pharmacopoeia " 2010 editions annex IXC, particulate matter mensuration is carried out to each solution after placement 0 ~ 4h, the results are shown in Table 7.
Particulate matter measurement result after table 7, ganciclovir for injection sample and 5% Dextrose and Sodium Chloride Inj. compatibility
As can be seen from the above results, contrast medicine A and contrast medicine B changes greatly with particulate matter after above-mentioned 5% Dextrose and Sodium Chloride Inj. compatibility, 2010 editions regulations that particulate matter does not meet " Chinese Pharmacopoeia ", and after placing 4h after investigational agent A of the present invention and investigational agent B and above-mentioned two kinds of injection liquid compatibilities, particulate matter all can meet the regulation of " Chinese Pharmacopoeia " 2010 editions completely.
Other embodiments of the invention product has also carried out identical experiment, and obtains the experimental result of same trend, but length limit, and the present invention will not enumerate.
Claims (11)
1. a ganciclovir crystalline compounds, is characterized in that, the X-ray powder diffraction that described ganciclovir crystalline compounds uses Cu-Ka radionetric survey to obtain is that 30 °, 35 °, 50 °, 60 °, 63 °, 74.5 ° places show characteristic peak place at 2 θ.
2. the preparation method of a ganciclovir crystalline compounds as claimed in claim 1, it is characterized in that, described preparation method comprises: get ganciclovir bulk drug, be dissolved in the aqueous sodium hydroxide solution of 5% ~ 20%, at room temperature stir 20 ~ 30 hours, be neutralized to neutrality with dilute hydrochloric acid solution, be cooled to 8 ~ 15 DEG C, leave standstill 1 ~ 3 hour, filtration obtains filter cake, by filter cake as recrystallization in water for injection, add 0.1 ~ 0.3%g/ml medicinal carbon, decolouring, filter, washing, dry, obtain white micro-crystals powder.
3. the novel compositions containing ganciclovir crystalline compounds according to claim 1.
4. novel compositions according to claim 3, is characterized in that, described novel compositions is ganciclovir freeze-dried preparation.
5. novel compositions according to claim 4, is characterized in that, by weight, described ganciclovir freeze-dried preparation comprises ganciclovir crystalline compounds 50 ~ 500 parts, 0.003 ~ 0.1 part, sodium-chlor, 8 ~ 80 parts, sodium hydroxide.
6. novel compositions according to claim 5, it is characterized in that, by weight, described ganciclovir freeze-dried preparation comprises ganciclovir crystalline compounds 50 parts, 0.008 part, sodium-chlor, sodium hydroxide 8, or ganciclovir crystalline compounds 250 parts, 0.05 part, sodium-chlor, 40 parts, sodium hydroxide, or ganciclovir crystalline compounds 300 parts, 0.06 part, sodium-chlor, 48 parts, sodium hydroxide, or ganciclovir 500 parts, 0.1 part, sodium-chlor, 80 parts, sodium hydroxide.
7. a preparation method for the novel compositions described in claim 5 or 6, is characterized in that, described preparation method comprises the following steps:
1) ganciclovir, sodium-chlor and sodium hydroxide is taken by described consumption; First use 20% water for injection dissolved hydrogen sodium oxide of full dose, for subsequent use; Again 60% water for injection of full dose is added in Agitation Tank, then add above-mentioned sodium hydroxide solution for subsequent use, add load weighted ganciclovir while stirring, continue stirring and make it dissolve, regulate liquid pH value 11.0 ~ 11.5, add water for injection to full dose;
2) adding medicinal carbon, whip attachment, circulates in Tuo Tan limit, limit, and after intermediate detection is qualified, Sterile Filtration, obtains filtrate;
3) by step 2) be filled in injection cillin bottle filtrate dividing of gained, partly jump a queue, put into Freeze Drying Equipment and carry out lyophilize, after freeze-drying terminates, total head plug, outlet.
8. preparation method according to claim 7, is characterized in that, step 1) in solution temperature when adding ganciclovir in Agitation Tank control between 5 ~ 20 DEG C.
9. preparation method according to claim 7, is characterized in that, step 2) for adding medicinal carbon whip attachment after 30 minutes, with 3 μm of titanium filter stick circulation decarbonization filterings; Intermediate detects qualified rear use 0.22 μm of filtering with microporous membrane.
10. preparation method according to claim 7, is characterized in that, step 3) described in lyophilize be divided into pre-freeze, primary drying and redrying three phases.
11. preparation methods according to claim 10, it is characterized in that, described pre-freeze is: shelf temperature was down to about-35 ~-50 DEG C in after product inlet about 1.5 hours, reach after eutectic point until sample temperature, keep 3 ~ 5 hours, cold hydrazine temperature is down to-55 DEG C ± 5 DEG C, is evacuated to vacuum tightness in case and reaches 10Pa ± 5Pa; Described primary drying is: shelf slowly heats up, and makes products temperature below product eutectic point, carry out low-temperature distillation to the completely dissolve of product ice crystal, then keeps 5 ~ 8 hours; Described redrying is: shelf temperature rises to 45 DEG C ± 5 DEG C, is incubated 4 ~ 6 hours, then is down to 35 DEG C ± 5 DEG C insulations 2 ~ 3 hours.
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| CN103340831B (en) * | 2013-07-16 | 2015-04-29 | 成都天台山制药有限公司 | Ganciclovir powder-injection for injection |
| 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 |
| CN104784124A (en) * | 2015-03-23 | 2015-07-22 | 山东北大高科华泰制药有限公司 | Ganciclovir powder injection medicinal composition for injection and preparation method |
| 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 |
| CN115504977B (en) * | 2022-09-23 | 2024-02-09 | 海南锦瑞制药有限公司 | Preparation method of ganciclovir and preparation method of ganciclovir for injection |
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| WO2004111049A1 (en) * | 2003-06-13 | 2004-12-23 | Lyogen Limited | Ganciclovir sodium salt in crystalline form |
| CN101851240A (en) * | 2009-04-03 | 2010-10-06 | 上海益威实业有限公司 | Ganciclovir purification process |
| CN102274197A (en) * | 2011-07-19 | 2011-12-14 | 江苏奥赛康药业股份有限公司 | Ganciclovir composition for injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004111049A1 (en) * | 2003-06-13 | 2004-12-23 | Lyogen Limited | Ganciclovir sodium salt in crystalline form |
| CN101851240A (en) * | 2009-04-03 | 2010-10-06 | 上海益威实业有限公司 | Ganciclovir purification process |
| CN102274197A (en) * | 2011-07-19 | 2011-12-14 | 江苏奥赛康药业股份有限公司 | Ganciclovir composition for injection and preparation method thereof |
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Denomination of invention: A Ganciclovir crystal compound and its novel composition and preparation method Effective date of registration: 20230920 Granted publication date: 20150520 Pledgee: Qingdao Qishun Investment Management Co.,Ltd. Pledgor: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980057940 |