CN102451167A - H1 accepter antagonist oral cavity disintegrating tablet and preparation method thereof - Google Patents
H1 accepter antagonist oral cavity disintegrating tablet and preparation method thereof Download PDFInfo
- Publication number
- CN102451167A CN102451167A CN2010105236277A CN201010523627A CN102451167A CN 102451167 A CN102451167 A CN 102451167A CN 2010105236277 A CN2010105236277 A CN 2010105236277A CN 201010523627 A CN201010523627 A CN 201010523627A CN 102451167 A CN102451167 A CN 102451167A
- Authority
- CN
- China
- Prior art keywords
- oral cavity
- receptor antagonist
- cavity disintegration
- disintegration tablet
- mixture
- 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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Images
Abstract
The invention relates to an H1 accepter antagonist oral cavity disintegrating tablet and a prescription and process for preparing the H1 accepter antagonist oral cavity disintegrating tablet by adopting a freeze-drying method. The H1 accepter antagonist oral cavity disintegrating tablet is prepared from a main medicament and pharmaceutical adjuvants. When the H1 accepter antagonist oral cavity disintegrating tablet is administered, water is not needed, and the H1 accepter antagonist oral cavity disintegrating tablet can be rapidly disintegrated after entering oral cavity; the H1 accepter antagonist oral cavity disintegrating tablet is suitable for being taken by patients with dysphagia such as the elder, children and the like, and simultaneously is suitable for being taken in the condition that water source is not easy to acquire in the trip; and the H1 accepter antagonist oral cavity disintegrating tablet has the advantages of convenience for administration, rapid absorption, small first pass effect, small irritation to mucous membrane of alimentary tract and the like, has broad market application prospect, and can obviously lower side effects of H1 accepter antagonist medicaments. In addition, the invention also relates to a preparation method of the H1 accepter antagonist oral cavity disintegrating tablet.
Description
Technical field:
The present invention relates to a kind of H1 receptor antagonist oral cavity disintegration tablet and preparation method thereof, particularly a kind of H1 receptor antagonist oral cavity disintegration tablet that adopts the freeze-drying preparation.
Background technology:
Anaphylactic disease is a kind of commonly encountered diseases and frequently-occurring disease; And under the influence that global ecological environment worsens; Each anaphylactoid reaction more demonstrates ever-increasing trend, and according to the data of The World Health Organization (WHO), the whole world has 2.5 hundred million people to suffer from anaphylactic disease at present; During by 2010, the whole world will have 40%～50% people to suffer from anaphylaxis.WHO classifies anaphylactic disease as 21 century and needs one of three big diseases of primary study and control.Allergy or allergy are claimed in anaphylaxis again, are meant a kind of unusual or pathologic immunoreation that body receives same antigenic substance to stimulate the back to produce once more.The material that causes allergic reaction comprises foreign sera, some animal proteinum, and airborne plant pollen and dust, and chemicals and medicine etc. are called anaphylactogen (or sensitinogen).
Histamine is one of anaphylaxis material, and it extensively is present in body tissue's cell.Because antigen antibody reaction or contact some material and physical stimulation; Histamine discharges from cell; Special receptors bind with in the various target cells produces a series of physiological reactions, promptly shows as people's common skin redness, pruritus, speckle and larynx and gastrointestinal convulsion, allergic rhinitis etc.According to different with the receptor in target cell of histamine competition, the antihistaminic medicine is divided into H1 receptor antagonist, bisfentidine, H3 receptor antagonist, H4 receptor antagonist.Wherein, the H1 receptor antagonist is mainly used in all kinds of anaphylactic diseases such as treatment urticaria, allergic rhinitis, allergic asthma, brings into play anti-allergic effects through retardance and antagonism H1 receptor.Through exploitation for many years, its product structure is perfect gradually, along with the update of product, develops into third generation kind from the first generation.
The dosage form of at present domestic granted H1 receptor antagonist has tablet, capsule, granule, syrup, effervescent tablet, dispersible tablet, injection and oral cavity disintegration tablet etc.See from hospital terminal medication in 2008, large usage quantity be tablet, account for 84%; The drop that is used for seasonality or catarrhus perennialis accounts for 6.24%, and dispersible tablet accounts for 6%, and syrup accounts for 2.9%; And capsule is not popular clinically, and proportion is less than 1%.Quiet notes administration is extremely inconvenient for the patient, and compliance is relatively poor; Common oral preparation such as tablet, capsule, granule, syrup, effervescent tablet, dispersible tablet; Must use water delivery service or itself just to be liquid preparation when the patient takes, then be not suitable for old people, child, the difficult change of bed position etc. and exist the patient of dysphagia to take.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,, be adapted at simultaneously in the tourism way for old people, child, the difficult change of bed position etc. exist taking medicine of dysphagia patients that great facility is provided; Be difficult for to obtain the medication under the condition at water source, and can reduce the burden of some inpatients and patient in family nursery work; 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 the gastrointestinal local excitation; It is thus clear that H1 receptor antagonist oral cavity disintegration tablet has more advantage than other dosage forms.
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 H1 receptor antagonist 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 ordinary tablet, and the prepared H1 receptor antagonist oral cavity disintegration tablet of the present invention all has the characteristics of bioavailability raising, side effect reduction, curative effect raising.
