CN103169660A - Prepared ribavirin lipidosome oral emulsion with high encapsulation efficiency - Google Patents
Prepared ribavirin lipidosome oral emulsion with high encapsulation efficiency Download PDFInfo
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Abstract
The invention discloses prepared ribavirin lipidosome oral emulsion with high encapsulation efficiency. The ratio of the ribavirin to the phospholipid in the prepared oral emulsion is 0.5:1 to 5:1; the prepared ribavirin lipidosome oral emulsion further comprises vitamin E, cholesterol, sorbitol, beta-cyclodextrin, polyethylene glycol (PEG2000-PEG5000), lactose and polyvinyl alcohol (PVA). The prepared ribavirin lipidosome oral emulsion is high in encapsulation efficiency and capable of satisfying pharmacopoeia requirements. Moreover, the prepared ribavirin lipidosome oral emulsion is capable of tolerating thermal sterilization treatment for 30 minutes at 121 DEG C, high in tolerance to a pH environment and low in leakage rate, so that the preparation requirements of large pH changes of the gastrointestinal tract after orally taking the emulsion are satisfied, the oral emulsion is digested, absorbed and transferred by a human body in the form of lipidosome, and the pharmacological effect of the ribavirin can be ensured.
Description
Technical field
The present invention relates to antiviral drugs novel form preparation technique field.A kind of oral breast of ribavirin liposome that meets the high envelop rate of existing " Good Manufacturing Practice and Quality Control of Drug " is provided.
Background technology
Ribavirin another name virazole, ribavirin.Be the inhibitor of a kind of strong monophosphate time purine nucleosides dehydrogenase, can suppress the activity of monophosphate time purine core, thereby stop the synthetic of viral nucleic acid, the antivirus action of wide spectrum is arranged.In laboratory, multiple virus there is inhibitory action.Be used for clinically the viral diseases such as influenza, hepatitis A, herpes of mouth, herpes zoster.
Product and the specification of ribavirin mainly contain: injection, every 100mg (1ml); Eye drop, 0.1%; Nasal drop, 0.5 %.Stronger teratogenesis is arranged, therefore forbid in the anemia of pregnant woman and might be about to conceived women.Heavy dose of this product (comprising collunarium) of using can cause heart damage.If respiratory tract has the disease patient, can cause the untoward reaction such as dyspnea, chest pain, after drug withdrawal, symptom can disappear.
Liposome is a kind of bimolecular film structure that Lipid composition is arranged, and can well medicine be sent in cell by the mode of " film fusion " by this frame mode.Due to mobility and the characteristic of modifying of liposome phospholipid bimolecular film, the liposome pharmaceutical technology has been subject to the extensive approval of all circles and highly research more.Liposome technology is used for the research of the transmission of natural product medicine and is also paid attention to widely.
Liposome can have medicine transmission preferably and targeting transmitting function, can reduce to a great extent the toxic and side effects of medicine.Patented technology " ribavirin liposome preparation (01128247.9) " provides the basic technology of preparation ribavirin liposome, the envelop rate that all there is no effectively to solve ribavirin liposome due to aforementioned patent is low, and the taste of product oral is relatively poor, can not satisfy the requirement of taking of the specification requirement of pharmacopeia and product, can't go on the market, can not bring the common people with the benefit of liposome product.
Summary of the invention
The objective of the invention is to have studied on the basis of formula of the oral breast of ribavirin liposome at ribavirin traditional liposomal medicine tranmission techniques and modification technique thereof, developed a kind of envelop rate high, the 121 ℃ of 30 minutes heat sterilizations that can tolerate that meet the pharmacopeia requirement are processed and the oral breast of ribavirin liposome stable and that have wide spectrum pH stability.The oral breast of ribavirin liposome of preparation is incubated to put at 35-40 ℃ and was kept the stable of dispersion in 3 hours, percolation ratio is low, meet the preparation requirement of oral rear stomach, the larger variation of intestinal pH, guarantee to be digested, absorb and transhipment by human body with the liposome form, can improve the pharmacology curative effect of ribavirin.This mature preparation process is stable, and meets existing " Good Manufacturing Practice and Quality Control of Drug " to the related request of final sterilization preparation.
