CN102451165A - Rotundine orally disintegrating tablets and preparation method thereof - Google Patents
Rotundine orally disintegrating tablets and preparation method thereof Download PDFInfo
- Publication number
- CN102451165A CN102451165A CN2010105235838A CN201010523583A CN102451165A CN 102451165 A CN102451165 A CN 102451165A CN 2010105235838 A CN2010105235838 A CN 2010105235838A CN 201010523583 A CN201010523583 A CN 201010523583A CN 102451165 A CN102451165 A CN 102451165A
- Authority
- CN
- China
- Prior art keywords
- rotundine
- oral cavity
- disintegration tablet
- cavity disintegration
- freeze
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
The invention relates to rotundine orally disintegrating tablets and a prescription and process for preparing the rotundine orally disintegrating tablets by adopting a freeze drying method. The rotundine orally disintegrating tablets are prepared from rotundine as a main medicine and pharmaceutic adjuvants, can be taken without water, are capable of rapidly disintegrating after entering the mouth, are suitable for taking by patients suffered from dysphagia, such as the old, children and the like, are simultaneously suitable for medications in the travel journey under the condition of being not easy to obtain a water source, has the advantages of convenience for taking, high absorption speed, small fast pass effect, little irritation to digestive tract mucosa, wide market application prospect and the like, and are capable of remarkably reducing side effects of rotundine. In addition, the invention also relates to a preparation method of the rotundine orally disintegrating tablets.
Description
Technical field:
The present invention relates to a kind of rotundine oral cavity disintegration tablet and preparation method thereof, particularly a kind of rotundine oral cavity disintegration tablet that adopts the freeze-drying preparation.
Background technology:
Rotundine (Rotundine) chemistry is called 2,3,9,10-tetramethoxy-5,8,13,13a-tetrahydrochysene-6H-dibenzo [a, g] quinolizine.Have analgesia, calmness, hypnosis and stable effect.The general antipyretic analgesic of analgesic activity is strong, and taking medicine analgesic activity occurred in back 10 minutes, and can keep 2-5 hour; The dull pain that gastrointestinal system is caused has good analgesic effect; Also effective for menstrual pain; More suitable for insomnia, the insomnia that especially causes because of pain, the back of waking up is lost effect without male offspring.A kind of non-narcotic analgesics for wide clinical application.
The dosage form of at present domestic granted rotundine has conventional tablet, injection, infusion solution and freeze-dried powder etc.When the conventional tablet patient takes, must use water delivery service, not only take inconvenience, be difficult for swallowing, and absorb slower; Though and injection can be brought into play drug effect rapidly, administration is inconvenient, and life-time service can cause suffering to the patient.And the rotundine oral cavity disintegration tablet need not used water delivery service, and saliva can make its disintegrate or dissolving, is particularly useful for the patient of old man, children's's dysphagia and the inconvenient person that fetches water takes medicine, and is adapted at simultaneously in the tourism way, is difficult for obtaining the medication under the condition at water source.Because oral cavity disintegration tablet is rapidly disintegrate in mouth, except that major part gets into the gastrointestinal tract with swallowing act, also have the considerable part trans-oral to absorb, thereby rapid-action, first pass effect is little.In addition, arrive the gastrointestinal tract rapid disintegrate of ability before and be dispersed into trickle granule at medicine, cause medicine to distribute in the gastrointestinal tract large tracts of land, absorption point increases, thereby has reduced rotundine to the gastrointestinal local excitation.It is thus clear that the rotundine oral cavity disintegration tablet has more advantage than other dosage forms of rotundine.
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.Domestic also have the scholar to adopt this dosage form of freeze-drying preparation, but most shortcoming that has all followed direct compression process has added a large amount of disintegrating agents and other excipient, the oral cavity disintegration tablet poor-performing that makes preparation.When the freeze-drying that the present invention adopts prepares; Need not add disintegrating agent; The adjuvant that is adopted all is water miscible; And consumption is less, makes preparation disintegrate rapidly in the oral cavity, no grittiness, and 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 rotundine oral cavity disintegration 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 the rotundine oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and the bioavailability of the rotundine oral cavity disintegration 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 the rotundine oral cavity disintegration 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 the rotundine oral cavity disintegration 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 the rotundine oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and the bioavailability of the rotundine oral cavity disintegration tablet of the present invention's preparation improves, side effect obviously reduces, on curative effect, also increases.
The rotundine oral cavity disintegration tablet that the present invention relates to comprises rotundine, skeleton proppant, binding agent, suspending agent and other adjuvant.Wherein other adjuvant is sweeting agent or aromatic or comprises sweeting agent and aromatic simultaneously.
The percentage by weight of each component of rotundine oral cavity disintegration tablet of the present invention is following:
Weight percentages of components
Rotundine 5-90%
Skeleton proppant 2-60%
Binding agent 3-70%
Suspending agent 0.10-8%
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
Rotundine 11.60-78.23%
Skeleton proppant 4.85-40.74%
Binding agent 7.82-46.38%
Suspending agent 0.27-4.10%
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; The adjuvant that plays the suspending effect that those skilled in the art were known when described suspending agent can be the preparation oral cavity disintegration tablet; Preferably from xanthan gum, Konjac glucomannan, natural origin glue, synthetic macromolecular compound, polypeptide, polysaccharide or their mixture; Wherein said natural origin glue is selected from alginate jelly, arabic gum, guar gum, agar, hydroxy methocel, carrageenin or pectin; Described synthetic macromolecular compound is a polyvinylpyrrolidone; Particularly preferably be xanthan gum, Konjac glucomannan, alginate jelly, polyvinylpyrrolidone or their combination, most preferably xanthan gum or Konjac glucomannan 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 rotundine oral cavity disintegration tablet of the present invention 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 that freeze-drying prepares the rotundine oral cavity disintegration tablet through a large amount of experimentatioies; Wherein in the method for preparing of rotundine oral cavity disintegration 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; The lyophilization 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 rotundine oral cavity disintegration tablet of the present invention comprises the steps:
(a) preparation of substrate liquid: rotundine, skeleton proppant, binding agent and other adjuvant are joined in the good suspending agent aqueous solution of abundant dissolving, 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.
