CN102579377A - Anti-anginal drug orally disintegrating tablet and producing method thereof - Google Patents
Anti-anginal drug orally disintegrating tablet and producing method thereof Download PDFInfo
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- CN102579377A CN102579377A CN2011100219710A CN201110021971A CN102579377A CN 102579377 A CN102579377 A CN 102579377A CN 2011100219710 A CN2011100219710 A CN 2011100219710A CN 201110021971 A CN201110021971 A CN 201110021971A CN 102579377 A CN102579377 A CN 102579377A
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- Prior art keywords
- mixture
- oral cavity
- aromatic
- agent
- disintegration tablet
- Prior art date
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses an anti-anginal drug orally disintegrating tablet and a producing method thereof, and relates to the anti-anginal drug orally disintegrating tablet and a prescription and a process utilizing the freeze-drying method to produce the anti-anginal drug orally disintegrating tablet. The anti-anginal drug orally disintegrating tablet is produced by main drug and pharmaceutic adjuvant, no water is needed while users take the tablet, and the tablet disintegrates rapidly after being delivered to the mouth, thereby the tablet is suitable for dysphagia patients such as the old, children and the like; the tablet is suitable for traveling under the condition that water is not easy to get; the non-steroidal anti-inflammatory drug orally disintegrating tablet has the advantages of convenience in taking, rapid working, small first pass effect, small irritation to digestive tract mucosa and the like, the tablet has a broad application prospect in the market, and the anti-anginal drug orally disintegrating tablet is capable of effectively reducing side effects of anti-anginal drugs. In addition, the invention further relates to the anti-anginal drug orally disintegrating tablet producing method.
Description
Technical field:
The present invention relates to a kind of antianginal drug oral cavity disintegration tablet and preparation method thereof, particularly a kind of antianginal drug oral cavity disintegration tablet that adopts the freeze-drying preparation.
Background technology:
Angina pectoris (angina pectoris) is the common sympton of coronary atherosclerosis property heart disease (coronary heart disease), by cardiac muscle rapid, temporary ischemia and anoxia cause, angina pectoris continues outbreak and can not get timely alleviation and then possibly develop into acute myocardial infarction.Anginal main pathophysiological mechanism is the dysequilibrium of aerobic and oxygen supply of cardiac muscle; Cause myocardium temporary hypoxic-ischemic; Metabolite (lactic acid, acetone acid, histamine, similar kassinin kinin appearance polypeptide, K+ etc.) is built up cardiac muscular tissue, stimulates myocardium autonomic nerve centripetal fiber tip to cause pain.Anyly cause that cardiac muscular tissue increases the demand of oxygen or/and coronary stenosis, spasm cause factor that cardiac muscular tissue's blood supply oxygen supply reduces all can become and bring out anginal inducement.Be divided into 1. fatigue property angina pectoris (angina of effort) according to clinical manifestation; 2. spontaneous angina pectoris (angina pectoris at rest); 3. mixed angina pectoris (mixed patternof angina).Anti-anginal drug commonly used at present can be through removing coronary spasm or promoting side Zhi Xunhuan to increase coronary blood supply; Also can be through weakening the ventricle wall muscular tension; Reduce myocardial contraction intensity and decreased heart rate and reduce myocardium requirementing keto quantity, recover the equilibrium of supply and demand of blood, oxygen and bring into play therapeutical effect.Antianginal drug mainly is divided into following several types: 1) nitrate esters and nitrous acid ester: comprise isosorbide mononitrate, sorbide nitrate etc.; 2) beta-2 adrenoceptor blocker: comprise bisoprolol etc.; 3) calcium antagonist: comprise diltiazem etc.; 4) other: comprise trimetazidine etc.
The basic role of nitrate esters and nitrous acid ester medicine is relaxing smooth muscle; But the selectivity to the different tissues organ has difference; Effect with to vascular smooth muscle is the most remarkable, through the mechanism of action relaxing smooth muscle identical with the endogenous endothelium-derived relaxing factor and don't depend on vascular endothelial cell.Therefore, there is the blood vessel of pathological changes still can play a role at endothelium.Sublingual administration nitrate esters and nitrous acid ester medicine can be alleviated all kinds angina pectoris rapidly, and medication also can prevent outbreak before expectation possibly show effect.The beta-2 adrenoceptor blocker can make angina pectoris patient angina pectoris attacks number of times reduce, improve the ischemic electrocardiogram, increase the patient moving tolerance, reduce myocardial oxygen consumption, improve the ischemic region metabolism; Dwindle myocardial infarct size, prevent and treat anginal medicine as a line at present.Calcium antagonist is the clinical anginal medicine commonly used that is used for preventing and treating, and is particularly best to the variant angina pectoris curative effect.
The dosage form of at present domestic granted antianginal drug has tablet, capsule, suppository, dispersible tablet, injection etc.See from the hospital terminal medication, large usage quantity be tablet, and capsule is not popular clinically, 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, 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.Patient with angina pectoris is in the majority with the old people, and its each item physiological function descends, handicapped, dysphagia; In addition, the hyperposia of taking medicine evening can influence old people's night's rest again; And need medicine onset rapidly during for the angina pectoris acute attack.Therefore develop a kind ofly do not need, swallow easily with water delivery service, patient's compliance and compliance preparation good, onset rapidly be very important.