On the basis of " liposome of stabilisation (200510092604.4) ", " ribavirin liposome preparation (01128247.9) " patent of invention, carried out the research of method.
The oral breast of preparation ribavirin liposome, is cultivated in 37 ℃ of insulations of 3 hours of buffer solution system of pH2-8 in dilution and undiluted situation because have wide spectrum pH stability, keeps the stable of dispersion.Ribavirin composition in product finally is absorbed with the liposome form and merges with the form of phospholipid bimolecular film medicine is sent to site of action, guaranteed good pharmacology curative effect.
Calculate with the oral breast of preparation 1000ml ribavirin liposome, formed by buffer and alcoholic solution.
One, the composition of alcoholic solution (1000ml calculates by preparation)
Composition title consumption remarks
Phosphatidase 12 0-100 gram natural phospholipid or decorated phospholipid are more than feed grade
Ethanol 30-250ml divide analytical pure
Vitamin E 3-30 gram biochemical reagents
Cholesterol 1-30 gram biochemical reagents
Two, the composition of buffer (1000ml calculates by preparation)
Composition title consumption remarks
Ribavirin 5-50 gram is by " it is qualified that Chinese pharmacopoeia detects
Sodium hydrogen phosphate 2-30 gram analytical pure
Sodium dihydrogen phosphate 0.2-10 gram analytical pure
Sorbitol 5-250 gram biochemical reagents
Beta-schardinger dextrin-5-100 gram medicinal raw material
PEG 3-80 gram-molecular weight 1000-400000
Lactose 1-40 gram biochemical reagents
The water of the appropriate purified water of purified water and above specification
Three, polyvinyl alcohol (PVA) solution
Composition title consumption remarks
Polyvinyl alcohol 2-60 gram standards of pharmacopoeia
The water of purified water 500ml purified water and above specification
Four, the preparation process that meets the oral breast of ribavirin liposome of existing " Good Manufacturing Practice and Quality Control of Drug " requirement.
Due to the needs of present technique industrialization, be exactly injection method and liposome technology is best suited for the technology of preparing of industrialization.For this reason, set forth this preparation method take injection method technique as the basis.Other liposome preparation technology all can adopt, but formula remains unchanged.
1) all raw and auxiliary materials for the production of the oral breast of preparation ribavirin liposome are tested according to the quality standard of correspondence, all should meet quality standard.
2) preparation phospholipid alcoholic solution.
2.1 weighing vitamin E, cholesterol, phospholipid are in same container respectively.
2.2 measure 95% ethanol or the dehydrated alcohol 250ml of recipe quantity, and pour in 2.1 container.
2.3 under 20-80 ℃ of water bath condition, in 2.1 container for stirring, speed of agitator is controlled to be 5-100rpm, makes it be dissolved into the solution of transparent homogeneous with stirring paddle.
2.4 filter 2.3 solution with the degerming filter membrane of 0.22 micron or filter, and filtered solution is carried out count of bacteria cultivate, should be less than 10CFU/10ml, the filtered solution sealing is stand-by, should finish using in 8 hours.
3) buffer of preparation ribavirin.
3.1 take successively the ribavirin, sodium hydrogen phosphate, sodium dihydrogen phosphate, sorbitol, beta-schardinger dextrin-, PEG-6000, lactose of recipe quantity in same container.
3.2 measure purified water 600ml, and pour in 3.1 described containers, room temperature or under 20-80 ℃ of water bath condition stirs with stirring paddle 5-200rpm in 3.1 containers and makes it fully dissolve the solution that becomes transparent homogeneous.
3.3 with the solution of degerming filter membrane (filter) the filter 23 .2 of 0.22 micron, and filtered solution is carried out count of bacteria cultivate, should be less than 10CFU/10ml.The filtered solution sealing is stand-by, should finish using in 8 hours.
