CN1443535A - Tegasevod maleate oral preparation and its preparation process-for curing intestinal irritability syndrome - Google Patents
Tegasevod maleate oral preparation and its preparation process-for curing intestinal irritability syndrome Download PDFInfo
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Abstract
The present invention relates to an oral medicine preparation for curing intestinal irritability syndrome using constipatino as main sympton-tijaseluo maleate. It is made up by using tijaseluo maleate as active component and adding proper auxiliary material through a certain preparation process, and can be made into various oral dosage forms of tablet, oral disintegrant table, effervescent tablet, capsule, suspension gel and powder preparation, etc.
Description
Technical field
The present invention relates to a kind of pharmaceutical product and preparation technology thereof, specifically, be a kind of with the treatment constipation be the oral formulations and the preparation technology thereof of the intestinal irritability syndrome medicine tegaserod maleate of cardinal symptom.
Technical background
Intestinal irritability syndrome (being called for short IBS) is with the common disease of stomachache with colon dysfunction, it is characterized in that not having inflammation to exist, agnogenio, diet, life style factors, infection and irrelevant inflammation situation all once were considered to possible virulence factor, and the medicine that does not still have treatment IBS special authorization at present in the world reaches " golden standard therapy ".IBS can be divided into a few types, and constipation is a kind of main type.
Constipation is made up of multiple symptom, comprise be hard and dry, dry and hard, difficult defecation or sense not to the utmost, and twice of all defecation or be lower than twice or the like.Pathophysiology feature by constipation can be divided into chronic slow-transit constipation and outlet obstructed type constipation.According to statistics, present 30% constipation patient either way has concurrently.
In world developed country, constipation is one of very common disease at present.The U.S. constipation situation latest survey result who delivered in 2002 according to the medical college associate professor Satish of U.S. Iowa university shows that in U.S.'s mid-aged population, women's constipation prevalence is 17% now, and the male is 12%.The France national gastroenterology chairman that continues educating, philippe professor Houcke claim that in the patient that France seeks medical advice, constipation is one of very common main suit at present, and the case of annual diagnosis can reach 4,500,000 person-times.
In China, the sickness rate of constipation also is the gesture of quick growth recent years.Show that according to relevant survey result among Beijing, Tianjin and the crowd of area, Xi'an more than 60 years old, chronic constipation patient leads up to 15%～20%.Among the adult of Beijing area, the chronic constipation prevalence is approximately about 6%, and wherein women's prevalence approximately is more than 4 times of male.And the age of constipation patient is just gradually to younger development.
The reason that produces constipation is a lot, and it and people's diet, living habit have substantial connection.As the quickening of the rhythm of life of people's work and study in recent years, pressure strengthens, and to making psychentonia, it is irregular to live, and defecation is untimely.A lot of white-collar job personnel sit office for a long time, and increasing people is crazy about online, sees TV, is seated for a long time, lacks physical exertion, and gastrointestinal peristalsis is few.Growth in the living standard is eaten no rice but is of finest quality some, polished rice flour outeat, and coarse grain eats like a bird, and lacks cellulose in the food.Some professional practitioner (as driver, canvasser, office manager etc.) hurries back and forth all the year round outside because of job demand, and defecation is irregular.Many women hanker after fat-reducing, also easily cause constipation.In recent years, a lot of local catering trades of China swept " Sichuan cuisine wind ", and chaffy dish is in vogue, and hot food is popular, and the food that spicy suffering is scalded is overeated and also aggravated the constipation generation.The old people is because body function descends, and the gastro-intestinal digestion ability weakens, and enterokinesia is slow, is the age bracket occurred frequently of constipation.In addition, the long-term bed person also suffers from constipation easily.Above factor has determined the sickness rate of constipation from now on also will constantly rise.
Modern medicine is verified through long-term clinical research and practice, and constipation greatly reduces patient's quality of life.It also with the confidential relation that has of diseases such as colon cancer, mastopathy, presenile dementia.Research is also found, lack the risk factor that cellulosic diet is not constipation, and Nervous and Mental Factors then is one of main high risk factor of constipation as depression, anorexia etc.
The big harm of another of constipation is that it is not often paid attention to by the people.By the common viewpoint of people, " indisposition " that constipation is seemingly worth mentioning.A lot of people always think that constipation is the topic of an embarrassment, are unwilling to go to a doctor or seek advice from Xiang the doctor, and often just taking some cathartics by rule of thumb simply eliminates the constipation symptom.In addition, a lot of medical workers do not take much count of constipation yet.Clinical medicine has the explanation of many cases, and prolonged constipation but gets the brush-off and tends to change into other serious disease, as colon cancer etc.Relevant medical expert points out; usually can run in the clinical practice prolonged constipation history person is much arranged; these people think little of this " indisposition " at ordinary times; be unwilling to seek medical advice; have blood in stool up to occurring, perhaps serious physically-draining is become thin and is caused and can't just go to go to a doctor during orthobiosis; and this moment, often the state of an illness was very serious, and the doctor is unable to save a deperate situation.
