CN102485221B - Sublingual pharmaceutical composition containing ibutilide and preparation method thereof - Google Patents

Sublingual pharmaceutical composition containing ibutilide and preparation method thereof Download PDF

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CN102485221B
CN102485221B CN 201010570623 CN201010570623A CN102485221B CN 102485221 B CN102485221 B CN 102485221B CN 201010570623 CN201010570623 CN 201010570623 CN 201010570623 A CN201010570623 A CN 201010570623A CN 102485221 B CN102485221 B CN 102485221B
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ibutilide
sublingual
preparation
pharmaceutical composition
administration
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CN102485221A (en
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李洪起
任晓文
徐为人
连潇嫣
王博
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Tianjin Institute of Pharmaceutical Research Co Ltd
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Abstract

The invention provides a sublingual pharmaceutical composition containing ibutilide and belongs to the technical field of medicine. The composition contains active component ibutilide or salt thereof and officinal excipient. The ibutilide sublingual pharmaceutical composition is 10-500 mg for per preparation, preferably 50-250 mg and more preferably 80-150 mg, and contains 0.0435-5.22 mg of main drug ibutilide or salt thereof (calculated by ibutilide), preferably 0.087-4.35 mg and more preferably 0.174-2.175 mg. The drug can be rapidly absorbed after administration and has advantages of fast effectiveness, accurate quantity and convenience for usage, so as to avoid first-pass effect of oral medicament and substantially increase bioavailability and curative effect. The production technology for preparing sublingual tablet is stable, repeatable and at low cost, can be used for industrialized production and has good clinic usage value and social benefits. The sublingual administrated preparation provided by the invention is used for treating arrhythmia.

Description

A kind of Sublingual pharmaceutical composition that contains ibutilide and preparation method thereof
Technical field
The invention belongs to medical technical field, relate to a kind of antiarrhythmic drug compositions, be specifically related to a kind of sublingual administration preparation that contains ibutilide.
Background technology
In recent years, along with cardiovascular diseases's fast rise, incidence of arrhythmia is corresponding to be increased, account for 20% of cardiovascular disease, ARR kind is a lot, and the frequency categorization so that arrhythmia takes place is broadly divided into the quick rhythm of the heart, the chronic rhythm of the heart and irregular early-age shrinkage three major types.The common performance of the rhythm of the heart is to go up ventricle arteries and veins atrial flutter, atrial fibrillation and ventricle frequency arteries and veins frequently fast, and the rhythm of the heart mainly is sinuatrial node pathological changes and atrioventricular conduction defect etc. at a slow speed.
ARR direct mortality influence is less, but it is normal with the danger that disables after cardiovascular thromboembolism or the apoplexy, be subjected to its incidence rate that influences non-valve patients with atrial fibrillation apoplexy will be higher than 5 times of ordinary peoples, and the patients with atrial fibrillation generation apoplexy probability of mitral stenosis is up to 17 times.Atrial fibrillation only accounts for 0.57% in the general population, and high times of the incidence rate in heart disease and old people, proportion accounts for 4%, has been subjected to great attention in clinical.
Auricular fibrillation (AF) belongs to one of malignant arrhythmia symptom, it is the longest arrhythmia of persistent period, jeopardized many people's life, in operation on heart, the atrial fibrillation incidence rate is 32%, though most patient can restrain oneself, tachycardia and atrial systole are undesired, cause patient's hypotension and congestive heart failure, the apoplexy danger coefficient is increased.With advancing age, the atrial tissue structure gradually changes, and atrium expansion, myocardial atrophy, conducting tissue reduce and Fibrotic influence, has caused the conduction of Surgicenter room to prolong and the reduction of arrhythmia threshold value, and the probability of postoperative undesirable element and atrial fibrillation is increased.
Up to now, human do not conquer preferably as yet for atrial fibrillation, chamber this difficult problem of quivering, statistics shows: have 7,200,000 heart patients to suffer from arrhythmia disease approximately in developed country, the ill crowd of the U.S. accounts for 30%; Annual constitutional atrial fibrillation hospitalizing is 21.5 ten thousand people, and the Secondary cases atrial fibrillation is above 1,400,000 person-times.
