CN102210686A - Pharmaceutical composition containing ganciclovir compound, and preparation method thereof - Google Patents
Pharmaceutical composition containing ganciclovir compound, and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition containing a ganciclovir compound, and a preparation method thereof. The pharmaceutical composition is composed of ganciclovir, polysorbate 80, sodium hydroxide and dextran. The ganciclovir pharmaceutical composition overcomes the irritation of the existing ganciclovir lyophilized powder injections on an injection site, and improves the stability of the ganciclovir lyophilized powder injection and the compliance of patients.
Description
Technical field
The present invention relates to the preparation of antiviral drugs, be specifically related to a kind of pharmaceutical composition that contains the ganciclovir chemical compound and preparation method thereof.
Background technology
Ganciclovir (ganciclovir), shown in I, chemical name is 9-(1,3-dihydroxy-2-third an oxygen methyl) guanine.
Formula I
This product is a white crystalline powder, and molecular formula is C
9H
13N
50
4, molecular weight is 255.23, slightly soluble in water (dissolubility under 25 ℃ in water is 2.6mg/mL) is almost insoluble in methanol, and is insoluble in dichloromethane; Molten at hydrochloric acid solution or sodium hydroxide solution part omitted.Dissolubility under 25 ℃ of its single sodium salts in water is 50mg/mL, and when the physiology pH value, the ganciclovir sodium salt exists with non-ionic form, and dissolubility is 6mg/mL.
Ganciclovir is an antiviral drugs commonly used clinically, has broad-spectrum antiseptic herpesvirus (HSV) activity, is the effective antiviral thing that first treatment human body cytomegalovirus (CMV) infects.
The main injection freeze-dried powder of existing listing kind, it is as follows to write out a prescription:
Prescription 1: ganciclovir 50g, sodium hydroxide 9.83g, dextran 50g, mannitol 50g, water for injection add to 3000ml;
Prescription 2: ganciclovir 250g, sodium hydroxide 7.83g, lactose 20g, dextran 50g add the injection water to 3000ml;
1 the preparation method of wherein writing out a prescription is: take by weighing ganciclovir, dextran, mannitol and sodium hydroxide by recipe quantity, add an amount of water for injection, control solution pH value 10.5-11.5 stirs to make and is dissolved into clear solutions, adds 0.5% needle-use activated carbon, stir after 30 minutes, filter through the 0.22um microporous filter membrane, filtrate adds the injection water to total amount, after the intermediate detection is qualified, filter membrane through 0.22um filters, and is to be filled; Get above-mentioned fine straining liquid, be sub-packed in the 10ml glass tube vial according to every bottle of 3ml (50mg specification), glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 3 hours, and in-45 ℃ of insulations 6 hours, open hutch water device refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, when vacuum pump is read near 20 handkerchiefs when following, the flaggy temperature that raises gradually is incubated 12 hours to-5 ℃, is warming up to 0 ℃ and continues 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 near the time finish lyophilizing, vacuum tamponade, roll lid, packing.
The preparation method of prescription 2: lactose, the dextran of recipe quantity are added in an amount of water for injection, be stirred to dissolving fully, get solution 1), sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5-11.5, get solution 2), merge solution 1) and 2), the active carbon of adding dose volume 0.5%, after boiling 30min, after taking off the charcoal processing after filtration, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, after the inspection of semifinished product is qualified, to be filled; The semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
There is following problems in above-mentioned technology:
1) in the medicinal liquid process for preparation, active carbon all adds in the medicinal liquid after the dissolving at raw material, adjuvant, and when active carbon was removed endotoxin etc., ganciclovir also had and is adsorbed on a small quantity, thereby content is reduced, and descends about 5.0%;
2) in the medicinal liquid process for preparation, because the ganciclovir dissolubility is little, need to add a large amount of sodium hydroxide, and the pH value 10.5-11.5 of control medicinal liquid, ganciclovir is become fully could dissolve behind the sodium salt thorough, but owing to medicinal liquid alkalescence is stronger, zest was big when clinical injection was used, the patient feels very uncomfortable because of pain, so make ganciclovir be dissolved in solvent near under the middle implementations as far as possible at pH value, thus improve the compliance of clinical use.
3) in freezing dry process freeze-drying time above 30 hours, freeze-drying time is long more, it is long more that ganciclovir is in the non-drying regime time, product quality is unstable more, energy consumption is big more simultaneously, production cost is also high more, improves freeze-dry process, shortens freeze-drying time and helps improving the quality of products and energy-conservation consumption.