The drug main of the constipation of China's treatment at present will be based on cathartic.Can be divided into four classes by its action principle.(1) osmotic laxative is for some are difficult for being absorbed and salt ion soluble in water by intestinal wall.The clothes back forms hypertonic salt solution at enteral, absorbs large quantity of moisture and stops intestinal absorption moisture, and the intestinal volume is increased, and intestinal mucosa is produced to stimulate, and produces defecation thereby strengthen enterokinesia.As magnesium sulfate, sodium sulfate etc.(2) irritant laxative, this type of medicine itself or its interior metabolism product stimulate intestinal wall, and intestinal peristalsis promoting is increased, thereby promote defecation.As bisacodyl, phenolphthalein, Semen Ricini wet goods.(3) emollient cathartic claims stool softener again, the lubricious intestinal wall of this type of medicine energy, and softening stool makes and is convenient to greatly discharge.As liquid paraffin, glycerol, glycerin etc.(4) wettability cathartic for some have the surfactant of soft stool effect, can reduce the stool surface tension, makes moisture content immerse stool, makes it to expand, soften, and is convenient to discharge.As docusate sodium etc.Also have some Chinese medicines in addition, as senna preparation, Fructus Cannabis Bolus or the like.
At present in China's nonprescription drugs catalogue, in tens treatment constipation such as existing magnesium sulfate, bisacodyl, lactulose, glycerin, glycerol, Fructus Cannabis Bolus, wuren runchang pills, CONGRONG TONGBIAN KOUFUYE, Herba Plantaginis Senna fruit composite particles, western drug recorded wherein.
According to investigations, China has 60%～70 the frequent oneself of constipation patient to take medicine for external use such as phenolphthalein irritant laxatives such as (main component are a phenolphthalein) and use glycerin approximately now.Some Chinese medicine preparation such as Folium Sennae are also used by many people in recent years.The emplastic that the doctor opens also is irritant laxative mostly.This mainly is that such medicine can be eliminated symptom quickly, and this class drug price is lower simultaneously, buys easily.
Point out according to relevant medical expert, take or abuse irritant laxative for a long time and may cause potentiality disorder serious in the body.As hypokalemia, chronic low blood sodium and progressivity renal insufficiency etc.Also may cause the variation of intestinal wall cell function and form, thereby cause the bran damage of big enteric epithelium.Also may cause the vicious cycle that this class cathartic is relied in addition.
Disease does not have size, and constipation is not an indisposition, and it has influenced people's quality of life, will be paid attention to by increasing people.From now on because all multifactor influences such as living standard, life style, dietary structure, increasing sharply of aging population in addition, old people Geng Yi suffers from constipation, and these all will make the sickness rate of China's constipation be the trend of continuous rising.The huge patient consumer group will effectively stimulate coprostasis curative market constantly to expand.
Coprostasis curative mostly is the OTC medicine greatly, the rapid growth period that China OTC medicine being at present, estimates that China OTC pharmaceutical market sales volume will be doubled in the five-year.Along with China's life with just enough food and clothing from now on gradually to moderately well-off transition, the emplastic of the quality of obviously making the life better will be subjected to doctor and patient's attention, can occupy bigger share in the OTC medicine.
Though be subjected to patient's quantity of constipation puzzlement very huge now, for a long time, the coprostasis curative situation is unsatisfactory.Quantity is few, and kind is aging, and effect is also little desirable, is in by unfrequented condition.Many pharmaceutical manufacturers think little of it, seldom have enterprise to drop into strength exploitation good effect, and side effect is little, medicine easy to use.Even the emplastic that has enterprise's exploitation to make new advances also unlike other OTC medicine, carries out the packing of product to its flower strength, advertising is done strong marketing.To such an extent as to present national neither one the coprostasis curative kind of ringing.
According to relevant medical expert's introduction, the medicine of effectively treating constipation is except irritant laxative, and bulking agent (main component is Testa Tritici, Psyllium etc.), permeability laxative (Polyethylene Glycol, lactulose etc.) or the like all are suitable for functional constipation.Motor activation regulator (cisapride, mosapride etc.) then is fit to the property transmitted constipation slowly etc.In China, the development of this type of medicine and application are just at the early-stage, and people also are unfamiliar with it, and does not sell in a lot of places yet, and the market share is very little.The market development space will be very huge from now on.The analyst of MorganStanley Dean Witter (MSDW) proposes the edge that the IBS treatment has been in innovation, and its potentiality can become the market of hundred million dollars of hundreds ofs.Therefore developing such medicine has good social meaning and economic benefit.
Tegaserod maleate is a kind of aminoguanidine indoles chemical compound, to 5-HT
4Receptor subtype has very high selectivity, is 5-HT
4The partial agonist of receptor is the triggering factor of wriggling reflection and full gastrointestinal tract dynamia.Be mainly used in treatment based on the IBS of constipation.The 5-HT of thumping majority is present in the EC cell of digestive tract gastrointestinal mucosa in the body.Owing to the existence of multiple 5-HT receptor subtype is arranged in the body, makes it become very complicated in gastral effect.The 5-HT receptor has four kinds of hypotypes, 5-HT at present
4Receptor is one of them, and this receptor also sees maincenter and peripheral nervous system, is positioned the 5-HT of gastrointestinal tract periphery
4The contraction of receptor-mediated gastrointestinal tract muscle and diastole, so 5-HT
4Imbalance has therapeutical effect to receptor stimulating agent to gastrointestinal tract dynamia.
Tegaserod maleate is compared with cisapride, it is stronger to the effect of full gastrointestinal motivator, studies show that, tegaserod maleate can shorten normal person's the total colectomy transhipment time, increase times of defecation, find simultaneously, tegaserod maleate can stimulate the intrinsic sensory neuron of intestinal to discharge calcio because of related peptides, thereby reduce visceral sense sensitivity, motivator and the dual function that reduces visceral sensitivity just because of this medicine, make symptoms such as IBS patient's stomachache, abdominal distention and stomach discomfort significantly improve, times of defecation increases simultaneously, the stool improved texture.
