CN102579375A - Lipid lowering medicament orally disintegrating tablets and preparation method thereof - Google Patents
Lipid lowering medicament orally disintegrating tablets and preparation method thereof Download PDFInfo
- Publication number
- CN102579375A CN102579375A CN2011100082991A CN201110008299A CN102579375A CN 102579375 A CN102579375 A CN 102579375A CN 2011100082991 A CN2011100082991 A CN 2011100082991A CN 201110008299 A CN201110008299 A CN 201110008299A CN 102579375 A CN102579375 A CN 102579375A
- Authority
- CN
- China
- Prior art keywords
- mixture
- oral cavity
- disintegration tablet
- cavity disintegration
- fat
- 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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- 210000000214 mouth Anatomy 0.000 claims description 130
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Abstract
The invention discloses lipid lowering medicament orally disintegrating tablets and a preparation method thereof, and relates to the lipid lowering medicament orally disintegrating tablets and a prescription and a process for preparing the lipid lowering medicament orally disintegrating tablets by using a freeze drying method. The lipid lowering medicament orally disintegrating tablets are prepared from a main medicine and medicinal auxiliary materials, are taken without water, can be quickly disintegrated in mouth and are suitable for dysphagia patients such as the old and children to take; meanwhile, the lipid lowering medicament orally disintegrating tablets are also suitable for cardiovascular patients who travel or go on business trips frequently to take, and have the advantages of convenience for taking, low first pass effect and low irritation to digestive tract mucosa and have board market application prospect; and the side effect of the lipid lowering medicament can be obviously reduced through the lipid lowering medicament orally disintegrating tablets provided by the invention. In addition, the invention also relates to the preparation method of the lipid lowering medicament orally disintegrating tablets.
Description
Technical field:
The present invention relates to a kind of fat-reducing medicament oral cavity disintegration tablet and preparation method thereof, particularly a kind of fat-reducing medicament oral cavity disintegration tablet that adopts the freeze-drying preparation.
Background technology:
Cardiovascular disease is to threaten one of the most serious human disease in the world today, and its M & M surpasses ND and leaps to the first.Prevent and treat cardiovascular disease in the past and stress the exploitation at vasodilation, still along with the continuous development of science, people recognize that hyperlipidemia is that coronary heart disease and hypertensive main hazard factor take place.Therefore, the exploitation of blood lipid regulation medicine becomes the emphasis of preventing and treating cardiovascular disease.Clinical fat-reducing medicament commonly used mainly contains Statins, nicotinic acid class, special type of shellfish, cholic acid chelating agent and polyenoid class etc. at present, and wherein statins is with the leading position of its unique curative effect in occupation of fat-reducing medicament.
The main effect of statins is through suppressing HMG CoA (HMG-CoA) reductase, with synthesizing of cholesterol in the minimizing liver, stimulating low density lipoprotein, LDL (LDL) receptor to produce simultaneously, and strengthen the removing of low density lipoprotein, LDL in the blood plasma.Statins is not only applicable to primary hypercholesterolemia, can be used for the treatment that hypercholesterolemia merges hypertriglyceridemia yet.Statins is as the line and the two wires medicine that prevent and treat cardiovascular disease.The expert indicates, and transfers the fat therapy to become the important method of angiocardiopathy preventing in this century.Main statins comprises simvastatin, atorvastatin, pravastatin, fluvastatin, Rosuvastatin etc. at present.
The dosage form of at present domestic granted fat-reducing medicament has tablet, capsule, granule, syrup, effervescent tablet, dispersible tablet, injection and oral cavity disintegration tablet etc.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.And hyperlipemic patients is in the majority with the old people, and its each item physiological function descends, handicapped, dysphagia, and most of hyperlipemic patients need adhere to taking medicine one period, and many gerontal patients be owing to need use water delivery service when taking medicine, inconvenience, and be unwilling to take.In addition, the hyperposia of taking medicine evening can influence old people's night's rest again.Therefore developing a kind of preparation that does not need with water delivery service, swallows easily, can take whenever and wherever possible is very important.
Fat-reducing medicament oral cavity disintegration tablet of the present invention need not used water delivery service; Saliva can make its disintegrate or dissolving; Overcome the bad smell and the bitterness of medicine, improved the compliance that the patient takes medicine for a long time, be particularly useful for the patient of old man, dysphagia and the inconvenient person that fetches water etc. and take medicine; Be adapted in the tourism way medication under the condition at difficult acquisition water source simultaneously; Because oral cavity disintegration tablet is disintegrate rapidly in mouth, except that major part gets into the gastrointestinal tract with swallowing act, also there is the considerable part trans-oral to absorb, reduced the first pass effect of liver; In addition; The rapid disintegrate of oral cavity disintegration tablet ability before medicine arrives gastrointestinal tract also is dispersed into trickle granule, causes medicine to distribute in the gastrointestinal tract large tracts of land, has avoided medicine too high at the gastrointestinal tract local concentration; Cause the local irritant shortcoming of gastrointestinal, untoward reaction reduces.It is thus clear that the fat-reducing medicament 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.And when adopting freeze-drying to prepare; Generally need not add disintegrating agent; The adjuvant that is adopted all is water miscible, 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 that through volunteer's oral mucosa permeability test in human mouth, the prepared fat-reducing medicament oral cavity disintegration tablet of the present invention has bigger mucosa permeability; Thereby explain that it can absorb by the oral mucosa, has reduced the first pass effect of liver.Through clinical trial, the discovery that the inventor is surprised is compared with the fat-reducing medicament oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and the side effect of the fat-reducing medicament oral cavity disintegration tablet that the present invention is prepared obviously reduces, on curative effect, also increases.
Summary of the invention:
Technical problem to be solved by this invention is the shortcoming to above-mentioned existence, and a kind of prescription and the method for preparing that can improve the fat-reducing medicament 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 fat-reducing medicament 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; And surprised discovery is compared with the fat-reducing medicament oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and the side effect of the fat-reducing medicament oral cavity disintegration tablet of the present invention's preparation obviously reduces, on curative effect, also increases.
