CN102178658A - Lappaconitine hydrobromide orally disintegrating tablets and preparation method thereof - Google Patents
Lappaconitine hydrobromide orally disintegrating tablets and preparation method thereof Download PDFInfo
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Abstract
The invention discloses lappaconitine hydrobromide orally disintegrating tablets. The lappaconitine hydrobromide orally disintegrating tablets consist of the following ingredients in part by weight: 5 to 10 parts of lappaconitine hydrobromide, 3 to 10 parts of disintegrating agent, 30 to 100 parts of filling agent, 2 to 10 parts of flavoring agent, 0 to 60 parts of adhesive, 0 to 3 parts of lubricating agent and 0 to 50 parts of stomach-soluble acrylic resin. The lappaconitine hydrobromide orally disintegrating tablets which do not comprise the stomach-soluble acrylic resin in the formula can be prepared by a wet pelleting tabletting method, a dry pelleting tabletting method or a direct tabletting method; and the lappaconitine hydrobromide orally disintegrating tablets which comprise the stomach-soluble acrylic resin in the formula are prepared by the steps of preparing the lappaconitine hydrobromide into smell concealing particles by using the stomach-soluble acrylic resin and then preparing the orally disintegrating tablets by the wet pelleting tabletting method, the dry pelleting tabletting method or the direct tabletting method. The lappaconitine hydrobromide orally disintegrating tablets have good mouthfeel, do not influence medicament release, have a simple preparation process, high yield and low cost, and are suitable for industrialized production.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of oral cavity disintegration tablet, particularly a kind of lappaconitine hydrobromide oral cavity disintegration tablet also relates to the preparation method of this oral cavity disintegration tablet.
Background technology
Lappaconitine is a kind of Diterpenes alkaloid that extracts from the root of ranunculaceae plant Aconitum sinomontanum Nakai (Aconitum sinomonatum), its hydrobromate commonly used clinically, non-addicted analgesics and the middle moderate analgesic of recommending of Ministry of Public Health " guidelines of cancer patient three step analgesia therapies " for China's initiative are applicable to diseases such as gastroenteritic ulcer, gastritis, hepatitis, cholecystitis, rheumatism, sciatica, toothache, postoperative pain, cancer pain.Its analgesic effect and Pethidine are suitable, though onset time is slower, duration of efficacy is longer.In addition, lappaconitine hydrobromide also has local anesthesia, cooling, analgesic and antiinflammatory action.
Existing lappaconitine hydrobromide preparation has injection, patch and conventional tablet etc., but owing to injection is not easy to carry, patch absorbs slowly, the conventional tablet onset waits problem to limit its extensive use clinically slowly.Therefore, exploitation a kind ofly portably use conveniently, onset rapidly the lappaconitine hydrobromide preparation have very strong practical value.Oral cavity disintegration tablet is a kind of water disintegrate or dissolved novel troche fast of not needing in the oral cavity, has the convenience of portably using, patient's compliance height, advantage such as rapid-action, is particularly suitable for the patient of old man, child, dysphagia, drinking-water inconvenience or stupor.Therefore, lappaconitine hydrobromide can be made oral cavity disintegration tablet to satisfy many-sided demand of clinical treatment.At present, do not see the research report of relevant lappaconitine hydrobromide oral cavity disintegration tablet both at home and abroad as yet.
Because disintegrate or dissolving promptly take place in oral cavity disintegration tablet in the oral cavity, requirement to mouthfeel is very high, and lappaconitine hydrobromide bitter in the mouth and numb feeling in the tongue is arranged, therefore, sensory issues is the technical barrier in the development of lappaconitine hydrobromide oral cavity disintegration tablet, otherwise this oral cavity disintegration tablet is lost patient's medication compliance because of bad mouthfeel probably, and therapeutic scheme can not be launched smoothly.But covering and being not easy of bitterness has 25 kinds of bitterness receptors at least in people's the mouth, and people are extremely low to the perception threshold of bitterness, and bitterness is difficult for eliminating than sweet taste, tart flavour longer duration.Therefore, effectively covering bitter taste of drug, improve the quality of the pharmaceutical preparations, is a major challenge that the pharmaceutical preparation worker faces.Although existing at present many methods of covering bitterness comprise correctivess such as spice, sweeting agent and aminoacid; Bitter tasting retarding agent; Cyclodextrin inclusion compound; Microencapsulation; Powder coating; Drug-ion exchange resin complexes etc., but do not have a kind of method to have universality as yet to improving bitterness.And, add that simple taste masking method such as correctives is strong for bitterness, the taste masking effect of the medicine of good water solubility is often not satisfactory, then there is complex process in taste masking methods such as cyclodextrin inclusion compound, microencapsulation, powder coating, yield is low and influence problem such as medicine stripping easily.Therefore, when exploitation lappaconitine hydrobromide oral cavity disintegration tablet, the subject matter that solve is how to make oral cavity disintegration tablet not only to have good mouthfeel but also does not influence the release of medicine, and preparation technology is simple, yield is high, cost is low, be fit to suitability for industrialized production.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of lappaconitine hydrobromide oral cavity disintegration tablet, not only had good mouthfeel but also do not influenced the release of medicine, and preparation technology is simple, yield is high, cost is low, be fit to suitability for industrialized production.