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 H1 receptor antagonist 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 H1 receptor antagonist oral cavity disintegration tablet of adjuvant of the present invention and prepared all 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 the H1 receptor antagonist oral cavity disintegration tablet of the present invention's preparation improves, side effect obviously reduces, on curative effect, also increases.
The H1 receptor antagonist oral cavity disintegration tablet that the present invention relates to comprises principal agent, 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 H1 receptor antagonist oral cavity disintegration tablet of the present invention is following:
Weight percentages of components
Principal agent 2-60%
Skeleton proppant 5-65%
Binding agent 8-70%
Suspending agent 0-10%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
The percentage by weight of preferred each component is following:
Weight percentages of components
Principal agent 3.85-49.70%
Skeleton proppant 19.61-46.15%
Binding agent 25.32-48.08%
Suspending agent 0-5.03%
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 H1 receptor antagonist 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 H1 receptor antagonist oral cavity disintegration tablet through a large amount of experimentatioies; Wherein in the method for preparing of H1 receptor antagonist 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 H1 receptor antagonist oral cavity disintegration tablet of the present invention is:
(a) with 2-60% principal agent, 5-65% skeleton proppant, 8-70% binding agent and sweeting agent or aromatic or sweeting agent and aromatic, join in the good 0-10% suspending agent aqueous solution of abundant dissolving, 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) mould is changed in the freeze dryer, lyophilization 1～10h under 0.01mbar～10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains H1 receptor antagonist 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 oral loratadine disintegrating tablet of the present invention is processed by the component of following weight percentage ratio:
Principal agent 0.5-5.00%
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 0-0.60%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 72.40-96.88%
Wherein each weight percentages of components sum is 100%.
Its preparation method is: with principal agent, 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 H1 receptor antagonist 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 principal agent, 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 H1 receptor antagonist 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.
H1 receptor antagonist oral cavity disintegration tablet provided by the invention; 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.
H1 receptor antagonist oral cavity disintegration tablet of the present invention has following advantage:
1, good mouthfeel, taking convenience: H1 receptor antagonist 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 H1 receptor antagonist 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 H1 receptor antagonist 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 H1 receptor antagonist oral cavity disintegration 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.
H1 receptor antagonist 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 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
Figure 21 gives the blood drug level-time graph behind R5 and the T21
Figure 22 gives the blood drug level-time graph behind R5 and the T22
Figure 23 gives the blood drug level-time graph behind R5 and the T23
Figure 24 gives the blood drug level-time graph behind R5 and the T24
Figure 25 gives the blood drug level-time graph behind R5 and the T25
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.
Embodiment 1
Pharmaceutical formulation of the present invention is composed of the following components:
Cetirizine hydrochloride 10.00g
Glycine 5.00g
Pullulan 5.60g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 179.00g
Process 1000 altogether.
Concrete method for preparing is described below: with cetirizine hydrochloride, glycine, Pullulan, sucralose, Herba Menthae essence, join in 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 ℃ freezing 6min, change in the freeze dryer through liquid nitrogen, lyophilizing 3h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains cetirizine hydrochloride oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Cetirizine hydrochloride 5.00g
Mannitol 5.60g
Pullulan 6.00g
Aspartame 1.00g
Purified water 182.40g
Process 1000 altogether.
Concrete method for preparing is described below: with cetirizine hydrochloride, mannitol, Pullulan, aspartame, join in 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 ℃ freezing 3min ,-10 ℃ of hatching 12h change in the freeze dryer through liquid nitrogen, and lyophilizing 6h under 0.1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains cetirizine hydrochloride oral cavity disintegration tablet of the present invention.
Embodiment 3
Pharmaceutical formulation of the present invention is composed of the following components:
Cetirizine hydrochloride 10.00g
Glycine 10.00g
Mannitol 10.00g
Dextran-20 .00g
Sucrose 2.00g
Orange flavor 2.00g
Purified water 146.00g
Process 1000 altogether.
Concrete method for preparing is described below: with cetirizine hydrochloride, glycine, mannitol, dextran, sucrose, orange flavor, join in 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-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 cetirizine hydrochloride oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Cetirizine hydrochloride 5.00g
Glycine 2.00g
Dextran 3.00g
Sucralose 0.20g
Purified water 189.80g
Process 1000 altogether.
Concrete method for preparing is described below: with cetirizine hydrochloride, glycine, dextran, sucralose, join in 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 ℃ 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 cetirizine hydrochloride oral cavity disintegration tablet of the present invention.
Embodiment 5
Pharmaceutical formulation of the present invention is composed of the following components:
Cetirizine hydrochloride 10.00g
Mannitol 9.60g
Pullulan 5.40g
Dextran 5.00g
Sucralose 0.40g
Strawberry essence 0.40g
Purified water 169.20g
Process 1000 altogether.
Concrete method for preparing is described below: with cetirizine hydrochloride, mannitol, Pullulan, dextran, sucralose, strawberry essence, join in the purified water of recipe quantity, mulser mixes to make becomes uniform solution; After solution carried out vacuum, accurately inject mould; Behind-60 ℃～-80 ℃ freezing 30min, lyophilizing 10h under 1mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains cetirizine hydrochloride oral cavity disintegration tablet of the present invention through turbo-expander.