The fat-reducing medicament oral cavity disintegration tablet that the present invention relates to comprises principal agent, skeleton proppant, binding agent, suspending agent, antioxidant 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 fat-reducing medicament 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 0-30%
Antioxidant 0-6%
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 5.23-64.43%
Skeleton proppant 5.31-78.00%
Binding agent 7.89-81.17%
Suspending agent 0-25.11%
Antioxidant 0-3.22%
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 15.38-54.71%
Skeleton proppant 18.20-36.92%
Binding agent 20.22-46.77%
Suspending agent 0-4.86%
Antioxidant 0-2.10%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
The adjuvant that plays skeleton support effect that those skilled in the art were known when skeleton proppant of the present invention can be the preparation oral cavity disintegration tablet; Preferred glycine, serine, arginine, mannitol, sorbitol, maltose alcohol, xylitol, lactose, erythritol, hydroxyl isomaltulose, 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 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 antioxidant can be the adjuvant that can play antioxidation that those skilled in the art know, one or more in preferred tertiary Butylated hydroxyanisole (BHA), di-tert-butyl hydroxy toluene (BHT), gallic acid and esters thereof, tert-butyl hydroquinone (TBHQ), citric acid, tocopherols, ascorbic acid and the derivant thereof; 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 fat-reducing medicament 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 fat-reducing medicament oral cavity disintegration tablet through a large amount of experimentatioies; Wherein in the method for preparing of fat-reducing medicament 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 fat-reducing medicament oral cavity disintegration tablet of the present invention comprises the steps:
(a) preparation of substrate liquid: principal agent, skeleton proppant, binding agent, antioxidant 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 fat-reducing medicament 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, 0-6% antioxidant and other adjuvant are joined in the good 0-30% 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 fat-reducing medicament oral cavity disintegration tablet of the present invention is following:
Principal agent 2-75%
Glycine or mannitol or its mixture 2-85%
Pullulan or sodium alginate or its mixture 4-90%
Xanthan gum or Konjac glucomannan or its mixture 0-30%
Antioxidant 0-6%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
Preferred fat-reducing medicament oral cavity disintegration tablet of the present invention, form by following components in weight percentage:
Principal agent 5.23-64.43%
Glycine or mannitol or its mixture 5.31-78.00%
Pullulan or sodium alginate or its mixture 7.89-81.17%
Xanthan gum or Konjac glucomannan or its mixture 0-25.11%
Antioxidant 0-3.22%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
Fat-reducing medicament oral cavity disintegration tablet most preferably of the present invention, form by following components in weight percentage:
Principal agent 15.38-54.71%
Glycine or mannitol or its mixture 18.20-36.92%
Pullulan or sodium alginate or its mixture 20.22-46.77%
Xanthan gum or Konjac glucomannan or its mixture 0-4.86%
Antioxidant 0-2.10%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
Preparation of the present invention is especially preferably filled a prescription and is made up of following components in weight percentage:
Simvastatin 49.60%
Glycine or mannitol or its mixture 19.84%
Pullulan or sodium alginate or its mixture 27.78%
Xanthan gum or Konjac glucomannan or its mixture 0.50%
Antioxidant 1.98%
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 fat-reducing medicament oral cavity disintegration tablet of the present invention is:
(a) preparation of substrate liquid: with principal agent, glycine or mannitol or its mixture, Pullulan or sodium alginate or its mixture, antioxidant 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 fat-reducing medicament 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.
Fat-reducing medicament oral cavity disintegration tablet of the present invention is processed by the component of following weight percentage ratio:
Principal agent 0.48-6.30%
Glycine or mannitol or its mixture 0.38-10.90%
Pullulan sodium alginate or its mixture 0.76-11.09%
Xanthan gum or Konjac glucomannan or its mixture 0-0.72%
Antioxidant 0-0.47%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 68.52-98.38%
Wherein each weight percentages of components sum is 100%.
The preferred fat-reducing medicament oral cavity disintegration tablet of the present invention is processed by the component of following weight percentage ratio:
Principal agent 1.25-5.41%
Glycine or mannitol or its mixture 1-10.00%
Pullulan or sodium alginate or its mixture 1.5-10.00%
Xanthan gum or Konjac glucomannan or its mixture 0-0.60%
Antioxidant 0-0.25%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 72.20-96.19%
Wherein each weight percentages of components sum is 100%.
The most preferred fat-reducing medicament oral cavity disintegration tablet of the present invention is processed by the component of following weight percentage ratio:
Principal agent 1.25-5.41%
Glycine or mannitol or its mixture 1.80-3.00%
Pullulan or sodium alginate or its mixture 2.00-3.80%
Xanthan gum or Konjac glucomannan or its mixture 0-0.48%
Antioxidant 0-0.20%
Sweeting agent 0.01-0.2%
Aromatic 0-0.10%
Purified water 88.33-92.16%
Wherein each weight percentages of components sum is 100%.
Fat-reducing medicament oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Principal agent 96-2521 part
Glycine or mannitol or its mixture 76-4360 part
Pullulan or sodium alginate or its mixture 152-4436 part
Xanthan gum or Konjac glucomannan or its mixture 0-288 part
Antioxidant 0-188 part
Sweeting agent 0-400 part
Aromatic 0-400 part
Purified water 14444-37736 part.
The preferred fat-reducing medicament oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Principal agent 250-2165 part
Glycine or mannitol or its mixture 200-4000 part
Pullulan or sodium alginate or its mixture 300-4000 part
Xanthan gum or Konjac glucomannan or its mixture 0-240 part
Antioxidant 0-100 part
Sweeting agent 0-400 part
Aromatic 0-400 part
Purified water 15220-36896 part.
The most preferred fat-reducing medicament oral cavity disintegration tablet of the present invention is processed by following components by part by weight:
Principal agent 250-2165 part
Glycine or mannitol or its mixture 380-1160 part
Pullulan or sodium alginate or its mixture 500-1520 part
Xanthan gum or Konjac glucomannan or its mixture 0-192 part
Antioxidant 0-80 part
Sweeting agent 2-80 part
Aromatic 0-40 part
Purified water 17668-36188 part.
