CN102764261A - Oral composition controlling release of trimetazidine dihydrochloride and preparation method of oral composition - Google Patents
Oral composition controlling release of trimetazidine dihydrochloride and preparation method of oral composition Download PDFInfo
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Abstract
The invention relates to an oral composition controlling release of trimetazidine dihydrochloride and a preparation method of the oral composition, belongs to the technical field of medicine, and is suitable for prevention and treatment of angina and auxiliary symptomatic treatment of dizziness and tinnitus. The oral composition controlling release of trimetazidine dihydrochloride is mainly prepared with chitosan, anionic polymer and trimetazidine dihydrochloride, and releasing of trimetazidine dihydrochloride is controlled by chitosan and anionic polymer. The oral composition controlling release of the trimetazidine dihydrochloride can release trimetazidine dihydrochloride for a long time, so that two or more than two polymers with different charges interact based on physiological PH change of a human body during releasing process for the human body, and form insoluble polymer films on the surface of tablets or granules, a composition system automatically becomes sustained-release tablets or granules or capsules with a joint controlled release mechanism of a film controlled type and a skeleton type.
Description
Technical field
The present invention relates to the composition and method of making the same that a kind of oral control Trimetazidine Hydrochloride discharges, it belongs to technical field of pharmaceuticals, is applicable to the complementary symptomatic treatment of anginal prevention and treatment, dizzy and tinnitus.
Background technology
The trimetazidine chemical name is 1-(2,3, a 4-2,4,5-trimethoxyphenyl methyl) piperazine, and structural formula is:
Trimetazidine can with sour salify, its dihydrochloride is widely used in clinically at home and abroad at present, is mainly used in the prophylactic treatment of angina pectoris attacks, and dizzy and complementary symptomatic treatment tinnitus.Along with the development of clinical research, it is expected to become a line medicine of resisting myocardial ischemia.
Trimetazidine also is the metabolism class medicaments for resisting myocardial ischemia that global first acquisition European and American countries is recommended, and is desirable new selection of control angina pectoris.Trimetazidine stops the decline of ATP level in the cell through protection ischemia, anoxybiotic cellular energy metabolism, thereby guarantees the normal operation of ionic pump and the transhipment of sodium potassium current, keeps the stable of intracellular environment simultaneously.Find that from angina pectoris patient's comparative study trimetazidine can increase coronary blood-flow volume, therefore postpone the inductive myocardial ischemia of excitability and take place, after treatment the 15th day, Trimetazidine Hydrochloride begins onset, suppresses blood pressure and changes fast, simultaneously to not influence of heart rate; Significantly reduce the angina pectoris occurrence frequency, significantly reduce the use of glyceryl trinitrate.The myocardial ischemia outbreak cycle with every day 4:00-8:00 be the peak, account for 40% of whole day outbreak number.But because traditional antianginal drug effect covering duration is limited; How to form the empty window phase in the morning; Can not effectively prevent the generation of myocardial ischemia, therefore select continuous and effective and can cover the medicaments for resisting myocardial ischemia of period in early morning very important preventing myocardial ischemia disease.Behind single oral Trimetazidine Hydrochloride ordinary tablet or the capsule 20mg, absorb rapidly, 1.8h promptly reaches plasma peaks 53.6 μ g ﹒ L
-1, area can reach 508.9 μ g ﹒ h ﹒ L under the medicine time graph
-1Each oral hydrochloride trimetazidine 20mg, every day 3 times, behind the 15d, peak plasma concentration can reach 84.8 μ g ﹒ L
-1, continuing to take for a long time, area can reach 831.4 μ g ﹒ h ﹒ L under the Cot curve
-1The trimetazidine bioavailability can reach 88.7%, and protein binding rate is about 16%, and the blood plasma distribution volume is 318.6L, T
1/2Be 6h, 80% medicine is from RE, and total body clearance is 37.45L.h
-1Therefore, the Trimetazidine Hydrochloride ordinary tablet can not be kept effective blood drug concentration for a long time, and trimetazidine hydrochloride sustained-release tablets then can promote medicine paddy concentration; Lasting peace is steady more to make effective blood drug concentration simultaneously; 24 hours control angina pectoris attackses have effectively been filled up the empty window phase of anginal treatment in early morning, and have further been strengthened the resisting myocardial ischemia curative effect of trimetazidine; Effectively the treatment intractable angina pectoris is safe and effective.