The compound method of wherein said step (a) mesostroma liquid is magnetic agitation, mechanical agitation or the method preparation of adopting mulser; The method of the degassing 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 in the said step (b); The pre-freeze method that is adopted in the said step (d) is for adopting turbine expander refrigeration, freon refrigeration, programmed cooling refrigeration, liquid nitrogen freezing; The pre-freeze temperature is-40 ℃～-170 ℃ in the said step (d), and the pre-freeze time is 1～60min; Or the pre-freeze temperature is-60 ℃～-150 ℃ in the said step (d), and the pre-freeze time is 2～30min; Or the pre-freeze temperature is-100 ℃～-130 ℃ in the said step (d), and the pre-freeze time is 3～6min; In addition; The step that after (d) step, can also add ice crystal hatching after the mould that is about to be marked with substrate liquid carries out pre-freeze, is put into-5 ℃～-60 ℃ low temperature environment; Time is 0.5～15h or puts into-10 ℃～-20 ℃ low temperature environment, and the time is 4～12h; Lyophilization temperature in the said step (e) is-30 ℃～30 ℃, and sublimation drying is 1～10h, and vacuum is 0.01mbar～10mbar; Or the lyophilization temperature in the said step (e) is-20 ℃～20 ℃, and sublimation drying is 2～8h, and vacuum is 0.01mbar～1mbar; Or the lyophilization temperature in the said step (e) is-20 ℃～20 ℃, and sublimation drying is 3～6h, and vacuum is 0.01mbar～0.1mbar.
The method for preparing of the preferred described rotundine oral cavity disintegration tablet of the present invention is:
(a) with 5-90% rotundine, 2-60% skeleton proppant, 3-70% binding agent and sweeting agent or aromatic or sweeting agent and aromatic, join in the good 0.10-8% suspending agent aqueous solution of abundant dissolving, form uniform solution;
(b) solution is outgased;
(c) solution after will outgasing injects mould;
(d) be precooling 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 rotundine oral cavity disintegration tablet of the present invention.
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 percentage by weight of each component of rotundine oral cavity disintegration tablet of the present invention is following:
Rotundine 5-90%
Glycine or mannitol or its mixture 2-60%
Pullulan or dextran or its mixture 3-70%
Xanthan gum or Konjac glucomannan or its mixture 0.10-8%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
Preferred rotundine oral cavity disintegration tablet of the present invention, form by following components in weight percentage:
Rotundine 11.60-78.23%
Glycine or mannitol or its mix agent 4.85-40.74%
Pullulan or dextran or its mixture 7.82-46.38%
Xanthan gum or Konjac glucomannan or its mixture 0.27-4.10%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
Preparation of the present invention is especially preferably filled a prescription and is made up of following components in weight percentage:
Rotundine 76.92%
Glycine or mannitol or its mixture 10.26%
Pullulan or dextran or its mixture 11.28%
Xanthan gum or Konjac glucomannan or its mixture 0.51%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
The method for preparing of rotundine oral cavity disintegration tablet of the present invention is:
(a) with rotundine, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent or aromatic or sweeting agent and aromatic; Join in the aqueous solution of the good xanthan gum of abundant dissolving or Konjac glucomannan or its mixture, form uniform solution;
(b) degassing: the solution of (a) step is outgased;
(c) injection molding: the solution after the degassing of (b) step is injected mould;
(d) pre-freeze: be pre-freeze 1～60min under-40 ℃～-170 ℃ the condition with the mould that is marked with solution in (c) step 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 rotundine oral cavity disintegration tablet of the present invention.
Also can add the step of ice crystal hatching in the said method after (d) step before (e) step, 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 method for preparing of the preferred rotundine oral cavity disintegration tablet of the present invention is:
(a) with 76.92% rotundine, 10.26% glycine or mannitol or its mixture, 11.28% Pullulan or dextran or its mixture and sweeting agent or aromatic or sweeting agent and aromatic; Join in the aqueous solution of the good xanthan gum of abundant dissolving or Konjac glucomannan or its mixture, form uniform solution;
(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 rotundine oral cavity disintegration tablet of the present invention.
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 preferred rotundine oral cavity disintegration tablet of the present invention is processed by the component of following weight percentage ratio:
Rotundine 1.08-17.26%
Glycine or mannitol or its mixture 0.41-14.73%
Pullulan or dextran or its mixture 0.58-15.09%
Xanthan gum or Konjac glucomannan or its mixture 0.01-1.56%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 49.36-97.92%
Wherein each weight percentages of components sum is 100%.
The preferred rotundine oral cavity disintegration tablet of the present invention is processed by the component of following weight percentage ratio:
Rotundine 2.5-15.00%
Glycine or mannitol or its mixture 1-10.00%
Pullulan or dextran or its mixture 1.5-10.00%
Xanthan gum or Konjac glucomannan or its mixture 0.03-0.80%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 62.20-94.97%
Wherein each weight percentages of components sum is 100%.
The preferred rotundine oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Rotundine 216-3452 part
Glycine or mannitol or its mixture 82-2946 part
Pullulan or dextran or its mixture 116-3018 part
Xanthan gum or Konjac glucomannan or its mixture 2-312 part
Sweeting agent 0-200 part
Aromatic 0-200 part
Purified water 9872-19584 part.
The preferred rotundine oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Rotundine 500-3000 part
Glycine or mannitol or its mixture 200-2000 part
Pullulan or dextran or its mixture 300-2000 part
Xanthan gum or Konjac glucomannan or its mixture 6-160 part
Sweeting agent 0-200 part
Aromatic 0-200 part
Purified water 12440-18994 part.
The preferred rotundine oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Rotundine 500-3000 part
Glycine or mannitol or its mixture 300-600 part
Pullulan or dextran or its mixture 300-650 part
Xanthan gum or Konjac glucomannan or its mixture 10-120 part
Sweeting agent 0-100 part
Aromatic 0-100 part
Purified water 15500-18500 part.