Pharmaceutical formulation of the present invention is composed of the following components:
Desloratadine 5.00g
Glycine 4.00g
Pullulan 4.40g
Xanthan gum 0.10g
Sucralose 0.15g
Orange flavor 0.40g
Purified water 185.95g
Process 1000 altogether.
Concrete method for preparing is described below: with Desloratadine, glycine, Pullulan, sucralose, 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, 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 Desloratadine oral cavity disintegration tablet of the present invention.
Embodiment 7
Pharmaceutical formulation of the present invention is composed of the following components:
Desloratadine 5.00g
Glycine 8.00g
Pullulan 8.40g
Xanthan gum 0.06g
Konjac glucomannan 0.40g
Herba Menthae essence 0.60g
Purified water 177.54g
Process 1000 altogether.
Concrete method for preparing is described below: with Desloratadine, glycine, Pullulan, 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 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 Desloratadine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Desloratadine 2.50g
Glycine 2.00g
Mannitol 2.60g
Dextran 5.00g
Xanthan gum 0.02g
Konjac glucomannan 0.18g
Sucrose 1.60g
Purified water 186.10g
Process 1000 altogether.
Concrete method for preparing is described below: with Desloratadine, glycine, mannitol, dextran, sucrose, 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 vacuum outgas, accurately inject mould; Behind-130 ℃～-150 ℃ freezing 2min ,-10 ℃ of hatching 5h change in the freeze dryer through liquid nitrogen, and lyophilizing 6.5h under 8mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains Desloratadine oral cavity disintegration tablet of the present invention.
Embodiment 9
Pharmaceutical formulation of the present invention is composed of the following components:
Desloratadine 5.00g
Mannitol 20.00g
Pullulan 12.00g
Dextran 8.00g
Konjac glucomannan 1.20g
Acesulfame potassium 2.00g
Flavoring pineapple essence 2.00g
Purified water 149.80g
Process 1000 altogether.
Concrete method for preparing is described below: with Desloratadine, mannitol, Pullulan, dextran, acesulfame potassium, flavoring pineapple 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-40 ℃～-60 ℃ freezing 60min ,-5 ℃ of hatching 15h change in the freeze dryer through freon, and lyophilizing 3.5h under 0.2mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains Desloratadine oral cavity disintegration tablet of the present invention.
Pharmaceutical formulation of the present invention is composed of the following components:
Desloratadine 2.50g
Mannitol 2.00g
Dextran 3.00g
Xanthan gum 0.06g
Purified water 192.44g
Process 1000 altogether.
Concrete method for preparing is described below: with Desloratadine, 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; Solution with after the sweeping degas by inert gas method degassing, is accurately injected mould; , behind-60 ℃～-80 ℃ freezing 15min, change in the freeze dryer through liquid nitrogen, lyophilizing 8h under 0.05mbar pressure ,-30 ℃ to 20 ℃ condition promptly obtains Desloratadine oral cavity disintegration tablet of the present invention.
Embodiment 11
Pharmaceutical formulation of the present invention is composed of the following components:
Levo-cetirizine hydrochloride 5.00g
Glycine 5.60g
Pullulan 6.00g
Sucralose 0.15g
Herba Menthae essence 0.15g
Purified water 183.10g
Process 1000 altogether.
Concrete method for preparing is described below: with levo-cetirizine hydrochloride, glycine, Pullulan, sucralose, Herba Menthae essence, join in 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 ℃ freezing 3min ,-15 ℃ of hatching 4h change in the freeze dryer, to 20 ℃ condition, freeze 4.5h 0.1mbar pressure ,-20 ℃, promptly obtain levo-cetirizine hydrochloride orally disintegrating tablets of the present invention through liquid nitrogen.
Pharmaceutical formulation of the present invention is composed of the following components:
Levo-cetirizine hydrochloride 2.50g
Glycine 1.40g
Mannitol 0.60
Pullulan 3.00g
Sucralose 0.20g
Purified water 192.30g
Process 1000 altogether.
Concrete method for preparing is described below: with levo-cetirizine hydrochloride, glycine, mannitol, Pullulan, sucralose, join in the purified water of recipe quantity, making under the mechanical agitation becomes uniform solution; After the degassing of solution ultrasonic wave concussion, accurately inject mould; , behind-80 ℃～-100 ℃ freezing 3min, change in the freeze dryer through liquid nitrogen, lyophilizing 5.5h under 5mbar pressure ,-20 ℃ to 25 ℃ condition promptly obtains levo-cetirizine hydrochloride orally disintegrating tablets of the present invention.
Embodiment 13
Pharmaceutical formulation of the present invention is composed of the following components:
Levo-cetirizine hydrochloride 5.00g
Mannitol 11.20g
Dextran 1 2.00g
Acesulfame potassium 0.80g
Orange flavor 0.80g
Purified water 170.20g
Process 1000 altogether.