In recent years, China's Incidence of CHD demonstrates ascendant trend year by year.In chronic disease was ill, blood circulation diseases (like heart disease, cerebrovascular, hypertension etc.), endocrine system disease (like diabetes) increased obviously, and breathe, the chronic disease of system such as digestion obviously descends.Ministry of Public Health announces that the main result of the 4th national health service observation shows, have blood circulation diseases example number that the doctor clarifies a diagnosis by 1993 0.37 hundred million be increased to 1.14 hundred million (wherein: the hyperpietic by 1,400 ten thousand be increased to 7,300 ten thousand, cerebrovascular is increased to 1,300 ten thousand by 5,000,000); The diabetes cases number is increased to 1,400 ten thousand from 2,000,000.According to another Ministry of Public Health " national health service research " statistics report, China's prevalence of coronary heart disease is about 4.6%., the acceleration along with the aging of population reaches more than 8,000,000 at present, thereby has driven the market demand of this type medicine.2006～2010 5 in the period of; China's control angina drug average rate of increase is 19.85%; 22 key cities sample hospitals prevented and treated nearly 800,000,000 yuan of angina pectoris clinical applications in 2010, went up on year-on-year basis to increase by 17.24% in 1 year, and the overall medication of hospital is about more than 30 hundred million yuan of scales.This shows that the exploitation trimetazidine hydrochloride sustained-release tablets has huge social benefit and economic benefit.
External at present slow releasing tablet of obeying twice in existing day; Domesticly also develop, because the Trimetazidine Hydrochloride water solublity is very good, so skeleton type sustained release preparation is not easy to control its rate of release; Need to add a large amount of framework material and blocker; Patent CN 1302663 has described a kind of substrate tablet that can discharge trimetazidine for a long time, it is characterized in that, this long-time release is to control through the use of cellulose derivatives copolymer (hydroxypropyl emthylcellulose); Be mainly the hydrophilic gel matrix tablet, discharge medicine through diffusion.Single dose 35mg, day clothes twice, it can obtain in human body greater than 70 μ g ﹒ L after taking medicine at every turn
-1PC, and can make PC up to take medicine more than or equal to 40 μ g ﹒ L next time
-1, but its 4 hours basic releases fully.And film-controlled slow-release preparation is because its complicated process of preparation; Production cost is often higher, as: CN 1124140 has described a kind of trimetazidine reservoir devices film control sheet, and its slow release is controlled by insoluble polymer and plasticizer; Also can be made into during small pieces incapsulate; The film coating material is mainly by ethyl cellulose, and acrylic acid derivative is formed, and plasticizer is mainly citroflex A-4, dibutyl sebacate.Single dose is 80mg, takes a slice every day, and sustainable even release is more than the 16h.Its major defect is that film material film-forming temperature is high, must add a large amount of plasticizer film forming, and plasticizer has very big influence to the release behavior of medicine, and this is unfavorable for keeping stable drug release curve; The 2nd, with the aqueous dispersion coating of above-mentioned film material, must handle more than the 24h at 40 ℃ to 60 ℃ after the completion, complex process, cost strengthens, and is also unfavorable to medicine stability.The domestic osmotic pump preparation that also prepares relevant trimetazidine, as: CN1931143 describes the trimetazidine pharmaceutical composition of oral sustained release, osmotic pumps (monolayer core body/double-deck core body), preferred single chamber double layer osmotic pump.External zero-order release, single dose contains 70mg, takes medicine every day once, and blood drug level is steady, and it is little to fluctuate, and lasting release can reach 16h.But osmotic pump preparation is also because its complex process often realizes suitability for industrialized production than difficulty.CN 200910220111.2 has described a kind of based on self-assembled composite membrane controlled sustained-release preparation and preparation method thereof, but its be mainly used in control water in dissolubility less than 100mgml
-1Medicine, like theophylline, acetaminophen, ligustrazine phosphate, aspirin, diclofenac sodium, glipizide, it does not indicate the release that is used for highly water soluble drugs, and the Trimetazidine Hydrochloride that is mentioned in this patent, its water solublity is higher (greater than 1gml
-1), therefore, the another one innovative point of this patent is exactly first the self-assembled composite membrane controlled sustained-release system to be applied to highly water soluble drugs.
