CN102451166A - Setron medicament oral cavity disintegrating tablet and preparation method thereof - Google Patents
Setron medicament oral cavity disintegrating tablet and preparation method thereof Download PDFInfo
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- CN102451166A CN102451166A CN2010105236135A CN201010523613A CN102451166A CN 102451166 A CN102451166 A CN 102451166A CN 2010105236135 A CN2010105236135 A CN 2010105236135A CN 201010523613 A CN201010523613 A CN 201010523613A CN 102451166 A CN102451166 A CN 102451166A
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- disintegrating tablet
- fine jade
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- class drug
- freeze
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Abstract
The invention relates to a setron medicament oral cavity disintegrating tablet and a prescription and process for preparing the setron medicament oral cavity disintegrating tablet by adopting a freeze-drying method. The setron medicament oral cavity disintegrating tablet provided by the invention is prepared from a main medicament and pharmaceutical adjuvants. When the setron medicament oral cavity disintegrating tablet is administered, water is not need, and the setron medicament oral cavity disintegrating tablet can be rapidly disintegrated after entering the oral cavity; the setron medicament oral cavity disintegrating tablet is suitable for being taken by the patients with dysphagia such as the elder, children and the like; and meanwhile, the setron medicament oral cavity disintegrating tablet is taken without need of water, thus the symptoms of nausea and vomiting are not aggravated, has better compliance and treatment effect to nausea and vomiting caused by chemotherapy, radiotherapy or operation, and can obviously lower the side effects of setron medicaments. In addition, the invention also relates to a preparation method of the setron medicament oral cavity disintegrating tablet.
Description
Technical field:
The present invention relates to a kind of department fine jade class drug port cavity disintegrating tablet and preparation method thereof, particularly a kind of department's fine jade class drug port cavity disintegrating tablet that adopts the freeze-drying preparation.
Background technology:
Chemotherapy, radiotherapy are the important method and the effective means of oncotherapy, but have 20%～30% patient the phenomenon of nausea and vomiting when accepting chemotherapy, radiotherapy, can occur, and patient Chang Yin can not tolerate and reduce even ends and treat.The high selectivity 5-HT3 receptor antagonist that grow up the nineties in 20th century is used for emesis in chemotherapy of tumors, radiotherapy process, effect is definite reliable, and toxic and side effects is low, and is clinical universal day by day, is acknowledged as the breakthrough progress on the emesis therapy.
Department's fine jade class medicine is a kind of strong effect high selectivity periphery and central nervous system 5-HT3 receptor antagonist; It has high selectivity to periphery and central nervous system 5-HT3 receptor; Its resisting emesis mechanism is highly selectively to block abdominal part vagus nerve end neuron; And the 5-HT3 receptor on the emetic receptive field of ventriculus quartus chemistry and the intestinal mucosa pheochromocyte, thereby the nausea and vomiting that the inhibition chemotherapy and radiation causes also is used to treat the nausea and vomiting after the surgery anesthesia.It does not have the common extrapyramidal system untoward reaction of common Bendectin, before treatment, gives single dose to most patients and promptly prevents n or V, and is not only convenient but also economical, and can improve patient dependence.
The dosage form of at present domestic granted department's fine jade class medicine has tablet, capsule, dispersible tablet, oral cavity disintegration tablet, injection.Quiet notes administration is extremely inconvenient for being used for chemotherapy of tumors, the nauseant treatment of radiotherapy for a long time, and patient's compliance extreme difference is considered from convenient with acceptable angle; Oral medication needs; Oral more being prone to absorbs through the near-end intestinal mucosa, produces a drug level higher than intravenous injection more near the position of periphery 5-HT3 receptor, and then at acceptor site; Vomiting to due to the cisplatin has trend to show that oral administration is more effective than vein; Tablet, capsule, dispersible tablet then are not suitable for the patient that there are dysphagia in old people, child, the difficult change of bed position etc., especially are not suitable for feeling sick, vomitting taking of patient; Oral cavity disintegration tablet is a kind of novel form that development in recent years is got up; Need not water when taking; In mouth, run into saliva and dissolve rapidly, for the difficult change of old people, child, bed position etc. exists taking medicine of dysphagia patients that great facility is provided, the long-term treatment of the vomiting that especially causes for chemotherapy of tumors, radiotherapy; Improve patient's compliance, can bring into play the therapeutical effect of medicine more fully.
The starting of the technology of preparing of oral cavity disintegration tablet is than later at home; Adopt direct compression process to prepare oral cavity disintegration tablet at present mostly; But owing to mainly be in this method through using disintegrating agent to make preparation disintegrate rapidly in the oral cavity; Therefore and most disintegrating agent is water insoluble, usually has grittiness after adopting the oral cavity disintegration tablet mouth of this method preparation to taste, thus mouthfeel and compliance when influencing the patient and taking; And the disintegrate of preparation also can be very slow.And adopt the freeze-drying preparation the time; Generally need not add disintegrating agent; The adjuvant that is adopted all is water miscible; Make preparation disintegrate rapidly in the oral cavity, no grittiness, oral cavity disintegration tablet disintegrate in the oral cavity of adopting the direct compression process preparation is slow, the shortcoming of grittiness thereby overcome.
In addition, discover through volunteer's oral mucosa permeability test, in human mouth; The prepared department's fine jade class drug port cavity disintegrating tablet of the present invention has bigger mucosa permeability; Thereby explain that it can absorb by the oral mucosa, onset rapidly reduces first pass effect.Through clinical trial, the discovery that the inventor is surprised is compared with ordinary tablet, and the bioavailability of department's fine jade class drug port cavity disintegrating tablet that the present invention is prepared improves, side effect obviously reduces, on curative effect, also increases.
Summary of the invention:
Technical problem to be solved by this invention is the shortcoming to above-mentioned existence, and a kind of prescription and the method for preparing that can improve department's fine jade class drug port cavity disintegrating tablet of the defective that prior art exists is provided.