3.4 preparation poly-vinyl alcohol solution.Get purified water, the poly-vinyl alcohol solution 500ml of preparation 3%.Room temperature or stir under 20-80 ℃ of water bath condition and make it dissolve colourless transparent solution thoroughly.
4) injection method prepares the oral breast of ribavirin liposome.
Prepare in container 4.1 the ribavirin buffer of 3.3 preparations is poured into the liposome of sealing, open under 40-80 ℃ of water bath condition and stir, rotating speed is controlled to be 50-1000rpm, and buffer should fully stir but not cause liquid splash.
4.2 by constant flow pump or manually slowly the phospholipid alcoholic solution is injected in the buffer that is stirring.The time of whole filling alcoholic solution is controlled to be 30-150 minute.After the phospholipid alcoholic solution injects and finishes, continue to stir 20-50 minute.
4.3 holding temperature is constant, replenishes 3.4 poly-vinyl alcohol solution to the ribavirin liposome oral Ruzhong of 4.2 preparations to 1000ml.Replenishing complete rear continuation stirred 15-30 minute.Make the oral lactobacterium bacteria count detection of sterilization proliposome with membrane-filter procedure, should be less than 100CFU/1ml.
4.4 the oral newborn sterilizing filter (film) with 0.22 micron of 4.3 ribavirin liposome is carried out aseptic filtration, at 121 ℃ of temperature, carries out 30 minutes moist heat sterilizations and process afterwards.It is stable that dispersion keeps.
4.5 the liposome solutions with 4.4 is the ultrafilter membrane ultrafiltration of 1KD-50KD with the molecular retention amount, to remove the medicine of not sealing.Solution 200-400ml is removed in ultrafiltration.Remaining 600-800ml is the liposome oral fluid product.
4.6 doing count of bacteria with membrane-filter procedure, the oral breast of the ribavirin liposome after the sterilization ultrafiltration detects, should be without bacterial growth.
4.7 the oral breast of the ribavirin liposome of operation 4.6 preparations separates with the Sephdex-A50 gel chromatography, measures its envelop rate greater than 80%.
5) envelop rate of the oral breast of ribavirin liposome test.
The oral breast of the ribavirin liposome of operation 4.6 preparations separates with the Sephdex-A50 gel chromatography, and the determinator envelop rate is greater than 80%.
5.1 the separation of the oral breast of ribavirin liposome: with Sephdex A-50 gel, with the ribavirin sealed with do not seal ribavirin and separate.
5.2 measure respectively the ribavirin seal and the amount of non-encapsulated ribavirin, the computational envelope rate.
The ribavirin ÷ (ribavirin of sealing+non-encapsulated ribavirin) * 100% of envelop rate=seal.
6) the oral newborn wide spectrum pH stability test of ribavirin liposome.
6.1 prepare respectively pH and be 2,4,6,8,9 buffer 10ml, be placed in the constant water bath box of 30-45 ℃ with the good container of labelling.
Join in the container of every group of pH 6.2 get respectively the oral newborn 0.1ml of ribavirin liposome, 1ml, the 5ml of 4.5 preparations, water bath with thermostatic control was cultivated 3 hours, and floccule or other inhomogenous situations should not appear in original finely dispersed system.
6.3 the percolation ratio of the oral breast of ribavirin liposome test.Add the oral breast of ribavirin liposome (10ml) in pH is 2,9 buffer (10ml), insulation is cultivated in the constant water bath box of 30-45 ℃, and sampling in every 1 hour 1 time is by 5) method measure its envelop rate, the reduction of envelop rate is percolation ratio.
Adopt the beneficial effect of the technical program to be:
The prepared oral newborn envelop rate of ribavirin liposome of the present invention meets the pharmacopeia requirement, can tolerate 121 ℃ of 30 minutes heat sterilizations processes, low pH environment there is high toleration, 37 ℃ of insulations of 3 hours of buffer solution system that can tolerate pH2-8 are cultivated and keep the stable of dispersion, and percolation ratio is low.Meet the requirement of oral medication, can guarantee good ribavirin pharmacology curative effect.