Summary of the invention
The present invention seeks in order to overcome the deficiency of prior art; The compositions that provides oral control Trimetazidine Hydrochloride to discharge, prescription of the present invention and preparation technology are simple, and clinical safety is effective; Contain chitosan and anionic polymer in the compositions; They can be under the gastrointestinal pH condition, the self assembly film forming, and controlled release system has the characteristics of skeleton type sustained release preparation and film controlling type slow releasing preparation concurrently; The various combination of polymer of the present invention can make medicine continue to discharge more than 8 hours or more than 16 hours, has big rate of release range of accommodation.
Another object of the present invention provides the preparation of compositions method that a kind of oral control Trimetazidine Hydrochloride discharges; Its process is simple; Can adopt the method for powder vertical compression, common wet granulation and dry granulation to prepare trimetazidine hydrochloride sustained-release tablets or granule or capsule; Be fit to suitability for industrialized production, production cost is low, and the medicine stability of preparation is good.
In order to achieve the above object, the present invention realizes through following technical proposals:
The compositions that oral control Trimetazidine Hydrochloride discharges, it mainly is to be prepared from chitosan, anionic polymer and Trimetazidine Hydrochloride, through the release of chitosan, anionic polymer control Trimetazidine Hydrochloride.
The compositions that above-mentioned oral control Trimetazidine Hydrochloride discharges, it is to be prepared from by said parts by weight following raw material: Trimetazidine Hydrochloride 7-25 part, chitosan 10-80 part, anionic polymer 10-80 part, other adjuvant 0-65 part.
Above-mentioned chitosan, its degree of deacetylation is at 50-95%, and molecular weight is at 50-600kDa.
Other above-mentioned adjuvant is one of wetting agent, binding agent, diluent, lubricant or its compositions.
Above-mentioned wetting agent is one of water, ethanol or its compositions; Binding agent is one of starch slurry, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone or its compositions; Diluent is one of starch, microcrystalline Cellulose, pregelatinized Starch, lactose, calcium hydrogen phosphate, Polyethylene Glycol or its compositions; Lubricant is one of magnesium stearate, Pulvis Talci, silicon dioxide, Polyethylene Glycol or its compositions.
Above-mentioned anionic polymer is sodium alginate, carrageenan, sodium carboxymethyl cellulose, acrylate copolymer; Described carrageenan comprises ι type carrageenan, λ type carrageenan; Described acrylate copolymer comprises carbomer 934 P, 971P and 974P, but is not restricted to this several kinds of anionic polymers; When preparing the trimetazidine hydrochloride sustained-release preparation of obeying twice day, preferred sodium alginate, sodium carboxymethyl cellulose, carbomer; Prepare when day obeying trimetazidine hydrochloride sustained-release preparation once preferred carrageenan.The preferred umber of anionic polymer is 15-75 part.
Under physiological pH change condition in human body, above-mentioned chitosan and anionic polymer can interact and form the insoluble polymer film, and the compositions system becomes slow releasing tablet or the granule or the slow releasing capsule of film controlling type and matrix type associating controlled release mechanism automatically.
The compositions that above-mentioned oral control Trimetazidine Hydrochloride discharges, when single dose is 30-40mg, twice of day clothes; Behind the single oral medicine, continue to discharge more than 8 hours, perhaps single dose is that 60-80mg is when being; Day obeys once, behind the single oral medicine, continues to discharge more than 16 hours.