The inventor has confirmed adjuvant of the present invention and technology through a large amount of experiments.Find to adopt department's fine jade class drug port cavity disintegrating tablet of adjuvant of the present invention and prepared to exist oral mucosa to absorb through volunteer's oral mucosa permeability test, bioequivalence test and clinical trial; Onset is rapid; And surprised discovery is compared with ordinary tablet, and the bioavailability of department's fine jade class drug port cavity disintegrating tablet of the present invention's preparation improves, side effect obviously reduces, on curative effect, also increases.
The department's fine jade class drug port cavity disintegrating tablet that the present invention relates to comprises principal agent, skeleton proppant, binding agent, and other adjuvant.Wherein other adjuvant is sweeting agent or aromatic or comprises sweeting agent and aromatic simultaneously.
The percentage by weight of department of the present invention each component of fine jade class drug port cavity disintegrating tablet is following:
Weight percentages of components
Principal agent 5-65%
Skeleton proppant 10-60%
Binding agent 15-70%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
The percentage by weight of preferred each component is following:
Weight percentages of components
Principal agent 11.36-52.47%
Skeleton proppant 17.71%-40.29%
Binding agent 28.52-50.91%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
The adjuvant that plays skeleton support effect that those skilled in the art were known when skeleton proppant of the present invention can be the preparation oral cavity disintegration tablet; Preferred glycine, serine, arginine, mannitol, sorbitol, maltose alcohol, xylitol, lactose, erythritol, hydroxyl isomaltulose, xylose, cottonseed sugar, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, sodium phosphate, sodium chloride, aluminium silicate or with the mixture of upper skeleton agent; Particularly preferably be mannitol, erythritol, glycine, serine, arginine or their mixture, most preferably glycine or mannitol or its mixture; The binding agent that those skilled in the art were known when described binding agent can be the preparation oral cavity disintegration tablet; Preferred Pullulan, dextran, sodium alginate, hyaluronic acid, modified starch, polyvinyl alcohol, chitosan or their mixture; Particularly preferably be Pullulan, dextran, sodium alginate or their mixture, most preferably Pullulan or dextran or its mixture; Described sweeting agent is one or more in the sweeting agent of natural or synthetic such as acesulfame potassium, sucralose, aspartame, sucrose; Described aromatic is one or more in the aromatic of natural or synthetic such as Herba Menthae, Fructus Citri sinensis, Fructus Ananadis comosi, Fructus Fragariae Ananssae.
The method for preparing of department of the present invention fine jade class drug port cavity disintegrating tablet is for adopting the freeze-drying preparation; In this preparation technology's the research of pre-freeze temperature, find the oral cavity disintegration tablet influence; The pre-freeze temperature is bigger to the appearance effects of oral cavity disintegration tablet; When temperature is too high, the oral cavity disintegration tablet rough surface that makes; Cross when low when temperature, then energy consumption is higher in the commercial process; In of the research of pre-freeze time, find that too short when the time, solution does not freeze reality, then the bubbling phenomenon can in dry run, occur, also can cause dwindling of oral cavity disintegration tablet volume the oral cavity disintegration tablet influence; Oversize when the time, then can cause the waste of the energy; In the research of freeze-drying process, find that freeze-drying process all has bigger influence for water content, mouldability, microstructure, the disintegrating property of oral cavity disintegration tablet to the oral cavity disintegration tablet influence.Temperature, the time of pre-freeze temperature, time and freeze-drying process when we finally confirm freeze-drying preparation department fine jade class drug port cavity disintegrating tablet through a large amount of experimentatioies; Wherein take charge of in the method for preparing of fine jade class drug port cavity disintegrating tablet, the pre-freeze temperature is-40 ℃～-170 ℃, and the pre-freeze time is 1～60min; Preferred pre-freeze temperature is-60 ℃～-150 ℃; The pre-freeze time is 2～30min, and more preferably the pre-freeze temperature is-100 ℃～-130 ℃, and the pre-freeze time is 3～6min; Freeze temperature is-30 ℃～30 ℃, preferred-20 ℃～20 ℃; Sublimation drying is 1～10h, and preferably 2～8h is more preferably 3～6h; Vacuum in the freezing dry process is 0.01mbar～10mbar, and preferably 0.01mbar～1mbar is more preferably 0.01mbar～0.1mbar.
The method for preparing of department of the present invention fine jade class drug port cavity disintegrating tablet is:
(a) 5-65% principal agent, 10-60% skeleton proppant, 15-70% binding agent and sweeting agent or aromatic or sweeting agent are mixed with aromatic, make abundant dissolving, form uniform solution to wherein adding an amount of purified water;
(b) solution is outgased;
(c) solution after will outgasing injects mould;
(d) be pre-freeze 1～60min under-40 ℃～-170 ℃ the condition in temperature.
(e) mould is changed in the freeze dryer, lyophilization 1～10h under 0.01mbar～10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains department of the present invention fine jade class drug port cavity disintegrating tablet.
Also can add the step that ice crystal is hatched before changing freeze dryer after the pre-freeze step in the said method, soon the mould that is marked with solution after the pre-freeze is put into-5 ℃～-60 ℃ low temperature environment, and the time is 0.5～15h.
The present invention preferably takes charge of fine jade class drug port cavity disintegrating tablet and is processed by the component of following weight percentage ratio:
Principal agent 1.41-5.52%
Glycine or mannitol or its mixture 1-10.00%
Pullulan or dextran or its mixture 1.5-10.00%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 72.48-96.09%
Wherein each weight percentages of components sum is 100%.
Its preparation method is: principal agent, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent, aromatic are dissolved in the purified water, and mulser mixes to make becomes uniform solution; After solution outgased, accurately inject mould; Behind pre-freeze 1～60min under the condition of liquid nitrogen-40 ℃～-170 ℃, change in the freeze dryer, lyophilization 1～10h under 0.01mbar～10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains department of the present invention fine jade class drug port cavity disintegrating tablet.Also can add the step that ice crystal is hatched before changing freeze dryer after the pre-freeze step in the said method, soon the mould that is marked with solution after the pre-freeze is put into-5 ℃～-60 ℃ low temperature environment, and the time is 0.5～15h.