The preferred rotundine oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
3000 parts of rotundine
400 parts in glycine or mannitol or its mixture
440 parts in Pullulan or dextran or its mixture
20 parts in xanthan gum or Konjac glucomannan or its mixture
20 parts of sweeting agents
20 parts of aromatic
16100 parts of purified water.
Its preparation method is: with rotundine, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent, aromatic; Join in the solution of the good xanthan gum of dissolving or Konjac glucomannan or its mixture, 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 rotundine oral cavity disintegration tablet of the present invention.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: with rotundine, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent, aromatic; Join in the solution of the good xanthan gum of dissolving or Konjac glucomannan or its mixture, mulser mixes 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 rotundine oral cavity disintegration tablet of the present invention; 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.
The most preferred rotundine oral cavity disintegration tablet of the present invention is processed by the component of following weight:
Rotundine 30.00g
Glycine 4.00g
Pullulan 4.40g
Xanthan gum 0.20g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 161.00g
Process 1000 altogether.
Its preparation method is: with rotundine, glycine, Pullulan, sucralose, Herba Menthae essence, join in the good xanthan gum solution of dissolving, 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 rotundine oral cavity disintegration tablet of the present invention.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.
Rotundine oral cavity disintegration tablet provided by the invention; Supplementary product consumption is less; And, make preparation in the oral cavity after the disintegrate because not use disintegrating agent, the adjuvant that is adopted is that the principle of water miscible disintegrate is the many porosities through staying after the solvent seasoning in the preparation all; 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.
Rotundine oral cavity disintegration tablet of the present invention has following advantage:
1, good mouthfeel, taking convenience: rotundine oral cavity disintegration tablet materials of the present invention 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; Be adapted in the tourism way medication under the condition at difficult acquisition water source simultaneously.
2, absorb soon, avoid the first pass effect of liver: the disintegrate rapidly in mouth of the rotundine oral cavity disintegration 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 the rotundine oral cavity disintegration 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 rotundine oral cavity disintegration tablet through the wonderful discovery the present invention preparation of clinical trial is compared with the rotundine oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and side effect significantly reduces, and curative effect increases to some extent.
Rotundine oral cavity disintegration tablet mouthfeel provided by the invention 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, R2 and the T1
Fig. 2 gives the blood drug level-time graph behind R1, R2 and the T2
Fig. 3 gives the blood drug level-time graph behind R1, R2 and the T3
Fig. 4 gives the blood drug level-time graph behind R1, R2 and the T4
Fig. 5 gives the blood drug level-time graph behind R1, R2 and the T5
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Fig. 7 gives the blood drug level-time graph behind R1, R2 and the T7
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Figure 10 gives the blood drug level-time graph behind R1, R2 and the T10
Figure 11 gives the blood drug level-time graph behind R1, R2 and the T11
Figure 12 gives the blood drug level-time graph behind R1, R2 and the T12
Figure 13 gives the blood drug level-time graph behind R1, R2 and the T13
Figure 14 gives the blood drug level-time graph behind R1, R2 and the T14
Figure 15 gives the blood drug level-time graph behind R1, R2 and the T15
Figure 16 gives the blood drug level-time graph behind R1, R2 and the T16
Figure 17 gives the blood drug level-time graph behind R1, R2 and the T17
Figure 18 gives the blood drug level-time graph behind R1, R2 and the T18
Figure 19 gives the blood drug level-time graph behind R1, R2 and the T19
Figure 20 gives the blood drug level-time graph behind R1, R2 and the T20
Figure 21 gives the blood drug level-time graph behind R1, R2 and the T21
Figure 22 gives the blood drug level-time graph behind R1, R2 and the T22
Figure 23 gives the blood drug level-time graph behind R1, R2 and the T23
Figure 24 gives the blood drug level-time graph behind R1, R2 and the T24
Figure 25 gives the blood drug level-time graph behind R1, R2 and the T25
Figure 26 gives the blood drug level-time graph behind R1, R2 and the T26
Figure 27 gives the blood drug level-time graph behind R1, R2 and the T27
Figure 28 gives the blood drug level-time graph behind R1, R2 and the T28
Figure 29 gives the blood drug level-time graph behind R1, R2 and the T29
Figure 30 gives the blood drug level-time graph behind R1, R2 and the T30
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:
Rotundine 30.00g
Glycine 4.00g
Pullulan 4.40g
Xanthan gum 0.20g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 161.00g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, Pullulan, sucralose, Herba Menthae essence, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-120 ℃～-130 ℃ pre-freeze 3min ,-10 ℃ of hatching 12h change in the freeze dryer through liquid nitrogen, and lyophilization 6h under 0.1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Mannitol 4.00g
Pullulan 4.40g
Xanthan gum 0.20g
Sucralose 0.20g
Herba Menthae essence 0.25g
Purified water 160.95g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, Pullulan, sucralose, Herba Menthae essence, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; , behind-110 ℃～-120 ℃ pre-freeze 4min, change in the freeze dryer through liquid nitrogen, lyophilization 4.5h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 3
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 2.20g
Mannitol 1.80g
Pullulan 4.40g
Konjac glucomannan 1.20g
Sucralose 0.15g
Herba Menthae essence 0.20g
Purified water 160.05g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, Pullulan, sucralose, Herba Menthae essence, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; , behind-100 ℃～-110 ℃ pre-freeze 6min, change in the freeze dryer through liquid nitrogen, lyophilization 3h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 6.00g
Dextran 5.60g
Xanthan gum 0.24g
Herba Menthae essence 1.00g
Purified water 157.16g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, dextran, Herba Menthae essence, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mixing to make under the mechanical agitation becomes uniform solution; After the online degassing of solution, accurately inject mould; , behind-130 ℃～-150 ℃ pre-freeze 2min, change in the freeze dryer through freon, lyophilization 8h under 1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 5
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 6.00g