China cardiovascular diseases's incidence rate has certain characteristics, be that low north, south is high generally, and existing rejuvenation and ever-increasing trend, the age of coronary heart disease interventional therapy and bypass surgery pushed ahead 5～10 years old, defibrillation in the non-drug therapy, pace-making, melt, developing rapidly of operation, though ARR treatment is had certain effect, but pharmacotherapy is still the important means of control tachy-arrhythmia, have simple and convenient, comply with the characteristics of patients ' psychological, can improve the complication relevant with atrial fibrillation preferably, key is to reduce myocardial infarction sudden death rate.
Ibolite fumarate (Ibutilide fumarate) belongs to the derivant of sulfonyloxy methyl amine, is a kind of III class antiarrhythmic drug of novel ion channel activity, and dissolubility is about 100mg/ml in water, and ibutilide LogP is 4.7.This product is developed by U.S. Pharmacia S.P.A., nineteen ninety-five, December obtained FDA approval, went on the market in the U.S. in 1996, be used for acute Atrial Fibrillation and atrial flutter disease, this medicine is to adopt the intravenously administrable mode, therapeutic effect is remarkable, is that treatment atrial fibrillation, room are pounced on and changeed multiple and provide novel good medicine for sinus rhythm.Its structural formula is:
Figure BDA0000035719000000021
Clinical research shows: Ibolite fumarate has high selectivity, interior to sodium ion stream slowly by activating, the outflow of blocking-up cardiac muscle cell potassium ion, increase the repolarization effect, effective over reach current potential time-histories prolongs the effective refractory period (ERP) of myocardial cell simultaneously, and it is more more effective than chamber property that medicine stops atrial arrhythmia, to atrium ERP effect than ventricle obvious 10 times, and make the defibrillation threshold reduction.
Ibolite fumarate is by intravenous administration, and pharmacokinetics and dosage are linear correlation, and plasma protein binding rate is 40%, and distribution volume is bigger, removes the half-life average out to 6 hours.This medicine after the metabolism, mainly excretes by urinary tract in liver.Clinical practice shows, Ibolite fumarate and calcium channel blocker or beta-blocker share, significantly influence is taken place as yet for its pharmacokinetics, safety and curative effect, and this product is that U.S.'s treatment atrial fibrillation and room are pounced on and made it to change rapidly to be the optimal drug therapy of sinus rhythm again.
Because the Ibolite fumarate oral agents has stronger first-pass metabolism, bioavailability is low, thus adopt intravenous administration, but the intravenously administrable poor compliance must have the professional health care personnel to operate again.So patent CN1650850A has invented a kind of formulation preparation scheme that sees through nasal-cavity administration.But there is certain shortcoming in nasal-cavity administration, as quantitatively inaccurate, absorbs not exclusively the drug distribution inequality.So patient need provide a kind of process stabilizing to repeat for convenience; Cost is low, convenient drug administration, the new drug-delivery preparation that patient compliance is stronger.
Summary of the invention
The purpose of this invention is to provide a kind of Sublingual pharmaceutical composition that contains ibutilide, the Sublingual is directly to be absorbed by hypoglossis mucous membrane with preparation, the hypoglossis mucous membrane surface area is big, penetrating power is strong, and has a large amount of blood capillaries to gather to internal jugular vein under the mucosa, directly enters blood circulation through superior vena cava, medicine absorbs rapidly after the administration, rapid-action, quantitatively accurate, easy to use, avoided the first pass effect of oral drugs, bioavailability and curative effect are improved greatly.And preparation Sublingual tablet stable processing technique can repeat, and cost is low, can carry out suitability for industrialized production, has clinical use value and social benefit preferably.
To achieve these goals, the invention provides following technical scheme:
Ibutilide Sublingual drug-delivery preparation is characterized in that containing principal agent ibutilide or its salt and excipient, excipient such as filler, disintegrating agent, correctives, essence, coloring agent, binding agent (wetting agent) and fluidizer.Ibutilide or its salt Sublingual are with the every preparation unit weight of preparation 10-500mg, preferred 50-250mg, more preferably 80-150mg wherein contains the principal agent ibutilide or its salt (in ibutilide) is 0.0435mg-5.22mg, preferred 0.087mg-4.35mg, more preferably 0.174mg-2.175mg.
Described ibutilide salt is citrate, fumarate, hydrochlorate, sulfate, tartrate, benzene sulfonate etc., wherein is preferably Ibutilide Fumarate, tartrate and citrate.
Described filler is pharmaceutic adjuvants such as lactose, microcrystalline Cellulose, mannitol, xylitol, sorbitol, pregelatinized Starch, Icing Sugar, cyclodextrin, erythrose, glucose and modified starch, is preferably mannitol, sorbitol, xylitol, lactose, microcrystalline Cellulose.