Antianginal drug oral cavity disintegration tablet of the present invention need not water when taking; In mouth, running into saliva dissolves rapidly; For old people, child, the difficult change of bed position etc. exist taking medicine of dysphagia patients that great facility is provided; Be adapted at simultaneously in the tourism way, be difficult for obtaining 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 the antianginal drug 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 antianginal drug 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; And when the angina pectoris acute attack, antianginal drug that can quick acting is a better choice for the patient.Through clinical trial, the discovery that the inventor is surprised is compared with the antianginal drug oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and the prepared antianginal drug oral cavity disintegration tablet of the present invention all has the characteristics of 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 antianginal drug 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 antianginal drug 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 and clinical trial; Onset is rapid; And surprised discovery is compared with the antianginal drug oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and the side effect of the antianginal drug oral cavity disintegration tablet of the present invention's preparation obviously reduces, on curative effect, also increases.
The antianginal drug 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 antianginal drug oral cavity disintegration tablet of the present invention is following:
Weight percentages of components
Principal agent 2-75%
Skeleton proppant 2-85%
Binding agent 4-90%
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 5.38-66.67%
Skeleton proppant 5.56-78.43%
Binding agent 8.11-81.63%
Suspending agent 0-3.53%
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 most preferred each component is following:
Weight percentages of components
Principal agent 19.03-49.26%
Skeleton proppant 19.70-38.05%
Binding agent 21.67-42.62%
Suspending agent 0-3.53%
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, dextran, 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, dextran, glycine, serine, arginine or their mixture, most preferably glycine or mannitol or dextran 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, alginate, cellulose and derivant, hyaluronic acid, modified starch, polyvinyl alcohol, chitosan or their mixture; Particularly preferably be Pullulan, alginate, cellulose and derivant thereof or their mixture, most preferably Pullulan or alginate 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 antianginal drug 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 freezing dry process, find that freezing dry 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 freezing dry process when we finally confirm that freeze-drying prepares the antianginal drug oral cavity disintegration tablet through a large amount of experimentatioies are wherein in the method for preparing of 5-HT receptor stimulating agent oral cavity disintegration tablet; The pre-freeze temperature is-40 ℃～-170 ℃; The pre-freeze time is 1～60min; The lyophilization temperature is-30 ℃～30 ℃; Sublimation drying is 1～10h; Vacuum in the freezing dry process is 0.01mbar～10mbar.
The method for preparing of antianginal drug oral cavity disintegration tablet of the present invention 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.
The method for preparing of the preferred described antianginal drug oral cavity disintegration tablet of the present invention is:
(a) preparation of substrate liquid: 2-75% principal agent, 2-85% skeleton proppant, 4-90% binding agent and other adjuvant are joined in the good 0-10% 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 percentage by weight of each component of antianginal drug oral cavity disintegration tablet of the present invention is following:
Principal agent 2-75%
Glycine or mannitol or dextran or its mixture 2-85%
Pullulan or sodium alginate or its mixture 4-90%
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%.
Preferred antianginal drug oral cavity disintegration tablet of the present invention, form by following components in weight percentage:
Principal agent 5.38-66.67%
Glycine or mannitol or dextran or its mixture 5.56-78.43%
Pullulan or sodium alginate or its mixture 8.11-81.63%
Xanthan gum or Konjac glucomannan or its mixture 0-3.53%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
Antianginal drug oral cavity disintegration tablet most preferably of the present invention, form by following components in weight percentage:
Principal agent 19.03-49.26%
Glycine or mannitol or dextran or its mixture 19.70-38.05%
Pullulan or sodium alginate or its mixture 21.67-42.62%
Xanthan gum or Konjac glucomannan or its mixture 0-3.53%
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:
Isosorbide mononitrate 35.91%
Glycine or mannitol or dextran or its mixture 30.88%
Pullulan or sodium alginate or its mixture 32.32%
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 antianginal drug oral cavity disintegration tablet of the present invention is:
(a) preparation of substrate liquid: with principal agent, glycine or mannitol or dextran or its mixture, Pullulan or sodium alginate 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 antianginal drug 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.
Antianginal drug oral cavity disintegration tablet of the present invention is processed by the component of following weight percentage ratio:
Principal agent 0.46-8.44%
Glycine or mannitol or dextran or its mixture 0.36-10.84%
Pullulan or sodium alginate or its mixture 0.74-11.03%
Xanthan gum or Konjac glucomannan or its mixture 0-1.02%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 66.67-98.44%
Wherein each weight percentages of components sum is 100%.
The preferred antianginal drug oral cavity disintegration tablet of the present invention is processed by the component of following weight percentage ratio:
Principal agent 1.25-7.50%
Glycine or mannitol or dextran or its mixture 1.00-10.00%
Pullulan or sodium alginate or its mixture 1.50-10.00%
Xanthan gum or Konjac glucomannan or its mixture 0-0.36%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 73.00-96.25%
Wherein each weight percentages of components sum is 100%.
The most preferred antianginal drug oral cavity disintegration tablet of the present invention is processed by the component of following weight percentage ratio:
Principal agent 1.25-7.50%
Glycine or mannitol or dextran or its mixture 2.00-5.00%
Pullulan or sodium alginate or its mixture 2.20-5.00%
Xanthan gum or Konjac glucomannan or its mixture 0-0.36%
Sweeting agent 0.01-1.00%
Aromatic 0.01-1.00%
Purified water 81.30-93.43%
Wherein each weight percentages of components sum is 100%.