Mannitol 6.00g
Konjac glucomannan 0.70g
Sucralose 0.30g
Purified water 143.00g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, dextran, sucralose, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mixing to make under the mechanical agitation becomes uniform solution; After the online degassing of solution, accurately inject mould; Behind-80 ℃～-100 ℃ pre-freeze 15min ,-30 ℃ of hatching 3h change in the freeze dryer through turbo-expander, and lyophilization 6.5h under 0.5mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Mannitol 8.40g
Dextran 8.00g
Xanthan gum 0.06g
Konjac glucomannan 0.50g
Sucralose 0.15g
Herba Menthae essence 0.20g
Purified water 152.69g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, dextran, sucralose, Herba Menthae essence, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mixing to make under the magnetic agitation becomes uniform solution; After solution carried out the centrifugal degassing, accurately inject mould; Behind-60 ℃～-80 ℃ pre-freeze 30min ,-20 ℃ of hatching 4h change in the freeze dryer through turbo-expander, and lyophilization 2h under 0.2mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 7
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 20.00g
Pullulan 20.00g
Xanthan gum 0.10g
Konjac glucomannan 1.50g
Sucralose 2.00g
Herba Menthae essence 2.00g
Purified water 124.40g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, Pullulan, sucralose, Herba Menthae essence, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; Behind-60 ℃～-80 ℃ pre-freeze 10min ,-40 ℃ of hatching 2h change in the freeze dryer through liquid nitrogen, and lyophilization 1h under 0.01mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 1.80g
Mannitol 1.80g
Pullulan 1.80g
Konjac glucomannan 1.00g
Sucralose 0.25g
Strawberry essence 0.50g
Purified water 161.65g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, Pullulan, dextran, sucralose, strawberry essence, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, making under the magnetic agitation becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-100 ℃～-110 ℃ pre-freeze 5min, change in the freeze dryer through turbo-expander, lyophilization 9h under 5mbar pressure ,-25 ℃ to 25 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 9
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Mannitol 5.00g
Pullulan 2.80g
Dextran 2.40g
Xanthan gum 0.04g
Konjac glucomannan 0.60g
Aspartame 1.60g
Flavoring pineapple essence 0.30g
Purified water 157.26g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, Pullulan, dextran, aspartame, flavoring pineapple essence, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out the centrifugal degassing, accurately inject mould; , behind-40 ℃～-60 ℃ pre-freeze 60min, change in the freeze dryer through freon, lyophilization 5h under 0.2mbar pressure ,-30 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 2.00g
Pullulan 7.00g
Konjac glucomannan 1.20g
Sucrose 0.80g
Herba Menthae essence 0.20g
Purified water 158.80g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, Pullulan, sucrose, Herba Menthae essence, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of 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-150 ℃～-170 ℃ pre-freeze 1min ,-5 ℃ of hatching 15h change in the freeze dryer through liquid nitrogen, and lyophilization 10h under 10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 11
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Mannitol 4.40g
Dextran 4.60g
Konjac glucomannan 1.40g
Sucralose 0.15g
Herba Menthae essence 0.20g
Purified water 159.25g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, dextran, sucralose, Herba Menthae essence, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; Behind-110 ℃～-120 ℃ pre-freeze 3min ,-15 ℃ of hatching 8h change in the freeze dryer through liquid nitrogen, and lyophilization 4h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 15.00g
Glycine 4.00g
Dextran 4.00g
Xanthan gum 0.16g
Konjac glucomannan 0.16g
Sucralose 0.30g
Purified water 176.38g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, dextran, sucralose, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mixing to make under the mechanical agitation becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-60 ℃～-80 ℃ pre-freeze 4min, change in the freeze dryer through freon, lyophilization 3h under 1mbar pressure ,-30 ℃ to 25 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 13
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 2.60g
Mannitol 3.00g
Pullulan 6.00g
Xanthan gum 0.20g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 157.80g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, Pullulan, sucralose, Herba Menthae essence, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; Behind-80 ℃～-100 ℃ pre-freeze 3min ,-60 ℃ of hatching 0.5h change in the freeze dryer through liquid nitrogen, and lyophilization 3.5h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 15.00g
Mannitol 9.60g
Pullulan 10.00g
Xanthan gum 0.12g
Konjac glucomannan 0.15g
Acesulfame potassium 1.00g
Orange flavor 1.00g
Purified water 163.13g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, Pullulan, acesulfame potassium, orange flavor, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of 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-130 ℃～-150 ℃ pre-freeze 8min ,-50 ℃ of hatching 15h change in the freeze dryer through liquid nitrogen, and lyophilization 6h under 0.1mbar pressure ,-25 ℃ to 30 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 15
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Mannitol 7.00g
Dextran 6.40g
Xanthan gum 0.15g
Sucralose 0.15g
Herba Menthae essence 0.20g
Purified water 156.10g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, dextran, sucralose, Herba Menthae essence, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-120 ℃～-130 ℃ pre-freeze 5min, change in the freeze dryer through liquid nitrogen, lyophilization 5.5h under 0.5mbar pressure ,-20 ℃ to 25 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 16
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 4.40g
Pullulan 2.00g
Dextran 2.00g
Xanthan gum 0.20g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 161.00g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, Pullulan, sucralose, Herba Menthae essence, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; Behind-100 ℃～-110 ℃ pre-freeze 3min ,-20 ℃ of hatching 6h change in the freeze dryer through liquid nitrogen, and lyophilization 4h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 17
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 5.00g
Glycine 0.80g
Mannitol 1.20g
Dextran 3.00g
Xanthan gum 0.06g
Purified water 189.94g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, dextran, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-40 ℃～-60 ℃ pre-freeze 45min, change in the freeze dryer through liquid nitrogen, lyophilization 8.5h under 8mbar pressure ,-25 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 18
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Mannitol 3.00g
Pullulan 3.60g
Konjac glucomannan 1.60g
Herba Menthae essence 0.80g
Purified water 161.00g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, Pullulan, Herba Menthae essence, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-80 ℃～-100 ℃ pre-freeze 20min, change in the freeze dryer through liquid nitrogen, lyophilization 4h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 19