For achieving the above object, the invention provides following technical scheme:
1. the lappaconitine hydrobromide oral cavity disintegration tablet is composed of the following components by weight: 5 ~ 10 parts of lappaconitine hydrobromide, 3 ~ 10 parts of disintegrating agents, 30 ~ 100 parts of filleies, 2 ~ 10 parts of correctivess, 0 ~ 60 part of binding agent, 0 ~ 3 part of lubricant, 0 ~ 50 part of Eudragit E;
Described disintegrating agent is any one or more in cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose and the citric acid-sodium bicarbonate;
Described filler is any one or more in microcrystalline Cellulose, lactose, modified starch-1500, mannitol, sorbitol, xylitol, erythrose and the Icing Sugar;
Described correctives is any one or more in aspartame, stevioside, glycyrrhizin, cyclamate, Suo Matian, neotame, citric acid, flavoring orange essence, orange flavor essence, flavoring pineapple essence, strawberry essence, chocolate essence and the Herba Menthae essence;
Described binding agent is any one or more in water, ethanol, starch slurry, hydroxypropyl emthylcellulose and the polyvinylpyrrolidone;
Described lubricant is any one or more in magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycol 6000 and the fumaric acid sodium stearate.
Technique scheme can be divided into two types according to whether containing the Eudragit E component in the prescription: one type is not contain the Eudragit E component in the prescription, be that such oral cavity disintegration tablet only adopts the method for adding correctives to cover the bitterness of lappaconitine hydrobromide, technology is simple, and is with low cost; Another kind of type is to contain the Eudragit E component in the prescription, be that such oral cavity disintegration tablet is to adopt the method for Eudragit E associating correctives to cover the bitterness of lappaconitine hydrobromide and improve mouthfeel, lappaconitine hydrobromide and Eudragit E are mixed and made into taste masked particle, because Eudragit E is at pH〉do not dissolve in 5 the oral cavity, then the release of lappaconitine hydrobromide in the oral cavity is blocked, reach the effect of taste masking, granule after the disintegrate is swallowed into stomach with saliva, Eudragit E dissolves rapidly in the gastric juice of pH＜5, discharge lappaconitine hydrobromide, quick acting.
Above-mentioned first type lappaconitine hydrobromide oral cavity disintegration tablet, preferably, composed of the following components by weight: 5 ~ 10 parts of lappaconitine hydrobromide, 3 ~ 8 parts of disintegrating agents, 30 ~ 70 parts of filleies, 5 ~ 8 parts of correctivess, 0 ~ 50 part of binding agent, 0.5 ~ 2 part of lubricant.Preferred, composed of the following components by weight: 5 parts of lappaconitine hydrobromide, 4.8 parts of crospolyvinylpyrrolidone, 15 parts of microcrystalline Cellulose, 30 parts in mannitol, 5 parts of aspartames, 30 parts in water, 0.5 part of magnesium stearate.
Above-mentioned second type lappaconitine hydrobromide oral cavity disintegration tablet, preferably, composed of the following components by weight: 5 ~ 10 parts of lappaconitine hydrobromide, 3 ~ 8 parts of disintegrating agents, 30 ~ 70 parts of filleies, 2 ~ 5 parts of correctivess, 0 ~ 50 part of binding agent, 0.5 ~ 2 part of lubricant, 5 ~ 25 parts of Eudragit Es.Described Eudragit E is preferably acrylic resin IV, Eudragit E100 or Eudragit EPO.Preferred, described lappaconitine hydrobromide oral cavity disintegration tablet is composed of the following components by weight: 10 parts of lappaconitine hydrobromide, 8 parts of low-substituted hydroxypropyl celluloses, 20 parts of microcrystalline Cellulose, 40 parts of xylitol, 4 parts of aspartames, 1 part of Pulvis Talci, 1 part of polyethylene glycol 6000,10 parts of Eudragit E100.