Antianginal drug oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Principal agent 92-2251 part
Glycine or mannitol or dextran or its mixture 72-4336 part
Pullulan or sodium alginate or its mixture 148-4412 part
Xanthan gum or Konjac glucomannan or its mixture 0-204 part
Sweeting agent 0-400 part
Aromatic 0-400 part
Purified water 14019-37842 part.
The preferred antianginal drug oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Principal agent 250-2000 part
Glycine or mannitol or dextran or its mixture 200-4000 part
Pullulan or sodium alginate or its mixture 300-4000 part
Xanthan gum or Konjac glucomannan or its mixture 0-72 part
Sweeting agent 0-400 part
Aromatic 0-400 part
Purified water 15350-37000 part.
The most preferred antianginal drug oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Principal agent 250-2000 part
Glycine or mannitol or dextran or its mixture 400-2000 part
Pullulan or sodium alginate or its mixture 440-2000 part
Xanthan gum or Konjac glucomannan or its mixture 0-72 part
Sweeting agent 2-400 part
Aromatic 2-400 part
Purified water 16260-33940 part.
The present invention preferably fills a prescription and is processed by following components by part by weight:
1000 parts of isosorbide mononitrates
500 parts in mannitol
360 parts of dextrans
900 parts of Pullulan
15 parts of sweeting agents
10 parts of aromatic
17215 parts of purified water.
The most preferred prescription of the present invention is processed by the component of following weight:
Isosorbide mononitrate 10.00g
Mannitol 5.00g
Dextran 3.60g
Pullulan 9.00g
Aspartame 0.15g
Herba Menthae essence 0.10g
Purified water 172.15g
Process 1000 altogether.
Its preparation method is: with principal agent, glycine or mannitol or dextran or its mixture, Pullulan or sodium alginate 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 antianginal drug 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 5～15h.
Antianginal drug 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 the oral disintegrated preparation that has overcome the direct compression process preparation has the defective of grittiness in the oral cavity.
Antianginal drug oral cavity disintegration tablet of the present invention has following advantage:
1, good mouthfeel, taking convenience: antianginal drug 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, rapid-action, avoid the first pass effect of liver: the disintegrate rapidly in mouth of the antianginal drug 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, gastrointestinal absorption fast, stimulate little: the antianginal drug oral cavity disintegration tablet of the present invention's preparation before medicine arrives gastrointestinal tract rapidly disintegrate also be dispersed into trickle granule; Cause medicine to distribute in the gastrointestinal tract large tracts of land; Absorption point increases, and has improved medicine greatly in the gastrointestinal infiltration rate, has avoided medicine too high at the gastrointestinal tract local concentration; Cause the local irritant shortcoming of gastrointestinal, untoward reaction reduces.
4, side effect is little; Curative effect improves: the antianginal drug oral cavity disintegration tablet through the wonderful discovery the present invention preparation of clinical trial is compared with the antianginal drug oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet; Side effect significantly reduces, and curative effect increases to some extent.
Antianginal drug 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.
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
Isosorbide mononitrate 10.00g
Mannitol 5.00g
Dextran 3.60g
Pullulan 9.00g
Aspartame 0.15g
Herba Menthae essence 0.10g
Purified water 172.15g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, dextran, Pullulan, aspartame, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; After solution carried out vacuum outgas, 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 isosorbide mononitrate orally disintegrating tablets 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.
Embodiment 2
Isosorbide mononitrate 10.00g
Glycine 5.00g
Dextran 3.60g
Pullulan 9.00g
Aspartame 0.15g
Herba Menthae essence 0.10g
Purified water 172.15g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, dextran, Pullulan, aspartame, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 3
Isosorbide mononitrate 10.00g
Mannitol 5.40g
Dextran 3.80g
Pullulan 6.20g
Sodium alginate 3.00g
Acesulfame potassium 0.20g
Orange flavor 0.20g
Purified water 171.20g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, dextran, Pullulan, sodium alginate, acesulfame potassium, orange flavor mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 4
Isosorbide mononitrate 10.00g
Mannitol 8.00g
Pullulan 9.00g
Acesulfame potassium 0.16g
Herba Menthae essence 0.12g
Purified water 172.72g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, Pullulan, acesulfame potassium, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 5
Isosorbide mononitrate 20.00g
Glycine 2.00g
Dextran 2.00g
Sodium alginate 6.00g
Purified water 370.00g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, dextran, sodium alginate mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 6
Isosorbide mononitrate 10.00g
Glycine 9.00g
Pullulan 6.00g
Sodium alginate 3.60g
Aspartame 0.18g
Flavoring pineapple essence 0.14g
Purified water 171.08g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, Pullulan, sodium alginate, aspartame, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 7
Isosorbide mononitrate 10.00g
Glycine 4.80g
Dextran 3.60g
Pullulan 9.60g
Sucralose 0.06g
Herba Menthae essence 0.08g
Purified water 171.86g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, dextran, Pullulan, sucralose, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 8
Isosorbide mononitrate 20.00g
Mannitol 11.60g
Dextran 8.00g
Pullulan 20.00g
Aspartame 0.60g
Herba Menthae essence 0.40g