The specific embodiment
Embodiment one:
Injection method prepares the oral breast of ribavirin liposome
1) all raw and auxiliary materials for the production of the oral breast of preparation ribavirin liposome are tested according to the quality standard of correspondence, all should meet quality standard.
2) preparation phospholipid alcoholic solution.
2.1 weighing vitamin E 10 grams, cholesterol 5 grams, phospholipid 75 grams are in same container respectively.
2.2 measure 95% ethanol or the dehydrated alcohol 250ml of recipe quantity, and pour in 2.1 container.
2.3 under 20-80 ℃ of water bath condition, in 2.1 container for stirring, speed of agitator is controlled to be 5-100rpm, makes it be dissolved into the solution of transparent homogeneous with stirring paddle.
2.4 filter 2.3 solution with the degerming filter membrane (filter) of 0.22 micron, and filtered solution is carried out count of bacteria cultivate, should be less than 10CFU/10ml.The filtered solution sealing is stand-by.
3) buffer of preparation ribavirin.
3.1 take successively ribavirin 13 grams, sodium hydrogen phosphate 18.6 grams, sodium dihydrogen phosphate 2.86 grams, sorbitol 25 grams, beta-schardinger dextrin-25 grams, PEG-6000 15 grams, lactose 8 grams of recipe quantity in same container.
3.2 measure purified water 600ml, and pour in 3.1 containers, room temperature or under 20-80 ℃ of water bath condition stirs with stirring paddle 5-200rpm in 3.1 containers and makes it fully dissolve the solution that becomes transparent homogeneous.
3.3 with the solution of degerming filter membrane (filter) the filter 23 .2 of 0.22 micron, and filtered solution is carried out count of bacteria cultivate, should be less than 10CFU/10ml.The filtered solution sealing is stand-by.
3.4 preparation poly-vinyl alcohol solution.Get purified water, the poly-vinyl alcohol solution 500ml of preparation 3%.Room temperature or stir under 20-80 ℃ of water bath condition and make it dissolve colourless transparent solution thoroughly.
4) injection method prepares the oral breast of ribavirin liposome.
Prepare in container 4.1 the buffer of 3.3 preparations is poured into the liposome of sealing, open under 40-80 ℃ of water bath condition and stir, rotating speed is controlled to be 50-1000rpm, and buffer should fully stir but not cause liquid splash.
4.2 by constant flow pump or manually slowly the phospholipid alcoholic solution is injected in the buffer that is stirring.The time of whole filling alcoholic solution is controlled to be 30-150 minute.After the phospholipid alcoholic solution injects and finishes, continue to stir 20-50 minute.
4.3 holding temperature is constant, replenishes 3.4 poly-vinyl alcohol solution to the ribavirin liposome oral Ruzhong of 4.2 preparations to 1000ml.Replenishing complete rear continuation stirred 15-30 minute.Make the oral lactobacterium bacteria count detection of sterilization proliposome with membrane-filter procedure, should be less than 100CFU/1ml.
4.4 the oral newborn sterilizing filter (film) with 0.22 micron of 4.3 ribavirin liposome is carried out aseptic filtration, at 121 ℃ of temperature, carries out 30 minutes moist heat sterilizations and process afterwards.It is stable that dispersion keeps.
4.5 the liposome solutions with 4.4 is the ultrafilter membrane ultrafiltration of 1KD-50KD with the molecular retention amount, to remove the medicine of not sealing.Solution 200-400ml is removed in ultrafiltration.Remaining 600-800ml is the liposome oral fluid product.
4.6 doing count of bacteria with membrane-filter procedure, the oral breast of the ribavirin liposome after the sterilization ultrafiltration detects, should be without bacterial growth.
Embodiment two:
The homogenate injection method prepares the oral breast of ribavirin liposome
1) all raw and auxiliary materials for the production of the oral breast of preparation ribavirin liposome are tested according to the quality standard of correspondence, all should meet quality standard.