With other 5-HT
4Receptor stimulating agent is compared, and this medicine is to 5-HT
4Receptor has selectivity completely, this medicine polarity is bigger simultaneously, be difficult to pass blood brain barrier and enter the central nervous system, therefore this medicine side effect is little, better tolerance, this medicine is different with cisapride simultaneously, and it is in the clinical treatment dosage range, the QT interval, do not had influence, thereby heart is not had genotoxic potential.
According to the clinical experimental study to 1519 this class of example patients, the result shows that tegaserod maleate can improve multiple symptoms such as stomachache, flatulence and constipation fast, and is easy to tolerance.Through 4 all basic after dates, patient accepts tegaserod maleate 6mg 2 times on the one or placebo at random, in 12 weeks of medication, follows up a case by regular visits to for 4 weeks again after treatment stops.Net assessment (SGA) score (comprising stomachache, intestinal function and general curative effect) that main terminal point is alleviated for patient's state of an illness.Secondary endpoints comprises the SGA of stomachache/abdominal discomfort, flatulence and constipation, intestinal habit satisfaction SGA.
The result, aspect the SGA of the SGA of alleviating SGA, abdominal discomfort and stomachache and intestinal habit, the effective percentage of this product group is evident as height than placebo group, and this result can see treatment in the 1st week, and it is keeping during the whole treatment, but the most remarkable in week at a 4-6 of treatment always.In addition, in the whole research, 3 kinds of intestinal relevance evaluations (defecation frequency, consistency and stress) are also visible significantly to be improved.Yet every day, the flatulence score only was significantly improved in 7 week of treatment.In addition, after treatment stopped, tegaserod maleate was better than the effective in cure all disappearances in 1 week of institute of placebo.
The modal untoward reaction of tegaserod maleate is headache.It is also common to suffer from diarrhoea, but is more common in for first week, and is temporary, and patient can continue treatment.
6 milligrams of twice pair of constipation type irritable bowel syndromes every day of tegaserod maleate (C-IBS) patient's curative effect and safety that Gastroenterology dept. of The Third Affiliated Hospital of Peking University has used experimental evaluation.
This research be a multicenter, at random, double blinding, parallel, placebo clinical research.Selected 510 examples meet the C-IBS patient of Rome II standard, test is 8 weeks by a definite date, comprise 2 all baseline period, twice of 4 all tegaserod maleates 6 milligrams of every day or placebo, (tegaserod maleate: placebo=1: 1) at random, double-blind treatment phase and two all drug withdrawals are with the anti-phase.Evaluation criteria: the whole IBS symptoms of patient are carried out net assessment, each IBS parameter of patient (comprising the constipation order of severity) and safety are assessed.The result: extremely the whole treatment phase all is significantly improved the main curative effect parameter of the overall IBS symptom of tegaserod maleate group patient since the 1st week.Extremely the whole treatment phase all is better than placebo group to other IBS curative effect parameter (as constipation, stomachache, abdominal discomfort, the abdominal distention) scorings of tegaserod maleate group since the 1st week.Illustrate that the tegaserod maleate curative effect is more obvious.In the drug withdrawal follow-up period, though each curative effect parameter scores of tegaserod maleate group and placebo group decreases, but all make moderate progress with respect to baseline period, but the former curative effect obviously is better than the latter, the curative effect of prompting tegaserod maleate can continue until two weeks after the drug withdrawal at least.The ratio of tegaserod maleate and placebo group generation adverse events is respectively 10% and 6%.The modal adverse events of tegaserod maleate group is diarrhoea, stomachache and dizzy, but incidence rate all lower (＜3%).Experimental result shows: can effectively alleviate tegaserod maleate 6 milligrams of every days overall IBS symptom of C-IBS patient and constipation, stomachache, abdominal discomfort, abdominal distention etc. for twice, its safety is good.
Goal of the invention
The present invention is by prepare the method for tegaserod maleate oral formulations, reaches stable and controllable for quality, taking medicine makes things convenient for and purpose safely and effectively.
Summary of the invention
For achieving the above object, the present invention adopts following technical scheme: oral formulations comprises tablet, for example oral ordinary tablet, Sublingual tablet, effervescent tablet, chewable tablet, enteric coatel tablets, buccal tablet, Film coated tablets, dispersible tablet, oral cavity disintegration tablet, fast-release tablet, slow releasing tablet and controlled release tablet etc.; Capsule, for example hard capsule, soft capsule, soft gelatin capsule, enteric coated capsule, quick-release capsules, slow releasing capsule and controlled release capsule etc.; Also comprise suspension, suspendible gel, dry suspension or powder etc.Active component wherein is a tegaserod maleate, and its chemical name is 1-(5-methoxyl group-1H-indole-3 methylene amino)-3-amyl group guanidine maleate, and structural formula is:
Molecular formula is: C
16H
23N
5OC
4H
4O
4, molecular weight is: 417.46, and the single dose of its treatment usefulness is 1mg to 20mg.
Maleic acid of the present invention replaces the preparation technology of additive color oral formulations: with tegaserod maleate and suitable adjuvant uniform mixing, by disk or the special-shaped flaky solid preparation that the preparation technique compacting forms, can make oral ordinary tablet, Sublingual tablet, effervescent tablet, chewable tablet, enteric coatel tablets, buccal tablet, Film coated tablets, dispersible tablet, oral cavity disintegration tablet, fast-release tablet, slow releasing tablet, controlled release tablet etc.
Maleic acid of the present invention is for the preparation technology of additive color oral formulations: tegaserod maleate is added suitable adjuvant such as diluent, fluidizer, disintegrating agent etc. make uniform powder or grain packing in Capsules, can make hard capsule.