The present invention preferably fills a prescription and is processed by following components by part by weight:
1000 parts of simvastatins
400 parts in glycine or mannitol or its mixture
560 parts in Pullulan or sodium alginate or its mixture
10 parts in xanthan gum or Konjac glucomannan or its mixture
40 parts of antioxidants
6 parts of sweeting agents
17984 parts of purified water.
The most preferred prescription of the present invention is processed by the component of following weight:
Simvastatin 10.00g
Glycine 4.00g
Pullulan 5.60g
Xanthan gum 0.10g
Butylhydroxy anisole 0.24g
Citric acid 0.16g
Acesulfame potassium 0.06g
Purified water 179.84g
Process 1000 altogether.
Its preparation method is: with principal agent, glycine or mannitol or its mixture, Pullulan or sodium alginate or its mixture, antioxidant 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 fat-reducing medicament 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.
Fat-reducing medicament 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.
Fat-reducing medicament oral cavity disintegration tablet of the present invention has following advantage:
1, good mouthfeel, taking convenience: fat-reducing medicament 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, reduce the first pass effect of liver: the disintegrate rapidly in mouth of the fat-reducing medicament oral cavity disintegration tablet of the present invention's preparation has the considerable part trans-oral to absorb, thereby can reduce the first pass effect of liver.
3, gastrointestinal absorption fast, stimulate little: the fat-reducing medicament 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, and curative effect improves: the fat-reducing medicament oral cavity disintegration tablet through the wonderful discovery the present invention preparation of clinical trial is compared with the fat-reducing medicament oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, and side effect significantly reduces, and curative effect increases to some extent.
Fat-reducing medicament oral cavity disintegration tablet mouthfeel provided by the invention is good, volume is little, sheet weighs moderate, difficult fragmentation, preparation technology is simple, 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
Pharmaceutical formulation of the present invention is composed of the following components:
Suffering is cut down his 10.00g
Glycine 4.00g
Pullulan 5.60g
Xanthan gum 0.10g
Butylhydroxy anisole 0.24g
Citric acid 0.16g
Acesulfame potassium 0.06g
Purified water 179.84g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, Pullulan, butylhydroxy anisole, citric acid, acesulfame potassium, join in the good xanthan gum solution of abundant dissolving, mixing to make becomes uniform solution; After solution outgased, accurately inject mould; Behind pre-freeze 1～60min under-40 ℃～-170 ℃ the condition, change in the freeze dryer, lyophilization 1～10h under 0.01mbar～10mbar pressure ,-30 ℃ to 30 ℃ condition promptly obtains simvastatin 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.
Embodiment 2
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Mannitol 4.00g
Pullulan 5.60g
Xanthan gum 0.10g
Butylhydroxy anisole 0.24g
Citric acid 0.16g
Acesulfame potassium 0.06g
Purified water 179.84g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, Pullulan, butylhydroxy anisole, citric acid, acesulfame potassium, 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 3
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Glycine 2.40g
Mannitol 2.00g
Pullulan 3.00g
Sodium alginate 2.80g
Konjac glucomannan 0.60g
Butylhydroxy anisole 0.24g
Citric acid 0.16g
Aspartame 0.05g
Herba Menthae essence 0.04g
Purified water 178.71g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, mannitol, Pullulan, sodium alginate, butylhydroxy anisole, citric acid, aspartame, Herba Menthae essence; 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 4
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Glycine 4.00g
Dextran 4.00g
Pullulan 10.00g
Xanthan gum 0.08g
Di-tert-butyl hydroxy toluene 0.24g
Citric acid 0.16g
Herba Menthae essence 0.20g
Purified water 171.32g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, dextran, Pullulan, di-tert-butyl hydroxy toluene, citric acid, Herba Menthae essence, 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 5
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 2.50g
Mannitol 2.00g
Pullulan 10.00g
Sodium alginate 10.00g
Xanthan gum 0.02g
Butylhydroxy anisole 0.12g
Purified water 175.36g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, Pullulan, sodium alginate, butylhydroxy anisole, 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 6
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Mannitol 4.00g
Dextran 2.00g
Pullulan 8.00g
Xanthan gum 0.06g
Konjac glucomannan 0.20g
Butylhydroxy anisole 0.48g
Acesulfame potassium 0.05g
Herba Menthae essence 0.10g
Purified water 175.11g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, dextran, Pullulan, butylhydroxy anisole, acesulfame potassium, Herba Menthae essence, 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 7
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Mannitol 4.60g
Sodium alginate 5.00g
Xanthan gum 0.08g
Konjac glucomannan 0.12g
Butylhydroxy anisole 0.24g
Citric acid 0.16g
Sucralose 0.02g
Orange flavor 0.10g
Purified water 179.68g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, sodium alginate, butylhydroxy anisole, citric acid, sucralose, orange flavor; 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 8
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 20.00g
Glycine 3.20g
Mannitol 4.00g
Pullulan 8.80g
Konjac glucomannan 1.92g
Butylhydroxy anisole 0.48g
Citric acid 0.32g
Sucrose 0.80g
Orange flavor 0.40g
Purified water 360.08g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, mannitol, Pullulan, butylhydroxy anisole, citric acid, sucrose, orange flavor, 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 9
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Mannitol 4.00g
Hydroxypropyl emthylcellulose 3.80g
Xanthan gum 0.09g
Di-tert-butyl hydroxy toluene 0.50g
Sucralose 0.03g
Orange flavor 0.08g
Purified water 181.50g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, hydroxypropyl emthylcellulose, di-tert-butyl hydroxy toluene, sucralose, orange flavor, 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 10
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 20.00g
Mannitol 4.00g
Pullulan 40.00g
Konjac glucomannan 2.40g
Butylhydroxy anisole 1.00g
Aspartame 4.00g
Strawberry essence 4.00g
Purified water 324.60g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, Pullulan, butylhydroxy anisole, aspartame, strawberry essence, 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 11
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Glycine 2.40g
Mannitol 2.40g
Pullulan 3.60g
Sodium alginate 2.00g
Polyvinylpyrrolidone 7.00g
Propyl gallate 0.23g
Citric acid 0.15g
Aspartame 0.10g
Purified water 172.12g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, mannitol, Pullulan, sodium alginate, propyl gallate, citric acid, aspartame; Join in the good kollidon solution of abundant dissolving, mixing to make becomes uniform solution; Following method for preparing is with embodiment 1.