2) preparation phospholipid alcoholic solution.
2.1 weighing vitamin E 10 grams, cholesterol 5 grams, phospholipid 75 grams are in same container respectively.
2.2 measure 95% ethanol or the dehydrated alcohol 250ml of recipe quantity, and pour in 2.1 container.
2.3 under 20-80 ℃ of water bath condition, in 2.1 container for stirring, speed of agitator is controlled to be 5-100rpm, makes it be dissolved into the solution of transparent homogeneous with stirring paddle.
2.4 filter 2.3 solution with the degerming filter membrane (filter) of 0.22 micron, and filtered solution is carried out count of bacteria cultivate, should be less than 10CFU/10ml.The filtered solution sealing is stand-by.
3) buffer of preparation ribavirin.
3.1 take successively ribavirin 23 grams, sodium hydrogen phosphate 18.6 grams, sodium dihydrogen phosphate 2.86 grams, sorbitol 25 grams, beta-schardinger dextrin-25 grams, PEG-6000 15 grams, lactose 8 grams of recipe quantity in same container.
3.2 measure purified water 600ml, and pour in 3.1 containers, room temperature or under 20-80 ℃ of water bath condition stirs with stirring paddle 5-200rpm in 3.1 containers and makes it fully dissolve the solution that becomes transparent homogeneous.
3.3 with the solution of degerming filter membrane (filter) the filter 23 .2 of 0.22 micron, and filtered solution is carried out count of bacteria cultivate, should be less than 10CFU/10ml.The filtered solution sealing is stand-by.
3.4 preparation poly-vinyl alcohol solution.Get purified water, the poly-vinyl alcohol solution 500ml of preparation 3%.Room temperature or stir under 20-80 ℃ of water bath condition and make it dissolve colourless transparent solution thoroughly.
4) injection method prepares the oral breast of ribavirin liposome.
4.1 the buffer of 3.3 preparations is poured in the container of the high-speed homogenization equipment that can control temperature, and controlling temperature is 40-80 ℃, opens refiner, controlled frequency is 1000-10000Hz, buffer should fully be stirred evenly but do not cause liquid splash.
4.2 by constant flow pump or manually slowly the phospholipid alcoholic solution is injected in the buffer of homogenized.The time of whole filling alcoholic solution is controlled to be 30-150 minute.The phospholipid alcoholic solution continues homogenate 20-50 minute after injecting and finishing.
4.3 holding temperature is constant, replenishes 3.4 poly-vinyl alcohol solution to the ribavirin liposome oral Ruzhong of 4.2 preparations to 1000ml.Replenish complete rear continuation homogenate 15-30 minute.Make the oral lactobacterium bacteria count detection of sterilization proliposome with membrane-filter procedure, should be less than 100CFU/1ml.
4.4 the oral newborn sterilizing filter (film) with 0.22 micron of 4.3 ribavirin liposome is carried out aseptic filtration, at 121 ℃ of temperature, carries out 30 minutes moist heat sterilizations and process afterwards.It is stable that dispersion keeps.
4.5 the liposome solutions with 4.4 is the ultrafilter membrane ultrafiltration of 1KD-50KD with the molecular retention amount, to remove the medicine of not sealing.Solution 200-400ml is removed in ultrafiltration.Remaining 600-800ml is the liposome oral fluid product.
4.6 doing count of bacteria with membrane-filter procedure, the oral breast of the ribavirin liposome after the sterilization ultrafiltration detects, should be without bacterial growth.
Embodiment three:
The oral newborn wide spectrum pH stability test of ribavirin liposome
1 to prepare respectively pH be 2,4,6,8,9 buffer 10ml, and buffering is not to limitting.Be placed in the constant water bath box of 30-45 ℃ with the good container of labelling.
The 2 oral newborn 0.1ml of ribavirin liposome, 1ml, 5ml, the 10ml that get respectively embodiment 1 or embodiment 2 4.4 preparations join in the container of every group of pH, 30-45 ℃ of water bath with thermostatic control cultivated 3 hours, and floccule or other inhomogenous situations should not appear in original finely dispersed system.