Its preferred manufacturing procedure is: principal agent, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent, aromatic are dissolved in the purified water, and mixing to make becomes uniform solution; After solution outgased, accurately inject mould; Behind pre-freeze 2～30min under-60 ℃～-150 ℃ the condition, change in the freeze dryer, lyophilization 2～8h under 0.01mbar～1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains department of the present invention fine jade class drug port cavity disintegrating tablet; Also can add the step that ice crystal is hatched before changing freeze dryer after the pre-freeze step in the said method, soon the mould that is marked with solution after the pre-freeze is put into-10 ℃～-20 ℃ low temperature environment, and the time is 4～12h.
Department provided by the invention fine jade class drug port cavity disintegrating tablet; Supplementary product consumption is less, and because not use disintegrating agent, the adjuvant that is adopted be water miscible all; The principle of disintegrate is the many porosities through staying after the solvent seasoning in the preparation; Make preparation in the oral cavity after the disintegrate, medicine and adjuvant can be scattered in the saliva fast and fully, thereby have overcome direct compression process and the oral disintegrated preparation of other lyophilization preparations have grittiness in the oral cavity defective.
Department of the present invention fine jade class drug port cavity disintegrating tablet has following advantage:
1, good mouthfeel, taking convenience: department of the present invention fine jade class drug port cavity disintegrating tablet materials are simple, good mouthfeel, no grittiness; Needn't use water delivery service, saliva can make its disintegrate or dissolving, is particularly useful for the patient of old man, children's, dysphagia and the inconvenient person that fetches water takes medicine.
2, absorb soon, avoid the first pass effect of liver: the disintegrate rapidly in mouth of department's fine jade class drug port cavity disintegrating tablet of the present invention's preparation, there is the considerable part trans-oral to absorb, thereby rapid-action, first pass effect is little.
3, GI irritation is little: the rapid disintegrate of department's fine jade class drug port cavity disintegrating tablet of the present invention's preparation ability before medicine arrives gastrointestinal tract also is dispersed into trickle granule; Cause medicine to distribute in the gastrointestinal tract large tracts of land; Absorption point increases, thereby has reduced medicine to the gastrointestinal local excitation.
4, side effect is little, and curative effect improves: the department's fine jade class drug port cavity disintegrating tablet through the wonderful discovery the present invention preparation of clinical trial is compared with ordinary tablet, and side effect significantly reduces, and curative effect increases to some extent.
Department provided by the invention fine jade class drug port cavity disintegrating tablet mouthfeel is good, volume is little, sheet weighs moderate, difficult fragmentation, preparation technology is simple, rapid-action, side effect is little, curative effect is high, be fit to industrialized great production.
Description of drawings
Fig. 1 gives the blood drug level-time graph behind R1 and the T1
Fig. 2 gives the blood drug level-time graph behind R1 and the T2
Fig. 3 gives the blood drug level-time graph behind R1 and the T3
Fig. 4 gives the blood drug level-time graph behind R1 and the T4
Fig. 5 gives the blood drug level-time graph behind R1 and the T5
Fig. 6 gives the blood drug level-time graph behind R2 and the T6
Fig. 7 gives the blood drug level-time graph behind R2 and the T7
Fig. 8 gives the blood drug level-time graph behind R2 and the T8
Fig. 9 gives the blood drug level-time graph behind R2 and the T9
Figure 10 gives the blood drug level-time graph behind R2 and the T10
Figure 11 gives the blood drug level-time graph behind R3 and the T11
Figure 12 gives the blood drug level-time graph behind R3 and the T12
Figure 13 gives the blood drug level-time graph behind R3 and the T13
Figure 14 gives the blood drug level-time graph behind R3 and the T14
Figure 15 gives the blood drug level-time graph behind R3 and the T15
Figure 16 gives the blood drug level-time graph behind R4 and the T16
Figure 17 gives the blood drug level-time graph behind R4 and the T17
Figure 18 gives the blood drug level-time graph behind R4 and the T18
Figure 19 gives the blood drug level-time graph behind R4 and the T19
Figure 20 gives the blood drug level-time graph behind R4 and the T20
The specific embodiment:
Below through the detailed explanation the present invention of embodiment, but the present invention should not be interpreted as and only limits to this.
Pharmaceutical formulation of the present invention is composed of the following components:
Navoban (Soz) 5.64g
Glycine 4.40g
Pullulan 8.40g
Acesulfame potassium 0.50g
Flavoring pineapple essence 0.50g
Purified water 180.56g
Process 1000 altogether
Concrete method for preparing is described below: with Navoban (Soz), glycine, Pullulan, acesulfame potassium, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; , behind-100 ℃～-110 ℃ freezing 6min, change in the freeze dryer through liquid nitrogen, lyophilizing 3h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Tropisetron hydrochloride oral disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Navoban (Soz) 2.82g
Mannitol 4.40g
Pullulan 8.40g
Aspartame 1.00g
Purified water 183.38g
Process 1000 altogether
Concrete method for preparing is described below: with Navoban (Soz), mannitol, Pullulan, aspartame mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-120 ℃～-130 ℃ freezing 3min ,-10 ℃ of hatching 12h change in the freeze dryer through liquid nitrogen, and lyophilizing 3.5h under 0.02mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Tropisetron hydrochloride oral disintegration tablet of the present invention.