Embodiment 12
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 20.00g
Mannitol 40.00g
Pullulan 28.00g
Sodium alginate 12.00g
Xanthan gum 0.04g
Di-tert-butyl hydroxy toluene 0.50g
Citric acid 0.34g
Acesulfame potassium 4.00g
Flavoring pineapple essence 4.00g
Purified water 291.12g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, Pullulan, sodium alginate, di-tert-butyl hydroxy toluene, citric acid, acesulfame potassium, flavoring pineapple essence, 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 13
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 2.50g
Glycine 1.50g
Mannitol 0.50g
Sodium alginate 3.00g
Xanthan gum 0.20g
Konjac glucomannan 1.00g
Propyl gallate 0.06g
Citric acid 0.04g
Purified water 191.20g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, mannitol, sodium alginate, propyl gallate, citric acid, 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 14
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 5.00g
Glycine 5.00g
Pullulan 6.00g
Xanthan gum 0.03g
Konjac glucomannan 0.18g
Butylhydroxy anisole 0.12g
Citric acid 0.08g
Acesulfame potassium 0.03g
Purified water 183.56g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, Pullulan, butylhydroxy anisole, citric acid, acesulfame potassium, 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 15
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 2.50g
Mannitol 20.00g
Pullulan 3.00g
Xanthan gum 0.02g
Di-tert-butyl hydroxy toluene 0.12g
Purified water 174.36g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, Pullulan, di-tert-butyl hydroxy toluene, 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 16
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 20.00g
Glycine 12.00g
Mannitol 28.00g
Pullulan 40.00g
Konjac glucomannan 2.40g
Propyl gallate 0.48g
Citric acid 0.32g
Sucralose 4.00g
Herba Menthae essence 4.00g
Purified water 288.80g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, mannitol, Pullulan, propyl gallate, citric acid, sucralose, Herba Menthae essence, 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 17
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Glycine 1.80g
Mannitol 2.20g
Sodium alginate 5.60g
Xanthan gum 0.06g
Konjac glucomannan 0.24g
Butylhydroxy anisole 0.12g
Propyl gallate 0.10g
Citric acid 0.15g
Acesulfame potassium 0.06g
Purified water 179.67g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, mannitol, sodium alginate, butylhydroxy anisole, propyl gallate, citric acid, acesulfame potassium; 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 18
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 20.00g
Glycine 16.00g
Mannitol 24.00g
Pullulan 4.00g
Sodium alginate 2.00g
Konjac glucomannan 1.20g
Butylhydroxy anisole 0.48g
Citric acid 0.32
Sucrose 4.00g
Strawberry essence 4.00g
Purified water 324.00g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, mannitol, Pullulan, sodium alginate, butylhydroxy anisole, citric acid, sucrose, strawberry essence; 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 19
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 2.50g
Glycine 6.00g
Pullulan 7.60g
Xanthan gum 0.03g
Butylhydroxy anisole 0.06g
Citric acid 0.04g
Acesulfame potassium 0.02g
Purified water 183.75g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, Pullulan, butylhydroxy anisole, citric acid, acesulfame potassium, 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 20
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 2.50g
Mannitol 2.00g
Sodium alginate 3.00g
Xanthan gum 0.02g
Di-tert-butyl hydroxy toluene 0.06g
Citric acid 0.04g
Purified water 192.38g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, sodium alginate, di-tert-butyl hydroxy toluene, citric acid, 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 21
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 10.00g
Mannitol 4.20g
Pullulan 3.20g
Sodium alginate 2.00g
Xanthan gum 0.10g
Butylhydroxy anisole 0.24g
Citric acid 0.16g
Sucrose 0.24g
Flavoring pineapple essence 0.05g
Purified water 179.81g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, mannitol, Pullulan, sodium alginate, butylhydroxy anisole, citric acid, sucrose, flavoring pineapple essence, 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 22
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 20.00g
Glycine 4.00g
Pullulan 6.00g
Xanthan gum 0.04g
Di-tert-butyl hydroxy toluene 1.00g
Purified water 368.96g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, Pullulan, di-tert-butyl hydroxy toluene, 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 23
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 2.50g
Glycine 20.00g
Sodium alginate 20.00g
Konjac glucomannan 1.20g
Propyl gallate 0.10g
Acesulfame potassium 2.00g
Herba Menthae essence 2.00g
Purified water 152.20g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, sodium alginate, propyl gallate, acesulfame potassium, Herba Menthae essence, 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 24
Pharmaceutical formulation of the present invention is composed of the following components:
Simvastatin 20.00g
Glycine 3.80g
Mannitol 3.80g
Pullulan 9.20g
Xanthan gum 0.32g
Butylhydroxy anisole 0.48g
Citric acid 0.32g
Acesulfame potassium 0.20g
Purified water 361.88g
Process 1000 altogether.
Concrete method for preparing is described below: with simvastatin, glycine, mannitol, Pullulan, butylhydroxy anisole, citric acid, acesulfame potassium, join in the good xanthan gum solution of abundant dissolving butylhydroxy anisole
Embodiment 25
Pharmaceutical formulation of the present invention is composed of the following components:
Atorvastatin calcium 10.82g
Glycine 4.00g
Pullulan 5.60g
Xanthan gum 0.12g
Sucralose 0.10g
Herba Menthae essence 0.10g
Purified water 179.26g
Process 1000 altogether.
