CN1868466A - Buluoweima slow-release tablet and its preparing method - Google Patents
Buluoweima slow-release tablet and its preparing method Download PDFInfo
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- CN1868466A CN1868466A CN 200510010028 CN200510010028A CN1868466A CN 1868466 A CN1868466 A CN 1868466A CN 200510010028 CN200510010028 CN 200510010028 CN 200510010028 A CN200510010028 A CN 200510010028A CN 1868466 A CN1868466 A CN 1868466A
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- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
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Abstract
A slow-release Buluoweima tablet for treating cold and its complecations (headache, fever, throat pain, etc) is composed of the color-layer particles prepared from ibuprofen, pseudoephedrine hydrochloride, acrylic resin B, hydroxypropyl methylcellulose, lactose, iron oxide, and talk powder, and the white-layer particles prepared from libuprofen, acrylic resin B, hydroxypropyl methylcellulose, talc powder and alcohol. Its preparing process is also disclosed.
Description
Technical field:
The present invention relates to a kind of people's medication, is a kind of oral antiinflammatory, analgesia, antipyretic Buluoweima slow releasing tablet, and the method for preparation.
Background technology:
Flu is that the upper respiratory tract mucosa that a lot of dissimilar viruses cause infects, and its cardinal symptom often is nasal obstruction, sneeze, dry cough, slight throat pain and heating etc., and systemic symptom is as whole body discomfort, headache and myalgia etc.Because of no specific therapy can be sayed,, can only adopt symptomatic therapy to impel many remissions of flu so the virus evaluation is then unnecessary.Because therefore the many symptoms that also do not have a kind of agents alleviate and deposit have various compound preparations to come out.These compound preparations select for use the medicine composition compound recipe of different drug effects to be used to alleviate simultaneous different symptoms.There is multiple symptom as patient,, then suits the medicine to the illness and use suitable compound preparation than more suitable with several individual event medicines, also more economical sometimes particularly at common cold initial stage.
Summary of the invention:
The purpose of this invention is to provide a kind of congestion of nasal sinus of flu, the compound preparation of common sympton and method of preparation thereof such as have sore throat, have a headache and fever alleviated.
Above-mentioned purpose realizes by following technical scheme:
The Buluoweima slow releasing tablet, its composition comprises: nonferrous layer granule and white layer granule, the ratio of weight and number of raw material stype Lip river sweet smell is 80 in the described nonferrous layer granule, the ratio of weight and number of pseudoephedrine hydrochloride is 30, acrylic resin II number ratio of weight and number is 40, the ratio of weight and number of hypromellose is 10, the ratio of weight and number of lactose is 10, the ratio of weight and number of ferrum oxide is 2～3, the Pulvis Talci ratio of weight and number that contains 1% ferrum oxide is 6.66, binding agent is to contain 2% polyacrylic resin II number and the ratio of weight and number of 80% alcoholic solution of 2% hypromellose is 28 in the nonferrous layer, the ratio of weight and number of ibuprofen is 120 in the described white layer granule, acrylic resin II number ratio of weight and number is 30, the ratio of weight and number of hypromellose is 5, the Pulvis Talci ratio of weight and number is 6.66, and wetting agent is that 80% ethanol ratio of weight and number is 30.
The preparation method of above-mentioned Buluoweima slow releasing tablet is: get ibuprofen, pseudoephedrine hydrochloride by above ratio of weight and number, ground 120 mesh sieves respectively, other crude drug are also crossed 120 mesh sieves earlier;
A: feed intake by described nonferrous layer granule prescription, grind, cross 120 mesh sieves, mixing adds binding agent, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 50 ℃～60 ℃ dryings 3～4 hours, be chilled to room temperature, cross 18 mesh sieve granulate, what add corresponding parts by weight grinds the Pulvis Talci that contains ferrum oxide 0.8% that mixing is crossed 120 mesh sieves in advance, and mixing is made for the nonferrous layer granule.
B: throw grain by white layer granule prescription, cross 40 mesh sieve mix homogeneously, add the binding agent of corresponding parts by weight, make suitable soft material, cross 120 mesh sieves, make wet granular,, take out in 50 ℃～60 ℃ dryings 3～4 hours, be chilled to room temperature, cross 18 mesh sieve materials all in one piece, add the Pulvis Talci of corresponding parts by weight, mixing is made for white particle.