Described disintegrating agent is pharmaceutic adjuvants such as carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose.Be preferably carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone.
Described correctives is pharmaceutic adjuvants such as aspartame, Icing Sugar, cyclamate, Mentholum, glycyrrhizin, stevioside, Borneolum Syntheticum and fumaric acid, citric acid, tartaric acid, lactic acid, malic acid, succinic acid and alkali metal salt thereof.Be preferably aspartame, cyclamate, citric acid, lactic acid.
Described essence is strawberry essence, orange flavor essence, apple essence, Fructus Citri Limoniae essence and Herba Menthae essence etc., is preferably orange flavor essence, Fructus Citri Limoniae essence.
Described binding agent is any one or the two or more mixture in purified water, ethanol, starch slurry, hypromellose, polyvidone, carbomer, gelatin, chitosan, sodium alginate, poloxamer, arabic gum and the syrup etc., is preferably hypromellose, polyvidone, purified water, ethanol.
Described fluidizer is that any one or the multiple mixing in stearic acid, magnesium stearate, calcium stearate, micropowder silica gel, hydrogenated vegetable oil, sodium lauryl sulphate, the fumaric acid sodium stearate used, and is preferably magnesium stearate, micropowder silica gel.
Described ibutilide Sublingual pharmaceutical composition, preparation technology are conventional wet method or dry granulation and powder vertical compression technology, are preferably powder vertical compression technology.
Adopt technology of the present invention, have following advantage:
1, the present invention adopts elite prescription, is prepared into the pharmaceutical preparation of ibutilide Sublingual, places the Sublingual when taking, can be in the Sublingual dispersing and dissolving progressively in 30 minutes, in preferred 15 minutes; Also can absorb by hypoglossis mucous membrane being no more than disintegrate dispersion rapidly in 5 minutes, directly enter blood circulation through jugular vein and superior vena cava, medicine absorbs rapidly after the administration, and the symptom rapid-action, that alleviation causes because of arrhythmia is easy to use.Simultaneously, the patient who is particularly suitable in the special environment water intaking difficulty and burst symptom takes.
2, ibutilide of the present invention or its salt Sublingual pharmaceutical preparation, by sublingual administration, all or part of by hypoglossis mucous membrane absorption onset.
3, since the present invention take and easy to carry, good mouthfeel, the patient for need are taken medicine has for a long time improved patient's compliance greatly, thereby guarantees therapeutic effect.
4, preparation method process stabilizing of the present invention, repeatability height are more suitable for industrialized great production.
Description of drawings
Fig. 1, each embodiment full stripping curve measurement result of writing out a prescription
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.Embodiment only is indicative content, means that never it limits the scope of the invention by any way.
Embodiment 1
The tartaric acid ibutilide 0.02g
Mannitol 6.5g
Lactose 3.0g
Carboxymethylstach sodium 0.3g
Cyclamate 0.03g
Polyvidone 0.1g
Magnesium stearate 0.05g
30% ethanol water In right amount
Preparation technology:
(1) earlier principal agent is crossed 100 mesh sieves, it is standby that all the other adjuvants are crossed 80 mesh sieves.
(2) with principal agent and adjuvant to increase progressively the dilution method mix homogeneously, add binding agent soft material processed, cross 30 mesh sieves and granulate, dry in 50 ℃ of aeration-drying baking ovens.
(3) take out dried granule and cross 24 mesh sieve granulate, add the magnesium stearate mix homogeneously, measure intermediate content, tabletting.
Embodiment 2
Ibolite fumarate 0.02g
Sorbitol 5.0g
Microcrystalline Cellulose 1.5g
Modified starch-1500 3.3g
Fructus Citri Limoniae essence 0.05g
Aspartame 0.05g
Stearic acid 0.08g
Preparation technology:
(1) earlier principal agent and stearic acid are crossed 100 mesh sieves respectively, all the other adjuvants are crossed 60 mesh sieves.
(2) with principal agent and adjuvant to increase progressively the dilution method mix homogeneously, by the labelled amount tabletting.
Embodiment 3
Ibolite fumarate 0.1g
Lactose 2.0g
Microcrystalline Cellulose 1.0g
Mannitol 6.2g
Polyvinylpolypyrrolidone 0.59g
Orange flavor essence 0.01g
The fumaric acid sodium stearate 0.1g
Preparation technology:
(1) earlier principal agent and fumaric acid sodium stearate are crossed 100 mesh sieves respectively, all the other adjuvants are crossed 40 mesh sieves.