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 10.00g
Glycine 16.00g
Pullulan 8.00g
Dextran 5.60g
Xanthan gum 0.07g
Konjac glucomannan 0.13g
Sucrose 0.40g
Flavoring pineapple essence 0.20g
Purified water 159.60g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, Pullulan, dextran, sucrose, flavoring pineapple essence, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out the centrifugal degassing, accurately inject mould; Behind-110 ℃～-120 ℃ pre-freeze 4min ,-40 ℃ of hatching 10h change in the freeze dryer through liquid nitrogen, and lyophilization 6h under 0.1mbar pressure ,-20 ℃ to 30 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 20
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 5.00g
Glycine 5.60g
Mannitol 4.80g
Dextran 9.60g
Xanthan gum 0.04g
Konjac glucomannan 0.14g
Sucralose 0.15g
Herba Menthae essence 0.20g
Purified water 174.47g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, dextran, sucralose, Herba Menthae essence, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; Behind-120 ℃～-130 ℃ pre-freeze 6min ,-10 ℃ of hatching 5h change in the freeze dryer through turbo-expander, and lyophilization 5h under 0.02mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 21
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 10.00g
Mannitol 4.00g
Pullulan 2.80g
Dextran 2.00g
Xanthan gum 0.10g
Purified water 181.10g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, Pullulan, dextran, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-100 ℃～-110 ℃ pre-freeze 3min ,-15 ℃ of hatching 4h change in the freeze dryer through liquid nitrogen, and lyophilization 5h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 22
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 10.00g
Glycine 4.60g
Mannitol 5.00g
Pullulan 9.00g
Xanthan gum 0.04g
Konjac glucomannan 0.12g
Acesulfame potassium 0.60g
Strawberry essence 2.00g
Purified water 168.64g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, Pullulan, acesulfame potassium, strawberry essence, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, making under the magnetic agitation becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-130 ℃～-150 ℃ pre-freeze 10min, change in the freeze dryer through liquid nitrogen, lyophilization 4h under 0.2mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 23
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 5.00g
Glycine 4.60g
Dextran 5.00g
Konjac glucomannan 0.20g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 184.80g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, dextran, sucralose, Herba Menthae essence, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; , behind-110 ℃～-120 ℃ pre-freeze 3min, change in the freeze dryer through liquid nitrogen, lyophilization 3h under 0.1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 24
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 15.00g
Mannitol 4.40g
Pullulan 2.80g
Konjac glucomannan 0.80g
Sucralose 0.20g
Herba Menthae essence 0.15g
Purified water 174.85g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, mannitol, Pullulan, dextran, sucralose, Herba Menthae essence, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-100 ℃～-110 ℃ pre-freeze 5min ,-10 ℃ of hatching 4h change in the freeze dryer through liquid nitrogen, and lyophilization 4.5h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 25
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 2.80g
Mannitol 2.00g
Pullulan 2.00g
Dextran 2.00g
Xanthan gum 0.20g
Aspartame 0.50g
Orange flavor 0.50g
Purified water 160.00g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, Pullulan, dextran, aspartame, orange flavor, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum outgas, accurately inject mould; Behind-120 ℃～-130 ℃ pre-freeze 4min ,-20 ℃ of hatching 8h change in the freeze dryer through liquid nitrogen, and lyophilization 3.5h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 26
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 5.00g
Glycine 16.00g
Pullulan 9.40
Konjac glucomannan 0.12g
Sucralose 0.40g
Herba Menthae essence 1.60g
Purified water 156.88g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, Pullulan, dextran, sucralose, Herba Menthae essence, joins in the good Konjac glucomannan solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-150 ℃～-170 ℃ pre-freeze 10min, change in the freeze dryer through liquid nitrogen, lyophilization 10h under 5mbar pressure ,-25 ℃ to 25 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 27
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 15.00g
Glycine 12.00g
Mannitol 8.00g
Pullulan 9.00g
Dextran 7.00g
Xanthan gum 0.13g
Konjac glucomannan 0.15g
Acesulfame potassium 0.30g
Herba Menthae essence 1.20g
Purified water 147.22
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, mannitol, Pullulan, dextran, acesulfame potassium, Herba Menthae essence, joins in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, making under the mechanical agitation becomes uniform solution; Solution with after the sweeping degas by inert gas method degassing, is accurately injected mould; Behind-110 ℃～-120 ℃ pre-freeze 6min ,-60 ℃ of hatching 12h change in the freeze dryer through turbo-expander, and lyophilization 3h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 28
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 4.00g
Pullulan 2.60g
Sodium alginate 1.80g
Xanthan gum 0.20g
Purified water 161.40g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, Pullulan, sodium alginate, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-60 ℃～-80 ℃ pre-freeze 20min, change in the freeze dryer through freon, lyophilization 7h under 0.5mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 29
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Glycine 3.00g
Erythritol 2.00g
Pullulan 6.00g
Polyvinylpyrrolidone 1.40g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 157.20g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, glycine, erythritol, Pullulan, sucralose, Herba Menthae essence, joins in the good polyvinylpyrrolidonesolution solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-120 ℃～-130 ℃ pre-freeze 3min, change in the freeze dryer through liquid nitrogen, lyophilization 4h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
Embodiment 30
Pharmaceutical formulation of the present invention is composed of the following components:
Rotundine 30.00g
Erythritol 4.20g
Sodium alginate 4.00g
Xanthan gum 0.18g
Sucralose 1.20g
Herba Menthae essence 0.60g
Purified water 159.82g
Process 1000 altogether.
Concrete method for preparing is described below: with rotundine, erythritol, sodium alginate, sucralose, Herba Menthae essence, joins in the good xanthan gum solution of abundant dissolving, and evenly mixed; Add an amount of purified water, make that the total amount of the above purified water that all adds is the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; Behind-100 ℃～-110 ℃ pre-freeze 4min ,-5 ℃ of hatching 4h change in the freeze dryer through liquid nitrogen, and lyophilization 6h under 0.1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains rotundine oral cavity disintegration tablet of the present invention.