Purified water 339.40g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, dextran, Pullulan, aspartame, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 9
Isosorbide mononitrate 10.00g
Mannitol 5.20g
Dextran 4.00g
Hydroxypropyl emthylcellulose 7.00g
Sucralose 0.10g
Flavoring pineapple essence 0.20g
Purified water 173.50g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, dextran, hydroxypropyl emthylcellulose, sucralose, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 10
Isosorbide mononitrate 2.50g
Glycine 10.00g
Mannitol 10.00g
Pullulan 20.00g
Sucrose 2.00g
Orange flavor 2.00g
Purified water 153.50g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, mannitol, Pullulan, sucrose, orange flavor mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 11
Isosorbide mononitrate 20.00g
Mannitol 20.00g
Pullulan 20.00g
Sucralose 0.40g
Purified water 339.60g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, Pullulan, sucralose mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 12
Isosorbide mononitrate 20.00g
Mannitol 30.00g
Dextran 10 .00g
Pullulan 2.00g
Sodium alginate 4.00g
Acesulfame potassium 4.00g
Strawberry essence 4.00g
Purified water 326.00g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, dextran, Pullulan, sodium alginate, acesulfame potassium, strawberry essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 13
Isosorbide mononitrate 2.50g
Mannitol 2.00g
Pullulan 2.50g
Sodium alginate 0.50g
Purified water 192.50g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, Pullulan, sodium alginate mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 14
Isosorbide mononitrate 5.00g
Mannitol 6.00g
Pullulan 6.40g
Aspartame 0.10g
Herba Menthae essence 0.06g
Purified water 182.44g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, Pullulan, aspartame, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 15
Isosorbide mononitrate 20.00g
Glycine 24.00g
Dextran 1 6.00g
Pullulan 32.00g
Sodium alginate 8.00g
Aspartame 4.00g
Flavoring pineapple essence 4.00g
Purified water 292.00g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, dextran, Pullulan, sodium alginate, aspartame, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 16
Isosorbide mononitrate 2.50g
Glycine 5.00g
Pullulan 5.60g
Aspartame 0.02g
Herba Menthae essence 0.02g
Purified water 186.86g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, Pullulan, aspartame, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 17
Isosorbide mononitrate 2.50g
Glycine 8.00g
Mannitol 12.00g
Pullulan 3.00g
Purified water 174.50g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, mannitol, Pullulan mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 18
Isosorbide mononitrate 10.00g
Mannitol 5.20g
Dextran 3.40g
Pullulan 8.80g
Aspartame 0.15g
Herba Menthae essence 0.10g
Purified water 172.35g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, dextran, Pullulan, aspartame, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 19
Isosorbide mononitrate 20.00g
Mannitol 2.00g
Dextran 2.00g
Pullulan 40.00g
Sucralose 4.00g
Herba Menthae essence 4.00g
Purified water 328.00g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, dextran, Pullulan, sucralose, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 20
Isosorbide mononitrate 10.00g
Mannitol 5.80g
Dextran 4.00g
Pullulan 10.00g
Aspartame 0.15g
Herba Menthae essence 0.10g
Purified water 169.95g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, mannitol, dextran, Pullulan, aspartame, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 21
Isosorbide mononitrate 20.00g
Glycine 12.00g
Dextran 8.00g
Pullulan 14.00g
Sodium alginate 6.00g
Sucrose 2.00g
Orange flavor 1.20g
Purified water 336.80g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, dextran, Pullulan, sodium alginate, sucrose, the fragrant mix homogeneously of Fructus Citri sinensis, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 22
Isosorbide mononitrate 2.50g
Glycine 2.00g
Pullulan 14.00g
Sodium alginate 6.00g
Purified water 175.50g
Process 1000 altogether.
Concrete method for preparing is described below: with isosorbide mononitrate, glycine, Pullulan, sodium alginate mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 23
Sorbide nitrate 5.00g
Mannitol 5.00g
Pullulan 5.40g
Xanthan gum 0.06g
Sucralose 0.20g
Herba Menthae essence 0.20g
Purified water 184.14g
Process 1000 altogether.
Concrete method for preparing is described below: with sorbide nitrate, mannitol, Pullulan, sucralose, Herba Menthae essence mix homogeneously, join in the good xanthan gum solution of abundant dissolving, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 24
Sorbide nitrate 10.00g
Glycine 4.00g
Pullulan 4.40g
Konjac glucomannan 0.72g
Sucrose 0.80g
Orange flavor 0.50g
Purified water 179.58g
Process 1000 altogether.
Concrete method for preparing is described below: with sorbide nitrate, glycine, Pullulan, sucrose, orange flavor mix homogeneously, join in the good Konjac glucomannan solution of abundant dissolving, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 25
Sorbide nitrate 5.00g
Glycine 2.30g
Mannitol 2.30g
Pullulan 3.00g
Sodium alginate 2.00g
Xanthan gum 0.02g
Konjac glucomannan 0.12g
Aspartame 0.40g
Flavoring pineapple essence 0.20g
Purified water 184.66g
Process 1000 altogether.
Concrete method for preparing is described below: with sorbide nitrate, glycine, mannitol, Pullulan, sodium alginate, aspartame, flavoring pineapple essence mix homogeneously; Join in the solution of good xanthan gum of abundant dissolving and Konjac glucomannan, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 26
Bisoprolol fumarate 5.00g
Glycine 6.00g
Pullulan 6.40g
Sucralose 0.04g
Herba Menthae essence 0.04g
Purified water 182.52g
Process 1000 altogether.
Concrete method for preparing is described below: with bisoprolol fumarate, glycine, Pullulan, sucralose, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 27
Bisoprolol fumarate 2.50g
Mannitol 5.00g
Pullulan 5.60g
Sucralose 0.02g
Herba Menthae essence 0.02g
Purified water 186.86g
Process 1000 altogether.