Embodiment 3
Pharmaceutical formulation of the present invention is composed of the following components:
Navoban (Soz) 2.82g
Glycine 2.00g
Pullulan 2.00g
Dextran-70 1.00g
Purified water 192.18g
Process 1000 altogether
Concrete method for preparing is described below: with Navoban (Soz), glycine, Pullulan, dextran-70 mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-110 ℃～-120 ℃ freezing 4min ,-40 ℃ of hatching 2h change in the freeze dryer through liquid nitrogen, and lyophilizing 4h under 0.1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Tropisetron hydrochloride oral disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Navoban (Soz) 5.64g
Glycine 10.00g
Mannitol 10.00g
Pullulan 8.00g
Sucralose 2.00g
Orange flavor 2.00g
Purified water 150.36g
Process 1000 altogether
Concrete method for preparing is described below: with Navoban (Soz), glycine, mannitol, Pullulan, dextran, sucralose, orange flavor mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make under the magnetic agitation becomes uniform solution; After solution carried out the centrifugal degassing, accurately inject mould; Behind-80 ℃～-100 ℃ freezing 10min ,-20 ℃ of hatching 4h change in the freeze dryer through freon, and lyophilizing 1h under 0.01mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains Tropisetron hydrochloride oral disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Navoban (Soz) 5.64g
Glycine 4.00g
Mannitol 3.00g
Herba Menthae essence 1.00g
Purified water 174.36g
Process 1000 altogether
Concrete method for preparing is described below: with Navoban (Soz), glycine, mannitol, dextran, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; , behind-60 ℃～-80 ℃ freezing 30min, change in the freeze dryer through turbo-expander, lyophilizing 10h under 1mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains Tropisetron hydrochloride oral disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Methanesulfonic acid tropisetron 6.00g
Glycine 4.40g
Pullulan 8.40g
Acesulfame potassium 0.50g
Flavoring pineapple essence 0.50g
Purified water 180.20g
Process 1000 altogether
Concrete method for preparing is described below: with methanesulfonic acid tropisetron, glycine, Pullulan, acesulfame potassium, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make under the mechanical agitation becomes uniform solution; After the degassing of solution ultrasonic wave concussion, accurately inject mould; Behind-120 ℃～-130 ℃ freezing 5min ,-15 ℃ of hatching 8h change in the freeze dryer through liquid nitrogen, and lyophilizing 2h under 0.02mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains methanesulfonic acid tropisetron oral cavity disintegration tablet of the present invention.
Embodiment 7
Pharmaceutical formulation of the present invention is composed of the following components:
Methanesulfonic acid tropisetron 6.00g
Mannitol 8.00g
Sucrose 1.20g
Purified water 173.20g
Process 1000 altogether
Concrete method for preparing is described below: with methanesulfonic acid tropisetron, mannitol, dextran, sucrose mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make under the mechanical agitation becomes uniform solution; After the online degassing of solution, accurately inject mould; , behind-150 ℃～-170 ℃ freezing 1min, change in the freeze dryer through liquid nitrogen, lyophilizing 8h under 0.5mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains methanesulfonic acid tropisetron oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Methanesulfonic acid tropisetron 3.00g
Glycine 1.00g
Mannitol 1.00g
Pullulan 3.00g
Purified water 192.00g
Process 1000 altogether
Concrete method for preparing is described below: with methanesulfonic acid tropisetron, glycine, mannitol, Pullulan mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-60 ℃～-80 ℃ freezing 15min ,-20 ℃ of hatching 6h change in the freeze dryer through liquid nitrogen, and lyophilizing 9h under 5mbar pressure ,-25 ℃ to 25 ℃ condition promptly obtains methanesulfonic acid tropisetron oral cavity disintegration tablet of the present invention.
Embodiment 9
Pharmaceutical formulation of the present invention is composed of the following components:
Methanesulfonic acid tropisetron 6.00g
Mannitol 20.00g
Pullulan 12.00g
Dextran 8.00g
Aspartame 2.00g
Orange flavor 2.00g
Purified water 150.00g
Process 1000 altogether
Concrete method for preparing is described below: with methanesulfonic acid tropisetron, mannitol, Pullulan, dextran, aspartame, orange flavor mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; Solution with after the sweeping degas by inert gas method degassing, is accurately injected mould; Behind-40 ℃～-60 ℃ freezing 60min ,-40 ℃ of hatching 10h change in the freeze dryer through freon, and lyophilizing 5h under 0.2mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains methanesulfonic acid tropisetron oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Methanesulfonic acid tropisetron 3.00g
Glycine 4.40g
Dextran 8.40g
Strawberry essence 0.70g
Purified water 183.50g
Process 1000 altogether
Concrete method for preparing is described below: with methanesulfonic acid tropisetron, glycine, dextran, strawberry essence mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-130 ℃～-150 ℃ freezing 2min ,-10 ℃ of hatching 5h change in the freeze dryer through liquid nitrogen, and lyophilizing 5.5h under 8mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains methanesulfonic acid tropisetron oral cavity disintegration tablet of the present invention.
Embodiment 11
Pharmaceutical formulation of the present invention is composed of the following components:
Ondansetron Hydrochloride 10.00g
Glycine 4.40g
Pullulan 8.40g
Acesulfame potassium 0.50g
Flavoring pineapple essence 0.50g
Purified water 176.20g
Process 1000 altogether
Concrete method for preparing is described below: with Ondansetron Hydrochloride, glycine, Pullulan, acesulfame potassium, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; , behind-100 ℃～-110 ℃ freezing 3min, change in the freeze dryer through liquid nitrogen, lyophilizing 3.5h under 0.1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Ondansetron Hydrochloride oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Ondansetron Hydrochloride 5.00g
Glycine 2.40g
Mannitol 2.00g
Dextran 8.40g
Flavoring pineapple essence 0.40g
Purified water 181.80g
Process 1000 altogether
Concrete method for preparing is described below: with Ondansetron Hydrochloride, glycine, mannitol, dextran, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-60 ℃～-80 ℃ freezing 4min ,-15 ℃ of hatching 4h change in the freeze dryer through liquid nitrogen, and lyophilizing 6h under 0.5mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Ondansetron Hydrochloride oral cavity disintegration tablet of the present invention.