Maleic acid of the present invention replaces the preparation technology of additive color oral formulations: the hard capsule of preparation is handled with suitable coating enteric material, can further be made the enteric hard capsule.
Maleic acid of the present invention replaces the preparation technology of additive color oral formulations: with one or more tegaserod maleate rapid releases, slow release, controlled release piller, filling or mixing back filling can be made rapid release, slow release, controlled release capsule in Capsules separately.
Maleic acid of the present invention is for the preparation technology of additive color oral formulations: maleic acid is dispersed in and is prepared into suspension or semi-solid thing in the suitable excipient for adding sieve, be sealed in spherical or the oval-shaped soft capsule, or drop pill is made soft capsule or drop pill.The soft capsule of preparation is handled with suitable coating enteric material, can further be made enteric soft capsules or enteric coated drop pill.
Maleic acid of the present invention replaces the preparation technology of additive color oral formulations: tegaserod maleate is dispersed in the liquid medium can makes oral administration mixed suspension.
Maleic acid of the present invention is for the preparation technology of additive color oral formulations: tegaserod maleate and proper auxiliary materials are made powder or shot-like particle, can make dry suspension, face the time spent and add the water jolting can be dispersed into the suspension confession oral.
Maleic acid of the present invention is for the preparation technology of additive color oral formulations: through pulverizing, uniform mixing can be made dry powdered powder with tegaserod maleate and proper auxiliary materials.
Maleic acid of the present invention is for the preparation technology of additive color oral formulations: suspendible gel or semi-solid gel agent that tegaserod maleate and the adjuvant that can form gel are made homogeneous.
Adjuvant in the pharmaceutical preparation of the present invention has filler, binding agent, surfactant, wetting agent, wetting agent, disintegrating agent, helps and collapse agent, suspending agent, fluidizer, lubricant, correctives, effervescent, adsorbent, suspensoid, coating material, coating material, enclose material, slow-release material, rapid release material, controlled-release material etc.
The used filler of pharmaceutical preparation of the present invention includes but not limited to lactose, sucrose, glucose, mannitol, sorbitol, calcium sulfate, calcium gluconate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium bicarbonate, starch, carboxymethyl starch, pregelatinized Starch, microcrystalline Cellulose etc.
The used wetting agent of pharmaceutical preparation of the present invention includes but not limited to water, ethanol etc.
The used binding agent of pharmaceutical preparation of the present invention includes but not limited to starch, pregelatinized Starch, gelatin, dextrin, maltose dextrin, sucrose, arabic gum, polyvinylpyrrolidone, various viscosity methylcellulose, low viscosity carboxymethyl cellulose, various viscosity ethyl cellulose, various viscosity polyvinyl alcohol, polyethylene glycol 6000, the following hydroxypropyl emthylcellulose of 50mpa.s etc.
The used disintegrating agent of pharmaceutical preparation of the present invention includes but not limited to starch, pregelatinized Starch, microcrystalline Cellulose, alginic acid, pure lignocellulose, carboxymethyl starch sodium, guar gum, crospolyvinylpyrrolidone, ion exchange resin, methylcellulose, sodium carboxymethyl cellulose etc.
The used fluidizer of pharmaceutical preparation of the present invention includes but not limited to micropowder silica gel.
The used lubricant of pharmaceutical preparation of the present invention includes but not limited to magnesium stearate, calcium stearate, zinc stearate, Pulvis Talci, glyceryl monostearate, Macrogol 4000, polyethylene glycol 6000, Polyethylene Glycol 8000, sodium benzoate, adipic acid, fumaric acid, boric acid, sodium chloride, enuatrol, triacetyl glycerine, polyoxyethylene monostearate, single Laurel sucrose acid ester, sodium chloride, sodium laurylsulfate, magnesium laurylsulfate etc.
The used adsorbent of pharmaceutical preparation of the present invention includes but not limited to silicon dioxide, crospolyvinylpyrrolidone, micropowder silica gel, Kaolin, alkali or magnesium carbonate, light magnesium oxide, aluminium hydroxide desiccant gel etc.
The used surfactant of pharmaceutical preparation of the present invention comprises but is not limited to sodium lauryl sulphate, poloxamer, Tween 80, bromination hexadecane trimethylamine, sodium laurylsulfate, stearyl alcohol sodium sulfonate, polyoxyethylene high fatty alcohol, sucrose ester, sorbitol fatty ester, soybean phospholipid etc.
The used effervescent of pharmaceutical preparation of the present invention includes but not limited to sodium dihydrogen phosphate, Sodium Acid Pyrophosphate, sodium sulfite, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium glycine carbonate, sodium sesquicarbonate, citric acid, tartaric acid, sodium glycine carbonate, fumaric acid, boric acid, maleic acid etc.
The used correctives of pharmaceutical preparation of the present invention includes but not limited to steviosin, fructose, glucose, high fructose syrup, Mel, aspartame, protein sugar, xylitol, mannitol, lactose, sorbitol, maltose alcohol, glycyrrhizin, phyllodulcin, Sodium Cyclamate, flavoring banana essence, flavoring pineapple essence, Fructus Citri tangerinae essence, Herba Menthae essence, Fructus Foeniculi, vanillin, Fructus Citri Limoniae essence, cherry essence, rose essence etc.