Concrete method for preparing is described below: with bisoprolol fumarate, mannitol, Pullulan, sucralose, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 28
Bisoprolol fumarate 5.00g
Glycine 3.00g
Mannitol 2.60g
Pullulan 4.00g
Sodium alginate 2.00g
Aspartame 0.10g
Strawberry essence 0.06g
Purified water 183.24g
Process 1000 altogether.
Concrete method for preparing is described below: with bisoprolol fumarate, glycine, mannitol, Pullulan, sodium alginate, aspartame, strawberry essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 29
Trimetazidine Hydrochloride 20.00g
Mannitol 12.00g
Dextran 8.00g
Pullulan 20.00g
Sucralose 3.00g
Herba Menthae essence 3.00g
Purified water 334.00g
Process 1000 altogether.
Concrete method for preparing is described below: with Trimetazidine Hydrochloride, mannitol, dextran, Pullulan, sucralose, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 30
Trimetazidine Hydrochloride 10.00g
Mannitol 5.00g
Dextran 3.60g
Pullulan 9.00g
Sucralose 1.00g
Herba Menthae essence 1.00g
Purified water 170.40g
Process 1000 altogether.
Concrete method for preparing is described below: with Trimetazidine Hydrochloride, mannitol, dextran, Pullulan, sucralose, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 31
Trimetazidine Hydrochloride 20.00g
Glycine 11.60g
Dextran 7.60g
Pullulan 16.00g
Sodium alginate 3.60g
Aspartame 4.00g
Flavoring pineapple essence 4.00g
Purified water 333.20g
Process 1000 altogether.
Concrete method for preparing is described below: with Trimetazidine Hydrochloride, glycine, dextran, Pullulan, sodium alginate, aspartame, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 32
Diltiazem hydrochloride 15.00g
Mannitol 5.80g
Dextran 4.00g
Pullulan 10.00g
Sucralose 1.20g
Herba Menthae essence 1.20g
Purified water 162.80g
Process 1000 altogether.
Concrete method for preparing is described below: with diltiazem hydrochloride, mannitol, dextran, Pullulan, sucralose, Herba Menthae essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 33
Diltiazem hydrochloride 15.00g
Mannitol 6.00g
Dextran 4.00g
Sodium alginate 8.00g
Aspartame 1.80g
Strawberry essence 1.80g
Purified water 163.40g
Process 1000 altogether.
Concrete method for preparing is described below: with diltiazem hydrochloride, mannitol, dextran, sodium alginate, aspartame, strawberry essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 34
Diltiazem hydrochloride 15.00g
Glycine 5.40g
Dextran 3.80g
Pullulan 9.60g
Acesulfame potassium 2.00g
Flavoring pineapple essence 1.60g
Purified water 162.60g
Process 1000 altogether.
Concrete method for preparing is described below: with diltiazem hydrochloride, glycine, dextran, Pullulan, acesulfame potassium, flavoring pineapple essence mix homogeneously, to the purified water that wherein adds recipe quantity, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
For a better understanding of the present invention, use disintegration, the mouthfeel description of test advantage of the present invention of the antianginal drug oral cavity disintegration tablet of preparation below; Through volunteer's oral mucosa permeability test and clinical trial; The effect that antianginal drug 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 antianginal drug oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and side effect obviously reduces, on curative effect, also increases.
1, disintegration:
Get the isosorbide mononitrate orally disintegrating tablets (R2 group) and the prepared isosorbide mononitrate orally disintegrating tablets (T group) (T1-T22 representes the oral cavity disintegration tablet of embodiment 1-embodiment 22 preparations respectively) of embodiment 1-22 of isosorbide mononitrate sheet (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 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 antianginal drug oral cavity disintegration tablet that the present invention is prepared will be much smaller than ordinary tablet and pressing oral cavity disintegration tablet; The prepared antianginal drug 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 antianginal drug oral cavity disintegration tablet of embodiment 1-34 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 isosorbide mononitrate orally disintegrating tablets (R2 group) and the prepared isosorbide mononitrate orally disintegrating tablets (T group) (T1-T22 representes the oral cavity disintegration tablet of embodiment 1-embodiment 22 preparations respectively) of embodiment 1-22 of isosorbide mononitrate sheet (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
Can know from table 2; In human mouth; The mucosa permeability (about about 20%～22%) of the antianginal drug oral cavity disintegration tablet that the present invention is prepared is apparently higher than the mucosa permeability (being about 0.80%) and the antianginal drug ordinary tablet (being about 0.016%) that adopt the prepared antianginal drug oral cavity disintegration tablet of pressing; Thereby explain that the prepared antianginal drug oral cavity disintegration tablet of the present invention can absorb by the oral mucosa, onset rapidly reduces first pass effect.
4, clinical trial
Experimental program:
According to the Unified National diagnostic criteria, select angina pectoris patient 105 examples, be divided into 3 groups at random, every group of each 35 people.Get rid of following situation: (1) 6 month with the interior patient who does not find myocardial infarction; (2) merge the patient of cardiac function more than 3 grades; (3) serious arrhythmia; (4) to using drug allergy; (5) liver, renal function are seriously incomplete.Selected patient withdraws other antianginal drugs in 1 week before test.Give isosorbide mononitrate orally disintegrating tablets 10mg (R2 group) or the prepared isosorbide mononitrate orally disintegrating tablets 10mg (T group) (T1-T22 representes the oral cavity disintegration tablet of embodiment 1-embodiment 22 preparations respectively) of the present invention that the patient takes isosorbide mononitrate 10mg (R1 group), pressing preparation respectively every day; Every day 3 times, be 4 weeks the course of treatment.The number of times that shows effect weekly with clinical symptoms, angina pectoris before and after the treatment and curative effects such as the time that continues, Electrocardiographic variation are as observation index, and blood before and after the treatment, urine, just routine, liver, renal function be as safe observation index.Adverse effect is observed and write down to duration of test, and a situation arises.