C: nonferrous layer granule and white layer granule are placed on the tablet machine, are pressed into double-layer tablet with the 10mm punch die.
Beneficial effect of the present invention:
1. the present invention has antiinflammatory action: the Cavia porcellus experiment, and stronger 16～32 times to the inhibitory action of ultraviolet erythema than aspirin; Rat experiment, the inhibitory action of on Carrageenan pedal swelling are better than Phenylbutazone and less than indometacin, are slightly less than Phenylbutazone and much smaller than indometacin for the inhibitory action of adjuvant-induced arthritis.
2. the present invention has analgesic activity; Mouse experiment, acetylcholine writhing method confirm that respectively its analgesic activity is about 28 times of aspirin, and its analgesic activity is a periphery; Rat experiment, the analgesic activity that causes scorching foot for yeast approaches 30 times of aspirin.
3. the present invention has refrigeration function: rat experiment is equivalent to 20 times of aspirin to the refrigeration function of yeast pyrogenicity.
4. the present invention has the effect of nose congestion: to acute or chronic apyetous rhinitis patient, single oral dose 60mg pseudoephedrine hydrochloride promptly produced the effect of significant nose congestion in 30 minutes, and its interaction energy was kept 4 hours, to nasal congestion decreased average 57%, its maximum congestion effect is identical with the nasal mist effect of ephedrine.
1.. materials and methods
Patient: 20 men and women volunteers, every patient all shows apyetous or chronic rhinitis symptom.
Experimental design: tested preceding 48 hours, patient must not use any medicine, in addition, only drinks fruit juice or water when experiment.Measure nasal meatus resistance, blood pressure, pulse and pseudoephedrine hydrochloride sheet blood drug level earlier.Make positive control with 1% ephedrine nasal spray, discharge rate 0.25ml measures the nasal meatus resistance after 10 minutes.
2.. the result
Left and right sides nasal meatus air pressure---flow curve behind patient's oral hydrochloride pseudoephedrine.Pass in time, curve downwards, be moved to the left, illustrate that asal resistance or mucous hyperemia reduce gradually.
It is identical that the maximum nose congestion effect that 240min produced behind the oral hydrochloride pseudoephedrine and spraying give the effect that ephedrine produces.Ephedrine can demonstrate the effect of maximum nose congestion, thus with it as positive control.
Resistance maximum behind patient's oral hydrochloride pseudoephedrine or the nasal spray ephedrine reduces percent (comparing with the comfort group), nasal congestion and there were significant differences between the asal resistance minimizing value of congested nose, and the nasal congestion patient takes behind pseudoephedrine hydrochloride or the ephedrine spray and asal resistance reduces not have significant difference between the value.
5. the present invention selects for use antipyretic-antalgic anti-inflammatory agent ibuprofen and nasal decongestant pseudoephedrine hydrochloride to form compound recipe, and it can alleviate the congestion of nasal sinus of flu, common sympton such as have sore throat, have a headache and fever.All there is this compound recipe conventional tablet the domestic and international market at present, the dosage of this product is determined with reference to these kinds, ibuprofen is one of kind the most successful in the NSAID (non-steroidal anti-inflammatory drug) of the world's development sixties, it has antiinflammatory, analgesia and antipyretic effect, and safety was good, is classified as one of essential drugs by the United Nations's health organization, from 1984, ibuprofen is as over-the-counter drug, is used to alleviate the mild pain of common cold etc. and analgesic.Ibuprofen absorbs rapidly in vivo, and at whole gastrointestinal tract good absorption is arranged all, and its biological half-life is about 2h, its common adverse effect is a gastrointestinal toxicity, incidence rate is relevant with dosage with degree, and be prepared into slow releasing tablet and can prolong curative effect, reduce toxic and side effects, and little to its bioavailability influence.
6. the present invention has antiinflammatory, analgesia and refrigeration function
Adopt animal: male rat weighs 100～140g, and male mice weighs 20～22g, and female Cavia porcellus weighs 500～800g.In experiment, animal fasting all overnight.Medicine is oral with 10% mucialga of arabic gummy form; Control animal is only taken rubber cement.