For a better understanding of the present invention, use disintegration, dissolution test, the mouthfeel description of test advantage of the present invention of the rotundine oral cavity disintegration tablet of preparation below; Through volunteer's oral mucosa permeability test, bioequivalence test and clinical trial; The effect that rotundine oral cavity disintegration tablet that the present invention prepares exists oral mucosa to absorb is described; Onset is rapid; And it is compared with the rotundine oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and bioavailability improves, side effect obviously reduces, on curative effect, also increases.
1, disintegration:
Get the rotundine oral cavity disintegration tablet (R2 group) and the prepared rotundine oral cavity disintegration tablet (T group) (T1-T30 representes the oral cavity disintegration tablet of embodiment 1-embodiment 30 preparations respectively) of embodiment 1-30 of Rotundine Tablets (R1 group), pressing preparation; 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 with stopwatch, 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.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 the rotundine oral cavity disintegration tablet that the present invention is prepared will be much smaller than the rotundine oral cavity disintegration tablet and the Rotundine Tablets of pressing preparation; The prepared rotundine oral cavity disintegration 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 rotundine oral cavity disintegration tablet of embodiment 1-30 respectively, after 90 healthy volunteer's mouths were tasted, this 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 rotundine oral cavity disintegration tablet (R2 group) and the prepared rotundine oral cavity disintegration tablet (T group) (T1-T30 representes the oral cavity disintegration tablet of embodiment 1-embodiment 30 preparations respectively) of embodiment 1-30 of Rotundine Tablets (R1 group), pressing preparation; 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.
Inspection according to the method described above, 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
The continuous mucosa permeability result of respectively organizing of table 2
Can know from table 2; In human mouth; The mucosa permeability (about 16%-17%) of the rotundine oral cavity disintegration tablet that the present invention is prepared is apparently higher than the mucosa permeability (being about 0.40%) and the Rotundine Tablets (being about 0.017%) that adopt the prepared rotundine oral cavity disintegration tablet of pressing; Thereby explain that the prepared rotundine oral cavity disintegration tablet of the present invention can absorb by the oral mucosa, onset rapidly reduces first pass effect.
5, bioequivalence test
Experimental program:
9 beasle dogs are divided into three groups at random, 3 every group.Behind the fasting 12h, give the rotundine oral cavity disintegration tablet (R2 group) of Rotundine Tablets (R1 group), pressing preparation or the rotundine oral cavity disintegration tablet 60mg (T group) (T1-T30 representes the oral cavity disintegration tablet of embodiment 1-embodiment 30 preparations respectively) of the present invention's preparation respectively.Respectively at before the administration and after the administration 0.25,0.5,0.75,1,1.5,2,3,5,8 and 12h lower limb vein get blood 4ml, centrifugal separation plasma, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.Get blood plasma after the Deproteinization pretreatment, adopt the blood drug level of high effective liquid chromatography for measuring rotundine.Use the DAS software processes, calculate main pharmacokinetic parameter tmax, Cmax, AUC (0-t) and AUC (0-∞), calculate relative bioavailability according to each group AUC0-t.
Respectively the rotundine oral cavity disintegration tablet of embodiment 1-30 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. 1～30.
Table 3 is respectively organized main pharmacokinetic parameter and relative bioavailability (n=3, Mean ± SD)
* relative bioavailability is that each organizes the result who compares and calculate with the rotundine tablet
Bioequivalence result of the test in the animal body, the rotundine oral cavity disintegration tablet of the present invention's preparation is compared with the rotundine oral cavity disintegration tablet of pressing preparation with Rotundine Tablets, and Tmax shifts to an earlier date, Cmax and AUC
0-tAll enlarge markedly, bioavailability improves.
6, clinical trial
Experimental program:
Choose outpatient service headache patient 90 examples that meet the diagnostic criteria that international headache association in 1988 drafts, be divided into three groups at random, every group of each 30 people.Give rotundine oral cavity disintegration tablet 30mg (R2 group) or the prepared rotundine oral cavity disintegration tablet 30mg (T group) (T1-T30 representes the oral cavity disintegration tablet of embodiment 1-embodiment 30 preparations respectively) of the present invention that three groups of patients take Rotundine Tablets 30mg (R1 group), pressing preparation respectively every day; Every day 3 times, be limited to 28d during treatment.Observe outbreak situation and the side reaction of headache after the medication a situation arises and make comparisons.
Efficacy assessment standard: (1) cures: headache stops not recurrence in 6 months; (2) effective: headache obviously alleviates, and the persistent period obviously shortens, and attack times reduces; (3) invalid: the headache outbreak does not have improvement or increases the weight of.Total effective rate (%)=(curing routine number+effective routine number)/this organizes total routine number * 100%.
Respectively the rotundine oral cavity disintegration tablet of embodiment 1-30 has been carried out clinical trial according to the method described above, the result sees table 4-table 5.