Curative effect determinate standard: (1) produce effects: the angina pectoris attacks number of times reduces more than 80%, and the angina pectoris classification improves 2 grades, or resting electrocardiogram is normal; (2) effective: the angina pectoris attacks number of times reduces 50%-80%, and the electrocardiogram classification improves 1 grade, or resting electrocardiogram S-T section rise i＞0.5mV; (3) invalid: the angina pectoris attacks number of times reduces below 50%, angina pectoris classification no change, and resting electrocardiogram does not have change.Total effective rate (%)=(produce effects example number+effective routine number)/this organizes total routine number * 100%.
Respectively sorbide nitrate is respectively organized preparation (dosage is 5mg, the sorbide nitrate oral cavity disintegration tablet (T group) (T23-T25 representes the oral cavity disintegration tablet of embodiment 23-embodiment 25 preparations respectively) that the sorbide nitrate oral cavity disintegration tablet (R4 group) of isosorbide dinitrate tablets (R3 group), pressing preparation or the present invention are prepared) according to the method described above; The bisoprolol fumarate respectively organizes preparation, and (dosage is 5mg; 2 times/day, bisoprolol fumarate's oral cavity disintegration tablet (T group) (T26-T28 representes the oral cavity disintegration tablet of embodiment 26-embodiment 28 preparations respectively) that bisoprolol fumarate's oral cavity disintegration tablet (R6 group) of bisoprolol fumarate's sheet (R5 group), pressing preparation or the present invention are prepared); Trimetazidine Hydrochloride is respectively organized preparation (dosage is 20mg, the oral disintegrating tablet of trimetazidine (T group) (T29-T31 representes the oral cavity disintegration tablet of embodiment 29-embodiment 31 preparations respectively) that the oral disintegrating tablet of trimetazidine (R8 group) of Trimetazidine Hydrochloride Tablets in healthy (R7 group), pressing preparation or the present invention are prepared); Diltiazem hydrochloride is respectively organized preparation, and (dosage is 30mg; The diltiazem hydrochloride oral cavity disintegration tablet (T group) (T32-T34 representes the oral cavity disintegration tablet of embodiment 32-embodiment 34 preparations respectively) that the diltiazem hydrochloride oral cavity disintegration tablet (R10 group) of diltiazem (R9 group), pressing preparation or the present invention are prepared) carried out clinical trial, the result sees table 3-table 6.
Table 3 isosorbide mononitrate is respectively organized clinical efficacy relatively (n=35, routine number)
| Group | Produce effects | Effectively | Invalid | Total effective rate (%) |
| The R1 group | 10 | 14 | 11 | 68.6 |
| The R2 group | 12 | 15 | 8 | 77.1 |
| T1 | 24 | 8 | 3 | 91.4 |
| T2 | 24 | 8 | 3 | 91.4 |
| T3 | 24 | 8 | 3 | 91.4 |
| T4 | 23 | 8 | 4 | 88.6 |
| T5 | 22 | 9 | 4 | 88.6 |
| T6 | 23 | 8 | 4 | 88.6 |
| T7 | 24 | 8 | 3 | 91.4 |
| T8 | 24 | 8 | 3 | 91.4 |
| T9 | 23 | 8 | 4 | 88.6 |
| T10 | 22 | 8 | 5 | 85.7 |
| T11 | 23 | 8 | 4 | 88.6 |
| T12 | 22 | 9 | 4 | 88.6 |
| T13 | 23 | 8 | 4 | 88.6 |
| T14 | 24 | 8 | 3 | 91.4 |
| T15 | 22 | 8 | 5 | 85.7 |
| T16 | 23 | 9 | 3 | 91.4 |
| T17 | 23 | 8 | 4 | 88.6 |
| T18 | 24 | 8 | 3 | 91.4 |
| T19 | 21 | 9 | 5 | 85.7 |
| T20 | 24 | 8 | 3 | 91.4 |
| T21 | 23 | 9 | 3 | 91.4 |
| T22 | 21 | 9 | 5 | 85.7 |
Table 4 isosorbide mononitrate is respectively organized the comparison (n=35) that the preparation untoward reaction takes place
| Group | Flush | Headache, dizziness | Feel sick, vomit |
| The R1 group | 8.57% (3 people) | 14.29% (5 people) | 5.71% (2 people) |
| The R2 group | 5.71% (2 people) | 11.43% (4 people) | 2.86% (1 people) |
| T1 | 0％ | 2.86% (1 people) | 0％ |
| T2 | 0％ | 2.86% (1 people) | 0％ |
| T3 | 0％ | 2.86% (1 people) | 0％ |
| T4 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T5 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T6 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T7 | 0％ | 2.86% (1 people) | 0％ |
| T8 | 0％ | 2.86% (1 people) | 0％ |
| T9 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T10 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T11 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T12 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T13 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T14 | 0％ | 2.86% (1 people) | 0％ |
| T15 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T16 | 0％ | 2.86% (1 people) | 0％ |