The suspensoid that pharmaceutical preparation of the present invention is used, suspending agent includes but not limited to that hot phenoxy group gathers ethoxy ethanol, alevaire, the sorbitol anhydride polyethylene glycol monooleate, polyoxyethylene monostearate, polyoxyethylene deriv, Tween 80, the polyoxyethylene alkylphenyl sodium sulfonate, sodium lauryl sulfate, arabic gum, polyvinylpyrrolidone, the tragakanta, pectin, gelatin, carboxymethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, guar gum, micropowder silica gel, Magnesiumaluminumsilicate, hydroxyethyl-cellulose, Kaolin, sodium alginate, kieselguhr, aluminium hydroxide etc.
The used coating material of pharmaceutical preparation of the present invention includes but not limited to cellulose and derivatives class thereof, crylic acid resin, ethene polymers etc.
The used coating material of pharmaceutical preparation of the present invention includes but not limited to gelatin, arabic gum, carboxymethyl cellulose, polyvinyl alcohol, polyacrylic acid, hydroxyethyl-cellulose, polylactic acid, ethyl cellulose, polyethylene, polyamide, stearic acid, celluloid, tristerin, Lac, Cellulose Acetate Phthalate.
The used enclose material of pharmaceutical preparation of the present invention includes but not limited to beta-schardinger dextrin-etc.
Used slow release, controlled release, the rapid release framework material of pharmaceutical preparation of the present invention includes but not limited to Brazil wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, Lac, gelatin, sodium alginate, chitosan, amylopectin, agar, carrageenin, guar gum, cellulose derivative, crylic acid resin, polyethylene kind, macromolecular material etc.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and mix with filler, disintegrating agent, surfactant, cosolvent, binding agent, guiding humid medium system soft material is granulated, drying, and granulate adds lubricant, and tabletting is made oral ordinary tablet.Should oral ordinary tablet bag film-coat or enteric coating can further make Film coated tablets or enteric coatel tablets.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and mix with filler, binding agent, guiding humid medium system soft material is granulated, drying, and granulate adds correctives, lubricant, and tabletting is made buccal tablet, chewable tablet, Sublingual tablet.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate with filler, disintegrating agent, help and collapse agent, surfactant, binding agent and mix, add correctives, lubricant, tabletting is made dispersible tablet, oral cavity disintegration tablet.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and filler, disintegrating agent, surfactant, solubilizing agent, help and collapse agent, effervescent, binding agent, correctives, mix lubricant, tabletting is made effervescent tablet.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and slow release and/or rapid release and/or controlled-release material and mix, guiding humid medium system soft material is granulated, drying, and granulate adds lubricant, and tabletting is made slow releasing tablet, fast-release tablet, controlled release tablet.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and mix with disintegrating agent, filler, surfactant, binding agent, guiding humid medium system soft material is granulated, and is filled into Capsules, makes hard capsule.The hard capsule of preparation can further be made enteric coated capsule with the processing of coating enteric material.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and slow release and/or rapid release and/or controlled-release material and make one or more slow release and/or rapid release or controlled release piller, be filled in the Capsules after filling or the mixing separately, make slow release and/or quick-release capsules or controlled release capsule.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and add in the suitable solvent, be prepared into suspension or semi-solid thing, be sealed in spherical or the oval-shaped soft capsule, make soft capsule or drop pill.Soft capsule or the drop pill made are handled with enteric-coating material, can further be made enteric soft capsules or enteric coated drop pill.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and mix with suspensoid, suspending agent, surfactant, antiseptic, correctives, add water, stir, single dose or multiple dose suspension or suspendible gel are made in packing.
The preparation technology of oral formulations of the present invention is: get tegaserod maleate and suspensoid, suspending agent, surfactant, fluidizer, adsorbent, correctives, lubricant mixing, single dose or multiple dose dry suspension or powder are made in packing.
Result of study shows, tegaserod maleate oral formulations steady quality of the present invention, controlled, safe and effective.
Below through detecting explanation beneficial effect of the present invention
Detect index and method
1. uniformity of dosage units detects and gets sample of the present invention, puts in the 100ml measuring bottle, and it is an amount of to add ethanol, ultrasonic make disintegrate after, from " ultrasonic dissolution 20 minutes ", measure content according to the method under the assay item in accordance with the law, should (two appendix X of Chinese Pharmacopoeia version in 2000 E) up to specification.
2. dissolution is got sample of the present invention, according to dissolution method (two appendix X of Chinese Pharmacopoeia version in 2000 C, second method), with 10% ethanol 1000ml is solvent, rotating speed is that per minute 75 changes, operation in accordance with the law, through 45 minutes, it is an amount of to get solution, filter, get subsequent filtrate, measure trap at the wavelength place of 310nm according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2000 A), it is an amount of that other gets the tegaserod maleate reference substance, the accurate title, decide, and makes the solution that contains tegaserod 6 μ g among every 1ml approximately with the dilution of 10% alcoholic solution, measures trap with method.Calculate every stripping quantity.
3. assay: get sample of the present invention, accurate claim fixed, porphyrize, precision takes by weighing in right amount (suitable approximately tegaserod 6mg), puts in the 100ml measuring bottle, and it is an amount of to add ethanol, supersound process 20 minutes makes the tegaserod maleate dissolving, adds ethanol dilution again to scale, shake up, filter, precision is measured in subsequent filtrate 5ml to the 50ml measuring bottle, add ethanol dilution to scale, shake up,, measure trap at the wavelength place of 315nm according to spectrophotography (two appendix IV of Chinese Pharmacopoeia version in 2000 A).It is an amount of that other gets the tegaserod maleate reference substance, and accurate the title decides, and adds the also quantitative dilution of dissolve with ethanol and make the solution that contains tegaserod 6 μ g among every 1ml approximately, measures trap with method, calculating, promptly.