Concrete method for preparing is described below: with Atorvastatin calcium, glycine, Pullulan, sucralose, Herba Menthae essence, 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 26
Pharmaceutical formulation of the present invention is composed of the following components:
Atorvastatin calcium 21.65g
Glycine 3.60g
Mannitol 3.60g
Sodium alginate 8.00g
Konjac glucomannan 1.92g
Sucralose 0.40g
Herba Menthae essence 0.40g
Purified water 360.43g
Process 1000 altogether.
Concrete method for preparing is described below: with Atorvastatin calcium, glycine, mannitol, sodium alginate, sucralose, Herba Menthae essence, 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 27
Pharmaceutical formulation of the present invention is composed of the following components:
Atorvastatin calcium 10.82g
Mannitol 4.40g
Pullulan 2.20g
Sodium alginate 3.00g
Xanthan gum 0.10g
Konjac glucomannan 0.12g
Acesulfame potassium 0.10g
Orange flavor 0.10g
Purified water 179.16g
Process 1000 altogether.
Concrete method for preparing is described below: with Atorvastatin calcium, mannitol, Pullulan, sodium alginate, acesulfame potassium, orange flavor, 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 28
Pharmaceutical formulation of the present invention is composed of the following components:
Pravastatin sodium 5.00g
Mannitol 5.00g
Pullulan 4.00g
Sodium alginate 2.00g
Aspartame 0.03g
Purified water 183.97g
Process 1000 altogether.
Concrete method for preparing is described below: with pravastatin sodium, mannitol, Pullulan, sodium alginate, aspartame 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
Pharmaceutical formulation of the present invention is composed of the following components:
Pravastatin sodium 10.00g
Glycine 5.60g
Pullulan 7.60g
Acesulfame potassium 0.06g
Orange flavor 0.06g
Purified water 176.68g
Process 1000 altogether.
Concrete method for preparing is described below: with pravastatin sodium, glycine, Pullulan, 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 30
Pharmaceutical formulation of the present invention is composed of the following components:
Pravastatin sodium 20.00g
Glycine 5.60g
Mannitol 5.60g
Pullulan 9.20g
Sodium alginate 6.00g
Sucralose 0.12g
Herba Menthae essence 0.12g
Purified water 353.36g
Process 1000 altogether.
Concrete method for preparing is described below: with pravastatin sodium, glycine, mannitol, Pullulan, sodium alginate, 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
Pharmaceutical formulation of the present invention is composed of the following components:
Fluvastatin sodium 20.00g
Glycine 11.20g
Pullulan 15.20g
Sucralose 0.15g
Herba Menthae essence 0.15g
Purified water 353.30g
Process 1000 altogether.
Concrete method for preparing is described below: with fluvastatin sodium, 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 32
Pharmaceutical formulation of the present invention is composed of the following components:
Fluvastatin sodium 10.00g
Glycine 2.80g
Mannitol 3.00g
Sodium alginate 5.80g
Acesulfame potassium 0.10g
Flavoring pineapple essence 0.08g
Purified water 178.22g
Process 1000 altogether.
Concrete method for preparing is described below: with fluvastatin sodium, glycine, mannitol, sodium alginate, 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.
Embodiment 33
Pharmaceutical formulation of the present invention is composed of the following components:
Fluvastatin sodium 20.00g
Mannitol 11.60g
Pullulan 8.00g
Sodium alginate 4.80g
Aspartame 0.40g
Strawberry essence 0.10g
Purified water 355.10g
Process 1000 altogether.
Concrete method for preparing is described below: with fluvastatin sodium, 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 34
Pharmaceutical formulation of the present invention is composed of the following components:
Rosuvastain calcium 10.40g
Glycine 4.00g
Pullulan 5.60g
Xanthan gum 0.10g
Sucrose 0.10g
Purified water 179.80g
Process 1000 altogether.
Concrete method for preparing is described below: with rosuvastain calcium, glycine, Pullulan, sucrose, 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 35
Pharmaceutical formulation of the present invention is composed of the following components:
Rosuvastain calcium 5.20g
Glycine 2.50g
Mannitol 2.50g
Sodium alginate 5.20g
Xanthan gum 0.02g
Konjac glucomannan 0.24g
Acesulfame potassium 0.03g
Purified water 184.31g
Process 1000 altogether.
Concrete method for preparing is described below: with rosuvastain calcium, glycine, mannitol, sodium alginate, acesulfame potassium, 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 36
Pharmaceutical formulation of the present invention is composed of the following components:
Rosuvastain calcium 10.40g
Mannitol 3.80g
Pullulan 3.00g
Sodium alginate 2.20g
Konjac glucomannan 0.60g
Sucralose 0.04g
Herba Menthae essence 0.10g
Purified water 179.86g
Process 1000 altogether.
Concrete method for preparing is described below: with rosuvastain calcium, mannitol, Pullulan, sodium alginate, sucralose, Herba Menthae essence, join in the good Konjac glucomannan solution of abundant dissolving, 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 fat-reducing medicament oral cavity disintegration tablet of preparation below; Through volunteer's oral mucosa permeability test and clinical trial; Explain that there is the effect that oral mucosa absorbs, first pass effect reduces in the fat-reducing medicament oral cavity disintegration tablet that the present invention prepares; And it is compared with the fat-reducing medicament 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 simvastatin oral cavity disintegration tablet (R2 group) and the prepared simvastatin oral cavity disintegration tablet (T group) (T1-T24 representes the oral cavity disintegration tablet of embodiment 1-embodiment 24 preparations respectively) of embodiment 1-24 of simvastatin 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 through No. 2 sieves up to the complete disintegrate of tablet.According to said method each sample is respectively checked 6.
Result's disintegration of each sample of being measured according to the method described above sees table 1.
Each sample disintegration time mensuration result of table 1
Can find out from the mensuration result of disintegration; The disintegration of the fat-reducing medicament oral cavity disintegration tablet that the present invention is prepared will be much smaller than the fat-reducing medicament oral cavity disintegration tablet and the fat-reducing medicament ordinary tablet of pressing preparation, and the prepared fat-reducing medicament oral cavity disintegration tablet of prompting the present invention can disintegrate rapidly in the oral cavity.