Concrete method for preparing is described below: with levo-cetirizine hydrochloride, mannitol, dextran, acesulfame potassium, orange flavor, join in 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 ℃ freezing 5min ,-60 ℃ of hatching 0.5h change in the freeze dryer through turbo-expander, and lyophilizing 7h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains levo-cetirizine hydrochloride orally disintegrating tablets of the present invention.
Embodiment 14
Pharmaceutical formulation of the present invention is composed of the following components:
Levo-cetirizine hydrochloride 5.00g
Glycine 12.00g
Mannitol 8.00g
Pullulan 10.00g
Aspartame 2.00g
Strawberry essence 2.00g
Purified water 151.00g
Process 1000 altogether.
Concrete method for preparing is described below: with levo-cetirizine hydrochloride, glycine, mannitol, Pullulan, dextran, aspartame, strawberry essence, join in 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 ℃ freezing 8min, change in the freeze dryer through liquid nitrogen, lyophilizing 5h under 1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains levo-cetirizine hydrochloride orally disintegrating tablets of the present invention.
Embodiment 15
Pharmaceutical formulation of the present invention is composed of the following components:
Levo-cetirizine hydrochloride 2.50g
Glycine 6.00g
Pullulan 3.40g
Dextran 3.00g
Acesulfame potassium 0.70g
Purified water 184.40g
Process 1000 altogether.
Concrete method for preparing is described below: with levo-cetirizine hydrochloride, glycine, Pullulan, dextran, acesulfame potassium, join in 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 ℃ freezing 6min ,-10 ℃ of hatching 4h change in the freeze dryer through freon, and lyophilizing 3h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains levo-cetirizine hydrochloride orally disintegrating tablets of the present invention.
Embodiment 16
Pharmaceutical formulation of the present invention is composed of the following components:
A-5610 1.00g
Glycine 6.00g
Pullulan 6.40g
Xanthan gum 0.04g
Sucralose 0.20g
Orange flavor 0.50g
Purified water 185.86g
Process 1000 altogether.
Concrete method for preparing is described below: with A-5610, glycine, Pullulan, sucralose, 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 the solution for vacuum degassing, accurately inject mould; Behind-100 ℃～-110 ℃ freezing 3min ,-20 ℃ of hatching 6h change in the freeze dryer through liquid nitrogen, and lyophilizing 4h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains A-5610 oral cavity disintegration tablet of the present invention.
Embodiment 17
Pharmaceutical formulation of the present invention is composed of the following components:
A-5610 1.00g
Glycine 5.80g
Mannitol 6.20g
Pullulan 12.00g
Konjac glucomannan 0.60g
Flavoring pineapple essence 0.40g
Purified water 174.00g
Process 1000 altogether.
Concrete method for preparing is described below: with A-5610, glycine, mannitol, Pullulan, flavoring pineapple 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 mechanical agitation becomes uniform solution; After the solution centrifugal degassing, accurately inject mould; , behind-40 ℃～-60 ℃ freezing 25min, change in the freeze dryer through freon, lyophilizing 9h under 10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains A-5610 oral cavity disintegration tablet of the present invention.
Embodiment 18
Pharmaceutical formulation of the present invention is composed of the following components:
A-5610 2.00g
Mannitol 5.20g
Dextran 6.00g
Xanthan gum 0.02g
Konjac glucomannan 0.70g
Sucralose 0.40g
Purified water 185.68g
Process 1000 altogether.
Concrete method for preparing is described below: with A-5610, mannitol, 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, mulser mixes to make becomes uniform solution; After the solution for vacuum degassing, accurately inject mould; , behind-60 ℃～-80 ℃ freezing 4min, change in the freeze dryer through liquid nitrogen, lyophilizing 5.5h under 0.2mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains A-5610 oral cavity disintegration tablet of the present invention.
Embodiment 19
Pharmaceutical formulation of the present invention is composed of the following components:
A-5610 1.00g
Mannitol 2.00g
Pullulan 1.80g
Dextran 1 .20g
Xanthan gum 0.04g
Acesulfame potassium 0.20g
Purified water 193.76g
Process 1000 altogether.
Concrete method for preparing is described below: with A-5610, mannitol, Pullulan, dextran, acesulfame potassium, 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-150 ℃～-170 ℃ freezing 5min ,-50 ℃ of hatching 1.5h change in the freeze dryer through liquid nitrogen, and lyophilizing 4h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains A-5610 oral cavity disintegration tablet of the present invention.
Embodiment 20
Pharmaceutical formulation of the present invention is composed of the following components:
A-5610 2.00g
Glycine 14.00g
Mannitol 6.00g
Dextran-20 .00g
Konjac glucomannan 1.20g
Sucrose 2.00g
Orange flavor 2.00g
Purified water 152.80g
Process 1000 altogether.
Concrete method for preparing is described below: with A-5610, glycine, mannitol, dextran, sucrose, orange flavor, 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-100 ℃～-110 ℃ freezing 3min ,-40 ℃ of hatching 10h change in the freeze dryer through liquid nitrogen, and lyophilizing 3h under 1mbar pressure ,-30 ℃ to 25 ℃ condition promptly obtains A-5610 oral cavity disintegration tablet of the present invention.