Table 4 is respectively organized clinical efficacy relatively (n=30, routine number)
| Group | Cure | Effectively | Invalid | Total effective rate (%) |
| The |
12 | 9 | 9 | 70.0 |
| The R2 group | 13 | 9 | 8 | 73.3 |
| T1 | 22 | 6 | 2 | 93.3 |
| T2 | 22 | 6 | 2 | 93.3 |
| T3 | 22 | 6 | 2 | 93.3 |
| T4 | 21 | 7 | 2 | 93.3 |
| T5 | 21 | 6 | 3 | 90.0 |
| T6 | 21 | 7 | 2 | 93.3 |
| T7 | 20 | 7 | 3 | 90.0 |
| T8 | 21 | 7 | 2 | 93.3 |
| T9 | 21 | 7 | 2 | 93.3 |
| T10 | 21 | 7 | 2 | 93.3 |
| T11 | 22 | 6 | 2 | 93.3 |
| T12 | 21 | 7 | 2 | 93.3 |
| T13 | 21 | 7 | 2 | 93.3 |
| T14 | 20 | 8 | 2 | 93.3 |
| T15 | 21 | 7 | 2 | 93.3 |
| T16 | 22 | 6 | 2 | 93.3 |
| T17 | 20 | 8 | 2 | 93.3 |
| T18 | 21 | 7 | 2 | 93.3 |
| T19 | 20 | 7 | 3 | 90.0 |
| T20 | 21 | 6 | 3 | 90.0 |
| T21 | 22 | 6 | 2 | 93.3 |
| T22 | 21 | 7 | 2 | 93.3 |
| T23 | 22 | 6 | 2 | 93.3 |
| T24 | 21 | 7 | 2 | 93.3 |
| T25 | 22 | 6 | 2 | 93.3 |
| T26 | 20 | 7 | 3 | 90.0 |
| T27 | 21 | 6 | 3 | 90.0 |
| T28 | 20 | 7 | 3 | 90.0 |
| T29 | 19 | 8 | 3 | 90.0 |
| T30 | 20 | 7 | 3 | 90.0 |
Table 5 is respectively organized the comparison (n=30) that untoward reaction takes place
| Group | Drowsiness | Dizzy | Weak | Feel sick |
| The R1 group | 33.33% (10 people) | 10% (3 people) | 3.33% (1 people) | 3.33% (1 people) |
| The R2 group | 26.67% (8 people) | 3.33% (1 people) | 3.33% (1 people) | 3.33% (1 people) |
| T1 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T2 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T3 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T4 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T5 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T6 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T7 | 10% (3 people) | 0％ | 0％ | 0％ |
| T8 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T9 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T10 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T11 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T12 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T13 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T14 | 10% (3 people) | 0％ | 0％ | 0％ |
| T15 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T16 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T17 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T18 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T19 | 10% (3 people) | 0％ | 0％ | 0％ |
| T20 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T21 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T22 | 10% (3 people) | 0％ | 0％ | 0％ |
| T23 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T24 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T25 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T26 | 10% (3 people) | 0％ | 0％ | 0％ |
| T27 | 10% (3 people) | 0％ | 0％ | 0％ |
| T28 | 6.67% (2 people) | 0％ | 0％ | 0％ |
| T29 | 10% (3 people) | 0％ | 0％ | 0％ |
| T30 | 6.67% (2 people) | 0％ | 0％ | 0％ |
Can find out that from the result of clinical trial the rotundine oral cavity disintegration tablet of the present invention's preparation is compared with the rotundine oral cavity disintegration tablet that adopts the pressing preparation with Rotundine Tablets, side effect obviously reduces, and curative effect increases.Thereby more favourable proof several big advantage and the characteristics of rotundine oral cavity disintegration tablet of the present invention: 1) can absorb by the oral mucosa; 2) reduced the gastrointestinal stimulation.
Claims (35)
1. rotundine oral cavity disintegration tablet, form by following components in weight percentage:
Rotundine 5-90%
Skeleton proppant 2-60%
Binding agent 3-70%
Suspending agent 0.10-8%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
2. rotundine oral cavity disintegration tablet, form by following components in weight percentage:
Rotundine 11.60-78.23%
Skeleton proppant 4.85-40.74%
Binding agent 7.82-46.38%
Suspending agent 0.27-4.10%
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 rotundine oral cavity disintegration 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 rotundine oral cavity disintegration 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. according to claim 1 or claim 2 rotundine oral cavity disintegration tablet is characterized in that described suspending agent selects one or more in the following raw material for use: xanthan gum, Konjac glucomannan, natural origin glue, synthetic macromolecular compound, polypeptide, polysaccharide.
6. rotundine oral cavity disintegration tablet, form by following components in weight percentage:
Rotundine 5-90%
Glycine or mannitol or its mixture 2-60%
Pullulan or dextran or its mixture 3-70%
Xanthan gum or Konjac glucomannan or its mixture 0.10-8%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
7. rotundine oral cavity disintegration tablet, form by following components in weight percentage:
Rotundine 11.60-78.23%
Glycine or mannitol or its mix agent 4.85-40.74%
Pullulan or dextran or its mixture 7.82-46.38%
Xanthan gum or Konjac glucomannan or its mixture 0.27-4.10%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
8. rotundine oral cavity disintegration tablet, form by following components in weight percentage:
Rotundine 76.92%
Glycine or mannitol or its mixture 10.26%
Pullulan or dextran or its mixture 11.28%
Xanthan gum or Konjac glucomannan or its mixture 0.51%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
9. rotundine oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Rotundine 1.08-17.26%
Glycine or mannitol or its mixture 0.41-14.73%
Pullulan or dextran or its mixture 0.58-15.09%
Xanthan gum or Konjac glucomannan or its mixture 0.01-1.56%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 49.36-97.92%
Wherein each weight percentages of components sum is 100%.
10. rotundine oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Rotundine 2.5-15.00%
Glycine or mannitol or its mixture 1-10.00%
Pullulan or dextran or its mixture 1.5-10.00%
Xanthan gum or Konjac glucomannan or its mixture 0.03-0.80%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 62.20-94.97%
Wherein each weight percentages of components sum is 100%.
11. like claim 1-2, each described rotundine oral cavity disintegration tablet among the 6-10 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.
12. like claim 1-2, each described rotundine oral cavity disintegration tablet among the 6-10 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.
13. a rotundine oral cavity disintegration tablet, it is processed by following components by part by weight:
Rotundine 216-3452 part
Glycine or mannitol or its mixture 82-2946 part
Pullulan or dextran or its mixture 116-3018 part
Xanthan gum or Konjac glucomannan or its mixture 2-312 part
Sweeting agent 0-200 part
Aromatic 0-200 part
Purified water 9872-19584 part.
14. a rotundine oral cavity disintegration tablet, it is processed by following components by part by weight:
Rotundine 500-3000 part
Glycine or mannitol or its mixture 200-2000 part
Pullulan or dextran or its mixture 300-2000 part
Xanthan gum or Konjac glucomannan or its mixture 6-160 part
Sweeting agent 0-200 part
Aromatic 0-200 part
Purified water 12440-18994 part.
