CN102319227A - Lomerizine hydrochloride osmotic pump tablet and preparation method thereof - Google Patents
Lomerizine hydrochloride osmotic pump tablet and preparation method thereof Download PDFInfo
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- CN102319227A CN102319227A CN201110288947A CN201110288947A CN102319227A CN 102319227 A CN102319227 A CN 102319227A CN 201110288947 A CN201110288947 A CN 201110288947A CN 201110288947 A CN201110288947 A CN 201110288947A CN 102319227 A CN102319227 A CN 102319227A
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Abstract
The invention discloses a lomerizine hydrochloride osmotic pump tablet and a preparation method thereof, belongs to the novel technical field of medicaments, and relates to a novel preparation formulation of lomerizine hydrochloride. The osmotic pump tablet is a preparation taking the lomerizine hydrochloride as a main component, and is coated by a semipermeable film which contains a tablet core and is provided with drug-release pores. The osmotic pump tablet has the advantages of taking zero-order release kinetics as a characteristic, continuously releasing a certain amount of drugs at a constant rate, maintaining long-term high-efficiency blood concentration in a body, improving the curative effect of drugs, reducing the administration times of patients, improving the preparation stability, and regulating the drug release rate by changing the semitransparent property, sizes of the pore diameters and other factors, having nothing to do with external factors and drug properties, and being insensitive to gastrointestinal tract and other variable factors, good in vitro-in vivo correlation and the like.
Description
Technical field
The invention belongs to medical manufacturing field, relate to a kind of novel form of lomerizine hydrochloride, be specifically related to a kind of lomerizine hydrochloride osmotic pump tablet and preparation method thereof.
Background technology
Lomerizine hydrochloride (Lomerizine Hydrochloride) is a kind of calcium antagonism type Medicine for treating migraine, belongs to third generation piperazines cerebral vasodilator.Develop jointly by Kanebo and Phamacia Upjohn company, at first in March, 1999 Japan get permission listing, promptly created the nearly 1,000,000,000 yen achievement of sales volume then.Through application practice, its curative effect has obtained the consistent of doctor and patient with safety to be approved, subsequently again in multinational listings such as America and Europes.Migraine be a kind of be the vascular headache of main repeated relapsing with one-sided, part patient possibly follow lifelong morbidity.With the quickening pace of modern life, modern's life pressure increases day by day, and migrainous sickness rate is continuous ascendant trend in China.China adult sickness rate is 7.7%-18.7% at present, and M-F is 1: 4.
Lomerizine hydrochloride, chemical name are 1-[two (4-fluorophenyl) methyl]-4-(2,3,4-trimethoxy benzyl) piperazine dihydrochloride.Structural formula is following:
The main feature that lomerizine hydrochloride is used for migraine treatment is: determined curative effect proves through clinical trial and a large amount of practical application; Lomerizine is to migrainous prevention and treat equal produce effects; Total effective rate reaches more than 50%; Significantly reduce migrainous attack times and pain degree, improve the quality of living; Safety is good.Lomerizine selectivity blood vessel dilating is the Ca that exists at present
+To central nervous system and the tool of cerebrovascular one of medicine optionally, thereby be difficult for causing tangible peripheral blood vessel untoward reaction in the antagonist; Suppress the cerebral cortex diffusion, lomerizine hydrochloride can effectively suppress the cerebral cortex diffusion, makes body pain system have stronger resistance; Protection brain lomerizine hydrochloride has good expansion of cerebral vascular effect, and the injury that can avoid brain to receive because of ischemia, oxygen can suppress neurogenic inflammation simultaneously, and neuroprotective unit is suitable especially for the patient that needs are taken medicine for a long time.Because many advantages of this product, the unit of declaring the clinical research official written reply is a lot, but really carries out the few of clinical trial.
Lomerizine hydrochloride is by flunarizine and the synthetic hexichol piperazine derivative of trimetazidine (trimetazidine).Different with calcium-channel antagonists such as flunarizine, these article have the dual retardation of calcium channel and sodium channel, also can block a
1-adrenoceptor and 5-are through tryptamines (5-H) receptor.But (corticalSpreadi eye depres-sion CSD), reduces the generation of ischemic neuron HZ, has the free radical scavenging effect for high selectivity cerebral blood flow increasing, inhibition cortex spreading depression.Experiment shows; These article are stronger than cinnarizine and flunarizine to the selectivity of cerebral vasodilators effect; The action time that increases the brain flow is longer, and the effect of this selectivity expansion of cerebral vascular is relevant with T-type voltage sensitivity calcium channel with its blocking-up Hippocampus CAI district's cone neurone L type.Electrophysiologic study shows that these article can be blocked the low-voltage and the activated calcium current of high voltage of hippocampal pyramidal neurons simultaneously, and preferentially combines with the low-voltage activation calcium channel of unactivated state with the mode that voltage relies on.Cortex spreading depression (CSD) is relevant from the increase of neurocyte release and energy metabolism with disorder, the excitatory amino acid of the interior ionic equilibrium of brain; A large amount of clinical researches prove; CSD is relevant with migrainous Pathophysiology, and it is strong at least 10 times than flunarizine that these article suppress the effect of CSD.