| T17 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T18 | 0％ | 2.86% (1 people) | 0％ |
| T19 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
| T20 | 0％ | 2.86% (1 people) | 0％ |
| T21 | 0％ | 2.86% (1 people) | 0％ |
| T22 | 2.86% (1 people) | 2.86% (1 people) | 0％ |
All the other respectively organize preparation clinical efficacy relatively (n=35, routine number) table 5
| Group | Produce effects | Effectively | Invalid | Total effective rate (%) |
| The R3 group | 9 | 14 | 12 | 65.7 |
| The R4 group | 11 | 15 | 9 | 74.3 |
| T23 | 23 | 9 | 3 | 91.4 |
| T24 | 23 | 9 | 3 | 91.4 |
| T25 | 22 | 10 | 3 | 91.4 |
| The R5 group | 12 | 13 | 10 | 71.4 |
| The R6 group | 13 | 14 | 8 | 77.1 |
| T26 | 25 | 8 | 2 | 94.3 |
| T27 | 24 | 9 | 2 | 94.3 |
| T28 | 25 | 8 | 2 | 94.3 |
| The R7 group | 12 | 12 | 11 | 68.6 |
| The R8 group | 13 | 13 | 9 | 74.3 |
| T29 | 25 | 7 | 3 | 91.4 |
| T30 | 25 | 7 | 3 | 91.4 |
| T31 | 24 | 8 | 3 | 91.4 |
| The R9 group | 8 | 15 | 12 | 65.7 |
| The R10 group | 10 | 16 | 9 | 74.3 |
| T32 | 23 | 9 | 3 | 91.4 |
| T33 | 24 | 8 | 3 | 91.4 |
| T34 | 23 | 9 | 3 | 91.4 |
All the other respectively organize the comparison (n=35) that the preparation untoward reaction takes place table 6
| Group | Flush | Headache, dizziness | Feel sick, vomit |
| The R3 group | 8.57% (3 people) | 14.29% (5 people) | 5.71% (2 people) |
| The R4 group | 5.71% (2 people) | 11.43% (4 people) | 2.86% (1 people) |
| T23 | 0％ | 2.86% (1 people) | 0％ |
| T24 | 0％ | 2.86% (1 people) | 0％ |
| T25 | 0％ | 2.86% (1 people) | 0％ |
| The R5 group | 2.86% (1 people) | 14.29% (5 people) | 5.71% (2 people) |
| The R6 group | 2.86% (1 people) | 11.43% (4 people) | 2.86% (1 people) |
| T26 | 0％ | 2.86% (1 people) | 0％ |
| T27 | 0％ | 2.86% (1 people) | 0％ |
| T28 | 0％ | 2.86% (1 people) | 0％ |
| The R7 group | 2.86% (1 people) | 11.43% (4 people) | 5.71% (2 people) |
| The R8 group | 2.86% (1 people) | 8.57% (3 people) | 2.86% (1 people) |
| T29 | 0％ | 2.86% (1 people) | 0％ |
| T30 | 0％ | 2.86% (1 people) | 0％ |
| T31 | 0％ | 2.86% (1 people) | 0％ |
| The R9 group | 5.71% (2 people) | 11.43% (4 people) | 5.71% (2 people) |
| The R10 group | 2.86% (1 people) | 8.57% (3 people) | 2.86% (1 people) |
| T32 | 0％ | 2.86% (1 people) | 0％ |
| T33 | 0％ | 2.86% (1 people) | 0％ |
| T34 | 0％ | 2.86% (1 people) | 0％ |
Can find out that from the result of clinical trial the antianginal drug oral cavity disintegration tablet of the present invention's preparation is compared with the antianginal drug oral cavity disintegration tablet that adopts the pressing preparation with its ordinary tablet, side effect obviously reduces, and curative effect increases.Thereby more favourable proof several big advantage and the characteristics of antianginal drug oral cavity disintegration tablet of the present invention: 1) can absorb by the oral mucosa; 2) reduced the gastrointestinal stimulation.
Claims (24)
1. antianginal drug oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 2-75%
Skeleton proppant 2-85%
Binding agent 4-90%
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. antianginal drug oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 5.38-66.67%
Skeleton proppant 5.56-78.43%
Binding agent 8.11-81.63%
Suspending agent 0-3.53%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
3. antianginal drug oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 19.03-49.26%
Skeleton proppant 19.70-38.05%
Binding agent 21.67-42.62%
Suspending agent 0-3.53%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
4. like the described antianginal drug oral cavity disintegration tablet of any claim among the claim 1-3, it 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, dextran, xylose, cottonseed sugar, maltose, glucose, galactose, trehalose, dextrin, hydroxypropyl cyclodextrin, sodium phosphate, sodium chloride, aluminium silicate.
5. like the described antianginal drug oral cavity disintegration tablet of any claim among the claim 1-3, it is characterized in that described binding agent selects one or more in the following raw material for use: Pullulan, alginate, cellulose and derivant thereof, hyaluronic acid, modified starch, polyvinyl alcohol, chitosan.
6. like the described antianginal drug oral cavity disintegration tablet of any claim among the claim 1-3, it 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.
7. antianginal drug oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 2-75%
Glycine or mannitol or dextran or its mixture 2-85%
Pullulan or sodium alginate or its mixture 4-90%
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%.