2. the preparation method of lappaconitine hydrobromide oral cavity disintegration tablet, dissimilar according to prescription, its preparation method is as follows respectively:
A. the lappaconitine hydrobromide oral cavity disintegration tablet that does not contain the Eudragit E component in the prescription
Adopt wet granule compression tablet method, compressing dry granulation or direct compression process to prepare oral cavity disintegration tablet, preferably adopt the wet granule compression tablet method;
Described wet granule compression tablet method is with lappaconitine hydrobromide, disintegrating agent, filler and correctives mixing, crosses 50 ~ 120 mesh sieves, adds binding agent system soft material, granulates, 40 ~ 60 ℃ are dried to moisture content≤3%, add lubricant, mixing again, tabletting, the control tablet hardness is 2 ~ 5Kg, promptly;
Described compressing dry granulation is with lappaconitine hydrobromide, disintegrating agent, filler and correctives mixing, crosses 50 ~ 120 mesh sieves, and dry granulation is pulverized, and adds lubricant again, mixing, and tabletting, the control tablet hardness is 2 ~ 5Kg, promptly;
Described direct compression process is with lappaconitine hydrobromide, disintegrating agent, filler, correctives and lubricant mixing, crosses 50 ~ 120 mesh sieves, tabletting, and the control tablet hardness is 2 ~ 5Kg, promptly;
B. the lappaconitine hydrobromide oral cavity disintegration tablet that contains the Eudragit E component in the prescription
Earlier with Eudragit E with dissolution with solvents after, under stirring condition, add lappaconitine hydrobromide, stir, volatilize solvent, the gained solid content was pulverized 80 ~ 150 mesh sieves and was made taste masked particle, adopt wet granule compression tablet method, compressing dry granulation or direct compression process to prepare oral cavity disintegration tablet again, preferably adopt direct compression process;
Described wet granule compression tablet method is with taste masked particle, disintegrating agent, filler and correctives mixing, crosses 50 ~ 120 mesh sieves, adds binding agent system soft material, granulates, 40 ~ 60 ℃ are dried to moisture content≤3%, and granulate adds lubricant, mixing again, tabletting, the control tablet hardness is 2 ~ 5Kg, promptly;
Described compressing dry granulation is with taste masked particle, disintegrating agent, filler and correctives mixing, crosses 50 ~ 120 mesh sieves, and dry granulation is pulverized, and adds lubricant again, mixing, and tabletting, the control tablet hardness is 2 ~ 5Kg, promptly;
Described direct compression process is with taste masked particle, disintegrating agent, filler, correctives and lubricant mixing, crosses 50 ~ 120 mesh sieves, tabletting, and the control tablet hardness is 2 ~ 5Kg, promptly.
In wet granule compression tablet method and compressing dry granulation, disintegrating agent can add (adding) in the part before granulation, part adds (adding after granulation), adds in also can be all or adds.Binding agent needs to add in the wet granule compression tablet method, and does not need to add in compressing dry granulation and direct compression process.Visual raw material of lubricant or situations such as particulate flowability, cohesiveness take the circumstances into consideration to add.
Beneficial effect of the present invention is: the present invention designs the prescription and the preparation technology of its oral cavity disintegration tablet according to the physicochemical property of lappaconitine hydrobromide, by a large amount of creative works, final optimization pass goes out a kind of lappaconitine hydrobromide oral cavity disintegration tablet, not only had good mouthfeel but also do not influenced the release of medicine, disintegrate rapidly in the oral cavity, non-stimulated to oral mucosa, stripping fast, onset in vivo, and preparation technology is simple, favorable reproducibility, product yield height, steady quality, less demanding, with low cost to adjuvant and equipment is fit to suitability for industrialized production.Wherein, the relative preparation technology of lappaconitine hydrobromide oral cavity disintegration tablet who does not contain the Eudragit E component in the prescription is simpler, yield is higher, cost is cheaper, and the medicine stripping is faster; And contain the relative taste masking better effects if of lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in the prescription.
Description of drawings
Fig. 1 is lappaconitine hydrobromide oral cavity disintegration tablet administration side oral mucosa part pathological section figure (100 times of amplifications), and wherein A is that oral mucosas tissue's structure is normal, does not see obvious pathological change, comments 0 fen; B is the oral mucosa epithelial cell degeneration or flattens, and comments 1 fen; C is the minimum infiltration of leukocyte (each high power field is less than 25), comments 1 fen; D is that the oral mucosa blood vessel is seldom congested, comments 1 fen; E is an oral mucosa blood vessel mild hyperaemia, comments 2 fens; F is the few edema of oral mucosa, comments 1 fen.
The specific embodiment
In order to make the purpose, technical solutions and advantages of the present invention clearer, the preferred embodiments of the present invention are described in detail below in conjunction with accompanying drawing.
Do not contain the preparation (wet granule compression tablet method) and the inspection of the lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in embodiment 1. prescriptions
Prescription: lappaconitine hydrobromide 5g, crospolyvinylpyrrolidone 4.8g, microcrystalline Cellulose 15g, mannitol 30g, aspartame 5g, water 30g, magnesium stearate 0.5g, make 1000 altogether.
Preparation technology: with lappaconitine hydrobromide, crospolyvinylpyrrolidone, microcrystalline Cellulose, mannitol and aspartame mixing, cross 100 mesh sieves 2 times, add water system soft material, 20 mesh sieves are granulated, and 60 ℃ are dried to moisture content≤3%, add magnesium stearate again, mixing, tabletting, the control tablet hardness is 3Kg, promptly gets the lappaconitine hydrobromide oral cavity disintegration tablet.
Prepare three batches of lappaconitine hydrobromide oral cavity disintegration tablets (101,102,103 batches, 10,000 every batch) according to above-mentioned prescription and preparation technology, carry out following every inspection:
(1) the technology repeatability is investigated
The preparation of three batches of lappaconitine hydrobromide oral cavity disintegration tablets the results are shown in Table 1, and the stable yield of visible three batches of lappaconitine hydrobromide oral cavity disintegration tablets illustrates preparation technology's favorable reproducibility.
The preparation result of three batches of lappaconitine hydrobromide oral cavity disintegration tablets of table 1
(2) uniformity of dosage units inspection
Carry out the uniformity of dosage units inspection according to two appendix of Chinese Pharmacopoeia version in 2010.The results are shown in Table 2, the visible three batches of equal A+1.80S of lappaconitine hydrobromide oral cavity disintegration tablet＜15.0, uniformity of dosage units is qualified.