The preparation of compositions method that a kind of above-mentioned oral control Trimetazidine Hydrochloride discharges is characterized in that powder directly is pressed into tablet with Trimetazidine Hydrochloride, chitosan, anionic polymer and other auxiliary materials and mixing; Perhaps mixing, wet granulation, drying, granulate becomes granule or is packed into capsule to get capsule or further be pressed into tablet; Perhaps mixing, dry granulation, granulate become granule or are packed into capsule to get capsule or further be pressed into tablet.
Its concrete method for preparing is following:
1) direct powder compression
Get the Trimetazidine Hydrochloride, chitosan, anionic polymer and other auxiliary materials and mixing that meet above-mentioned umber ratio, powder directly is pressed into tablet.
2) wet granulation
It is even to get the Trimetazidine Hydrochloride, chitosan, anionic polymer, the mixing diluents that meet above-mentioned umber ratio; Add wetting agent or binding agent system soft material; Granulate, be positioned under the 40-80 ℃ of condition and dry, granulate obtains sustained-release granular formulation; Perhaps be packed into capsule, obtain capsule; Perhaps, add lubricant through extruding method granulations such as round as a ball, mixing, tabletting promptly gets.
3) dry granulation
Get mix homogeneously such as the Trimetazidine Hydrochloride that meets above-mentioned umber ratio, chitosan, anionic polymer, diluent; Equipment with suitable is pressed into sheet (tablet machine or dry granulation machine), and then is broken into the granule of suitable size, obtains sustained-release granular formulation; Perhaps be packed into capsule, obtain capsule; Perhaps add lubricant, mixing, tabletting promptly gets.
Owing to adopt technique scheme, make the present invention have following advantage and effect:
Preparation technology of the present invention is simple, under the situation of change of gastrointestinal tract pH value, independently forms insoluble film in tablet surface in vivo, and system has matrix type and film controlling type slow releasing preparation characteristics concurrently, thereby reaches good slow controlled-release effect.Clinical safety of the present invention is effective; Contain chitosan and anionic polymer in the compositions; They can be under the gastrointestinal pH condition, the self assembly film forming, and controlled release system has the characteristics of skeleton type sustained release preparation and film controlling type slow releasing preparation concurrently; The various combination of polymer of the present invention can make medicine continue to discharge more than 8 hours or more than 16 hours, has big rate of release range of accommodation.
Method for preparing of the present invention is simple, can adopt the method for powder vertical compression, common wet granulation and dry granulation to prepare trimetazidine hydrochloride sustained-release tablets or granule or capsule, is fit to suitability for industrialized production, and production cost is low, and the medicine stability of preparation is good.
Description of drawings
Fig. 1 is embodiment 1,2,3 and 4.With chitosan and sodium alginate is the curve chart of master's mixed-matrix control Trimetazidine Hydrochloride release.
Fig. 2 is embodiment 5,6,7.Be respectively with chitosan and carbomer, chitosan and sodium carboxymethyl cellulose, chitosan and hyaluronate sodium is the curve chart of master's mixed-matrix control Trimetazidine Hydrochloride release.
Fig. 3 is embodiment 8,9.With chitosan and carrageenan is the curve chart of master's mixed-matrix control Trimetazidine Hydrochloride release.
Fig. 4 is embodiment 10,11,12 and 13.The curve chart that the mixed-matrix control Trimetazidine Hydrochloride that is the master with chitosan and two kinds of anionic polymers discharges.
Because the present invention has prepared day twice of a clothes and a day clothes slow releasing preparation once respectively; And at present the commercial preparation mainly with day clothes be main twice; For the ease of the release profiles of rating unit embodiment, measured the releasing effect of obeying twice commercially available slow releasing tablet (VASTAREL MR) day simultaneously, see Fig. 2.
The specific embodiment
Below in conjunction with embodiment the present invention is described further.Following examples are merely several specific embodiment of the present invention, but design concept of the present invention is not limited thereto, and allly utilize this design that the present invention is carried out the change of unsubstantiality, all should belong to the behavior of invading protection domain of the present invention.
Method among the following embodiment if no special instructions, is conventional method.
Percentage composition among the following embodiment is the quality percentage composition if no special instructions.