Embodiment 21
Pharmaceutical formulation of the present invention is composed of the following components:
Ebastine 10.00g
Glycine 4.80g
Pullulan 5.20g
Xanthan gum 0.14g
Sucralose 0.20g
Flavoring pineapple essence 0.20g
Purified water 179.46g
Process 1000 altogether.
Concrete method for preparing is described below: with ebastine, glycine, Pullulan, sucralose, flavoring pineapple 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 ℃ freezing 4min ,-20 ℃ of hatching 8h change in the freeze dryer through liquid nitrogen, and lyophilizing 5h under 0.05mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains ebastine oral cavity disintegration tablet of the present invention.
Embodiment 22
Pharmaceutical formulation of the present invention is composed of the following components:
Ebastine 5.00g
Glycine 2.40g
Mannitol 2.20g
Pullulan 6.00g
Konjac glucomannan 0.60g
Herba Menthae essence 0.20g
Purified water 183.60g
Process 1000 altogether.
Concrete method for preparing is described below: with loratadine, glycine, 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-110 ℃～-120 ℃ freezing 6min, change in the freeze dryer through liquid nitrogen, lyophilizing 5h under 0.1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains ebastine oral cavity disintegration tablet of the present invention.
Embodiment 23
Pharmaceutical formulation of the present invention is composed of the following components:
Ebastine 5.00g
Glycine 1.00g
Mannitol 1.00g
Pullulan 1.20g
Dextran 1 .80g
Xanthan gum 0.06g
Purified water 189.94g
Process 1000 altogether.
Concrete method for preparing is described below: with ebastine, glycine, 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, making under the magnetic agitation becomes uniform solution; Solution with after the sweeping degas by inert gas method degassing, is accurately injected mould; Behind-150 ℃～-170 ℃ freezing 10min ,-60 ℃ of hatching 12h change in the freeze dryer through freon, and lyophilizing 2h under 5mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains ebastine oral cavity disintegration tablet of the present invention.
Embodiment 24
Pharmaceutical formulation of the present invention is composed of the following components:
Ebastine 10.00g
Glycine 4.20g
Mannitol 3.80g
Pullulan 5.00g
Dextran 5.00g
Xanthan gum 0.06g
Konjac glucomannan 0.60g
Aspartame 0.50g
Purified water 170.84g
Process 1000 altogether.
Concrete method for preparing is described below: with ebastine, glycine, mannitol, Pullulan, dextran, aspartame, 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 vacuum outgas, accurately inject mould; Behind-80 ℃～-100 ℃ freezing 20min ,-5 ℃ of hatching 4h change in the freeze dryer through liquid nitrogen, and lyophilizing 6h under 1mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains ebastine oral cavity disintegration tablet of the present invention.
Embodiment 25
Pharmaceutical formulation of the present invention is composed of the following components:
Ebastine 10.00g
Glycine 6.00g
Mannitol 14.00g
Pullulan 20.00g
Konjac glucomannan 1.20g
Acesulfame potassium 2.00g
Herba Menthae essence 2.00g
Purified water 144.80g
Process 1000 altogether.
Concrete method for preparing is described below: with ebastine, glycine, mannitol, Pullulan, acesulfame potassium, 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 degassing of solution ultrasonic wave concussion, accurately inject mould; Behind-40 ℃～-60 ℃ freezing 6min ,-30 ℃ of hatching 3h change in the freeze dryer through liquid nitrogen, and lyophilizing 4.5h under 0.01mbar pressure ,-20 ℃ to 20 ℃ condition promptly obtains ebastine 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 the H1 receptor antagonist oral cavity disintegration tablet of preparation below; Through volunteer's oral mucosa permeability test, bioequivalence test and clinical trial; The effect that H1 receptor antagonist oral cavity disintegration 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 H1 receptor antagonist oral cavity disintegration tablet (T group) of Cetirizine hydrochloride Tablets (R1 group), Desloratadine sheet (R2 group), levo-cetirizine hydrochloride sheet (R3 group), A-5610 sheet (R4 group), ebastine (R5 group) and embodiment 1-25 (T1-T25 representes the oral cavity disintegration tablet of embodiment 1-embodiment 25 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 with stopwatch; Also can add suitable quantity of water in case of necessity and get screen cloth express developed up to the complete disintegrate of tablet through No. 2 sieves.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 H1 receptor antagonist oral cavity disintegration tablet that the present invention is prepared will be much smaller than ordinary tablet; The prepared H1 receptor antagonist 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 H1 receptor antagonist oral cavity disintegration tablet of embodiment 1-25 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 prepared H1 receptor antagonist oral cavity disintegration tablet (T group) of Cetirizine hydrochloride Tablets (R1 group), Desloratadine sheet (R2 group), levo-cetirizine hydrochloride sheet (R3 group), A-5610 sheet (R4 group), ebastine (R5 group) and the present invention (T1-T25 representes the oral cavity disintegration tablet of embodiment 1-embodiment 25 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 1-25 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
The continuous mucosa permeability result of respectively organizing of table 2
Can know from table 2; In human mouth; The mucosa permeability of the H1 receptor antagonist oral cavity disintegration tablet that the present invention is prepared is apparently higher than the mucosa permeability of its ordinary tablet; Thereby explain that the prepared H1 receptor antagonist oral cavity disintegration tablet of the present invention can absorb by the oral mucosa, onset rapidly reduces first pass effect.