The uniformity of dosage units of three batches of lappaconitine hydrobromide oral cavity disintegration tablets of table 2
(3) disintegration time is measured and the mouthfeel evaluation
Adopt volunteer's intraoral method: after 6 volunteers gargle with clear water, get 1 sample and place on the tongue,, write down volunteer main suit's mouthfeel simultaneously with the time of the complete disintegrate of stopwatch record sample.The results are shown in Table 3, visible three batches of lappaconitine hydrobromide oral cavity disintegration tablets all can disintegrate in 30s, and mouthfeel is good, no bitterness and numb feeling in the tongue.
The disintegration time and the mouthfeel of three batches of lappaconitine hydrobromide oral cavity disintegration tablets of table 3
(4) dissolution determination
Adopt the little slurry method of cuvette to measure.The accumulation dissolution of commercially available lappaconitine hydrobromide ordinary tablet and three batches of lappaconitine hydrobromide oral cavity disintegration tablets sees Table 4 and table 5 respectively, and visible commercially available lappaconitine hydrobromide ordinary tablet 10min stripping is less than 20%, just stripping about 80% of 45min; Go out to surpass 90% and lappaconitine hydrobromide oral cavity disintegration tablet 2min of the present invention is instant, stripping is complete substantially during 5min; And the stripping behavior basically identical of three batch samples further specifies preparation technology's favorable reproducibility.
The accumulation dissolution of the commercially available lappaconitine hydrobromide ordinary tablet of table 4
The accumulation dissolution of three batches of lappaconitine hydrobromide oral cavity disintegration tablets of table 5
(5) study on the stability
101 batches of lappaconitine hydrobromide oral cavity disintegration tablets respectively at placing 10 days under illumination (4500LUX), high humidity (92.5%RH) or high temperature (60 ℃) condition, are investigated character, disintegration time, content and the related substance variation of sample before and after placing.The results are shown in Table 6, visible lappaconitine hydrobromide oral cavity disintegration tablet of the present invention content under illumination, high humidity, hot conditions all descends to some extent, and impurity all increases to some extent, but all in prescribed limit; Wherein, variation under the hot conditions is more obvious, interpret sample is unstable under hot conditions, in addition because used adjuvant hygroscopicity is stronger, sample moisture absorption weightening finish under super-humid conditions is more, and disintegration time obviously shortens after the moisture absorption, and prompting is palpus strictly controlled environment temperature and humidity in production, transportation, and should adopt damp-prrof packing.
Influence factor's test of table 6 lappaconitine hydrobromide oral cavity disintegration tablet
(6) the oral mucosa zest is investigated
30 of the yellow susliks of depletion are divided into blank oral cavity disintegration tablet group, lappaconitine hydrobromide oral cavity disintegration tablet (101 batches) low dose group (5mg/ only) and high dose group (10mg/ only), 10 every group at random.Every group of counter sample put the local contact of rat cheek pouch 4 hours/day, successive administration 5 days, take off cervical vertebra execution at last and respectively organize rat, win administration side (right side) cheek pouch and control sides (left side) cheek pouch of every rat, put volume fraction and be in 10% the formalin solution and draw materials according to a conventional method, paraffin wax flaking, HE dyeing, the natural gum sealing, observe and pickup image with OLYMPUSBX51 microscope biology and pathological tissue image analysis system, according to " oral mucosas tissue's pathological reaction standards of grading " and " pathological reaction classification ", to the pathological reaction classification of every animal control sides and administration side oral mucosa, and react classification situation according to each treated animal oral mucosa pathology and carry out the medicine irritation evaluation.
The result: A. checks substantially: each is organized rat cheek pouch size, shape, color and luster, quality and shows no obvious abnormalities.
B. histological examination: lappaconitine hydrobromide oral cavity disintegration tablet administration side oral mucosa part pathological section figure sees Fig. 1, lappaconitine hydrobromide oral cavity disintegration tablet oral mucosa stimulates the pathological reaction scoring to see Table 7, and visible lappaconitine hydrobromide oral cavity disintegration tablet high dose group and low dose group are to the equal nonirritant of Golden Hamster oral mucosa.
Table 7 lappaconitine hydrobromide oral cavity disintegration tablet oral mucosa stimulates the pathological reaction scoring
Do not contain the preparation (compressing dry granulation) of the lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in embodiment 2. prescriptions
Prescription: lappaconitine hydrobromide 10g, crospolyvinylpyrrolidone 5g, modified starch-1500 40g, sorbitol 30g, glycyrrhizin 2g, the sweet 5g of rope horse, Herba Menthae essence 1g, magnesium stearate 1g, Pulvis Talci 1g, make 1000 altogether.
Preparation technology: with lappaconitine hydrobromide, crospolyvinylpyrrolidone, modified starch-1500, sorbitol, glycyrrhizin, Suo Matian and Herba Menthae essence mixing, cross 120 mesh sieves 3 times, dry granulation, pulverize, cross 20 mesh sieves, add magnesium stearate and Pulvis Talci again, mixing, tabletting, the control tablet hardness is 5Kg, promptly gets the lappaconitine hydrobromide oral cavity disintegration tablet.