Embodiment 13
Pharmaceutical formulation of the present invention is composed of the following components:
Ondansetron Hydrochloride 10.00g
Mannitol 20.00g
Pullulan 20.00g
Sucrose 2.00g
Strawberry essence 2.00g
Purified water 146.00g
Process 1000 altogether
Concrete method for preparing is described below: with Ondansetron Hydrochloride, mannitol, Pullulan, sucrose, strawberry essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make under the magnetic agitation becomes uniform solution; After solution carried out the ultrasonic wave concussion degassing, accurately inject mould; , behind-80 ℃～-100 ℃ freezing 3min, change in the freeze dryer through turbo-expander, lyophilizing 3h under 0.1mbar pressure ,-30 ℃ to 25 ℃ condition promptly obtains Ondansetron Hydrochloride oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Ondansetron Hydrochloride 10.00g
Glycine 8.40g
Pullulan 6.00g
Dextran 6.00g
Sucralose 0.20g
Purified water 169.40g
Process 1000 altogether
Concrete method for preparing is described below: with Ondansetron Hydrochloride, glycine, Pullulan, dextran, sucralose mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make under the mechanical agitation becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-130 ℃～-150 ℃ freezing 8min ,-5 ℃ of hatching 15h change in the freeze dryer through liquid nitrogen, and lyophilizing 5h under 2mbar pressure ,-30 ℃ to 20 ℃ condition promptly obtains hydrochloric acid Ge Laangdan oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Ondansetron Hydrochloride 5.00g
Glycine 0.80g
Mannitol 1.20g
Pullulan 3.00g
Purified water 190.00g
Process 1000 altogether
Concrete method for preparing is described below: with Ondansetron Hydrochloride, glycine, mannitol, Pullulan mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-40 ℃～-60 ℃ freezing 45min ,-60 ℃ of hatching 0.5h change in the freeze dryer through freon, and lyophilizing 4.5h under 0.4mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Ondansetron Hydrochloride oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Azasetron hydrochloride 11.04g
Glycine 4.40g
Pullulan 8.40g
Acesulfame potassium 0.50g
Flavoring pineapple essence 0.50g
Purified water 175.16g
Process 1000 altogether
Concrete method for preparing is described below: with Azasetron hydrochloride, glycine, Pullulan, acesulfame potassium, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-110 ℃～-120 ℃ freezing 4min ,-10 ℃ of hatching 4h change in the freeze dryer through liquid nitrogen, and lyophilizing 2.5h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Azasetron hydrochloride oral cavity disintegration tablet of the present invention.
Embodiment 17
Pharmaceutical formulation of the present invention is composed of the following components:
Azasetron hydrochloride 11.04g
Glycine 14.00g
Mannitol 6.00g
Dextran-20 .00g
Aspartame 2.00g
Herba Menthae essence 2.00g
Purified water 144.96g
Process 1000 altogether
Concrete method for preparing is described below: with Azasetron hydrochloride, glycine, mannitol, dextran, aspartame, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After the online degassing of solution, accurately inject mould; Behind-130 ℃～-150 ℃ freezing 10min ,-50 ℃ of hatching 1.5h change in the freeze dryer through turbo-expander, and lyophilizing 8.5h under 10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains Azasetron hydrochloride oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Azasetron hydrochloride 5.52g
Mannitol 2.00g
Dextran 3.00g
Purified water 189.48g
Process 1000 altogether
Concrete method for preparing is described below: with Azasetron hydrochloride, mannitol, dextran mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make under the mechanical agitation becomes uniform solution; After solution carried out the ultrasonic wave concussion degassing, accurately inject mould; , behind-60 ℃～-80 ℃ freezing 8min, change in the freeze dryer through freon, lyophilizing 5.5h under 5mbar pressure ,-20 ℃ to 25 ℃ condition promptly obtains Azasetron hydrochloride oral cavity disintegration tablet of the present invention.
Embodiment 19
Pharmaceutical formulation of the present invention is composed of the following components:
Azasetron hydrochloride 11.04g
Glycine 7.60g
Orange flavor 1.60g
Purified water 165.76g
Process 1000 altogether
Concrete method for preparing is described below: with Azasetron hydrochloride, glycine, dextran, orange flavor mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-100C～-110 ℃ freezing 5min ,-30 ℃ of hatching 3h change in the freeze dryer through liquid nitrogen, and lyophilizing 3h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Azasetron hydrochloride oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Azasetron hydrochloride 5.52g
Glycine 2.20g
Mannitol 2.20g
Pullulan 4.00g
Dextran 4.40g
Sucrose 1.70g
Purified water 179.98g
Process 1000 altogether
Concrete method for preparing is described below: with Azasetron hydrochloride, glycine, mannitol, Pullulan, dextran, sucrose mix homogeneously, to the purified water that wherein adds recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-120 ℃～-130 ℃ freezing 4min ,-20 ℃ of hatching 8h change in the freeze dryer through liquid nitrogen, and lyophilizing 4.5h under 0.1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Azasetron hydrochloride oral cavity disintegration tablet of the present invention.
For a better understanding of the present invention, use disintegration, the mouthfeel description of test advantage of the present invention of department's fine jade class drug port cavity disintegrating tablet of preparation below; Through volunteer's oral mucosa permeability test, bioequivalence test and clinical trial; The effect that department's fine jade class drug port cavity disintegrating tablet that the present invention prepares exists oral mucosa to absorb is described; Onset is rapid; And it is compared with ordinary tablet, and bioavailability improves, side effect obviously reduces, on curative effect, also increases.
1, disintegration:
Get the prepared department's fine jade class drug port cavity disintegrating tablet (T group) of Navoban (Soz) sheet (R1 group), methanesulfonic acid tropisetron sheet (R2 group), Ondansetron Hydrochloride sheet (R3 group), Azasetron hydrochloride sheet (R4 group) and embodiment 1-20 (T1-T20 representes the oral cavity disintegration tablet of embodiment 1-embodiment 20 preparations respectively).Measure according to following method: get 1 in each sample, put respectively in the test tube that is added with 2ml water (37 ℃ ± 1 ℃), pick up counting, also can add suitable quantity of water in case of necessity and get screen cloth express developed through No. 2 sieves up to the complete disintegrate of tablet with stopwatch.According to said method each sample is respectively checked 6.