Embodiment four:
The envelop rate of the oral breast of ribavirin liposome, percolation ratio are measured
Test condition: Sephdex A-50 gel column, pH6.8 phosphate buffer
The separation of the 1 oral breast of ribavirin liposome: with Sephdex A-50 gel, with the ribavirin sealed with do not seal ribavirin and separate.
2 measure respectively the ribavirin seal and the amount of non-encapsulated ribavirin, computational envelope rate.
The ribavirin ÷ (ribavirin of sealing+non-encapsulated ribavirin) * 100% of envelop rate=seal.
The percolation ratio test of the 3 oral breasts of ribavirin liposome.Add the oral breast of ribavirin liposome (10ml) in pH is 2,9 buffer (10ml), insulation is cultivated in the constant water bath box of 30-45 ℃, and its envelop rate is measured in sampling in every 1 hour 1 time, and the reduction of envelop rate is percolation ratio.
4, test result.
4.1 the oral newborn envelop rate of ribavirin liposome: 81.1%.
4.2 the oral newborn percolation ratio of ribavirin liposome.Cultivating temperature is 37.6 degree.
。
Claims (1)
1. oral breast of ribavirin liposome for preparing high envelop rate, it is characterized in that: prepared oral Ruzhong ribavirin and the ratio of phospholipid are 0.5:1---5:1, and it is PEG2000 that its composition includes vitamin E, cholesterol, sorbitol, beta-schardinger dextrin-, Polyethylene Glycol---PEG50000, lactose, polyvinyl alcohol are PVA;
Ethanol with 95% or dehydrated alcohol, phosphate buffer prepare required solution as solvent, and the polymer substance of employing is that polyvinyl alcohol is that PVA and Polyethylene Glycol are PEG2000---PEG50000;
Make the oral breast of ribavirin liposome can tolerate 121 ℃ of 30 minutes heat sterilizations, keep the stable of dispersion;
37 ℃ of insulations of 3 hours of buffer solution system that can tolerate pH2-8 are cultivated, and keep the stable of dispersion, and percolation ratio is low, meets the preparation requirement of oral rear stomach, the larger variation of intestinal pH;
The injection method preparation process that meets the oral breast of ribavirin liposome of the high envelop rate that current edition " Good Manufacturing Practice and Quality Control of Drug " requires is:
1) all raw and auxiliary materials for the production of the oral breast of preparation ribavirin liposome are tested according to the quality standard of correspondence, all should meet quality standard;
2) preparation phospholipid alcoholic solution:
2.1 weighing vitamin E 10 grams, cholesterol 5 grams, phospholipid 75 grams are in same container respectively;
2.2 measure 95% ethanol or the dehydrated alcohol 250ml of recipe quantity, and pour in 2.1 described containers;
2.3 under 20-80 ℃ of water bath condition, in 2.1 described container for stirring, speed of agitator is controlled to be 5-100rpm, makes it be dissolved into the solution of transparent homogeneous with stirring paddle;
2.4 filter 2.3 solution with the degerming filter membrane filter of 0.22 micron, and filtered solution is carried out count of bacteria cultivate, should be less than 10CFU/10ml, the filtered solution sealing is stand-by, should finish using in 8 hours;
3) buffer of preparation ribavirin:
3.1 take successively ribavirin 13 grams, sodium hydrogen phosphate 18.6 grams, sodium dihydrogen phosphate 2.86 grams, sorbitol 25 grams, beta-schardinger dextrin-25 grams, PEG-6000 25 grams, lactose 8 grams of recipe quantity in same container;
3.2 measure purified water 600ml, and pour in 3.1 container, room temperature or under 20-80 ℃ of water bath condition stirs with stirring paddle 5-200rpm in 3.1 container and makes it fully dissolve the solution that becomes transparent homogeneous;