Similar to embodiment 1 gained oral cavity disintegration tablet, the lappaconitine hydrobromide oral cavity disintegration tablet that present embodiment makes is rapid disintegrate in the 1min in the oral cavity, substantially, stripping is complete during 5min in water, to the oral mucosa nonirritant, mouthfeel is better, do not have obvious bitterness and numb feeling in the tongue, the refrigerant sense of Herba Menthae is arranged.Compressing dry granulation does not contact damp and hot, and medicine is more stable in preparation process, just for the pharmaceutical factory that does not have the dry granulation machine, acquires the dry granulation machine because of needs and causes production cost that certain increase is arranged.
Do not contain the preparation (direct compression process) of the lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in embodiment 3. prescriptions
Prescription: lappaconitine hydrobromide 5g, cross-linking sodium carboxymethyl cellulose 3g, microcrystalline Cellulose 15g, sorbitol 15g, glycyrrhizin 2g, aspartame 2g, citric acid 1g, flavoring orange essence 1g, magnesium stearate 0.5g, make 1000 altogether.
Preparation technology: with lappaconitine hydrobromide, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose, sorbitol, glycyrrhizin, aspartame and chocolate essence mixing, cross 80 mesh sieves 3 times, add magnesium stearate again, mixing, tabletting, the control tablet hardness is 4Kg, promptly gets the lappaconitine hydrobromide oral cavity disintegration tablet.
Similar to embodiment 1 gained oral cavity disintegration tablet, the lappaconitine hydrobromide oral cavity disintegration tablet that present embodiment makes is rapid disintegrate in the 1min in the oral cavity, and stripping is complete substantially during 5min in water, to the oral mucosa nonirritant, sweet mouthfeel does not have obvious bitterness and numb feeling in the tongue, and the Fructus Citri tangerinae taste is arranged.Direct compression process is simpler than granulating tabletting process technology, and just powder flowbility is poor slightly, so tablet machine is had relatively high expectations.
Contain the preparation (direct compression process) and the inspection of the lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in embodiment 4. prescriptions
Prescription: lappaconitine hydrobromide 10g, low-substituted hydroxypropyl cellulose 8g, microcrystalline Cellulose 20g, xylitol 40g, aspartame 4g, Pulvis Talci 1g, polyethylene glycol 6000 1g, Eudragit E100 10g, make 1000 altogether.
Preparation technology: with Eudragit E100 with dissolve with ethanol after, under the high-speed stirred condition, add lappaconitine hydrobromide, stir, volatilize solvent, the gained solid content was pulverized 80 mesh sieves and was made taste masked particle, added low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, xylitol, aspartame, Pulvis Talci and Polyethylene Glycol mixing again, cross 80 mesh sieves 3 times, tabletting, the control tablet hardness is 2.5Kg, promptly gets the lappaconitine hydrobromide oral cavity disintegration tablet.
Prepare three batches of lappaconitine hydrobromide oral cavity disintegration tablets (201,202,203 batches, 10,000 every batch) according to above-mentioned prescription and preparation technology, carry out following every inspection:
(1) the technology repeatability is investigated
The preparation of three batches of lappaconitine hydrobromide oral cavity disintegration tablets the results are shown in Table 8, and the stable yield of visible three batches of lappaconitine hydrobromide oral cavity disintegration tablets illustrates preparation technology's favorable reproducibility.
The preparation result of three batches of lappaconitine hydrobromide oral cavity disintegration tablets of table 8
(2) uniformity of dosage units inspection
Carry out the uniformity of dosage units inspection according to two appendix of Chinese Pharmacopoeia version in 2010.The results are shown in Table 9, the visible three batches of equal A+1.80S of lappaconitine hydrobromide oral cavity disintegration tablet＜15.0, uniformity of dosage units is qualified.
The uniformity of dosage units of three batches of lappaconitine hydrobromide oral cavity disintegration tablets of table 9
(3) disintegration time is measured and the mouthfeel evaluation
Adopt volunteer's intraoral method to measure: after 6 volunteers gargle with clear water, to get 1 sample and place on the tongue,, write down volunteer main suit's mouthfeel simultaneously with the time of the complete disintegrate of stopwatch record sample.The results are shown in Table 10, visible three batches of lappaconitine hydrobromide oral cavity disintegration tablets all can disintegrate in 30s, and mouthfeel is good, no bitterness and numb feeling in the tongue.
The disintegration time and the mouthfeel of three batches of lappaconitine hydrobromide oral cavity disintegration tablets of table 10
(4) dissolution determination
Adopt the little slurry method of cuvette to measure.The accumulation dissolution of commercially available lappaconitine hydrobromide ordinary tablet and three batches of lappaconitine hydrobromide oral cavity disintegration tablets sees Table 4 and table 11 respectively, and visible commercially available lappaconitine hydrobromide ordinary tablet 10min stripping is less than 20%, just stripping about 80% of 45min; Go out to surpass 90% and lappaconitine hydrobromide oral cavity disintegration tablet 2min of the present invention is instant, stripping is complete substantially during 5min; And the stripping behavior basically identical of three batch samples further specifies preparation technology's favorable reproducibility.