2, mouthfeel experiment:
Get the prepared fat-reducing medicament oral cavity disintegration tablet of embodiment 1-36 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 simvastatin oral cavity disintegration tablet (R2 group) and the prepared simvastatin oral cavity disintegration tablet (T group) (T1-T24 representes the oral cavity disintegration tablet of embodiment 1-embodiment 24 preparations respectively) of embodiment 1-24 of simvastatin 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 12%～14%) of the fat-reducing medicament oral cavity disintegration tablet that the present invention is prepared is apparently higher than the mucosa permeability (being about 0.27%) and the fat-reducing medicament ordinary tablet (being about 0.012%) that adopt the prepared fat-reducing medicament oral cavity disintegration tablet of pressing; Thereby explain that the prepared fat-reducing medicament oral cavity disintegration tablet of the present invention can absorb by the oral mucosa, reduce first pass effect.
4, clinical trial
Experimental program:
According in " the adult Chinese dyslipidemia guideline of prevention and treatment " announced in 2007 about the regulation of hyperlipidemia diagnostic criteria; Choose hyperlipemia 105 examples; The Secondary cases hyperlipidemia patient of getting rid of hypothyroidism, liver and gall diseases and nephropathy, hypoproteinemia, having excessive drinking history, drug influence to cause, selected patient did not all take any fat regulation medicine in 4 weeks before treatment.Be divided into three groups according to the randomized, double-blind principle; Every group 35 people; Take the simvastatin oral cavity disintegration tablet 20mg (R2 group) of simvastatin sheet 20mg (R1 group), pressing preparation or the simvastatin oral cavity disintegration tablet 20mg (T group) of the present invention preparation (T1-T24 respectively represent oral cavity disintegration tablet that embodiment 1-embodiment 24 prepare) in giving three groups of patients respectively just before going to bed every day, and be 8 weeks the course of treatment.A situation arises for the variation of T-CHOL (TC), low-density lipoprotein cholesterol (LDL-C), HDL-C (HDL-C), triglyceride (TG) and untoward reaction before and after the observation medication.
Curative effect judging standard: according to the relevant regulations in " the medicine for cardiovascular system clinical research guideline " of Ministry of Public Health promulgation: (1) produce effects: reach following any one person, TC descends >=20%, and TG descends >=40%, HDL-C rising >=0.26mmol/L; (2) effective: reach following any one person, TC descends 10%～20%, and TG descends 20%～40%, the HDL-C 0.10～0.26mmol/L that rises; (3) invalid: as not reach above index; (4) worsen: reach following each person, TC rises >=10%, and TG rises >=10%, and HDL-C decline >=0.1mmol/L, TC/HDL-C raise >=10%.Total effective rate (%)=(produce effects example number+effective routine number)/this organizes total routine number * 100%.
Respectively Atorvastatin calcium is respectively organized preparation (dosage 10mg, the Atorvastatin calcium oral cavity disintegration tablet (T group) (T25-T27 representes the oral cavity disintegration tablet of embodiment 25-embodiment 27 preparations respectively) that the Atorvastatin calcium oral cavity disintegration tablet (R4 group) of atorvastatin calcium tablet (R3 group), pressing preparation or the present invention are prepared) according to the method described above; Pravastatin sodium is respectively organized preparation (dosage 20mg, the pravastatin sodium oral cavity disintegration tablet (T group) (T28-T30 representes the oral cavity disintegration tablet of embodiment 28-embodiment 30 preparations respectively) that the pravastatin sodium oral cavity disintegration tablet (R6 group) of pravastatin sodium sheet (R5 group), pressing preparation or the present invention are prepared); Fluvastatin sodium is respectively organized preparation (dosage 40mg, the fluvastatin sodium oral cavity disintegration tablet (T group) (T31-T33 representes the oral cavity disintegration tablet of embodiment 31-embodiment 33 preparations respectively) that the fluvastatin sodium oral cavity disintegration tablet (R8 group) of fluvastatin sodium sheet (R7 group), pressing preparation or the present invention are prepared); Rosuvastain calcium is respectively organized preparation (dosage 5mg; The rosuvastain calcium oral cavity disintegration tablet (T group) (T34-T36 representes the oral cavity disintegration tablet of embodiment 34-embodiment 36 preparations respectively) that the rosuvastain calcium oral cavity disintegration tablet (R10 group) of Rosuvastatin calcium tablet (R9 group), pressing preparation or the present invention are prepared) carried out clinical trial, the result sees table 3-table 6.