4) freeze-dried powder uses carriers such as cooperating glucose often and medicine together to inject use, and infection can appear in injection place, pain, side effect such as phlebitis, and injectable powder have draw moist.
In order to increase its result of extraction: rich former Tushan, December in 2009 Bangbu on the 28th pharmaceutical applications 200910260198.6, name is called a kind of injection ganciclovir lyophilized formulations and preparation method thereof, disclose by 50～250 parts of ganciclovirs, the lyophilized formulations of 100～200 parts of compositions of HP-, though because HP-has good water-solubility and solubilizing effect, FDA (Food and Drug Adminstration) (FDA) has up to the present only ratified the long-acting subcutaneous implant of Itraconazole injection and levonorgestrel and has used this adjuvant.Domestic have the manufacturer of two these adjuvants of family carrying out clinical research together with corresponding preparation, at present not approval production as yet.There is data to show that this adjuvant has certain nephrotoxicity and hemolytic, carcinogenecity is also arranged, and may have unknown more serious toxic and side effects.
And the glad Pharmaceutical application of the anti-occasion in Shandong, 02 month Shandong on the 01st in 2005 200510005177.1, the name be called ganciclovir injection and preparation method thereof, the injection of being made up of ganciclovir and sodium hydroxide, water for injection is disclosed.The dissolution of ganciclovir reduces in this invention, can not satisfy the injection requirement of ganciclovir.
In order to overcome the shortcoming of the existing dosage form of ganciclovir, need provide a kind of avoid injecting or during the infusion ganciclovir to the zest of blood vessel, it is moist to improve drawing of ganciclovir freeze-dried powder simultaneously.
Summary of the invention
The purpose of this invention is to provide a kind of can the minimizing to local blood vessel irritation, the hygroscopic ganciclovir pharmaceutical composition of minimizing.
A kind of pharmaceutical composition that contains the ganciclovir chemical compound provided by the invention is made up of ganciclovir, sodium hydroxide, polyoxyethylene sorbitan monoleate and dextran.
A kind of pharmaceutical composition that contains the ganciclovir chemical compound provided by the invention, preferably, said composition is grouped into by the one-tenth of following weight portion: ganciclovir 250, dextran 50, sodium hydroxide 5-8, polyoxyethylene sorbitan monoleate 20-130.
A kind of pharmaceutical composition that contains the ganciclovir chemical compound provided by the invention, further preferred, said composition is grouped into by the one-tenth of following weight portion: ganciclovir 250, dextran 50, sodium hydroxide 6-8 and polyoxyethylene sorbitan monoleate 50-100.
A kind of pharmaceutical composition that contains the ganciclovir chemical compound provided by the invention, further preferred, said composition is grouped into by the one-tenth of following weight portion: ganciclovir 250, dextran 50, sodium hydroxide 6.5-7.83 and polyoxyethylene sorbitan monoleate 60-80.
Wherein in the mentioned component:
Described dextran is selected from one or more in medium molecular dextran (mean molecule quantity 60,000-80,000), low molecular dextran (mean molecule quantity 20,000-40,000) or the Dextran 10 (mean molecule quantity 10,000-20,000).
Described dextran is preferably one or more in dextran-70, dextran-40, dextran-20 or the dextran-10.
Described polyoxyethylene sorbitan monoleate claims tween 80 again;
The present invention also provides a kind of pharmaceutical composition that contains the ganciclovir chemical compound, and this pharmaceutical composition is injection or injection freeze-dried powder, preferred injection freeze-dried powder.
The present invention also provides the preparation method of the freeze-dried powder of ganciclovir pharmaceutical composition, may further comprise the steps:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5-11.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Ganciclovir of the present invention is almost insoluble in methanol, and is insoluble in dichloromethane; Molten at hydrochloric acid solution or sodium hydroxide solution part omitted, with the urapidil different in kind.In order to seek to be more suitable for the freeze-dried powder of ganciclovir, the inventor has carried out a large amount of experimentatioies.
The adjuvant that is usually used in freeze-dried powder is solubilizing agent, emulsifying agent, chelating agent, antibacterial, antioxidant, liposome material, novel nano-material, wherein the preferred polyoxyethylene sorbitan monoleate of solubilizing agent, polyoxyethylene castor oil; The preferred poloxamer of emulsifying agent, the preferred disodium edetate of chelating agent, the preferred benzyl alcohol of antibacterial, the preferred sodium sulfite of antioxidant, liposome material preferably lecithin, novel nano-material is selected from chitosan.