Embodiment 1
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 35.00g
Chitosan 87.50g
Sodium alginate 87.50g
Microcrystalline Cellulose 38.25g
Magnesium stearate 1.25g
Micropowder silica gel 0.50g
Sheet is 250mg heavily, processes 1000
Preparation technology:
Said medicine and adjuvant are crossed 80 mesh sieves, and each composition is by the equivalent method mixing that progressively increases, powder vertical compression.Said chitosan molecule amount is 400kDa, and deacetylated is 86.5%.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 1.
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 35.00g
Chitosan 35.00g
Sodium alginate 140.00g
Pregelatinized Starch 138.25g
Magnesium stearate 1.25g
Micropowder silica gel 0.50g
The heavy 350mg of sheet processes 1000
Preparation technology:
Said medicine and adjuvant are crossed 80 orders, and each composition is pressed into sheet (tablet machine or dry granulation machine) with suitable equipment, and then is broken into the granule of suitable size by the equivalent method mixing that progressively increases, and adds lubricant, mixing, and tabletting promptly gets.Said chitosan molecule amount is 50kDa, and deacetylated is 95%.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 1.
Embodiment 3
Trimetazidine hydrochloride sustained-release granule/sheet:
Trimetazidine Hydrochloride 35.00g
Chitosan 36.50g
Sodium alginate 225.00g
Magnesium stearate 2.25g
Pulvis Talci 1.25g
The heavy 300mg of sheet processes 1000
Preparation technology:
Said medicine and adjuvant are crossed 100 orders,, add binding agent 10%PVP ethanol-water solution system soft material earlier with chitosan, sodium alginate mixing; Granulate, be positioned over 70-80 ℃ of oven dry, granulate obtains sustained-release granular formulation, perhaps through extruding method granulations such as round as a ball, adds lubricant, mixing, and tabletting promptly gets.Said chitosan molecule amount is 100kDa, and deacetylated is 50%.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 1.
Embodiment 4:
Trimetazidine hydrochloride sustained-release capsule/sheet:
Trimetazidine Hydrochloride 35.00g
Chitosan 75.00g
Sodium alginate 30.00g
Lactose 58.25g
Magnesium stearate 1.25g
Micropowder silica gel 0.50g
The heavy 200mg of capsule 's content or sheet processes 1000/sheet
Preparation technology:
Trimetazidine Hydrochloride, chitosan, sodium alginate, diluent mixing with recipe quantity; Add 20% ethanol system soft material; 16 orders are granulated, and are positioned over 70-80 ℃ of oven dry, and 12 order granulate, filler particles get slow releasing capsule in capsule, or add magnesium stearate, micropowder silica gel, mixing, and tabletting promptly gets.Said chitosan molecule amount is 400kDa, and deacetylated is 86.5%.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 1.
Embodiment 5:
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 35.00g
Chitosan 25.00g
Carbomer 974 P 150.00g
Calcium hydrogen phosphate 38.25g
Magnesium stearate 1.25g
Micropowder silica gel 0.50g
Sheet is 250mg heavily, processes 1000
Preparation technology:
Said medicine and adjuvant are crossed 80 orders, and each composition is by the equivalent method mixing that progressively increases, the powder vertical compression, and said chitosan molecule amount is 600kDa, deacetylated is 50%.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 2.
Embodiment 6:
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 30.00g
Chitosan 288.00g
Sodium carboxymethyl cellulose 36.00g
Lactose 5.00g
Magnesium stearate 1.00g
Sheet is 360mg heavily, processes 1000
Preparation technology:
Said medicine and adjuvant are crossed 80 orders, and each composition is by the equivalent method mixing that progressively increases, powder vertical compression.Said chitosan molecule amount is 400kDa, and deacetylated is 95%; Said sodium carboxymethyl cellulose molecular weight is 800-1200kDa.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 2.
Embodiment 7:
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 35.00g
Chitosan 52.50g
Hyaluronate sodium 52.50g
Microcrystalline Cellulose 108.25g
Magnesium stearate 1.25g
Pulvis Talci 0.50g
The heavy 250mg of sheet processes 1000
Preparation technology:
Trimetazidine Hydrochloride, chitosan, hyaluronate sodium, microcrystalline Cellulose mixing with recipe quantity; Add 5%PVP ethanol-water solution system soft material; 20 orders are granulated, and are positioned over 70-80 ℃ of oven dry, 16 order granulate; Add magnesium stearate, Pulvis Talci, mixing, tabletting promptly gets.Said chitosan molecule amount is 50kDa, and deacetylated is 86.5%.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 2.