Result's disintegration of each sample of being measured according to the method described above sees table 1.
Each sample disintegration time mensuration result of table 1
Can find out from the mensuration result of disintegration; The disintegration of department's fine jade class drug port cavity disintegrating tablet that the present invention is prepared will be much smaller than ordinary tablet; The prepared department's fine jade class drug port cavity disintegrating tablet of prompting the present invention can disintegrate rapidly in the oral cavity, and then reaches the action effect of quick acting.
2, mouthfeel experiment:
Get the prepared department's fine jade class drug port cavity disintegrating tablet of embodiment 1-20 respectively, after 90 healthy volunteer's mouths were tasted, each preparation good mouthfeel: place on the tongue back disintegrate rapid, sugariness, aromaticity were moderate, do not have bitter, no grittiness.
3, volunteer's oral mucosa permeability test
Experimental technique:
Get the prepared department's fine jade class drug port cavity disintegrating tablet (T group) of Navoban (Soz) sheet (R1 group), methanesulfonic acid tropisetron sheet (R2 group), Ondansetron Hydrochloride sheet (R3 group), Azasetron hydrochloride sheet (R4 group) and the present invention (T1-T20 representes the oral cavity disintegration tablet of embodiment 1-embodiment 20 preparations respectively); Be placed on respectively and contain 1min on the tongue; Medicine and gargle and wash the oral cavity spues after reaching the time; The mensuration medicament contg that spues, thus calculate the oral mucosa permeability.
According to the method described above embodiment 1-20 is made an experiment, the mucosa permeability result of each group is seen table 2.
Table 2 is respectively organized the mucosa permeability result
The continuous mucosa permeability result of respectively organizing of table 2
The continuous mucosa permeability result of respectively organizing of table 2
Can know from table 2; In human mouth; The mucosa permeability (about about 23%) of department's fine jade class drug port cavity disintegrating tablet that the present invention is prepared is apparently higher than ordinary tablet (being about 0.015%-0.017%); Thereby explain that the prepared department's fine jade class drug port cavity disintegrating tablet of the present invention can absorb by the oral mucosa, onset rapidly reduces first pass effect.
4, bioequivalence test
Experimental program:
24 beasle dogs are divided into 8 groups at random, 3 every group.Behind the fasting 12h, give the prepared department's fine jade class drug port cavity disintegrating tablet (T group) of Navoban (Soz) sheet (R1 group), methanesulfonic acid tropisetron sheet (R2 group), Ondansetron Hydrochloride sheet (R3 group), Azasetron hydrochloride sheet (R4 group) and the present invention (T1-T20 representes the oral cavity disintegration tablet of embodiment 1-embodiment 20 preparations respectively) respectively.
Dosage regimen and blood specimen collection process are respectively:
1) gives Navoban (Soz) sheet and the present invention prepared Tropisetron hydrochloride oral disintegration tablet 10mg; Respectively at before the administration and administration after 0.67,1,1.5,2,2.5,4,8,12 and 24h lower limb vein get blood 3ml; Anticoagulant heparin; Centrifugal separation plasma 1ml, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.
2) give methanesulfonic acid tropisetron sheet and the present invention prepared methanesulfonic acid tropisetron oral cavity disintegration tablet 12mg; Respectively at before the administration and administration after 0.67,1,1.5,2,2.5,4,8,12 and 24h lower limb vein get blood 3ml; Anticoagulant heparin; Centrifugal separation plasma 1ml, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.
3) give Ondansetron Hydrochloride sheet and the present invention prepared Ondansetron Hydrochloride oral cavity disintegration tablet 8mg; Respectively at before the administration and administration after 0.67,1,1.5,2,3,6,8,12 and 16h lower limb vein get blood 3ml; Anticoagulant heparin; Centrifugal separation plasma 1ml, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.
4) give Azasetron hydrochloride sheet and the present invention prepared Azasetron hydrochloride oral cavity disintegration tablet 10mg.Respectively at before the administration and after the administration 0.33,0.67,1,1.5,2,3,5,8 and 12h lower limb vein get blood 3ml, anticoagulant heparin, centrifugal separation plasma 1ml, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.
Get above-mentioned blood plasma after the Deproteinization pretreatment, adopt the blood drug level of each medicine of high effective liquid chromatography for measuring, use the DAS software processes, calculate main pharmacokinetic parameter t
Max, C
Max, AUC
(0-t)And AUC
(0-∞), according to each group AUC
0-tCalculate relative bioavailability.
Respectively department's fine jade class drug port cavity disintegrating tablet of embodiment 1-20 has been carried out the bioequivalence test according to the method described above, main pharmacokinetic parameter and relative bioavailability result see table 3, and blood drug level-time graph is seen Fig. 1～20.
Table 3 is respectively organized main pharmacokinetic parameter and relative bioavailability (n=3, Mean ± SD)
* relative bioavailability be the present invention prepared respectively organize the result that oral cavity disintegration tablet and its conventional tablet that contains the same medicine active component are compared and calculated
Bioequivalence result of the test in the animal body, department's fine jade class drug port cavity disintegrating tablet of the present invention's preparation is compared with ordinary tablet, Tmax in advance, Cmax and AUC
0-tAll enlarge markedly, bioavailability improves.
5, clinical trial
Experimental program:
Choose and be diagnosed as malignant tumor, need the row chemotherapy; And 24h does not vomit and did not take Bendectin before the chemotherapy; Patient's 320 examples of vomiting such as no intestinal obstruction property disease.Be divided into 8 groups according to the randomized, double-blind principle; Every group 40 people; In every day department's fine jade class drug port cavity disintegrating tablet (T group) that preceding 1 hour of chemotherapy takes Navoban (Soz) sheet 5mg (R1 group), methanesulfonic acid tropisetron sheet 6mg (R2 group), Ondansetron Hydrochloride sheet 8mg (R3 group), Azasetron hydrochloride sheet 10mg (R4 group) or the present invention for respectively 8 groups of patients to prepare (T1-T20 representes the oral cavity disintegration tablet that embodiment 1-embodiment 20 prepares respectively; Each dosage of organizing oral cavity disintegration tablet contains the ordinary tablet of same medicine active component with it consistent); Second took inferior to taking medicine for the first time in back 12 hours, was limited to 1～5d during treatment.Observe feel sick after the medication, a situation arises and make comparisons for vomiting and side reaction.