Check result
One, example 1 sample detection result
1. uniformity of dosage units: 6.2%.
2. dissolution: 92.3%.
3. content: 98.9%.
Two, example 2 sample detection results
1. uniformity of dosage units: 7.6%.
2. dissolution: 90.3%.
3. content: 102.3%.
Three, example 3 sample detection results
1. uniformity of dosage units: 1.2%.
2. dissolution: 99.6%.
3. content: 99.3%.
The specific embodiment one, example 1 prescription:
Tegaserod maleate 6g (in tegaserod)
Lactose 50g
Sucrose 25g
Crospolyvinylpyrrolidone 26g
Glyceryl monostearate 8g
Poloxamer 1.5g
Polyoxyethylene sorbitan monoleate 1.5g
30 POVIDONE K 30 BP/USP 30 2.5g
50% alcoholic solution 40ml
Make 1000
Preparation technology:
1. tegaserod maleate raw material and adjuvant mix grinding are pulverized, and smashing fineness can pass through 200 mesh sieves.With the micronization of raw material and adjuvant, help the stripping of medicine.
2. surfactant, binding agent join in wetting agent 50% ethanol, can heat and stir to make dissolving, can make full and uniform being dispersed in crude drug and the adjuvant of surfactant like this, play the hydrotropy effect, strengthen the stripping of medicine.(also the lubricant glyceryl monostearate can be added in the wetting agent, 50 ℃ of stirrings make its dissolving).
3. wetting agent joins in the mixed powder of crude drug and adjuvant, stirs the back and granulates, sieve with 16 order steel, the drying baker inner drying granule below 80 ℃ 4 hours, treat particle drying after, with being directly compressible behind the 14 order nylon mesh granulate.
4. the adjusting of tablet machine plunger pressure, the slice, thin piece pressure that makes extrusion is at 6～8kg/cm
2, the punch die garden type punch die of φ 6.5mm, the heavily about 0.12g of sheet.
Two, example 2
Prescription:
Tegaserod maleate 6g (in tegaserod)
Lactose 50g
Sucrose 25g
Crospolyvinylpyrrolidone 26g
Glyceryl monostearate 8g
Poloxamer 1.5g
Polyoxyethylene sorbitan monoleate 1.5g
30 POVIDONE K 30 BP/USP 30 2.5g
50% alcoholic solution 40ml
Make 1000
Preparation technology:
1. tegaserod maleate raw material and adjuvant mix grinding are pulverized, and smashing fineness can pass through 200 mesh sieves.With the micronization of raw material and adjuvant, help the stripping of medicine.
2. surfactant, binding agent join in wetting agent 50% ethanol, can heat and stir to make dissolving, can make full and uniform being dispersed in crude drug and the adjuvant of surfactant like this, play the hydrotropy effect, strengthen the stripping of medicine.
3. wetting agent joins in the mixed powder of crude drug and adjuvant, stirs the back and granulates, and sieves with 16 order steel, the drying baker inner drying granule below 80 ℃ 4 hours, treats granulate behind the particle drying, inserts in the Capsules.
Three, example 3
Prescription:
Tegaserod maleate 6g (in tegaserod)
Crospolyvinylpyrrolidone 20g
Sodium carboxymethyl cellulose 30g
Microcrystalline Cellulose 50g
Micropowder silica gel 30g
Polyvinylpyrrolidone 20g
Polyoxyethylene sorbitan monoleate 2g
Sodium lauryl sulphate 5g
Poloxamer 2g
Mannitol 50g
Steviosin 10g
Essence is an amount of
Glyceryl monostearate 10g
Make 1000
Preparation technology:
Get the abundant mix homogeneously of tegaserod maleate and adjuvant, tabletting.
Claims (28)
1. tegaserod maleate oral formulations, it is characterized in that: it is oral ordinary tablet, dispersible tablet, Film coated tablets, Sublingual tablet, effervescent tablet, oral cavity disintegration tablet, chewable tablet, enteric coatel tablets, buccal tablet, slow releasing tablet, controlled release tablet, the hard capsule of making by preparation technique with single dose tegaserod maleate 1mg to 30mg and adjuvant, oral formulations such as soft capsule, soft gelatin capsule, enteric coated capsule, enteric soft capsules, enteric soft gelatin capsule, slow releasing capsule, quick-release capsules, controlled release capsule, suspension, suspendible gel, dry suspension or powder.
2. tegaserod maleate oral formulations according to claim 1 is characterized in that: the chemical name of tegaserod maleate is: 1-(5-methoxyl group-1H-indole-3 methylene amino)-3-amyl group guanidine maleate, and structural formula is:
Molecular formula is: C
16H
23N
5OC
4H
4O
4, molecular weight is: 417.46.
3. tegaserod maleate oral formulations according to claim 1, it is characterized in that: get tegaserod maleate and mix with filler, disintegrating agent, surfactant, cosolvent, binding agent, guiding humid medium system soft material, granulate, drying, granulate adds lubricant, tabletting is made oral ordinary tablet.Should oral ordinary tablet bag film-coat or enteric coating can further make Film coated tablets or enteric coatel tablets.
4. tegaserod maleate oral formulations according to claim 1 is characterized in that: get tegaserod maleate and mix guiding humid medium system soft material with filler, binding agent, granulate drying, granulate, add correctives, lubricant, tabletting is made buccal tablet, chewable tablet, Sublingual tablet.
5. tegaserod maleate oral formulations according to claim 1, it is characterized in that: get tegaserod maleate with filler, disintegrating agent, help and collapse agent, surfactant, binding agent and mix, add correctives, lubricant, tabletting is made dispersible tablet, oral cavity disintegration tablet.