4, bioequivalence test
Experimental program:
30 beasle dogs are divided into 10 groups at random, 3 every group.Behind the fasting 12h, give the prepared H1 receptor antagonist class drug port cavity disintegrating tablet (T group) of Cetirizine hydrochloride Tablets (R1 group), levo-cetirizine hydrochloride sheet sheet (R2 group), Desloratadine sheet (R3 group), ebastine sheet (R4 group), A-5610 sheet (R5 group) and the present invention (T1-T25 representes the oral cavity disintegration tablet of embodiment 1-embodiment 25 preparations respectively) respectively.
Dosage regimen and blood specimen collection process are respectively:
1) gives Cetirizine hydrochloride Tablets and the present invention prepared Cetirizine hydrochloride Tablets oral cavity disintegration tablet 20mg; Respectively at before the administration and administration after 0.25,0.5,0.75,1,1.5,2,3,5,9 and 14h lower limb vein get blood 4ml; Anticoagulant heparin; Centrifugal separation plasma, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.
2) give levo-cetirizine hydrochloride sheet and the present invention prepared levo-cetirizine hydrochloride orally disintegrating tablets 10mg; Respectively at before the administration and administration after 0.25,0.5,0.75,1,1.5,2,4,8,12 and 24h lower limb vein get blood 3ml; Anticoagulant heparin; Centrifugal separation plasma, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.
3) give Desloratadine sheet and the present invention prepared Desloratadine oral cavity disintegration tablet 8mg; Respectively at before the administration and administration after 0.5,1,1.5,2,3,5,8,12,24 and 36h lower limb vein get blood 5ml; Anticoagulant heparin; Centrifugal separation plasma, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.
4) give ebastine sheet and the present invention prepared ebastine oral cavity disintegration tablet 10mg.Respectively at before the administration and after the administration 0.5,1,2,3,4,6,8,12,24 and 36h lower limb vein get blood 4ml, anticoagulant heparin, centrifugal separation plasma, film-20 ℃ of refrigerators of being honored as a queen and putting are preserved pending analysis.
5) give A-5610 sheet and the present invention prepared A-5610 oral cavity disintegration tablet 4mg.Respectively at before the administration and after the administration 0.5,1,2,3,4,6,8,12,24 and 36h lower limb vein get blood 5ml, anticoagulant heparin, centrifugal separation plasma, 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 HPLC (wherein 3) and 5) employing LC-MS/MS method) measure the blood drug level of each medicine, 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 the H1 receptor antagonist class drug port cavity disintegrating tablet of embodiment 1-25 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. 1～25.
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, the H1 receptor antagonist 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.
6, clinical trial
Experimental program:
Choose standard compliant outpatient service chronic urticaria patient 210 examples, be divided into 6 groups at random, every group of each 35 people.Giving 6 groups of patients every day takes the prepared H1 receptor antagonist oral cavity disintegration tablet (T group) of Cetirizine hydrochloride Tablets 10mg (R1 group), Desloratadine sheet 5mg (R2 group), levo-cetirizine hydrochloride sheet 5mg (R3 group), A-5610 sheet 2mg (R4 group), ebastine 10mg (R5 group) and the present invention respectively (T1-T25 representes the oral cavity disintegration tablet of embodiment 1-embodiment 25 preparation respectively; Each dosage of organizing oral cavity disintegration tablet contains the ordinary tablet of same medicine active component with it consistent); Every day 1 time, be limited to 28d during treatment.(7d ± 1d), the 2nd week, (14d ± 1d) (28d ± 1d) patient's symptom integral is assessed, the record adverse events was also analyzed with the 4th week respectively at the 1st week after the administration.Before and after treatment, respectively look into 1 time routine blood test, routine urinalysis, hepatic and renal function and electrocardiogram.
As evaluating basis, concrete computational methods are with symptom integral decline index (therapeutic index) after the medication: therapeutic index=(adding up to score value-treatment back to add up to score value before the treatment)/(adding up to score value before the treatment) * 100%.
Curative effect judging standard: (1) recovery from illness: gargalesthesia disappears, and erythra disappears fully, and the erythra score value reduces more than 90%; (2) produce effects: gargalesthesia obviously alleviates, and the erythra score value reduces more than 60%; (3) progressive: gargalesthesia alleviates, and the erythra score value reduces by 20%～60%; (4) invalid: the same or aggravation of gargalesthesia, the erythra score value reduces less than 20%.Total effective rate (%)=(the routine number of fully recovering+produce effects example number)/this organizes total routine number * 100%.