8. antianginal drug oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 5.38-66.67%
Glycine or mannitol or dextran or its mixture 5.56-78.43%
Pullulan or sodium alginate or its mixture 8.11-81.63%
Xanthan gum or Konjac glucomannan or its mixture 0-3.53%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
9. antianginal drug oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 19.03-49.26%
Glycine or mannitol or dextran or its mixture 19.70-38.05%
Pullulan or sodium alginate or its mixture 21.67-42.62%
Xanthan gum or Konjac glucomannan or its mixture 0-3.53%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
10. antianginal drug oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Principal agent 0.46-8.44%
Glycine or mannitol or dextran or its mixture 0.36-10.84%
Pullulan or sodium alginate or its mixture 0.74-11.03%
Xanthan gum or Konjac glucomannan or its mixture 0-1.02%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 66.67-98.44%
Wherein each weight percentages of components sum is 100%.
11. an antianginal drug oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Principal agent 1.25-7.50%
Glycine or mannitol or dextran or its mixture 1.00-10.00%
Pullulan or sodium alginate or its mixture 1.50-10.00%
Xanthan gum or Konjac glucomannan or its mixture 0-0.36%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 73.00-96.25%
Wherein each weight percentages of components sum is 100%.
12. an antianginal drug oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Principal agent 1.25-7.50%
Glycine or mannitol or dextran or its mixture 2.00-5.00%
Pullulan or sodium alginate or its mixture 2.20-5.00%
Xanthan gum or Konjac glucomannan or its mixture 0-0.36%
Sweeting agent 0.01-1.00%
Aromatic 0.01-1.00%
Purified water 81.30-93.43%
Wherein each weight percentages of components sum is 100%.
13. like claim 1-3; The described antianginal drug oral cavity disintegration tablet of any claim among the 7-12 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.
14. like claim 1-3, the described antianginal drug oral cavity disintegration tablet of any claim among the 7-12 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.
15. an antianginal drug oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 92-2251 part
Glycine or mannitol or dextran or its mixture 72-4336 part
Pullulan or sodium alginate or its mixture 148-4412 part
Xanthan gum or Konjac glucomannan or its mixture 0-204 part
Sweeting agent 0-400 part
Aromatic 0-400 part
Purified water 14019-37842 part.
16. an antianginal drug oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 250-2000 part
Glycine or mannitol or dextran or its mixture 200-4000 part
Pullulan or sodium alginate or its mixture 300-4000 part
Xanthan gum or Konjac glucomannan or its mixture 0-72 part
Sweeting agent 0-400 part
Aromatic 0-400 part
Purified water 15350-37000 part.
17. an antianginal drug oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 250-2000 part
Glycine or mannitol or dextran or its mixture 400-2000 part
Pullulan or sodium alginate or its mixture 440-2000 part
Xanthan gum or Konjac glucomannan or its mixture 0-72 part
Sweeting agent 2-400 part
Aromatic 2-400 part
Purified water 16260-33940 part.
18. an isosorbide mononitrate orally disintegrating tablets is made up of following components in weight percentage:
Isosorbide mononitrate 35.91%
Glycine or mannitol or dextran or its mixture 30.88%
Pullulan or sodium alginate or its mixture 32.32%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
19. an isosorbide mononitrate orally disintegrating tablets, it is processed by following components by part by weight:
1000 parts of isosorbide mononitrates
500 parts in mannitol
360 parts of dextrans
900 parts of Pullulan
15 parts of sweeting agents
10 parts of aromatic
17215 parts of purified water.
20. an isosorbide mononitrate orally disintegrating tablets, it is processed by following component:
Isosorbide mononitrate 10.00g
Mannitol 5.00g
Dextran 3.60g
Pullulan 9.00g
Aspartame 0.15g
Herba Menthae essence 0.10g
Purified water 172.15g
Process 1000 altogether.
21. like any described antianginal drug of claim among the claim 1-17, comprise isosorbide mononitrate, sorbide nitrate, bisoprolol, trimetazidine, diltiazem etc. with and pharmaceutically acceptable salt, ester, solvate, derivant or optical isomer.
22., it is characterized in that this method comprises the steps: like the method for preparing of any described antianginal drug oral cavity disintegration tablet of claim among the claim 1-3
(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.
23. the method for preparing like any described antianginal drug oral cavity disintegration tablet of claim among the claim 7-9,18 is characterized in that adopting following steps to make:
(a) preparation of substrate liquid: with principal agent, glycine or mannitol or dextran or its mixture, Pullulan or sodium alginate 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 antianginal drug 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.
24. the method for preparing like any described antianginal drug oral cavity disintegration tablet of claim among claim 10-12, the 15-17,19,20 is characterized in that adopting following steps to make:
With principal agent, glycine or mannitol or dextran or its mixture, Pullulan or sodium alginate 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 antianginal drug 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 5～15h.
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| CN113599387A (en) * | 2021-09-15 | 2021-11-05 | 山东中医药大学附属医院 | Compound preparation and application thereof in preparing medicament for treating angina |
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 |
| CN101067004A (en) * | 2007-06-07 | 2007-11-07 | 华东理工大学 | A kind of mugwort leaf polysaccharide and its application |
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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 |
| CN101067004A (en) * | 2007-06-07 | 2007-11-07 | 华东理工大学 | A kind of mugwort leaf polysaccharide and its application |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113599387A (en) * | 2021-09-15 | 2021-11-05 | 山东中医药大学附属医院 | Compound preparation and application thereof in preparing medicament for treating angina |
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