6. tegaserod maleate oral formulations according to claim 1, it is characterized in that: get tegaserod maleate and filler, disintegrating agent, surfactant, solubilizing agent, help and collapse agent, effervescent, binding agent, correctives, mix lubricant, tabletting is made effervescent tablet.
7. tegaserod maleate oral formulations according to claim 1 is characterized in that: get tegaserod maleate and slow release and/or rapid release and/or controlled-release material and mix guiding humid medium system soft material, granulate drying, granulate, add lubricant, tabletting is made slow releasing tablet, fast-release tablet, controlled release tablet.
8. tegaserod maleate oral formulations according to claim 1, it is characterized in that: get tegaserod maleate and mix with disintegrating agent, filler, surfactant, binding agent, guiding humid medium system soft material is granulated, be filled into Capsules, make hard capsule.The hard capsule of preparation can further be made enteric coated capsule with the processing of coating enteric material.
9. tegaserod maleate oral formulations according to claim 1, it is characterized in that: get tegaserod maleate and slow release and/or rapid release and/or controlled-release material and make one or more slow release and/or rapid release or controlled release piller, be filled in the Capsules after filling or the mixing separately, make slow release and/or quick-release capsules or controlled release capsule.
10. tegaserod maleate oral formulations according to claim 1, it is characterized in that: get tegaserod maleate and add in the suitable solvent, be prepared into suspension or semi-solid thing, be sealed in spherical or the oval-shaped soft capsule, make soft capsule or drop pill.Soft capsule or the drop pill made are handled with enteric-coating material, can further be made enteric soft capsules or enteric coated drop pill.
11. tegaserod maleate oral formulations according to claim 1, it is characterized in that: get tegaserod maleate and mix, add water, stir with suspensoid, suspending agent, surfactant, antiseptic, correctives, single dose or multiple dose suspension or suspendible gel are made in packing.
12. tegaserod maleate oral formulations according to claim 1, it is characterized in that: get tegaserod maleate and suspensoid, suspending agent, surfactant, fluidizer, adsorbent, correctives, lubricant mixing, single dose or multiple dose dry suspension or powder are made in packing.
13. the adjuvant of tegaserod maleate oral formulations according to claim 1 has adjuvant filler, binding agent, surfactant, wetting agent, wetting agent, disintegrating agent to be arranged, help and collapse agent, suspending agent, fluidizer, lubricant, correctives, effervescent, adsorbent, suspensoid, coating material, coating material, enclose material, slow-release material, rapid release material, controlled-release material etc.
14. the described filler of claim 13 includes but not limited to lactose, sucrose, glucose, mannitol, sorbitol, calcium sulfate, calcium gluconate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, calcium bicarbonate, starch, carboxymethyl starch, pregelatinized Starch, microcrystalline Cellulose etc.
15. the described binding agent of claim 13 includes but not limited to starch, pregelatinized Starch, gelatin, dextrin, maltose dextrin, sucrose, arabic gum, polyvinylpyrrolidone, various viscosity methylcellulose, low viscosity carboxymethyl cellulose, various viscosity ethyl cellulose, various viscosity polyvinyl alcohol, polyethylene glycol 6000, the following hydroxypropyl emthylcellulose of 50mpa.s etc.
16. the described disintegrating agent of claim 13 includes but not limited to starch, pregelatinized Starch, microcrystalline Cellulose, alginic acid, pure lignocellulose, carboxymethyl starch sodium, guar gum, crospolyvinylpyrrolidone, ion exchange resin, methylcellulose, sodium carboxymethyl cellulose etc.
17. the described fluidizer of claim 13 includes but not limited to micropowder silica gel.
18. the described lubricant of claim 13 includes but not limited to magnesium stearate, calcium stearate, zinc stearate, Pulvis Talci, glyceryl monostearate, Macrogol 4000, polyethylene glycol 6000, Polyethylene Glycol 8000, sodium benzoate, adipic acid, fumaric acid, boric acid, sodium chloride, enuatrol, triacetyl glycerine, polyoxyethylene monostearate, single Laurel sucrose acid ester, sodium chloride, sodium laurylsulfate, magnesium laurylsulfate etc.
19. the described adsorbent of claim 13 includes but not limited to silicon dioxide, crospolyvinylpyrrolidone, micropowder silica gel, Kaolin, alkali or magnesium carbonate, light magnesium oxide, aluminium hydroxide desiccant gel etc.
, the described surfactant of claim 13 is not limited to sodium lauryl sulphate, poloxamer, Tween 80, bromination hexadecane trimethylamine, sodium laurylsulfate, stearyl alcohol sodium sulfonate, polyoxyethylene high fatty alcohol, sucrose ester, sorbitol fatty ester, soybean phospholipid etc. 20. comprising.
21. the described effervescent of claim 13 includes but not limited to sodium dihydrogen phosphate, Sodium Acid Pyrophosphate, sodium sulfite, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium glycine carbonate, sodium sesquicarbonate, citric acid, tartaric acid, sodium glycine carbonate, fumaric acid, boric acid, maleic acid etc.
22. the described correctives of claim 13 includes but not limited to steviosin, fructose, glucose, high fructose syrup, Mel, aspartame, protein sugar, xylitol, mannitol, lactose, sorbitol, maltose alcohol, glycyrrhizin, phyllodulcin, Sodium Cyclamate, flavoring banana essence, flavoring pineapple essence, Fructus Citri tangerinae essence, Herba Menthae essence, Fructus Foeniculi, vanillin, Fructus Citri Limoniae essence, cherry essence, rose essence etc.