The accumulation dissolution of three batches of lappaconitine hydrobromide oral cavity disintegration tablets of table 11
(5) study on the stability
201 batches of lappaconitine hydrobromide oral cavity disintegration tablets respectively at placing 10 days under illumination (4500LUX), high humidity (92.5%RH) or high temperature (60 ℃) condition, are investigated character, disintegration time, content and the related substance variation of sample before and after placing.The results are shown in Table 12, visible lappaconitine hydrobromide oral cavity disintegration tablet of the present invention content under illumination, high humidity, hot conditions all descends to some extent, and impurity all increases to some extent, but all in prescribed limit; Wherein, variation under the hot conditions is more obvious, interpret sample is unstable under hot conditions, in addition because used adjuvant hygroscopicity is stronger, sample moisture absorption weightening finish under super-humid conditions is more, and disintegration time obviously shortens after the moisture absorption, and prompting is palpus strictly controlled environment temperature and humidity in production, transportation, and should adopt damp-prrof packing.
Influence factor's test of table 12 lappaconitine hydrobromide oral cavity disintegration tablet
(6) the oral mucosa zest is investigated
30 of the yellow susliks of depletion are divided into blank oral cavity disintegration tablet group, lappaconitine hydrobromide oral cavity disintegration tablet (201 batches) low dose group (5mg/ only) and high dose group (10mg/ only), 10 every group at random.Every group of counter sample put the local contact of rat cheek pouch 4 hours/day, successive administration 5 days, take off cervical vertebra execution and respectively organize rat, win administration side (right side) cheek pouch and control sides (left side) cheek pouch of every rat, put volume fraction and be in 10% the formalin solution and draw materials according to a conventional method, paraffin wax flaking, HE dyeing, the natural gum sealing, observe and pickup image with OLYMPUSBX51 microscope biology and pathological tissue image analysis system, according to " oral mucosas tissue's pathological reaction standards of grading " and " pathological reaction classification ", to the pathological reaction classification of every animal control sides and administration side oral mucosa, and react classification situation according to each treated animal oral mucosa pathology and carry out the medicine irritation evaluation.The result shows, each is organized rat cheek pouch size, shape, color and luster, quality and shows no obvious abnormalities; Lappaconitine hydrobromide oral cavity disintegration tablet high dose group and low dose group are to the equal nonirritant of Golden Hamster oral mucosa.
Embodiment 1 is compared with embodiment 4, and the relative preparation technology of lappaconitine hydrobromide oral cavity disintegration tablet who does not contain the Eudragit E component in the visible prescription is simpler, yield is higher, cost is cheaper, and the medicine stripping is faster; And contain the relative taste masking better effects if of lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in the prescription.Flowability is relatively poor during because of direct powder compression, so do not contain the preferred wet granule compression tablet method of preparation method of the lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in the prescription; And contain the lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in the prescription, because of making taste masked particle tabletting more earlier, particulate flowability is good than powder, so the preferred direct compression process of its preparation method.
Contain the preparation (compressing dry granulation) of the lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in embodiment 5. prescriptions
Prescription: lappaconitine hydrobromide 5g, carboxymethyl starch sodium 4g, microcrystalline Cellulose 20g, erythrose 15g, glycyrrhizin 2g, aspartame 1g, chocolate essence 1g, micropowder silica gel 1g, fumaric acid sodium stearate 1g, acrylic resin IV 15g, make 1000 altogether.
Preparation technology: with the acrylic resin IV with dissolve with ethanol after, under the high-speed stirred condition, add lappaconitine hydrobromide, stir, volatilize solvent, the gained solid content was pulverized 120 mesh sieves and was made taste masked particle, add carboxymethyl starch sodium, microcrystalline Cellulose, erythrose, glycyrrhizin, aspartame and chocolate essence mixing again, cross 80 mesh sieves 3 times, dry granulation is pulverized, cross 20 mesh sieves, add micropowder silica gel and fumaric acid sodium stearate again, mixing, tabletting, the control tablet hardness is 5Kg, promptly gets the lappaconitine hydrobromide oral cavity disintegration tablet.
Similar to embodiment 4 gained oral cavity disintegration tablets, the lappaconitine hydrobromide oral cavity disintegration tablet that present embodiment makes is rapid disintegrate in the 1min in the oral cavity, and stripping is complete substantially during 5min in water, to the oral mucosa nonirritant, the cool taste sweetness, no bitterness and numb feeling in the tongue, but little grittiness arranged.
Contain the preparation (wet granule compression tablet method) of the lappaconitine hydrobromide oral cavity disintegration tablet of Eudragit E component in embodiment 6. prescriptions
Prescription: lappaconitine hydrobromide 10g, low-substituted hydroxypropyl cellulose 6g, lactose 30g, mannitol 30g, stevioside 2g, mass fraction are 5% starch slurry 50g, micropowder silica gel 1g, polyethylene glycol 6000 1g, Eudragit EPO 25g, make 1000 altogether.
Preparation technology: with Eudragit EPO with dissolve with ethanol after, under the high-speed stirred condition, add lappaconitine hydrobromide, stir, volatilize solvent, the gained solid content was pulverized 100 mesh sieves and was made taste masked particle, add low-substituted hydroxypropyl cellulose, lactose, mannitol and stevioside mixing again, cross 50 mesh sieves 3 times, the adding mass fraction is 5% starch slurry system soft material, and 20 mesh sieves are granulated, 40 ℃ are dried to moisture content≤3%, add micropowder silica gel and polyethylene glycol 6000 again, mixing, tabletting, the control tablet hardness is 3Kg, promptly gets the lappaconitine hydrobromide oral cavity disintegration tablet.