The toxicological study genetoxic: microorganism reverse mutation test, chromosomal aberration test and mouse microkernel test result are all negative.Genotoxicity: the nontoxic dose to the male rat fertility is 100mg/kg/ day, female rats be 30mg/kg/ day.The young period of organogenesis of fetal rat toxicity test shows, the dose groups that female rats 10mg/kg/ day is above, and visible abnormal labor, young Mus natality descend; 30mg/kg/ daily dose group is it is thus clear that parent vaginal hemorrhage, weight increase inhibition and food ration reduce, and it is the abnormality in outer shape that mainly shows that the young death toll increase of tire, body weight attenuating reach with the finger disappearance.Nontoxic dose to female Mus, the young Mus of tire Mus and birth back is 3mg/kg/ day.The rabbit tire is young period of organogenesis toxicity test result show, 5,15, three the dose groups administrations of 45mg/kg/ day do not see obvious influence to the parent animal.Organize the young mortality rate of visible tire 45mg/kg/ day and rise, decrease in survival rate is not seen teratogenesis.The safe dose of pregnant rabbit is 45mg/kg/ day, and what the rabbit tire was young is 15mg/kg/ day.The toxicity test result of rat perinatal stage and age of sucking shows that the visible parent weight increase of 30mg/kg/ daily dose group suppresses, the childbirth obstacle, and general situation deterioration, weight loss, survival rate that occurring because of suckling is bad appears in visible simultaneously young on the same group Mus reduce.Between age of sucking, it is low that the visible young Mus of above dose groups of administration 10mg/kg/ day has under-weight tendency and auricle to separate completion rate.Perinatal stage and age of sucking, the safe dose of female Mus was 10mg/kg/ day, young Mus be 3mg/kg/ day.
These article oral absorption rapidly and blood drug level be dose dependent and increase.Oral back reached the blood peak concentration of drug in 2-3 hour, and taking medicine continuously reached steady plasma-drug concentration in 10 days.Bioavailability is 30%-70%, and the half-life is 4-9 hour, mainly at liver through combining metabolism with glucuronic acid, pass through homaluria on a small quantity.
These article are mainly used in disordered brain function due to cerebral vasospasm and the cerebral blood supply insufficiency.External 53 tame hospitals are divided into 3 groups at random to 135 routine migraineurs and carry out parallel double blind controling test, A group oral article 10mg 45 example every day, B group oral article 20mg 45 example every day; C organizes 45 examples and takes placebo; Effective percentage is respectively 62%, 71% and 36% as a result, and adverse reaction rate is respectively 7%, 2% and 3%, and the dosage that A group and B group are had a headache occurrence frequency, persistent period and taken analgesic all reduces; And there were significant differences for reduction degree and C group; And A group and B group no significant difference point out these article safe and effective to the treatment migraine, and best oral dose is 10mg every day., carrying out cerebral infarction outside the native land and waiting indefinitely and damage the clinical trial of disease because of the brain function due to cerebral tissue ischemia, the anoxia because but these article high selectivity expansion of cerebral vascular, cerebral blood flow increasing and inhibition CSD have protective effect to ischemia and anoxia-induced apoptosis neuron.Compare with cinnarizine, flunarizine class calcium antagonist, these article have following characteristics: 1. cerebrovascular effect is had more specificity; 2. the CSD of inhibition and neuro-protective effect are arranged; 3. better tolerance is safe, does not have obvious peripheral blood vessel untoward reaction, like hypotension, cardiopalmus and reflex tachycardia.Its The extrapyramidal symptoms is also few and little than cinnarizine and flunarizine with depressed untoward reaction.
The lomerizine hydrochloride approved is used for migrainous prevention and treatment, can reduce the migraine number of times, reduces the effect of suppressive drug, improves prodrome and accessory symptom.Oral, the adult recommends the each 5mg of consumption, every day 2 times.In taking after the meal or before sleeping, can suitably increase and decrease according to the disease kind or the state of an illness.Every day, dose generally should not surpass 20mg.Statistics is found in the therapeutic process, and adverse reaction rate is about 4.0%, generally reacts slight and of short duration, mainly comprises drowsiness, dizzy, nauseating and fever, and indexs such as the visible ALT of order, AST, LDH, ALP are unusual.