Respectively the H1 receptor antagonist oral cavity disintegration tablet of embodiment 1-25 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=35, routine number)
| Group | Recovery from illness | Produce effects | Progressive | Invalid | Total effective rate (%) |
| R1 | 11 | 12 | 8 | 4 | 65.7 |
| |
12 | 12 | 9 | 3 | 68.6 |
| R3 | 13 | 11 | 9 | 3 | 68.6 |
| |
10 | 12 | 8 | 5 | 62.9 |
| R5 | 9 | 13 | 7 | 6 | 62.9 |
| T1 | 26 | 5 | 4 | 0 | 88.6 |
| T2 | 25 | 6 | 4 | 0 | 88.6 |
| T3 | 24 | 6 | 5 | 0 | 85.7 |
| T4 | 25 | 6 | 4 | 0 | 88.6 |
| T5 | 25 | 5 | 5 | 0 | 85.7 |
| T6 | 28 | 4 | 3 | 0 | 91.4 |
| T7 | 27 | 4 | 4 | 0 | 88.6 |
| T8 | 27 | 5 | 3 | 0 | 91.4 |
| T9 | 25 | 6 | 4 | 0 | 88.6 |
| T10 | 26 | 6 | 3 | 0 | 91.4 |
| T11 | 28 | 4 | 3 | 0 | 91.4 |
| T12 | 26 | 6 | 3 | 0 | 91.4 |
| T13 | 27 | 4 | 4 | 0 | 88.6 |
| T14 | 25 | 6 | 4 | 0 | 88.6 |
| T15 | 26 | 6 | 3 | 0 | 91.4 |
| T16 | 25 | 5 | 5 | 0 | 85.7 |
| T17 | 24 | 5 | 6 | 0 | 82.9 |
| T18 | 24 | 6 | 5 | 0 | 85.7 |
| T19 | 23 | 7 | 5 | 0 | 85.7 |
| T20 | 23 | 6 | 6 | 0 | 82.9 |
| T21 | 25 | 5 | 5 | 0 | 85.7 |
| T22 | 24 | 6 | 5 | 0 | 85.7 |
| T23 | 24 | 5 | 6 | 0 | 82.9 |
| T24 | 23 | 7 | 5 | 0 | 85.7 |
| T25 | 23 | 6 | 6 | 0 | 82.9 |
Table 5 is respectively organized the comparison (n=35) that untoward reaction takes place
| Group | Xerostomia | Drowsiness or tired | Stomachache |
| R1 | 28.57% (10 people) | 28.57% (10 people) | 2.86% (1 people) |
| R2 | 25.71% (9 people) | 25.71% (9 people) | 2.86% (1 people) |
| R3 | 25.71% (9 people) | 25.71% (9 people) | 2.86% (1 people) |
| R4 | 31.43% (11 people) | 28.57% (10 people) | 5.71% (2 people) |
| R5 | 31.43% (11 people) | 28.57% (10 people) | 5.71% (2 people) |
| T1 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T2 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T3 | 5.71% (2 people) | 5.71% (2 people) | 0％ |
| T4 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T5 | 5.71% (2 people) | 5.71% (2 people) | 0％ |
| T6 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T7 | 8.57% (3 people) | 2.86% (1 people) | 0％ |
| T8 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T9 | 5.71% (2 people) | 5.71% (2 people) | 0％ |
| T10 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T11 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T12 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T13 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T14 | 5.71% (2 people) | 5.71% (2 people) | 0％ |
| T15 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T16 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T17 | 5.71% (2 people) | 5.71% (2 people) | 0％ |
| T18 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T19 | 5.71% (2 people) | 5.71% (2 people) | 0％ |
| T20 | 8.57% (3 people) | 2.86% (1 people) | 0％ |
| T21 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T22 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T23 | 5.71% (2 people) | 2.86% (1 people) | 0％ |
| T24 | 5.71% (2 people) | 5.71% (2 people) | 0％ |
| T25 | 8.57% (3 people) | 2.86% (1 people) | 0％ |
Can find out that from the result of clinical trial the H1 receptor antagonist oral cavity disintegration tablet of the present invention's preparation is compared with its ordinary tablet, side effect obviously reduces, and curative effect increases.Thereby more favourable proof several big advantage and the characteristics of H1 receptor antagonist oral cavity disintegration tablet of the present invention: 1) can absorb by the oral mucosa; 2) reduced the gastrointestinal stimulation.
Claims (32)
1. H1 receptor antagonist oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 2-60%
Skeleton proppant 5-65%
Binding agent 8-70%
Suspending agent 0-10%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
2. H1 receptor antagonist oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 3.85-49.70%
Skeleton proppant 19.61-46.15%
Binding agent 25.32-48.08%
Suspending agent 0-5.03%
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 H1 receptor antagonist 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 H1 receptor antagonist 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 H1 receptor antagonist 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. H1 receptor antagonist oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 2-60%
Glycine or mannitol or its mixture 5-65%
Pullulan or dextran or its mixture 8-70%
Xanthan gum or Konjac glucomannan or its mixture 0-10%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
7. H1 receptor antagonist oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 3.85-49.70%
Glycine or mannitol or its mixture 19.61-46.15%
Pullulan or dextran or its mixture 25.32-48.08%
Xanthan gum or Konjac glucomannan or its mixture 0-5.03%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
8. H1 receptor antagonist oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Principal agent 0.26-6.04%
Glycine or mannitol or its mixture 0.25-14.08%
Pullulan or dextran or its mixture 0.47-14.56%
Xanthan gum or Konjac glucomannan or its mixture 0-1.19%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 62.13-99.02%
Wherein each weight percentages of components sum is 100%.