15. a rotundine oral cavity disintegration tablet, it is processed by following components by part by weight:
Rotundine 500-3000 part
Glycine or mannitol or its mixture 300-600 part
Pullulan or dextran or its mixture 300-650 part
Xanthan gum or Konjac glucomannan or its mixture 10-120 part
Sweeting agent 0-100 part
Aromatic 0-100 part
Purified water 15500-18500 part.
16. a rotundine oral cavity disintegration tablet, it is processed by following components by part by weight:
3000 parts of rotundine
400 parts in glycine or mannitol or its mixture
440 parts in Pullulan or dextran or its mixture
20 parts in xanthan gum or Konjac glucomannan or its mixture
20 parts of sweeting agents
20 parts of aromatic
16100 parts of purified water.
17. a rotundine oral cavity disintegration tablet, it is processed by following component:
Rotundine 30.00g
Glycine 4.00g
Pullulan 4.40g
Xanthan gum 0.20g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 161.00g
Process 1000 altogether.
18., it is characterized in that this method comprises the steps: like the method for preparing of the described rotundine oral cavity disintegration tablet of each claim of claim 1-2
(a) preparation of substrate liquid: rotundine, skeleton proppant, binding agent and other adjuvant are joined in the good suspending agent aqueous solution of abundant dissolving, 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.
19. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18, 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.
20. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18, the compound method that it is characterized in that said step (a) mesostroma liquid is for adopting the method preparation of mulser.
21. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18 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.
22. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18, 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.
23. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18, 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.
24. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18 is characterized in that the pre-freeze temperature is-40 ℃～-170 ℃ in the said step (d), the pre-freeze time is 1～60min.
25. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18 is characterized in that the pre-freeze temperature is-60 ℃～-150 ℃ in the said step (d), the pre-freeze time is 2～30min.
26. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18 is characterized in that the pre-freeze temperature is-100 ℃～-130 ℃ in the said step (d), the pre-freeze time is 3～6min.
27. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18; 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.
28. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18; 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.
29. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18 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.
30. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18 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.
31. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 18 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.
32. the method for preparing like any described rotundine oral cavity disintegration tablet of claim among the claim 6-8 is characterized in that adopting following steps to make:
(a) with rotundine, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent or aromatic or sweeting agent and aromatic; Join in the solution of the good xanthan gum of abundant dissolving or Konjac glucomannan or its mixture, form uniform solution;
(b) degassing: the solution of (a) step is outgased;
(c) injection molding: the solution after the degassing of (b) step is injected mould;
(d) pre-freeze: be pre-freeze 1～60min under-40 ℃～-170 ℃ the condition with the mould that is marked with solution in (c) step 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 rotundine oral cavity disintegration tablet of the present invention,
Also can add the step of ice crystal hatching in the said method after (d) step before (e) step, 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.
33. the method for preparing like any described rotundine oral cavity disintegration tablet of claim among claim 9-10, the 13-16 is characterized in that adopting following steps to make:
With rotundine, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent, aromatic, join in the solution of the good xanthan gum of abundant dissolving or Konjac glucomannan or its mixture, 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 rotundine oral cavity disintegration tablet of the present invention; 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.
34. the method for preparing like any described rotundine oral cavity disintegration tablet of claim among claim 9-10, the 13-16 is characterized in that adopting following steps to make:
With rotundine, glycine or mannitol or its mixture, Pullulan or dextran or its mixture and sweeting agent, aromatic, join in the solution of the good xanthan gum of abundant dissolving or Konjac glucomannan or its mixture, 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 rotundine oral cavity disintegration tablet of the present invention; 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.
35. the method for preparing of the rotundine oral cavity disintegration tablet described in claim 17 is characterized in that adopting following steps to make:
With rotundine, glycine, Pullulan, sucralose, Herba Menthae essence, join in the good xanthan gum solution of abundant dissolving, 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 rotundine oral cavity disintegration tablet of the present invention; 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.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191023A (en) * | 2013-03-22 | 2013-07-10 | 海南卫康制药(潜山)有限公司 | Low-temperature pressing method of rapidly disintegrating tablet |
| CN108685862A (en) * | 2018-06-05 | 2018-10-23 | 山东华辰制药有限公司 | A kind of amoxicillin and clavulanate potassium oral disnitegration tablet and preparation method thereof |
| CN111066776A (en) * | 2019-11-09 | 2020-04-28 | 无锡市人民医院 | Ovum freezing protective agent and application thereof |
| CN112220764A (en) * | 2020-10-21 | 2021-01-15 | 合肥康诺生物制药有限公司 | NAD orally disintegrating tablet, preparation method and application thereof |
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| 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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- 2010-10-22 CN CN2010105235838A patent/CN102451165A/en active Pending
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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103191023A (en) * | 2013-03-22 | 2013-07-10 | 海南卫康制药(潜山)有限公司 | Low-temperature pressing method of rapidly disintegrating tablet |
| CN103191023B (en) * | 2013-03-22 | 2014-06-25 | 海南卫康制药(潜山)有限公司 | Low-temperature pressing method of rapidly disintegrating tablet |
| CN108685862A (en) * | 2018-06-05 | 2018-10-23 | 山东华辰制药有限公司 | A kind of amoxicillin and clavulanate potassium oral disnitegration tablet and preparation method thereof |
| CN108685862B (en) * | 2018-06-05 | 2020-12-15 | 山东华辰制药有限公司 | Amoxicillin and clavulanate potassium orally disintegrating tablet and preparation method thereof |
| CN111066776A (en) * | 2019-11-09 | 2020-04-28 | 无锡市人民医院 | Ovum freezing protective agent and application thereof |
| CN112220764A (en) * | 2020-10-21 | 2021-01-15 | 合肥康诺生物制药有限公司 | NAD orally disintegrating tablet, preparation method and application thereof |
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Application publication date: 20120516 |