Embodiment 8:
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 60.00g
Chitosan 60.00g
ι carrageenan 80.00g
Starch 36.50g
Magnesium stearate 2.50g
Micropowder silica gel 1.00g
Sheet is 240mg heavily, processes 1000
Preparation technology:
Trimetazidine Hydrochloride, chitosan, ι carrageenan, diluent mixing with recipe quantity; Add 10% starch slurry system soft material; 16 orders are granulated, and are positioned over 40-60 ℃ of oven dry, 12 order granulate; Add magnesium stearate, micropowder silica gel, mixing, tabletting promptly gets.Said chitosan molecule amount is 200kDa, and deacetylated is 86.5%.This prescription and preparation technology are used to obtain a day clothes slow releasing preparation once, and the stripping result of preparation in the simulation gastrointestinal conditions sees accompanying drawing 3.
Embodiment 9
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 80.00g
Chitosan 100.00g
λ carrageenan 320.00g
Microcrystalline Cellulose 56.15g
Magnesium stearate 2.75g
Polyethylene Glycol 1.10g
Sheet is 560mg heavily, processes 1000
Preparation technology:
Trimetazidine Hydrochloride, chitosan, λ carrageenan, microcrystalline Cellulose mixing with recipe quantity; Add 50% ethanol-water solution system soft material; 16 orders are granulated, and are positioned over 50-70 ℃ of oven dry, 12 order granulate; Add magnesium stearate, Polyethylene Glycol, mixing, tabletting promptly gets.Said chitosan molecule amount is 400kDa, and deacetylated is 86.5%.This prescription and preparation technology are used to obtain a day clothes slow releasing preparation once, and the stripping result of preparation in the simulation gastrointestinal conditions sees accompanying drawing 3.
Embodiment 10:
Trimetazidine hydrochloride sustained-release tablets
Trimetazidine Hydrochloride 30.00g
Chitosan 40.00g
Sodium alginate 240.00g
λ carrageenan 40.00g
Sheet is 350mg heavily, processes 1000
Preparation technology:
Said medicine and adjuvant are crossed 80 orders, and each composition is by the equivalent method mixing that progressively increases, powder vertical compression.Said chitosan molecule amount is 400kDa, and deacetylated is 60%.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 4.
Embodiment 11
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 35.00g
Chitosan 87.50g
Sodium alginate 87.50g
Sodium carboxymethyl cellulose 37.50g
Magnesium stearate 1.25g
Micropowder silica gel 1.25g
Preparation technology:
Sheet is 250mg heavily, processes 1000
Preparation technology:
Said medicine and adjuvant are crossed 80 orders, and each composition is by the equivalent method mixing that progressively increases, the powder vertical compression, and said chitosan molecule amount is 400kDa, deacetylated is 50%; Said sodium carboxymethyl cellulose molecular weight is 800-1200kDa.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 4.
Trimetazidine hydrochloride sustained-release tablets:
Trimetazidine Hydrochloride 35.00g
Chitosan 39.00g
Hyaluronate sodium 35.00g
Sodium carboxymethyl cellulose 10.00g
Microcrystalline Cellulose 120.00g
Lactose 100.00g
Magnesium stearate 1.00g
Preparation technology:
Sheet is 340mg heavily, processes 1000
Preparation technology:
Said medicine and adjuvant are crossed 80 orders, and each composition is by the equivalent method mixing that progressively increases, the powder vertical compression, and said chitosan molecule amount is 100kDa, deacetylated is 86.5%; Said sodium carboxymethyl cellulose molecular weight is 800-1200kDa.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 4.