(2) with principal agent and adjuvant to increase progressively the dilution method mix homogeneously, by the labelled amount tabletting.
Embodiment 4
Ibolite fumarate 0.5g
Glucose 4.0g
Sorbitol 4.0g
Microcrystalline Cellulose 1.0g
Low-substituted hydroxypropyl cellulose 0.35g
Fumaric acid 0.1g
2% carbomer aqueous solution (in carbomer) 0.2g
Micropowder silica gel 0.03g
Magnesium stearate 0.02g
Preparation technology:
(1) earlier principal agent is crossed 100 mesh sieves, it is standby that all the other adjuvants are crossed 80 mesh sieves respectively.
(2) with principal agent and adjuvant to increase progressively the dilution method mix homogeneously, add binding agent 2% carbomer aqueous solution soft material processed, the granulation of 30 mesh sieves.Dry in 50 ℃ of aeration-drying baking ovens.
(3) take out dried granule and cross 24 mesh sieve granulate, add micropowder silica gel and magnesium stearate mix homogeneously, measure intermediate content, tabletting.
Embodiment 5
Lactose 6.5g
Hypromellose 1.0g
Water In right amount
Ibolite fumarate 0.05g
Microcrystalline Cellulose 1.8g
Cross-linking sodium carboxymethyl cellulose 0.5g
Mentholum 0.05g
Calcium stearate 0.1g
Preparation technology:
(1) earlier principal agent is crossed 100 mesh sieves, it is standby that all the other adjuvants are crossed 80 mesh sieves respectively.
(2) principal agent be added to the water the dissolving make binding agent, standby.Earlier with lactose and hypromellose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, add binding agent soft material processed, the granulation of 30 mesh sieves.Dry in 60 ℃ of aeration-drying baking ovens.
(3) take out dried granule and cross 24 mesh sieve granulate, add remaining adjuvant Mentholum, fumaric acid sodium stearate mix homogeneously, tabletting behind the mensuration intermediate.
Embodiment 6
Mannitol 7.5g
Polyvidone 0.7g
30% ethanol water In right amount
The citric acid ibutilide 0.15g
Modified starch-1500 1.55g
Herba Menthae essence 0.05g
Magnesium stearate 0.05g
Preparation technology is with embodiment 5.
Embodiment 7
Ibutilide 0.02g
Lactose (FlowLac100) 3.2g
Mannitol (P200SD) 6.1g
Polyvinylpolypyrrolidone 0.45g
Citric acid 0.1g
Fructus Citri Limoniae essence 0.03g
The fumaric acid sodium stearate 0.1g
Preparation technology:
(1) earlier principal agent and fumaric acid sodium stearate are crossed 100 mesh sieves respectively, all the other adjuvants are crossed 40 mesh sieves.
(2) with principal agent with locate adjuvant to increase progressively dilution method mix homogeneously, tabletting.
Embodiment 8
Ibutilide 0.02g
Lactose (FlowLac100) 7.0g
Mannitol (P200SD) 2.3g
Cross-linked carboxymethyl cellulose sodium 0.45g
Fumaric acid 0.1g
Herba Menthae essence 0.03g
Magnesium stearate 0.1g
Preparation technology:
(1) earlier principal agent and fumaric acid sodium stearate are crossed 100 mesh sieves respectively, all the other adjuvants are crossed 40 mesh sieves.
(2) with principal agent with locate adjuvant to increase progressively dilution method mix homogeneously, tabletting.
Embodiment 9
The rat overnight fasting was tested in the next morning.The sublingual administration group: rat is anaesthetized in advance, gets the sample of different embodiment, and pulverize is made pasty state with normal saline, takes by weighing medicine according to dosage and places the rat sublingual administration; The oral administration group, with the sample powder of difference prescription with 0.5%CMC suspendible, gastric infusion; The intravenous injection group is with the direct administration of injection.Dosage is 2mg/kg, every group of 3 rats.1,5,15,30,60 minute, 2,4,6,8 hours mensuration is got each 0.3ml of blood after the administration of vein group; 15,30,60 minutes, 2,4,6,8 hours mensuration is got each 0.3ml of blood after the oral group of administration; 5,10,15,30,60 minutes, 2,4,6,8 hours mensuration is got each 0.3ml of blood after the group administration of Sublingual.Separation of serum behind precipitation with alcohol albumen, is handled Deproteinization with pre-column, and the HPLC-MS method is measured blood drug level.Be 100% to calculate absolute bioavailability with average area under the curve of intravenous injection group.The results are shown in Table, show the sample sublingual administration of 3 embodiment after, improved bioavailability, the peak concentration time of occurrence is very fast, is suitable for acute treatment.