Similar to embodiment 4 gained oral cavity disintegration tablets, the lappaconitine hydrobromide oral cavity disintegration tablet that present embodiment makes is rapid disintegrate in the 1min in the oral cavity, and stripping is complete substantially during 5min in water, to the oral mucosa nonirritant, mouthfeel is better, no bitterness and numb feeling in the tongue, but grittiness is more obvious.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and the spirit and scope of the present invention that do not depart from appended claims and limited.
Claims (7)
1. the lappaconitine hydrobromide oral cavity disintegration tablet is characterized in that: composed of the following components by weight: 5 ~ 10 parts of lappaconitine hydrobromide, 3 ~ 10 parts of disintegrating agents, 30 ~ 100 parts of filleies, 2 ~ 10 parts of correctivess, 0 ~ 60 part of binding agent, 0 ~ 3 part of lubricant, 0 ~ 50 part of Eudragit E;
Described disintegrating agent is any one or more in cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium and the low-substituted hydroxypropyl cellulose;
Described filler is any one or more in microcrystalline Cellulose, lactose, modified starch-1500, mannitol, sorbitol, xylitol and the erythrose;
Described correctives is any one or more in aspartame, stevioside, glycyrrhizin, cyclamate, Suo Matian, neotame, citric acid, flavoring orange essence, orange flavor essence, flavoring pineapple essence, strawberry essence, chocolate essence and the Herba Menthae essence;
Described binding agent is any one or more in water, ethanol, starch slurry, hydroxypropyl emthylcellulose and the polyvinylpyrrolidone;
Described lubricant is any one or more in magnesium stearate, calcium stearate, micropowder silica gel, Pulvis Talci, polyethylene glycol 6000 and the fumaric acid sodium stearate.
2. lappaconitine hydrobromide oral cavity disintegration tablet according to claim 1 is characterized in that: composed of the following components by weight: 5 ~ 10 parts of lappaconitine hydrobromide, 3 ~ 8 parts of disintegrating agents, 30 ~ 70 parts of filleies, 5 ~ 8 parts of correctivess, 0 ~ 50 part of binding agent, 0.5 ~ 2 part of lubricant.
3. lappaconitine hydrobromide oral cavity disintegration tablet according to claim 2 is characterized in that: composed of the following components by weight: 5 parts of lappaconitine hydrobromide, 4.8 parts of crospolyvinylpyrrolidone, 15 parts of microcrystalline Cellulose, 30 parts in mannitol, 5 parts of aspartames, 30 parts in water, 0.5 part of magnesium stearate.
4. lappaconitine hydrobromide oral cavity disintegration tablet according to claim 1 is characterized in that: composed of the following components by weight: 5 ~ 10 parts of lappaconitine hydrobromide, 3 ~ 8 parts of disintegrating agents, 30 ~ 70 parts of filleies, 2 ~ 5 parts of correctivess, 0 ~ 50 part of binding agent, 0.5 ~ 2 part of lubricant, 5 ~ 25 parts of Eudragit Es.
5. according to claim 1 or 4 described lappaconitine hydrobromide oral cavity disintegration tablets, it is characterized in that: described Eudragit E is acrylic resin IV, Eudragit E100 or Eudragit EPO.
6. lappaconitine hydrobromide oral cavity disintegration tablet according to claim 5 is characterized in that: composed of the following components by weight: 10 parts of lappaconitine hydrobromide, 8 parts of low-substituted hydroxypropyl celluloses, 20 parts of microcrystalline Cellulose, 40 parts of xylitol, 4 parts of aspartames, 1 part of Pulvis Talci, 1 part of polyethylene glycol 6000,10 parts of Eudragit E100.