3.3 with the solution of the degerming filter membrane filter filter 23 .2 of 0.22 micron, and filtered solution is carried out count of bacteria cultivate, should be less than 10CFU/10ml; The filtered solution sealing is stand-by, should finish using in 8 hours;
3.4 preparation poly-vinyl alcohol solution; Get purified water, the poly-vinyl alcohol solution 500ml of preparation 3%; Room temperature or stir under 20-80 ℃ of water bath condition and make it dissolve colourless transparent solution thoroughly;
4) injection method prepares the oral breast of ribavirin liposome;
Prepare in container 4.1 the ribavirin buffer of 3.3 preparations is poured into the liposome of sealing, open under 40-80 ℃ of water bath condition and stir, rotating speed is controlled to be 50-1000rpm, and buffer should fully stir but not cause liquid splash;
4.2 by constant flow pump or manually slowly sharp phospholipid alcoholic solution is injected in the buffer that is stirring; The time of whole filling alcoholic solution is controlled to be 30-150 minute, after phospholipid ethanol alcoholic solution injects and finishes, continues to stir 20-50 minute;
4.3 holding temperature is constant, replenishes 3.4 poly-vinyl alcohol solution to the ribavirin liposome oral Ruzhong of 4.2 preparations to 1000ml, replenishes complete rear continuation and stirs 15-30 minute; Make the oral lactobacterium bacteria count detection of sterilization proliposome with membrane-filter procedure, should be less than 100CFU/1ml;
4.4 oral newborn sterilizing filter or the film with 0.22 micron of 4.3 ribavirin liposome carried out aseptic filtration, at 121 ℃ of temperature, carries out 30 minutes moist heat sterilizations and process afterwards; It is stable that dispersion keeps;
4.5 the liposome solutions with 4.4 is the ultrafilter membrane ultrafiltration of 1KD-50KD with the molecular retention amount, to remove the medicine of not sealing, solution 200-400ml is removed in ultrafiltration; Remaining 600-800ml is the liposome oral fluid product;
4.6 doing count of bacteria with membrane-filter procedure, the oral breast of the ribavirin liposome after the sterilization ultrafiltration detects, should be without bacterial growth;
4.7 the oral breast of the ribavirin liposome of operation 4.6 preparations separates with the Sephdex-A50 gel chromatography, measures its envelop rate greater than 80%.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103860470A (en) * | 2014-03-05 | 2014-06-18 | 贵州中泰生物科技有限公司 | Preparation method of oral high-density lipoprotein liposome |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1346633A (en) * | 2001-10-08 | 2002-05-01 | 沈阳药科大学 | Ribavirin liposome preparation |
| CN1451388A (en) * | 2000-06-07 | 2003-10-29 | 蔡海德 | Medicine for preventing and treating infectious diseases caused by virus, e.g. SARS |
| CN1915219A (en) * | 2005-08-16 | 2007-02-21 | 天津华立达生物工程有限公司 | Stabilized liposome |
| US20080138394A1 (en) * | 2006-11-09 | 2008-06-12 | Mogam Biotechnology Research Institute | Composite For Liver-Specific Delivery and Release of Therapeutic Nucleic Acids or Drugs |
-
2013
- 2013-04-15 CN CN201310129433.2A patent/CN103169660B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1451388A (en) * | 2000-06-07 | 2003-10-29 | 蔡海德 | Medicine for preventing and treating infectious diseases caused by virus, e.g. SARS |
| CN1346633A (en) * | 2001-10-08 | 2002-05-01 | 沈阳药科大学 | Ribavirin liposome preparation |
| CN1915219A (en) * | 2005-08-16 | 2007-02-21 | 天津华立达生物工程有限公司 | Stabilized liposome |
| US20080138394A1 (en) * | 2006-11-09 | 2008-06-12 | Mogam Biotechnology Research Institute | Composite For Liver-Specific Delivery and Release of Therapeutic Nucleic Acids or Drugs |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103860470A (en) * | 2014-03-05 | 2014-06-18 | 贵州中泰生物科技有限公司 | Preparation method of oral high-density lipoprotein liposome |
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