The infiltration rate of table 1, each embodiment sample and bioavailability
Peak time (minute) Bioavailability
Raw material is oral 60 5％
Feed injection 1 100％
Embodiment 3 5 35％
Embodiment
5 5 40％
Embodiment 7 10 28％
Embodiment 10
Investigation the results are shown in Table 2 after above-described embodiment prepared tabletting
The hardness of compressed tablet, disintegration time are measured and the mouthfeel investigation table under table 2, each embodiment
Embodiment Hardness (kg) Disintegration time (min) Mouthfeel
1 5 6 Sweet taste
2 4.8 4 Sweet taste
3 5.3 3 Refrigerant
4 5.5 5 Tart flavour
5 5.1 3 Refrigerant
6 5.6 4 Refrigerant
7 5.5 3 Tart flavour
8 5.4 2 Tart flavour
Embodiment 11
Each embodiment full dissolution determination of writing out a prescription the results are shown in Table 3:
HPLC condition determination: C18ODS chromatographic column 5 μ 250 * 4.6mm
Mobile phase: 0.01mol/L potassium dihydrogen phosphate aqueous solution: acetonitrile: triethylamine=39: 61: 1
Flow velocity: 1.0ml/min
Wavelength: 230nm
Dissolution determination condition: instrument: ZRS-8G medicament dissolution instrument, 50 rev/mins of rotating speeds, solvent 100ml, 37.5 ℃ of temperature
Get this product, according to dissolution determination method (Chinese Pharmacopoeia two appendix XC the 3rd methods in 2010), 100ml is solvent with 0.1mol/L salt sour water, rotating speed is 50 rev/mins, operation in accordance with the law, it is an amount of to get solution respectively at 3,5,10,15,20,30 minutes, filters as need testing solution.It is an amount of that other gets fumaric acid Erie Boot reference substance, adds same solvent supersonic and make and dissolve fully and be diluted to the solution that concentration is 1ug/ml, product solution in contrast.Measure test sample and reference substance solution, shine high effective liquid chromatography for measuring, go out every stripping quantity by the external standard method calculated by peak area.
Table 3, each embodiment dissolution determination result
Time (branch) Embodiment 1 Embodiment 2 Embodiment 3 Embodiment 4 Embodiment 5 Embodiment 6 Embodiment 7 Embodiment 8
0 0.00％ 0.00％ 0.00％ 0.00％ 0.00％ 0.00％ 0.00％ 0.00％
3 4.36％ 7.85％ 11.20％ 9.78％ 6.35％ 5.35％ 8.94％ 6.88％
5 12.30％ 24.60％ 28.60％ 24.70％ 21.60％ 15.60％ 27.80％ 23.50％
10 27.60％ 41.30％ 40.20％ 36.70％ 38.60％ 34.20％ 43.50％ 35.50％
15 60.80％ 70.40％ 67.10％ 75.60％ 71.50％ 64.10％ 66.40％ 62.10％
20 81.60％ 84.60％ 90.30％ 89.10％ 86.90％ 80.30％ 85.20％ 82.40％
30 92.60％ 97.50％ 99.40％ 96.80％ 99.80％ 96.20％ 94.80％ 97.60％

Claims (3)

1. Sublingual pharmaceutical composition that contains ibutilide is characterized in that being prepared from according to following prescription:
Figure FDA00003060816000011
2. Sublingual pharmaceutical composition that contains ibutilide is characterized in that being prepared from according to following prescription:
3. Sublingual pharmaceutical composition that contains ibutilide is characterized in that being prepared from according to following prescription:
Figure FDA00003060816000013
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CN1293863C (en) * 2004-12-15 2007-01-10 北京国药龙立生物医药新技术有限公司 Ibolite fumarate nasal cavity administration preparation
CN1977827A (en) * 2005-12-02 2007-06-13 浙江九旭药业有限公司 Ibutilide fumarate lyophilized powderinjection preparation and its preparing method
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