Wherein polyoxyethylene sorbitan monoleate is the freeze-dried powder adjuvant of using always, but the part anaphylaxis appears in the injection that contains polyoxyethylene sorbitan monoleate, but whether anaphylaxis is relevant with polyoxyethylene sorbitan monoleate, has certain dispute, and the cardinal symptom of Chu Xianing is erythra, strips off dermatitis clinically; Cough, xerostomia, tachypnea, dyspnea, acute lung edema, nauseating, vomiting, anaphylactic shock, allergic asthma, laryngeal edema etc., severe patient generation anaphylactic shock, in addition dead.Tracing it to its cause, may be to sneak into impurity in the product to cause; Simultaneously, polyoxyethylene sorbitan monoleate itself is exactly a kind of mixture, and wherein there is sensitization in a part, and modern study confirms that there be close getting in touch in the sensitization of polyoxyethylene sorbitan monoleate and its quality.
The inventor has used Tween-80 for the dissolubility that increases ganciclovir, the unexpected discovery, when itself and dextran, when the sodium hydroxide compatibility is applied to ganciclovir injection, not only increased the stripping of ganciclovir, can also reduce the consumption of sodium hydroxide, reduce the blood vessel irritation that sodium hydroxide causes; The addition of Tween-80 is less simultaneously, the allergy of having avoided polyoxyethylene sorbitan monoleate to cause again.
The specific embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
1, prescription (weight: mg): ganciclovir 250, dextran 50, sodium hydroxide 6.5 and polyoxyethylene sorbitan monoleate 60.
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Embodiment 2
1, prescription (weight: mg): ganciclovir 250, dextran 50, sodium hydroxide 6.5 and polyoxyethylene sorbitan monoleate 80.
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 11.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Embodiment 3
1, prescription (weight: mg): ganciclovir 250, dextran 50, sodium hydroxide 6.5 and polyoxyethylene sorbitan monoleate 70.
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 11.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Embodiment 4:
1, prescription (weight: mg): ganciclovir 250, dextran 50, sodium hydroxide 8 and polyoxyethylene sorbitan monoleate 80.
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Embodiment 5:
1, prescription (weight: mg): ganciclovir 250, dextran 50, sodium hydroxide 7.53 and polyoxyethylene sorbitan monoleate 60.
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Embodiment 6:
1, prescription (weight: mg): ganciclovir 250, dextran 50, sodium hydroxide 7.53 and polyoxyethylene sorbitan monoleate 130.
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Embodiment 7:
1, prescription (weight: mg): ganciclovir 250, dextran 50, sodium hydroxide 7.53 and polyoxyethylene sorbitan monoleate 50.
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Embodiment 8:
1, prescription (weight: mg): ganciclovir 250, dextran 50, sodium hydroxide 7.53 and polyoxyethylene sorbitan monoleate 40.
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Comparative Examples 1:(adopts existing prescription 1)
1, prescription: ganciclovir 50g, sodium hydroxide 9.83g, dextran 50g, mannitol 50g, water for injection add to 3000ml;
2, preparation method:
1) takes by weighing ganciclovir, dextran, mannitol and sodium hydroxide by recipe quantity, add an amount of water for injection, control solution pH value 10.5-11.5 stirs to make and is dissolved into clear solutions, adds 0.5% needle-use activated carbon, stir after 30 minutes, filter through 0.22 μ m microporous filter membrane, filtrate adds the injection water to total amount, after the intermediate detection is qualified, filter membrane through 0.22 μ m filters, and is to be filled;
2) get above-mentioned fine straining liquid, be sub-packed in the 10ml glass tube vial according to every bottle of 3ml (50mg specification), glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 3 hours, and in-45 ℃ of insulations 6 hours, open hutch water device refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, when vacuum pump is read near 20 handkerchiefs when following, the flaggy temperature that raises gradually is incubated 12 hours to-5 ℃, is warming up to 0 ℃ and continues 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 near the time finish lyophilizing, vacuum tamponade, roll lid, packing.
Comparative Examples 2:(adopts existing prescription 2)
1, prescription: ganciclovir 250g, sodium hydroxide 7.83g, lactose 20g, dextran 50g add the injection water to 3000ml;
2, preparation method:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1., sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5-11.5, solution 2., 1. and 2. merge solution, add the active carbon of dose volume 0.5%, after boiling 30min, after taking off the charcoal processing after filtration, add water for injection, be filtered to storage tank through germ tight filter again to bright entirely, after the inspection of semifinished product is qualified, to be filled;
2) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
Comparative Examples 3:(adopts 200510005177.1 embodiment 1)
Take by weighing ganciclovir 75g, water 1500g, ganciclovir is added to the water, and dropping sodium solution to solution pH value is 11 under stirring, and continuing to be stirred to ganciclovir dissolves fully, the needle-use activated carbon that adds overall solution volume 0.02% (g/ml), stirred 30 minutes, and filtered, supplementing water to liquor capacity equals the former volume that adds entry in filtrate, filtering with microporous membrane with 0.45um, in the embedding ampoule, sterilized 20 minutes, and promptly got ganciclovir injection of the present invention for 100 ℃.