Embodiment 13:
Trimetazidine hydrochloride sustained-release tablets
Trimetazidine Hydrochloride 35.00g
Chitosan 80.00g
Hyaluronic acid 50.00g
Gelatin 110.00g
Lactose 223.50g
Magnesium stearate 1.00g
Micropowder silica gel 0.50g
Preparation technology:
Sheet is 500mg heavily, processes 1000
Trimetazidine Hydrochloride, chitosan, hyaluronate sodium, gelatin, microcrystalline Cellulose mixing with recipe quantity; Add 3% hypromellose ethanol-water solution system soft material; 20 orders are granulated, and are positioned over 40-50 ℃ of oven dry, 16 order granulate; Add lubricant, mixing, tabletting promptly gets.Said chitosan molecule amount is 50kDa, and deacetylated is 70%.This prescription and preparation technology are used to obtain the slow releasing preparation of twice of day clothes, and the stripping result of preparation in simulating gastrointestinal conditions sees accompanying drawing 4.
In order to investigate the release in vitro effect of embodiment of the invention 1-13,, adopt the device of dissolution determination (appendix ⅹ CD first method) according to Chinese Pharmacopoeia version drug release determination in 2010 method (appendix ⅹ D first method); 900mL is a release medium with hydrochloric acid solution (7 mL are diluted to 1000); Replace hydrochloric acid solution with phosphate buffer (pH6.8) 900mL after 2 hours, continuation is measured 10 hours (day twice slow releasing preparation of clothes) or 22 hours (slow releasing preparation of day clothes), temperature: 37.0 ± 0.5 ℃; Rotating speed: 100r/min; Operation in accordance with the law in 1,2,4,6,8,10,12 hour sampling 5mL, filters with 0.45 μ m microporous filter membrane.And replenish isothermal, isopyknic fresh medium immediately.Adopt HPLC (HPLC) to measure release amount of medicine.
Visible by above-mentioned experimental result; Not commensurability chitin-sodium alginate compositions can be used to control the release of Trimetazidine Hydrochloride; It has an outstanding feature simultaneously; That is: medicine is behind the process rapid release of preceding 2h, and 10h is near the zero level release dynamics in the back, and this drug release character helps medicine and forms more stable blood drug level (Fig. 1) in vivo; In the present embodiment; The release profiles of the slow releasing preparation of chitosan-sodium carboxymethyl cellulose compositions, chitosan-carbomer preparation of compositions and the release profiles of commercial preparation are approaching, and chitosan-hyaluronic acid composition of sodium also can make trimetazidine hydrochloride sustained-release more than 8 hours (Fig. 2); The compositions of chitosan and carrageenan system can be used in preparation makes Trimetazidine Hydrochloride continue discharge the slow releasing preparation more than 16 hours, and it can significantly reduce the medicine unexpected release effects (Fig. 3) in early stage, and this can be avoided too high blood drug level in early stage; Share of chitosan and two kinds of anionic polymers can make Trimetazidine Hydrochloride discharge for a long time, and kind and the ratio of changing anionic polymer can obtain different drug release profiles (Fig. 4).Can find out from embodiment 1-13; After chitosan and different anions polymer share; Not only can prepare the slow releasing preparation of slow release more than 8 hours, and can prepare the slow releasing preparation of slow release more than 16 hours, also can prepare the slow releasing preparation similar with the commercial preparation rate of releasing drug.Than the trimetazidine hydrochloride sustained-release preparation that patent CN 1124140, CN1931143 are mentioned to, the preparation technology of all embodiment is simple, and rate of releasing drug is regulated more easily.
Claims (9)
1. the compositions that oral control Trimetazidine Hydrochloride discharges is characterized in that it mainly is to be prepared from chitosan, anionic polymer and Trimetazidine Hydrochloride, through the release of chitosan, anionic polymer control Trimetazidine Hydrochloride.
2. the compositions that oral control Trimetazidine Hydrochloride according to claim 1 discharges; It is characterized in that it is to be prepared from by said parts by weight following raw material: Trimetazidine Hydrochloride 7-25 part; Chitosan 10-80 part, anionic polymer 10-80 part, other adjuvant 0-65 part.
3. the compositions that oral control Trimetazidine Hydrochloride according to claim 1 and 2 discharges is characterized in that described chitosan, and its degree of deacetylation is at 50-95%, and molecular weight is at 50-600kDa.