According to the WHO Bendectin evaluation grade scale nauseating, the vomiting control degree is divided into: 1) control fully: nothing is felt sick, is vomitted or sense is nauseating slightly; 2) basic controlling: 1～2 time/d of vomiting, or do not have vomiting, but in having, severe feels sick; 3) control is arranged slightly: 3～5 times/d of vomiting; 4) invalid: vomit 5 times/more than the d.Total effective rate (%)=(controlling routine number+basic controlling example number fully)/this organizes total routine number * 100%.
Respectively department's fine jade class drug port cavity disintegrating tablet of embodiment 1-20 has been carried out clinical trial according to the method described above, the result sees table 4-table 5.
Table 4 is respectively organized the control effect (example) that patient 1～5d feels sick, vomits
Table 5 is respectively organized adverse reactions of patients relatively (%)
Can find out that from the result of clinical trial department's fine jade class drug port cavity disintegrating tablet of the present invention's preparation is compared with ordinary tablet, side effect obviously reduces, and curative effect increases.Thereby more favourable proof several big advantage and the characteristics of department of the present invention fine jade class drug port cavity disintegrating tablet: 1) can absorb by the oral mucosa; 2) reduced the gastrointestinal stimulation; 3) less liver metabolism.
Claims (31)
1. take charge of fine jade class drug port cavity disintegrating tablet for one kind, form by following components in weight percentage:
Principal agent 5-65%
Skeleton proppant 10-60%
Binding agent 15-70%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
2. take charge of fine jade class drug port cavity disintegrating tablet for one kind, form by following components in weight percentage:
Principal agent 11.36-52.47%
Skeleton proppant 17.71%-40.29%
Binding agent 28.52-50.91%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
3. according to claim 1 or claim 2 department's fine jade class drug port cavity disintegrating tablet is characterized in that described skeleton proppant selects one or more in the following raw material for use: glycine, serine, arginine, mannitol, sorbitol, maltose alcohol, xylitol, lactose, erythritol, hydroxyl isomaltulose, xylose, cottonseed sugar, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, sodium phosphate, sodium chloride, aluminium silicate.
4. according to claim 1 or claim 2 department's fine jade class drug port cavity disintegrating tablet is characterized in that described binding agent selects one or more in the following raw material for use: Pullulan, dextran, sodium alginate, hyaluronic acid, modified starch, polyvinyl alcohol, chitosan.
5. take charge of fine jade class drug port cavity disintegrating tablet for one kind, form by following components in weight percentage:
Principal agent 5-65%
Glycine or mannitol or its mixture 10-60%
Pullulan or dextran or its mixture 15-70%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
6. take charge of fine jade class drug port cavity disintegrating tablet for one kind, form by following components in weight percentage:
Principal agent 11.36-52.47%
Glycine or mannitol or its mixture 17.71%-40.29%
Pullulan or dextran or its mixture 28.52-50.91%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
7. take charge of fine jade class drug port cavity disintegrating tablet for one kind, its component by following weight percentage ratio is processed:
Principal agent 0.62-6.84%
Glycine or mannitol or its mixture 0.56-14.89%
Pullulan or dextran or its mixture 0.79-13.75%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 62.52-98.03%
Wherein each weight percentages of components sum is 100%.
8. take charge of fine jade class drug port cavity disintegrating tablet for one kind, its component by following weight percentage ratio is processed:
Principal agent 1.41-5.52%
Glycine or mannitol or its mixture 1-10.00%
Pullulan or dextran or its mixture 1.5-10.00%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 72.48-96.09%
Wherein each weight percentages of components sum is 100%.
9. like claim 1-2, each described department fine jade class drug port cavity disintegrating tablet among the 5-8 is characterized in that described sweeting agent is one or more in the sweeting agent of natural or synthetic such as acesulfame potassium, sucralose, aspartame, sucrose.
10. like claim 1-2, each described department fine jade class drug port cavity disintegrating tablet among the 5-8 is characterized in that described aromatic is one or more in the aromatic of natural or synthetic such as Herba Menthae, Fructus Citri sinensis, Fructus Ananadis comosi, Fructus Fragariae Ananssae.
11. department's fine jade class drug port cavity disintegrating tablet, it is processed by following components by part by weight:
Principal agent 124-1368 part
Glycine or mannitol or its mixture 112-2978 part
Pullulan or dextran or its mixture 158-2750 part
Sweeting agent 0-200 part
Aromatic 0-200 part
Purified water 12504-19606 part
12. department's fine jade class drug port cavity disintegrating tablet, it is processed by following components by part by weight:
Principal agent 282-1104 part
Glycine or mannitol or its mixture 200-2000 part
Pullulan or dextran or its mixture 300-2000 part
Sweeting agent 0-200 part
Aromatic 0-200 part
Purified water 14496-19218 part
13. department's fine jade class drug port cavity disintegrating tablet, it is processed by following components by part by weight:
Principal agent 282-1104 part
Glycine or mannitol or its mixture 400-800 part
Pullulan or dextran or its mixture 600-1000 part
Sweeting agent 0-170 part
Aromatic 0-100 part
Purified water 17500-18500 part
14. the method for preparing like the described department of each claim fine jade class drug port cavity disintegrating tablet among the claim 1-2 is characterized in that this method comprises the steps:
(a) preparation of substrate liquid: principal agent, skeleton proppant, binding agent and other adjuvant are dissolved in the purified water, form substrate liquid;
(b) degassing: the substrate liquid that above-mentioned (a) step is prepared outgases;
(c) injection molding: the substrate liquid that step (b) is handled through the degassing injects mould;
(d) pre-freeze: the mould that is marked with substrate liquid in the step (c) is carried out pre-freeze;
(e) lyophilization: the preparation lyophilization with (d) obtains, remove and desolvate, promptly get.
15. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14, the compound method that it is characterized in that said step (a) mesostroma liquid are magnetic agitation, mechanical agitation or the method preparation of adopting mulser.
16. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14, the compound method that it is characterized in that said step (a) mesostroma liquid is for adopting the method preparation of mulser.
17. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14 is characterized in that the method for the degassing in the said step (b) is the direct degassing method of vacuum pump, centrifugal degassing method, ultrasonic wave concussion degassing method, sweeping degas by inert gas method or online degassing method.
18. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14, the pre-freeze method that it is characterized in that being adopted in the said step (d) is for adopting turbine expander refrigeration, freon refrigeration, programmed cooling refrigeration, liquid nitrogen freezing.
19. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14, the pre-freeze method that it is characterized in that being adopted in the said step (d) is for adopting the method for liquid nitrogen freezing.
20. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14 is characterized in that the pre-freeze temperature is-40 ℃～-170 ℃ in the said step (d), the pre-freeze time is 1～60min.
21. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14 is characterized in that the pre-freeze temperature is-60 ℃～-150 ℃ in the said step (d), the pre-freeze time is 2～30min.
22. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14 is characterized in that the pre-freeze temperature is-100 ℃～-130 ℃ in the said step (d), the pre-freeze time is 3～6min.
23. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14; It is characterized in that to add the step that ice crystal is hatched after (d) step in this method; After the mould that is about to be marked with substrate liquid carries out pre-freeze; Put into-5 ℃～-60 ℃ low temperature environment, the time is 0.5～15h.
24. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14; It is characterized in that to add the step that ice crystal is hatched after (d) step in this method; After the mould that is about to be marked with substrate liquid carries out pre-freeze; Put into-10 ℃～-20 ℃ low temperature environment, the time is 4～12h.
25. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14 is characterized in that the lyophilization temperature in the said step (e) is-30 ℃～30 ℃, sublimation drying is 1～10h, and vacuum is 0.01mbar～10mbar.
26. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14 is characterized in that the lyophilization temperature in the said step (e) is-20 ℃～20 ℃, sublimation drying is 2～8h, and vacuum is 0.01mbar～1mbar.
27. the method for preparing of the department's fine jade class drug port cavity disintegrating tablet described in claim 14 is characterized in that the lyophilization temperature in the said step (e) is-20 ℃～20 ℃, sublimation drying is 3～6h, and vacuum is 0.01mbar～0.1mbar.
28. the method for preparing like the described department of each claim fine jade class drug port cavity disintegrating tablet among the claim 5-6 is characterized in that adopting following steps to make:
(a) principal agent, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent or aromatic or sweeting agent are mixed with aromatic, make abundant dissolving, form uniform solution to wherein adding an amount of purified water;
(b) solution is outgased;
(c) solution after will outgasing injects mould;
(d) be pre-freeze 1～60min under-40 ℃～-170 ℃ the condition in temperature;
(e) then mould is changed in the freeze dryer, lyophilization 1～10h under 0.01mbar～10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains department of the present invention fine jade class drug port cavity disintegrating tablet,
Also can add the step that ice crystal is hatched before changing freeze dryer after the pre-freeze step in the said method, soon the mould that is marked with solution after the pre-freeze is put into-5 ℃～-60 ℃ low temperature environment, and the time is 0.5～15h.
29. the method for preparing like the described department of each claim fine jade class drug port cavity disintegrating tablet among claim 7-8, the 11-13 is characterized in that adopting following steps to make:
Principal agent, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent, aromatic are dissolved in the purified water, and mixing to make becomes uniform solution; After solution outgased, accurately inject mould; Behind pre-freeze 1～60min under-40 ℃～-170 ℃ the condition, change in the freeze dryer, lyophilization 1～10h under 0.01mbar～10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains department of the present invention fine jade class drug port cavity disintegrating tablet; Also can add the step that ice crystal is hatched before changing freeze dryer after the pre-freeze step in the said method, soon the mould that is marked with solution after the pre-freeze is put into-5 ℃～-60 ℃ low temperature environment, and the time is 0.5～15h.
30. the method for preparing like the described department of each claim fine jade class drug port cavity disintegrating tablet among claim 7-8, the 11-13 is characterized in that adopting following steps to make:
Principal agent, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent, aromatic are dissolved in the purified water, and mixing to make becomes uniform solution; After solution outgased, accurately inject mould; Behind pre-freeze 2～30min under-60 ℃～-150 ℃ the condition, change in the freeze dryer, lyophilization 2～8h under 0.01mbar～1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains department of the present invention fine jade class drug port cavity disintegrating tablet; Also can add the step that ice crystal is hatched before changing freeze dryer after the pre-freeze step in the said method, soon the mould that is marked with solution after the pre-freeze is put into-10 ℃～-20 ℃ low temperature environment, and the time is 4～12h.
31. like the described department of each claim fine jade class medicine among the claim 1-30, comprise 5-hydroxy tryptamine 3 receptor antagonist pharmaceuticals such as tropisetron, ondansetron, azasetron with and pharmaceutically useful salt, ester, optical isomer.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010105236135A CN102451166A (en) | 2010-10-22 | 2010-10-22 | Setron medicament oral cavity disintegrating tablet and preparation method thereof |
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|---|---|
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689649A (en) * | 2004-04-30 | 2005-11-02 | 量子高科（北京）研究院有限公司 | Oral cavity quick dissolving preparation and production method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689649A (en) * | 2004-04-30 | 2005-11-02 | 量子高科（北京）研究院有限公司 | Oral cavity quick dissolving preparation and production method thereof |
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