7. the preparation method of the described lappaconitine hydrobromide oral cavity disintegration tablet of claim 1 is characterized in that:
A. the lappaconitine hydrobromide oral cavity disintegration tablet that does not contain the Eudragit E component in the prescription
Adopt wet granule compression tablet method, compressing dry granulation or direct compression process to prepare oral cavity disintegration tablet;
Described wet granule compression tablet method is with lappaconitine hydrobromide, filler and correctives mixing, crosses 50 ~ 120 mesh sieves, adds binding agent system soft material, granulates, 40 ~ 60 ℃ are dried to moisture content≤3%, add lubricant, mixing again, tabletting, the control tablet hardness is 2 ~ 5Kg, promptly;
Described compressing dry granulation is with lappaconitine hydrobromide, disintegrating agent, filler and correctives mixing, crosses 50 ~ 120 mesh sieves, and dry granulation is pulverized, and adds lubricant again, mixing, and tabletting, the control tablet hardness is 2 ~ 5Kg, promptly;
Described direct compression process is with lappaconitine hydrobromide, disintegrating agent, filler, correctives and lubricant mixing, crosses 50 ~ 120 mesh sieves, tabletting, and the control tablet hardness is 2 ~ 5Kg, promptly;
B. the lappaconitine hydrobromide oral cavity disintegration tablet that contains the Eudragit E component in the prescription
Earlier with Eudragit E with dissolution with solvents after, under stirring condition, add lappaconitine hydrobromide, stir, volatilize solvent, the gained solid content was pulverized 80 ~ 150 mesh sieves and was made taste masked particle, adopted wet granule compression tablet method, compressing dry granulation or direct compression process to prepare oral cavity disintegration tablet again;
Described wet granule compression tablet method is with taste masked particle, disintegrating agent, filler and correctives mixing, crosses 50 ~ 120 mesh sieves, adds binding agent system soft material, granulates, 40 ~ 60 ℃ are dried to moisture content≤3%, and granulate adds lubricant, mixing again, tabletting, the control tablet hardness is 2 ~ 5Kg, promptly;
Described compressing dry granulation is with taste masked particle, disintegrating agent, filler and correctives mixing, crosses 50 ~ 120 mesh sieves, and dry granulation is pulverized, and adds lubricant again, mixing, and tabletting, the control tablet hardness is 2 ~ 5Kg, promptly;
Described direct compression process is with taste masked particle, disintegrating agent, filler, correctives and lubricant mixing, crosses 50 ~ 120 mesh sieves, tabletting, and the control tablet hardness is 2 ~ 5Kg, promptly.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2513580C1 (en) * | 2013-02-01 | 2014-04-20 | Закрытое акционерное общество "Фармцентр ВИЛАР" | Drug preparation for treating cardiac arrhythmia |
| CN105012262A (en) * | 2015-08-20 | 2015-11-04 | 广东安诺药业股份有限公司 | Azithromycin dispersible tablets with bitterness covering function and preparation method of azithromycin dispersible tablets |
| CN105997949A (en) * | 2016-06-02 | 2016-10-12 | 云南省药物研究所 | Oral dissolving film preparation containing bulleyaconitine A and preparation technology of oral dissolving film preparation |
| RU2664668C1 (en) * | 2017-03-15 | 2018-08-21 | Федеральное Государственное Бюджетное Научное Учреждение Уфимский Федеральный Исследовательский Центр Российской Академии Наук (Уфиц Ран) | Antiarrhythmic drug |
| US10273424B2 (en) * | 2012-03-09 | 2019-04-30 | B.C.B. International Limited | Alcohol-containing compositions useful as solid fuels and processes for their manufacture |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850077A (en) * | 2006-02-24 | 2006-10-25 | 关长安 | Lappaconitine hydrobromide dispersible tablet and its preparing method |
| CN1903181A (en) * | 2006-08-08 | 2007-01-31 | 云南昊邦制药有限公司 | Enteric quick-dissolving tablets contg. aconitine, and its prepn. method |
| CN101574331A (en) * | 2009-01-08 | 2009-11-11 | 甘肃奇正藏药有限公司 | Lappaconitine transdermal patch and preparation method thereof |
-
2011
- 2011-05-03 CN CN2011101126427A patent/CN102178658B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850077A (en) * | 2006-02-24 | 2006-10-25 | 关长安 | Lappaconitine hydrobromide dispersible tablet and its preparing method |
| CN1903181A (en) * | 2006-08-08 | 2007-01-31 | 云南昊邦制药有限公司 | Enteric quick-dissolving tablets contg. aconitine, and its prepn. method |
| CN101574331A (en) * | 2009-01-08 | 2009-11-11 | 甘肃奇正藏药有限公司 | Lappaconitine transdermal patch and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《中国优秀博硕士学位论文全文数据库 (硕士)--医药卫生科技辑》 20050915 胡雪莲 "矫味口腔崩解片的研究" 第25页第4段 1-7 , 第5期 2 * |
Cited By (7)
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|---|---|---|---|---|
| US10273424B2 (en) * | 2012-03-09 | 2019-04-30 | B.C.B. International Limited | Alcohol-containing compositions useful as solid fuels and processes for their manufacture |
| RU2513580C1 (en) * | 2013-02-01 | 2014-04-20 | Закрытое акционерное общество "Фармцентр ВИЛАР" | Drug preparation for treating cardiac arrhythmia |
| CN105012262A (en) * | 2015-08-20 | 2015-11-04 | 广东安诺药业股份有限公司 | Azithromycin dispersible tablets with bitterness covering function and preparation method of azithromycin dispersible tablets |
| CN105012262B (en) * | 2015-08-20 | 2018-04-13 | 广东安诺药业股份有限公司 | Cover Azithromycin dispersible tablet of bitter taste and preparation method thereof |
| CN105997949A (en) * | 2016-06-02 | 2016-10-12 | 云南省药物研究所 | Oral dissolving film preparation containing bulleyaconitine A and preparation technology of oral dissolving film preparation |
| RU2664668C1 (en) * | 2017-03-15 | 2018-08-21 | Федеральное Государственное Бюджетное Научное Учреждение Уфимский Федеральный Исследовательский Центр Российской Академии Наук (Уфиц Ран) | Antiarrhythmic drug |
| RU2664668C9 (en) * | 2017-03-15 | 2018-10-22 | Федеральное Государственное Бюджетное Научное Учреждение Уфимский Федеральный Исследовательский Центр Российской Академии Наук (Уфиц Ран) | Antiarrhythmic drug |
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