23. the described suspensoid of claim 13, suspending agent includes but not limited to that hot phenoxy group gathers ethoxy ethanol, alevaire, the sorbitol anhydride polyethylene glycol monooleate, polyoxyethylene monostearate, polyoxyethylene deriv, Tween 80, the polyoxyethylene alkylphenyl sodium sulfonate, sodium lauryl sulfate, arabic gum, polyvinylpyrrolidone, the tragakanta, pectin, gelatin, carboxymethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, guar gum, micropowder silica gel, Magnesiumaluminumsilicate, hydroxyethyl-cellulose, Kaolin, sodium alginate, kieselguhr, aluminium hydroxide etc.
24. the described coating material of claim 13 includes but not limited to cellulose and derivatives class thereof, crylic acid resin, ethene polymers etc.
25. the described coating material of claim 13 includes but not limited to gelatin, arabic gum, carboxymethyl cellulose, polyvinyl alcohol, polyacrylic acid, hydroxyethyl-cellulose, polylactic acid, ethyl cellulose, polyethylene, polyamide, stearic acid, celluloid, tristerin, Lac, Cellulose Acetate Phthalate.
26. the described enclose material of claim 13 includes but not limited to beta-schardinger dextrin-etc.
27. the described slow release of claim 13, rapid release, controlled release matrix material include but not limited to Brazil wax, castor oil hydrogenated, castor wax, hydrogenated soya phosphatide, Lac, gelatin, sodium alginate, chitosan, amylopectin, agar, carrageenin, guar gum, cellulose derivative, crylic acid resin, polyethylene kind, macromolecular material etc.
28. the described wetting agent of claim 13 includes but not limited to water, ethanol etc.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03107856 CN1443535A (en) | 2003-03-25 | 2003-03-25 | Tegasevod maleate oral preparation and its preparation process-for curing intestinal irritability syndrome |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03107856 CN1443535A (en) | 2003-03-25 | 2003-03-25 | Tegasevod maleate oral preparation and its preparation process-for curing intestinal irritability syndrome |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1443535A true CN1443535A (en) | 2003-09-24 |
Family
ID=27814488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03107856 Pending CN1443535A (en) | 2003-03-25 | 2003-03-25 | Tegasevod maleate oral preparation and its preparation process-for curing intestinal irritability syndrome |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100333717C (en) * | 2003-11-24 | 2007-08-29 | 上海医药工业研究院 | Oral solid preparation of water indissoluble medicine and/or acid sensitive medicinal composition |
| CN100352436C (en) * | 2003-03-31 | 2007-12-05 | 诺瓦提斯公司 | Oral suspension of tegaserod |
| CN100356918C (en) * | 2004-09-30 | 2007-12-26 | 吴筑华 | Enteric-coated quick releasing formulation of tannic acid and total matrine for treating enteritis |
| CN100372530C (en) * | 2006-06-14 | 2008-03-05 | 江苏奥赛康药业有限公司 | Tegaserod maleate oral prepn. |
| CN100425242C (en) * | 2005-09-26 | 2008-10-15 | 云南昊邦制药有限公司 | Erigeron breviscapus effervescent dry mixed suspension and its making method |
| CN107960532A (en) * | 2016-10-20 | 2018-04-27 | 湖南晶天科技实业有限公司 | A kind of feed addictive and a kind of feed |
| CN108313367A (en) * | 2018-02-27 | 2018-07-24 | 湖南尔康制药股份有限公司 | A kind of vitamin C Yinqiao tablet of filling with inert gas packaging |
| CN111803493A (en) * | 2020-09-04 | 2020-10-23 | 郑州大学 | Application of tegaserod maleate in the preparation of antitumor drugs |
| WO2022151532A1 (en) * | 2021-01-12 | 2022-07-21 | 陈璋辉 | Application of tegaserod maleate in treatment of acute myelocytic leukemia and colorectal cancer |
-
2003
- 2003-03-25 CN CN 03107856 patent/CN1443535A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100352436C (en) * | 2003-03-31 | 2007-12-05 | 诺瓦提斯公司 | Oral suspension of tegaserod |
| CN100333717C (en) * | 2003-11-24 | 2007-08-29 | 上海医药工业研究院 | Oral solid preparation of water indissoluble medicine and/or acid sensitive medicinal composition |
| CN100356918C (en) * | 2004-09-30 | 2007-12-26 | 吴筑华 | Enteric-coated quick releasing formulation of tannic acid and total matrine for treating enteritis |
| CN100425242C (en) * | 2005-09-26 | 2008-10-15 | 云南昊邦制药有限公司 | Erigeron breviscapus effervescent dry mixed suspension and its making method |
| CN100372530C (en) * | 2006-06-14 | 2008-03-05 | 江苏奥赛康药业有限公司 | Tegaserod maleate oral prepn. |
| CN107960532A (en) * | 2016-10-20 | 2018-04-27 | 湖南晶天科技实业有限公司 | A kind of feed addictive and a kind of feed |
| CN108313367A (en) * | 2018-02-27 | 2018-07-24 | 湖南尔康制药股份有限公司 | A kind of vitamin C Yinqiao tablet of filling with inert gas packaging |
| CN111803493A (en) * | 2020-09-04 | 2020-10-23 | 郑州大学 | Application of tegaserod maleate in the preparation of antitumor drugs |
| WO2022151532A1 (en) * | 2021-01-12 | 2022-07-21 | 陈璋辉 | Application of tegaserod maleate in treatment of acute myelocytic leukemia and colorectal cancer |
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