4. the compositions that oral control Trimetazidine Hydrochloride according to claim 2 discharges is characterized in that described other adjuvant is one of wetting agent, binding agent, diluent, lubricant or its compositions.
5. the compositions that oral control Trimetazidine Hydrochloride according to claim 4 discharges is characterized in that described wetting agent is one of water, ethanol or its compositions; Binding agent is one of starch slurry, hydroxypropyl cellulose, hypromellose, polyvinylpyrrolidone or its compositions; Diluent is one of starch, microcrystalline Cellulose, pregelatinized Starch, lactose, calcium hydrogen phosphate, Polyethylene Glycol or its compositions; Lubricant is one of magnesium stearate, Pulvis Talci, silicon dioxide, Polyethylene Glycol or its compositions.
6. the compositions that oral control Trimetazidine Hydrochloride according to claim 1 discharges; It is characterized in that described anionic polymer is one of sodium alginate, carrageenan, sodium carboxymethyl cellulose, acrylate copolymer or its compositions; Described carrageenan comprises ι type carrageenan, λ type carrageenan, and described acrylate copolymer comprises carbomer 934 P, 971P and 974P.
7. the compositions that oral control Trimetazidine Hydrochloride according to claim 1 discharges; It is characterized in that ought be in human body under the physiological pH change condition; Chitosan and anionic polymer can interact and form the insoluble polymer film, and the compositions system becomes slow releasing tablet or the granule or the slow releasing capsule of film controlling type and matrix type associating controlled release mechanism automatically.
8. the compositions that oral control Trimetazidine Hydrochloride according to claim 1 and 2 discharges is characterized in that when single dose is 30-40mg, twice of day clothes; Behind the single oral medicine; Continue to discharge more than 8 hours, perhaps single dose is 60-80mg when being, day clothes once; Behind the single oral medicine, continue to discharge more than 16 hours.
9. the preparation of compositions method that discharges of claim 1 or 2 described oral control Trimetazidine Hydrochlorides is characterized in that powder directly is pressed into tablet with Trimetazidine Hydrochloride, chitosan, anionic polymer and other auxiliary materials and mixing; Perhaps mixing, wet granulation, drying, granulate becomes granule or is packed into capsule to get capsule or further be pressed into tablet; Perhaps mixing, dry granulation, granulate become granule or are packed into capsule to get capsule or further be pressed into tablet.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012102674781A CN102764261A (en) | 2012-07-30 | 2012-07-30 | Oral composition controlling release of trimetazidine dihydrochloride and preparation method of oral composition |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012102674781A CN102764261A (en) | 2012-07-30 | 2012-07-30 | Oral composition controlling release of trimetazidine dihydrochloride and preparation method of oral composition |
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| CN102764261A true CN102764261A (en) | 2012-11-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2012102674781A Pending CN102764261A (en) | 2012-07-30 | 2012-07-30 | Oral composition controlling release of trimetazidine dihydrochloride and preparation method of oral composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111803459A (en) * | 2019-04-10 | 2020-10-23 | 沈阳药科大学 | Metoprolol succinate sustained-release tablet and preparation method thereof |
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| CN1931143A (en) * | 2006-10-19 | 2007-03-21 | 广州贝氏药业有限公司 | Orally taken control released trimetazidine medicine composition |
| CN101700235A (en) * | 2009-11-24 | 2010-05-05 | 沈阳药科大学 | Self-assembling compound film-controlled slow-release preparation and preparation method thereof |
| CN102091053A (en) * | 2009-12-14 | 2011-06-15 | 常州善美药物研究开发中心有限公司 | Particle composite controlled-release tablets |
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| CN1124140A (en) * | 1994-03-24 | 1996-06-12 | 阿迪尔公司 | Pharmaceutical compositions permitting the prolonged release of trimetazidine after oral administration |
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| CN101700235A (en) * | 2009-11-24 | 2010-05-05 | 沈阳药科大学 | Self-assembling compound film-controlled slow-release preparation and preparation method thereof |
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