Drawing lomerizine hydrochloride according to clinical research is satisfied to migrainous treatment; Side effect significantly is lower than control drug; Particularly long-term prescription does not see that curative effect descends and side effect increases, so be a kind of effective, safe, can be used for the medicine of migrainous defence and treatment for a long time.Municipalization capsule and tablet for keeping long-term efficient blood drug level in the body, improve curative effect of medication in the market; Need multiple dosing in a day; Increased patient's not compliance, used, reduced untoward reaction for making things convenient for patient; Improve the market share of these article, the new formulation that works out 0 grade of release of a kind of lomerizine hydrochloride is extremely urgent.
Known at present, can in the specific time, discharge a certain amount of medicine as the controlled release preparation of pharmaceutics new development direction by particular rate.Wherein, be the osmotic pumps of release power with the osmotic pressure, ideal.The dissolubility of its rate of releasing drug and medicine is closely related, and the osmotic pump tablet of exploitation is main with water soluble drug at present.Osmotic pump preparation makes medicine discharge with zero level speed, and blood drug level is stably remained in the treatment concentration range, has reduced peak valley phenomenon, and the toxicity that the medicine blood concentration fluctuation is produced is reduced to minimum, is very suitable for the little medicine of therapeutic index; Obviously prolong (being generally 12～24 hours) with respect to the ordinary preparation medicine constant release time, therefore can reduce medicining times, make things convenient for the patient, quite suitable for the medicine that the half-life weak point need frequently be taken; Receive external environment factor (like pH value, gastrointestinal motility etc.) influence little with respect to its rate of releasing drug of other sustained-release preparation, so individual variation is little.
Summary of the invention:
The objective of the invention is to overcome the deficiency of lomerizine hydrochloride tablet and capsule general formulation, is osmotic pump controlled release tablet of processing of principal agent and preparation method thereof with the lomerizine hydrochloride.It is a characteristic with the zero level release dynamics, continues to discharge a certain amount of medicine with constant rate of speed, keeps long-term efficient blood drug level in the body; Improve curative effect of medication; Reduce patient's medication number of times, improve preparation stability, can also regulate rate of releasing drug through changing factors such as translucent character, pore size.Have with extraneous factor, pharmaceutical properties irrelevantly, do not receive the influence of variable factors such as gastrointestinal tract, numerous advantages such as the inside and outside dependency is good.
Lomerizine hydrochloride osmotic pump tablet provided by the invention utilizes the release principle of osmotic pressure, and moisture gets into label through semipermeable membrane, and pushing piece in-core substance dissolves and swelling produce hyperosmosis.Coating membrane is the relative stiffness structure, gets into moisture, in label, produces higher hydrostatic pressing, forces drug solution from small delivery aperture, to continue to discharge with constant rate of speed.
Lomerizine hydrochloride osmotic pump tablet provided by the invention is made up of pastille label and coatings two parts, and concrete weight ratio is following: described label weight consists of:
Lomerizine hydrochloride: 0.1%～1.5%
Cosolvent: 2%～15%
Filler: 6%～80%
Short penetrating agent: 5%～90%
Binding agent: 1%～8%
Lubricant: 0.3%～4%
The each component sum is 100%
Described semi-permeable membrane coating solution weight consists of:
Coating material: 8%～20%
Plasticizer: 1%～5%
Film coating weightening finish for sheet heavy 2%～10%
Described drug release hole is in label one side machine drilling and laser boring.
A kind of osmotic pump controlled release tablet that contains lomerizine hydrochloride of the present invention is realized through following Technology: lomerizine hydrochloride and adjuvant were ground 100 mesh sieves respectively; Make soft material after adding water behind the mix homogeneously, cross 24 orders and granulate, 60 ℃ of dryings 2 hours; Cross 18 order granulate; Add lubricant, mix homogeneously is pressed into the label that hardness is 2-8kg.Semi-permeable membrane coating and plasticizer are dissolved in the acetone, and mix homogeneously obtains coating solution, places coating pan to carry out coating label, and 50 ℃ solidified 15 hours behind the coating.Use mechanical punching machine or laser-beam drilling machine aperture at a diameter 0.2-0.8mm of label one side preparation.
Description of drawings
Fig. 1 is the releasing curve diagram in the aqueous solution of 0.25% sodium lauryl sulphate in embodiment 1, the embodiment 2 lomerizine hydrochloride osmotic pump tablets.