Comparative Examples 4:(adopts 200410049988.7 embodiment 3, replaces urapidil with the ganciclovir of identical molal quantity)
Get dextran 30g, add injection water 100ml, add 0.1% active carbon, boiled filtered while hot 15 minutes; Other gets the 0.395g ganciclovir, adds injection water 100ml, regulates pH value 2.3 with the 1mol/L hydrochloric acid solution, heated and stirred makes solution by filtering the carbon-coating of dextran solution, and filtrate is mixed with dextran solution, adds the injection water to 800ml, mixing is regulated pH value 5.4 with the 0.1mol/L sodium hydroxide solution, adds the injection water to 100ml, mixing is measured intermediate content, qualified back filtering with microporous membrane, embedding, sterilized 30 minutes down at 115 ℃, lamp inspection is used glass bottle packaging.
Experimental example 1: safety testing
Ganciclovir injection powder pin to embodiment and Comparative Examples preparation carries out the safety testing investigation, and test method and result are as follows:
One, blood vessel irritation experiment
Get body weight and be 78 of the healthy rabbits of 2.0-2.5kg, be divided into blank group, positive experiment 1-8 group, experiment 1-4 group at random, 6 every group, adopt rabbit ear edge vein slowly to inject, injection volume is 10ml/kg.Wherein the blank group adopts sodium chloride injection, positive control 1-8 group adopts embodiment 1-8 to prepare the ganciclovir freeze-dried powder respectively, experiment 1-4 group adopts the ganciclovir freeze-dried powder of Comparative Examples 1-4 preparation respectively, adds injection water dissolving back injection respectively.
Once a day, successive administration 7 days, cut short the rabbit ear in last administration after 24 hours, place 10% formalin fixed preparation, send then pathology carry out histological examination (5 places at rabbit ear edge venous different parts draw materials, promptly from inject initial position begin entad to hold every 1cm do a section).
Through rabbit ear edge vein pathological examination, the auricular vein tube wall of blank group and positive control 1-8 group is complete, and the endotheliocyte structure is clear, does not have obvious pathological changes, the slight dilatation and congestion of blood vessel, no cell infiltration.The slight dilatation and congestion of part blood vessel appears in experiment 1-4 group, and each experimental group blood vessel of the present invention is normal, does not see obvious stimulation such as slightly expansion of blood vessel, vascular degeneration, necrosis are arranged reaction.
Two, hemolytic experiment
Laboratory observation sodium chloride blank group, positive control 1-8 group and the external haemolysis of experiment 1-4 group to tame Sanguis Leporis seu oryctolagi, wherein the blank group adopts sodium chloride injection, positive control 1-8 group adopts embodiment 1-8 to prepare the ganciclovir freeze-dried powder respectively, experiment 1-4 group adopts the ganciclovir freeze-dried powder of Comparative Examples 1-4 preparation respectively, adds injection water dissolving back injection respectively.
The result shows 37 ℃, 3 hours, and the erythrocyte aggregation phenomenon has appearred in experiment 1-4 group, and all the other blank groups and positive control 1-8 group all do not have haemolysis, and show cell aggregation phenomenon does not occur.
Three, allergic experiment
Observe the anaphylaxis of Cavia porcellus intravenous injection sodium chloride blank group, positive experiment 1-8 group and experiment 1-4 group, wherein the blank group adopts sodium chloride injection, positive control 1-8 group adopts embodiment 1-8 to prepare the ganciclovir freeze-dried powder respectively, experiment 1-4 group adopts the ganciclovir freeze-dried powder of Comparative Examples 1-4 preparation respectively, adds injection water dissolving back injection respectively.
Concrete grammar is: laboratory animal every other day gives the ganciclovir injection sensitization of lumbar injection Comparative Examples 1, continuous three times, then laboratory animal is divided into blank group, positive control 1-8 group, experiment 1-4 group, totally 12 groups, and the 14th day and 21 days of beginning in sensitization attack administration respectively, observed immediately 1 hour.
The result shows that phenomenons such as perpendicular hair, dyspnea, sneeze, retch, cough or rale, tic, collapse, death have appearred in experiment 1-4 group, and above-mentioned phenomenon does not appear in all the other each groups.