9. H1 receptor antagonist oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Principal agent 0.5-5.00%
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 0-0.60%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 72.40-96.88%
Wherein each weight percentages of components sum is 100%.
10. like claim 1-2, each described H1 receptor antagonist oral cavity disintegration tablet among the 6-9 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.
11. like claim 1-2, each described H1 receptor antagonist oral cavity disintegration tablet among the 6-9 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.
12. a H1 receptor antagonist oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 52-1208 part
Glycine or mannitol or its mixture 50-2816 part
Pullulan or dextran or its mixture 94-2912 part
Xanthan gum or Konjac glucomannan or its mixture 0-238 part
Sweeting agent 0-200 part
Aromatic 0-200 part
Purified water 12426-19804 part.
13. a H1 receptor antagonist oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 100-1000 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 0-120 part
Sweeting agent 0-200 part
Aromatic 0-200 part
Purified water 14480-19376 part.
14. a H1 receptor antagonist oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 100-1000 part
Glycine or mannitol or its mixture 300-700 part
Pullulan or dextran or its mixture 400-800 part
Xanthan gum or Konjac glucomannan or its mixture 0-100 part
Sweeting agent 0-160 part
Aromatic 0-100 part
Purified water 16900-18800 part.
15. the method for preparing like any described H1 receptor antagonist of claim oral cavity disintegration 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 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.
16. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15, 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.
17. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15, the compound method that it is characterized in that said step (a) mesostroma liquid is for adopting the method preparation of mulser.
18. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15 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.
19. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15, 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.
20. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15, 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.
21. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15 is characterized in that the pre-freeze temperature is-40 ℃～-170 ℃ in the said step (d), the pre-freeze time is 1～60min.
22. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15 is characterized in that the pre-freeze temperature is-60 ℃～-150 ℃ in the said step (d), the pre-freeze time is 2～30min.
23. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15 is characterized in that the pre-freeze temperature is-100 ℃～-130 ℃ in the said step (d), the pre-freeze time is 3～6min.
24. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15; 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.
25. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15; 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.
26. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15 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.
27. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15 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.
28. the method for preparing of the H1 receptor antagonist oral cavity disintegration tablet described in claim 15 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.
29. the method for preparing like any described H1 receptor antagonist of claim oral cavity disintegration tablet among the claim 6-7 is characterized in that adopting following steps to make:
(a) with principal agent, 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) 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 H1 receptor antagonist 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.
30. the method for preparing like any described H1 receptor antagonist of claim oral cavity disintegration tablet among claim 8-9, the 12-14 is characterized in that adopting following steps to make:
With principal agent, 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 oral loratadine disintegrating 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.
31. the method for preparing like any described H1 receptor antagonist of claim oral cavity disintegration tablet among claim 8-9, the 12-14 is characterized in that adopting following steps to make:
With principal agent, 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 oral loratadine disintegrating 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.
32. like the described H1 receptor antagonist of any claim among the claim 1-31, comprise cetirizine, Desloratadine, azelastine, ebastine etc. with and pharmaceutically useful salt, ester, optical isomer.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8937178B2 (en) | 2013-03-13 | 2015-01-20 | Flatley Discovery Lab | Phthalazinone compounds and methods for the treatment of cystic fibrosis |
| CN105769795A (en) * | 2016-04-06 | 2016-07-20 | 合肥华方医药科技有限公司 | Desloratadine citrate disodium freeze-dried oral instant tablets and preparing method thereof |
| CN114568708A (en) * | 2020-11-30 | 2022-06-03 | 河北菲瑞生物技术有限公司 | Lactoferrin preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN1915215A (en) * | 2005-08-17 | 2007-02-21 | 量子高科（北京）研究院有限公司 | Oral cavity disintegration preparation |
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Patent Citations (2)
| 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 |
| CN1915215A (en) * | 2005-08-17 | 2007-02-21 | 量子高科（北京）研究院有限公司 | Oral cavity disintegration preparation |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8937178B2 (en) | 2013-03-13 | 2015-01-20 | Flatley Discovery Lab | Phthalazinone compounds and methods for the treatment of cystic fibrosis |
| US9783529B2 (en) | 2013-03-13 | 2017-10-10 | Flatley Discovery Lab, Llc | Pyridazinone compounds and methods for the treatment of cystic fibrosis |
| US9790215B2 (en) | 2013-03-13 | 2017-10-17 | Flatley Discovery Lab, Llc | Pyridazinone compounds and methods for the treatment of cystic fibrosis |
| CN105769795A (en) * | 2016-04-06 | 2016-07-20 | 合肥华方医药科技有限公司 | Desloratadine citrate disodium freeze-dried oral instant tablets and preparing method thereof |
| CN105769795B (en) * | 2016-04-06 | 2018-11-06 | 合肥华方医药科技有限公司 | A kind of Chinese holly Desloratadine freeze-drying oral instant-dissolving tablet and preparation method thereof |
| CN114568708A (en) * | 2020-11-30 | 2022-06-03 | 河北菲瑞生物技术有限公司 | Lactoferrin preparation and preparation method thereof |
| CN114568708B (en) * | 2020-11-30 | 2023-12-12 | 湖北菲瑞生物药业有限公司 | Lactoferrin preparation and preparation method thereof |
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