The specific embodiment
The osmotic pump controlled release tablet that contains lomerizine hydrochloride that the present invention obtains has that method is simple, good stability, characteristics that quality is high.Below implement explanation the present invention, but do not limit the present invention in any way.
Embodiment 1:
Prescription:
Method for making:
Lomerizine hydrochloride, meglumine, starch, mannitol, 30 POVIDONE K 30 BP/USP 30 were ground 100 mesh sieves respectively, made soft material after adding water behind the mix homogeneously, and crossed 24 orders and granulate; 60 ℃ of dryings 2 hours, cross 18 order granulate, add magnesium stearate; Mix homogeneously is pressed into the label that hardness is 2-8kg.Ethyl cellulose, triethyl citrate are dissolved in the acetone, and mix homogeneously obtains coating solution, places coating pan to carry out coating label, and 50 ℃ solidified 15 hours behind the coating.Use mechanical punching machine or laser-beam drilling machine aperture at a diameter 0.2-0.8mm of label one side preparation.
Embodiment 2:
Prescription:
Method for making:
Lomerizine hydrochloride, poloxamer, pregelatinized Starch, lactose, 30 POVIDONE K 30 BP/USP 30 were ground 100 mesh sieves respectively, made soft material after adding water behind the mix homogeneously, and crossed 24 orders and granulate; 60 ℃ of dryings 2 hours, cross 18 order granulate, add magnesium stearate; Mix homogeneously is pressed into the label that hardness is 2-8kg.Methylcellulose, citrate are dissolved in the acetone, and mix homogeneously obtains coating solution, places coating pan to carry out coating label, and 50 ℃ solidified 15 hours behind the coating.Use mechanical punching machine or laser-beam drilling machine aperture at a diameter 0.2-0.8mm of label one side preparation.
The release degree of lomerizine hydrochloride osmotic pump tablet in the aqueous solution of 0.25% sodium lauryl sulphate investigated
Lomerizine hydrochloride osmotic pump tablet to processing carries out drug release determination.
Drug release determination: getting the lomerizine hydrochloride osmotic pump controlled release tablet, adopt 2010 editions two appendix XD drug release determinations of Chinese Pharmacopoeia method, second method, is solvent with the aqueous solution 100ml of 0.25% sodium lauryl sulphate; 37.5 ℃; Rotating speed is that per minute 50 changes, and operation is got solution 10ml respectively at 1h, 2h, 4h, 8h, 12h in accordance with the law; Add the release medium of uniform temp, equal volume simultaneously; Institute's sample thief filters immediately, gets subsequent filtrate as need testing solution, measures according to HPLC (two appendix V of Chinese Pharmacopoeia version in 2010 D).Use octadecylsilane chemically bonded silica to be filler: with acetonitrile-oxolane-water (water intaking 1000ml adds triethylamine 2ml, regulates pH value to 6.5 with phosphoric acid) (85: 0.1: 15) is mobile phase; The detection wavelength is 224nm, and number of theoretical plate is pressed the lomerizine hydrochloride peak and calculated, and should be not less than 2500.Precision is measured need testing solution 20 μ l, injects chromatograph of liquid, the record chromatogram; Precision takes by weighing the lomerizine hydrochloride reference substance 10mg that is dried to constant weight through 105 ℃, puts in the 100ml measuring bottle, is diluted to scale with mobile phase, and mixing as reference substance solution (0.1mg/ml), is measured with method,, promptly gets with calculated by peak area by external standard method.Measure the result and see table 1.
Table 1 lomerizine hydrochloride osmotic pump controlled release tablet release degree is investigated table (dissolution medium: the aqueous solution of 0.25% sodium lauryl sulphate)
| | 2h | 4h | 8h | 12h | ||
| Embodiment 1 | 21.50％ | 39.70％ | 59.30％ | 82.60％ | 98.90％ | |
| Embodiment 2 | 15.90％ | 38.40％ | 55.40％ | 77.40％ | 91.50％ |
Claims (10)
1. lomerizine hydrochloride osmotic pump tablet and preparation method thereof, it is characterized in that: this osmotic pump tablet is to be the preparation that main component is processed with the lomerizine hydrochloride.This osmotic pump tablet is made up of pastille label and semi-permeable membrane coating.
Described label weight consists of:
Lomerizine hydrochloride: 0.1%～1.5%
Cosolvent: 2%～15%
Filler: 6%～80%
Short penetrating agent: 5%～90%
Binding agent: 1%～8%
Lubricant: 0.3%～4%
The each component sum is 100%
Described semi-permeable membrane coating solution weight consists of:
Coating material: 8%～20%
Plasticizer: 1%～5%
Film coating weightening finish for sheet heavy 2%～10%
Described drug release hole is in label one side machine drilling and laser boring.
2. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: said cosolvent is an a kind of or mixture in meglumine, the poloxamer.
3. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: said filler is an a kind of or mixture in starch, the pregelatinized Starch.
4. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: said binding agent is a 30 POVIDONE K 30 BP/USP 30.
5. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: said short penetrating agent is one or more mixture in lactose, mannitol, sodium chloride, sucrose, the potassium sulfate.
6. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: said lubricant is one or more mixture in magnesium stearate, Pulvis Talci, the polyethylene glycol 6000.
7. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: said coating material is one or more mixture in cellulose acetate, ethyl cellulose, the methylcellulose.
8. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: said plasticizer is one or more mixture in citrate, triethyl citrate, glycerol, the propylene glycol.
9. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: described drug release hole is for adopting machine drilling and laser boring in label one side.Hole is 0.2-0.8mm.
10. lomerizine hydrochloride osmotic pump tablet according to claim 1 and preparation method thereof is characterized in that: lomerizine hydrochloride and adjuvant were ground 100 mesh sieves respectively, make soft material after adding water behind the mix homogeneously; Granulate; At 45-60 ℃ of drying 2 hours, granulate, add lubricant; Mix homogeneously is pressed into the label that hardness is 2-8kg.Semi-permeable membrane coating and plasticizer are dissolved in the acetone, and mix homogeneously obtains coating solution, places coating pan to carry out coating label, 40-55 ℃ of curing behind the coating.Use mechanical punching machine or laser-beam drilling machine aperture at a diameter 0.2-0.8mm of label one side preparation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103462919A (en) * | 2013-09-22 | 2013-12-25 | 南京正亮医药科技有限公司 | Lomerizine hydrochloride tablet and preparation method thereof |
| CN109580836A (en) * | 2018-12-31 | 2019-04-05 | 辰欣药业股份有限公司 | A kind of lomerizine hydrochloride raw material and detection method of the preparation in relation to substance |
| CN111991364A (en) * | 2020-09-03 | 2020-11-27 | 四川省百草生物药业有限公司 | Lomerizine hydrochloride osmotic pump tablet and preparation method thereof |
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| CN101152158A (en) * | 2007-08-21 | 2008-04-02 | 浙江大学 | Method of producing double-layer core permeation pump patch of medicament |
| CN101606937A (en) * | 2008-06-16 | 2009-12-23 | 北京德众万全药物技术开发有限公司 | Solid composite medicament of a kind of lomerizine and preparation method thereof |
| CN101966203A (en) * | 2009-07-28 | 2011-02-09 | 安徽中医学院 | Study and application of release technique of effective compound group of traditional Chinese Medical prescription |
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2011
- 2011-09-27 CN CN 201110288947 patent/CN102319227B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101152158A (en) * | 2007-08-21 | 2008-04-02 | 浙江大学 | Method of producing double-layer core permeation pump patch of medicament |
| CN101606937A (en) * | 2008-06-16 | 2009-12-23 | 北京德众万全药物技术开发有限公司 | Solid composite medicament of a kind of lomerizine and preparation method thereof |
| CN101966203A (en) * | 2009-07-28 | 2011-02-09 | 安徽中医学院 | Study and application of release technique of effective compound group of traditional Chinese Medical prescription |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103462919A (en) * | 2013-09-22 | 2013-12-25 | 南京正亮医药科技有限公司 | Lomerizine hydrochloride tablet and preparation method thereof |
| CN103462919B (en) * | 2013-09-22 | 2015-12-02 | 南京正宽医药科技有限公司 | A kind of Lomerizine hydrochloride tablet and preparation method thereof |
| CN109580836A (en) * | 2018-12-31 | 2019-04-05 | 辰欣药业股份有限公司 | A kind of lomerizine hydrochloride raw material and detection method of the preparation in relation to substance |
| CN111991364A (en) * | 2020-09-03 | 2020-11-27 | 四川省百草生物药业有限公司 | Lomerizine hydrochloride osmotic pump tablet and preparation method thereof |
| CN111991364B (en) * | 2020-09-03 | 2022-07-22 | 四川省百草生物药业有限公司 | Lomerizine hydrochloride osmotic pump tablet and preparation method thereof |
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Address after: 210038 Jiangsu Province, Nanjing economic and Technological Development Zone No. 3 Huimeilu Patentee after: NANJING ZHENGKE PHARMACEUTICAL CO., LTD. Address before: 210038 Jiangsu city in Nanjing Province Economic Development Zone No. 3 Xingang Avenue Huimeilu Patentee before: Nanjing Zenkom Pharmaceutical Co., Ltd. |