Experimental example 2: stability experiment
Placed under the room temperature 9 months, and placed 0 day, 1 month, 3 months, 6 months, 9 months and 12 months respectively and detect clarity, observe solution appearance, the results are shown in following table according to regulation among second appendix IX of Chinese Pharmacopoeia version in 2000 B:
Table 1: Detection of Stability data
Table 2: Detection of Stability data
The result shows: Comparative Examples 1,2,4 is after 1 month, and solution is slightly muddy, and after 3 months, muddiness all appears in 4 Comparative Examples; And the embodiment outward appearance and the clarity of the present invention's preparation remain on stable status always.
Though, above used general explanation, the specific embodiment and experiment, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, and this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (8)
1. a pharmaceutical composition that contains the ganciclovir chemical compound is characterized in that, said composition is made up of ganciclovir, dextran, sodium hydroxide and polyoxyethylene sorbitan monoleate.
2. pharmaceutical composition according to claim 1 is characterized in that, said composition is grouped into by the one-tenth of following weight portion: ganciclovir 250, dextran 50, sodium hydroxide 5-8, polyoxyethylene sorbitan monoleate 20-130.
3. pharmaceutical composition according to claim 2 is characterized in that, said composition is grouped into by the one-tenth of following weight portion: ganciclovir 250, dextran 50, sodium hydroxide 6-8 and polyoxyethylene sorbitan monoleate 50-100.
4. according to claim 2 or 3 described pharmaceutical compositions, it is characterized in that said composition is grouped into by the one-tenth of following weight portion: ganciclovir 250, dextran 50, sodium hydroxide 6.5-7.83 and polyoxyethylene sorbitan monoleate 60-80.
5. according to each described pharmaceutical composition of claim 1-4, it is characterized in that described dextran is selected from one or more in medium molecular dextran, low molecular dextran or the Dextran 10.
6. pharmaceutical composition according to claim 5 is characterized in that described dextran is preferably one or more in dextran-70, dextran-40, dextran-20 or the dextran-10.
7. according to each described pharmaceutical composition of claim 1-4, it is characterized in that this pharmaceutical composition is the injection freeze-dried powder.
8. a method for preparing the described pharmaceutical composition of claim 7 is characterized in that, this method may further comprise the steps:
1) lactose, the dextran with recipe quantity adds in an amount of water for injection, is stirred to dissolving fully, gets solution 1);
2) sodium hydroxide added in an amount of water for injection dissolve, add ganciclovir and stir, control pH value 10.5-11.5, solution 2);
3) merge solution 1) and 2), add the active carbon of dose volume 0.5%, boil 30min after, take off the charcoal processing after filtration after, benefit adds to the full amount of water for injection, and is filtered to storage tank through germ tight filter again, and is after the inspection of semifinished product is qualified, to be filled;
4) the semi-finished product medicinal liquid is sub-packed in fill in the 10ml glass tube vial according to every bottle of 5ml, glass tube vial is put lyophilization mechanical goods chamber flaggy, be cooled to-45 ℃ in 4 hours, and in-45 ℃ of insulations 8 hours, open water vessel refrigeration switch, after the pre-freeze insulation finishes, open vacuum pump, reduce to 20 handkerchiefs when following when the vacuum pump reading, the flaggy temperature that raises gradually is to-5 ℃, be incubated 12 hours, be warming up to 0 ℃ and continue insulation 4 hours, when products temperature and flaggy temperature near the time, continuation rising flaggy temperature to 30 ℃ also is incubated 8 hours, when products temperature and flaggy temperature near the time finish lyophilizing, vacuum tamponade, roll lid, visual inspection, packing.
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| CN103330687A (en) * | 2013-07-16 | 2013-10-02 | 成都天台山制药有限公司 | Stable ganciclovir freeze-dried powder 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 |
| CN117643573A (en) * | 2024-01-29 | 2024-03-05 | 天津医科大学眼科医院 | Nanometer eye drop capable of delivering medicine to posterior segment of eye, preparation method and application thereof |
| CN117643573B (en) * | 2024-01-29 | 2024-05-03 | 天津医科大学眼科医院 | Nanometer eye drop capable of delivering medicine to posterior segment of eye, preparation method and application thereof |
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| CN117643573A (en) * | 2024-01-29 | 2024-03-05 | 天津医科大学眼科医院 | Nanometer eye drop capable of delivering medicine to posterior segment of eye, preparation method and application thereof |
| CN117643573B (en) * | 2024-01-29 | 2024-05-03 | 天津医科大学眼科医院 | Nanometer eye drop capable of delivering medicine to posterior segment of eye, preparation method and application thereof |
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