Table 3 simvastatin is respectively organized preparation clinical efficacy relatively (n=35, routine number)
| Group | Produce effects | Effectively | Invalid | Worsen | Total effective rate |
| The R1 group | 16 | 10 | 6 | 3 | 74.3％ |
| The R2 group | 17 | 11 | 5 | 2 | 80.0％ |
| T1 | 22 | 11 | 2 | 0 | 94.3％ |
| T2 | 22 | 11 | 2 | 0 | 94.3％ |
| T3 | 22 | 11 | 2 | 0 | 94.3％ |
| T4 | 21 | 11 | 3 | 0 | 91.4％ |
| T5 | 20 | 11 | 4 | 0 | 88.6％ |
| T6 | 21 | 11 | 3 | 0 | 91.4％ |
| T7 | 22 | 11 | 2 | 0 | 94.3％ |
| T8 | 21 | 12 | 2 | 0 | 94.3％ |
| T9 | 20 | 12 | 3 | 0 | 91.4％ |
| T10 | 19 | 12 | 4 | 0 | 88.6％ |
| T11 | 21 | 11 | 3 | 0 | 91.4％ |
| T12 | 20 | 11 | 4 | 0 | 88.6％ |
| T13 | 19 | 12 | 4 | 0 | 88.6％ |
| T14 | 22 | 11 | 2 | 0 | 94.3％ |
| T15 | 20 | 12 | 3 | 0 | 91.4％ |
| T16 | 19 | 12 | 4 | 0 | 88.6％ |
| T17 | 21 | 12 | 2 | 0 | 94.3％ |
| T18 | 20 | 11 | 4 | 0 | 88.6％ |
| T19 | 22 | 11 | 2 | 0 | 94.3％ |
| T20 | 20 | 12 | 3 | 0 | 91.4％ |
| T21 | 22 | 11 | 2 | 0 | 94.3％ |
| T22 | 20 | 12 | 3 | 0 | 91.4％ |
| T23 | 20 | 11 | 4 | 0 | 88.6％ |
| T24 | 21 | 12 | 2 | 0 | 94.3％ |
Table 4 simvastatin is respectively organized the comparison (n=35) that the preparation untoward reaction takes place
All the other respectively organize preparation clinical efficacy relatively (n=35, routine number) table 5
| Group | Produce effects | Effectively | Invalid | Worsen | Total effective rate |
| The R3 group | 17 | 9 | 6 | 3 | 74.3％ |
| The R4 group | 18 | 10 | 5 | 2 | 80.0％ |
| T25 | 23 | 10 | 2 | 0 | 94.3％ |
| T26 | 23 | 10 | 2 | 0 | 94.3％ |
| T27 | 22 | 11 | 2 | 0 | 94.3％ |
| The R5 group | 16 | 9 | 6 | 4 | 71.4％ |
| The R6 group | 17 | 10 | 5 | 3 | 77.1％ |
| T28 | 21 | 11 | 3 | 0 | 91.4％ |
| T29 | 21 | 11 | 3 | 0 | 91.4％ |
| T30 | 21 | 11 | 3 | 0 | 91.4％ |
| The R7 group | 15 | 10 | 6 | 4 | 71.4％ |
| The R8 group | 16 | 11 | 5 | 3 | 77.1％ |
| T31 | 20 | 12 | 3 | 0 | 91.4％ |
| T32 | 20 | 12 | 3 | 0 | 91.4％ |
| T33 | 21 | 11 | 3 | 0 | 91.4％ |
| The R9 group | 19 | 8 | 6 | 2 | 77.1％ |
| The R10 group | 20 | 9 | 4 | 2 | 82.9％ |
| T34 | 23 | 11 | 1 | 0 | 97.1％ |
| T35 | 23 | 11 | 1 | 0 | 97.1％ |
| T36 | 23 | 11 | 1 | 0 | 97.1％ |
All the other respectively organize the comparison (n=35) that the preparation untoward reaction takes place table 6
Can find out that from the result of clinical trial the fat-reducing medicament oral cavity disintegration tablet of the present invention's preparation is compared with the fat-reducing medicament oral cavity disintegration tablet that adopts the pressing preparation with ordinary tablet, side effect significantly reduces, and curative effect increases.Thereby more favourable proof several big advantage and the characteristics of fat-reducing medicament oral cavity disintegration tablet of the present invention: 1) can absorb by the oral mucosa, rapidly onset; 2) reduced the gastrointestinal stimulation; 3) less liver metabolism.
Claims (25)
1. fat-reducing medicament 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 0-30%
Antioxidant 0-6%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
2. fat-reducing medicament oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 5.23-64.43%
Skeleton proppant 5.31-78.00%
Binding agent 7.89-81.17%
Suspending agent 0-25.11%
Antioxidant 0-3.22%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
3. fat-reducing medicament oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 15.38-54.71%
Skeleton proppant 18.20-36.92%
Binding agent 20.22-46.77%
Suspending agent 0-4.86%
Antioxidant 0-2.10%
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 fat-reducing medicament 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 fat-reducing medicament 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 fat-reducing medicament 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. like the described fat-reducing medicament oral cavity disintegration tablet of any claim among the claim 1-3, it is characterized in that described antioxidant selects one or more in the following raw material for use: butylhydroxy anisole, di-tert-butyl hydroxy toluene, gallic acid and esters thereof, tert-butyl hydroquinone, citric acid, tocopherols, ascorbic acid and derivant thereof.
8. fat-reducing medicament oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 2-75%
Glycine or mannitol or its mixture 2-85%
Pullulan or sodium alginate or its mixture 4-90%
Xanthan gum or Konjac glucomannan or its mixture 0-30%
Antioxidant 0-6%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
9. fat-reducing medicament oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 5.23-64.43%
Glycine or mannitol or its mixture 5.31-78.00%
Pullulan or sodium alginate or its mixture 7.89-81.17%
Xanthan gum or Konjac glucomannan or its mixture 0-25.11%
Antioxidant 0-3.22%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
10. fat-reducing medicament oral cavity disintegration tablet, form by following components in weight percentage:
Principal agent 15.38-54.71%
Glycine or mannitol or its mixture 18.20-36.92%
Pullulan or sodium alginate or its mixture 20.22-46.77%
Xanthan gum or Konjac glucomannan or its mixture 0-4.86%
Antioxidant 0-2.10%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
11. a fat-reducing medicament oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Principal agent 0.48-6.30%
Glycine or mannitol or its mixture 0.38-10.90%
Pullulan sodium alginate or its mixture 0.76-11.09%
Xanthan gum or Konjac glucomannan or its mixture 0-0.72%
Antioxidant 0-0.47%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 68.52-98.38%
Wherein each weight percentages of components sum is 100%.
12. a fat-reducing medicament oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Principal agent 1.25-5.41%
Glycine or mannitol or its mixture 1-10.00%
Pullulan or sodium alginate or its mixture 1.5-10.00%
Xanthan gum or Konjac glucomannan or its mixture 0-0.60%
Antioxidant 0-0.25%
Sweeting agent 0-1.00%
Aromatic 0-1.00%
Purified water 72.20-96.19%
Wherein each weight percentages of components sum is 100%.
13. a fat-reducing medicament oral cavity disintegration tablet, its component by following weight percentage ratio is processed:
Principal agent 1.25-5.41%
Glycine or mannitol or its mixture 1.80-3.00%
Pullulan or sodium alginate or its mixture 2.00-3.80%
Xanthan gum or Konjac glucomannan or its mixture 0-0.48%
Antioxidant 0-0.20%
Sweeting agent 0.01-0.2%
Aromatic 0-0.10%
Purified water 88.33-92.16%
Wherein each weight percentages of components sum is 100%.
14. like claim 1-3; The described fat-reducing medicament oral cavity disintegration tablet of any claim among the 8-13 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.
15. like claim 1-3, the described fat-reducing medicament oral cavity disintegration tablet of any claim among the 8-13 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.
16. a fat-reducing medicament oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 96-2521 part
Glycine or mannitol or its mixture 76-4360 part
Pullulan or sodium alginate or its mixture 152-4436 part
Xanthan gum or Konjac glucomannan or its mixture 0-288 part
Antioxidant 0-188 part
Sweeting agent 0-400 part
Aromatic 0-400 part
Purified water 14444-37736 part.
17. a fat-reducing medicament oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 250-2165 part
Glycine or mannitol or its mixture 200-4000 part
Pullulan or sodium alginate or its mixture 300-4000 part
Xanthan gum or Konjac glucomannan or its mixture 0-240 part
Antioxidant 0-100 part
Sweeting agent 0-400 part
Aromatic 0-400 part
Purified water 15220-36896 part.
18. a fat-reducing medicament oral cavity disintegration tablet, it is processed by following components by part by weight:
Principal agent 250-2165 part
Glycine or mannitol or its mixture 380-1160 part
Pullulan or sodium alginate or its mixture 500-1520 part
Xanthan gum or Konjac glucomannan or its mixture 0-192 part
Antioxidant 0-80 part
Sweeting agent 2-80 part
Aromatic 0-40 part
Purified water 17668-36188 part.
19. a simvastatin oral cavity disintegration tablet is made up of following components in weight percentage:
Simvastatin 49.60%
Glycine or mannitol or its mixture 19.84%
Pullulan or sodium alginate or its mixture 27.78%
Xanthan gum or Konjac glucomannan or its mixture 0.50%
Antioxidant 1.98%
All the other are sweeting agent or aromatic or sweeting agent and aromatic, and wherein each weight percentages of components sum is 100%.
20. a simvastatin oral cavity disintegration tablet, it is processed by following components by part by weight:
1000 parts of simvastatins
400 parts in glycine or mannitol or its mixture
560 parts in Pullulan or sodium alginate or its mixture
10 parts in xanthan gum or Konjac glucomannan or its mixture
40 parts of antioxidants
6 parts of sweeting agents
17984 parts of purified water.
21. a simvastatin oral cavity disintegration tablet, it is processed by following component:
Simvastatin 10.00g
Glycine 4.00g
Pullulan 5.60g
Xanthan gum 0.10g
Butylhydroxy anisole 0.24g
Citric acid 0.16g
Acesulfame potassium 0.06g
Purified water 179.84g
Process 1000 altogether.
22. like any described fat-reducing medicament of claim among the claim 1-18, comprise simvastatin, atorvastatin, pravastatin, fluvastatin, Rosuvastatin etc. with and pharmaceutically acceptable salt, ester, solvate, derivant or optical isomer.
23., it is characterized in that this method comprises the steps: like the method for preparing of any described fat-reducing medicament oral cavity disintegration tablet of claim among the claim 1-3
(a) preparation of substrate liquid: principal agent, skeleton proppant, binding agent, antioxidant 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.
24. the method for preparing like any described fat-reducing medicament oral cavity disintegration tablet of claim among the claim 8-10,19 is characterized in that adopting following steps to make:
(a) preparation of substrate liquid: with principal agent, glycine or mannitol or its mixture, Pullulan or sodium alginate or its mixture, antioxidant 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 fat-reducing medicament 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.
25. the method for preparing like any described fat-reducing medicament oral cavity disintegration tablet of claim among claim 11-13, the 16-18,20,21 is characterized in that adopting following steps to make:
With principal agent, glycine or mannitol or its mixture, Pullulan or sodium alginate or its mixture, antioxidant 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 fat-reducing medicament oral cavity disintegration tablet of the present invention; Also can add the step that ice crystal is hatched before changing freeze dryer after the pre-freeze step in the said method, soon the mould that is marked with solution after the pre-freeze is put into-5 ℃～-60 ℃ low temperature environment, and the time is 0.5～15h.
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| CN2011100082991A CN102579375A (en) | 2011-01-14 | 2011-01-14 | Lipid lowering medicament orally disintegrating tablets and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110652513A (en) * | 2018-06-28 | 2020-01-07 | 黑龙江珍宝岛药业股份有限公司 | Pharmaceutical composition containing rosuvastatin calcium and preparation method and application thereof |
| CN114588121A (en) * | 2021-05-05 | 2022-06-07 | 鲁南贝特制药有限公司 | Simvastatin tablet and preparation method thereof |
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 |
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2011
- 2011-01-14 CN CN2011100082991A patent/CN102579375A/en active Pending
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 (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110652513A (en) * | 2018-06-28 | 2020-01-07 | 黑龙江珍宝岛药业股份有限公司 | Pharmaceutical composition containing rosuvastatin calcium and preparation method and application thereof |
| CN114588121A (en) * | 2021-05-05 | 2022-06-07 | 鲁南贝特制药有限公司 | Simvastatin tablet and preparation method thereof |
| CN114588121B (en) * | 2021-05-05 | 2024-01-26 | 鲁南贝特制药有限公司 | Simvastatin tablet and preparation method thereof |
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Address after: 102200 Changping District Road, Beijing, No. 8, No. 11 building Applicant after: Quantum Hi-Tech Research Institute (Beijing) Co., Ltd. Address before: 065201 Langfang Yanjiao economic and Technological Development Zone Hebei Yingbin North Road quantum hi tech (Beijing) Research Institute Co., Ltd. Applicant before: Quantum Hi-Tech Research Institute (Beijing) Co., Ltd. |
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Application publication date: 20120718 |