(1) antiinflammatory action
1.. Cavia porcellus ultraviolet erythema
According to Adams and Cobb
[2]Described method is divided into according to estimating the erythema rank with 0 to 4 grade of system.The presentation of results of table 1, the effect of ibuprofen is stronger 16 to 32 times than aspirin, and the effect of ibuprofen sodium salt is equal to ibuprofen.
Table 1 ibuprofen and aspirin are to the effect of Cavia porcellus ultraviolet erythema
| Chemical compound | Oral dose | Average erythematous response |
| Contrast aspirin ibuprofen | / 40 80 160 1.25 | 3.9 4.0 2.5 0.2 3.8 |
2.. erythema due to the human body nicotine hydrogen bran ester
According to Adams and Cobb
[2]Described method is with the fixed red rank of Lovibond reflection tone instrumentation.The results are shown in Table 2.The experiment of 2 placebo shows that the erythema of this method is stable.Ibuprofen can significantly weaken erythema, even it is also effective to take ibuprofen (capsule) before 24 hours at application nicotine hydrogen bran ester.
3.. rat hind paw edema due to the carrageenin
Table 3 has compared the effect of ibuprofen and a series of other anti-inflammatory drugs.This experiment in, with aspirin as standard.
Table 2 ibuprofen is to the effect of erythema due to the human body nicotine hydrogen bran ester
| Oral dose | Application nicotine hydrogen bran ester and time of administration every | Average erythema grade * | P ** |
| Placebo 1 placebo 2 ibuprofen 300mg | 45min 45min 45min 3hr 7hr 24hr 48hr 96hr | 2.18 2.16 1.48 1.22 1.44 1.56 1.80 2.02 | / / ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 |
*Each value is represented 5 people's average erythema grade
*Calculate by variation analysis
According to the slope of the not good dose-effect curve of five medicines, only can be arranged as according to its effect rising order approx: the stupid acetic acid of isobutyl group, Phenylbutazone, hydrocortisone sodium succinate, ibuprofen, indometacin.
4.. rat assist agent arthritis
Male CFE chain rat heavily is 120～140g, and the afterbody subcutaneous injection is assessed the arthritic order of severity of rear solid end (0～4 grade) with the 6mg/ml liquid paraffin suspension of the tubercule bacillus of the death of human body chain PN, DT and C acquisition after 21 days.21 days afterwards inherent 9:00 and 14:00 take medicine twice every day, estimate the arthritic order of severity during end once more.The results are shown in Table 4.Show that ibuprofen has certain effect that alleviates to the arthritis of establishing, but effect is slightly less than Phenylbutazone, much smaller than indometacin.
The effect of rat hind paw edema due to the different anti-inflammatory drug on Carrageenan of table 3
| Chemical compound | Oral dose mg/kg | Rat quantity | Average suppression ratio % | Oral aspirin mg/kg | Rat quantity | Average suppression ratio % |
| Brufen ibufenac phenylbutazone indocin hydrocortisone sodium succinate | 0.67 2 6 18 54 11 33 100 300 5.6 16.7 50 150 0.67 2 6 18 1 3 9 27 | 10 16 16 16 9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 | 11.2 7.3 34.9 38.5 47.0 31.9 24.5 40.4 52.5 20.3 26.4 47.9 60.3 13.6 28.8 38.8 48.4 19.7 19.0 34.7 44.8 | 33 100 300 33 100 300 33 100 300 33 100 300 30 100 300 | 15 16 16 9 10 10 10 10 10 10 10 10 9 10 10 | 3.7 22.9 64.2 19.7 44.9 73.4 20.2 34.3 74.6 26.0 41.9 84.4 19.7 44.9 73.4 |
Table 4 Phenylbutazone, indometacin, ibuprofen are to the effect of rat assist agent arthritis
| Chemical compound | Oral dose mg/kg/day | Weight increase % during 3 all administrations | The average arthritis grade of metapedes | The arthritis order of severity changes % | |
| Before the administration | After the administration | ||||
| Contrast | / | 29.6 | 6.00 | 6.90 | +15.0 |
| Phenylbutazone indocin brufen | 3.33 10 30 90 0.1 0.3 0.9 15 45 | 32.2 38.6 45.4 45.4 35.6 33.7 47.4 27.3 40.0 | 5.60 5.60 5.50 5.90 5.50 5.90 5.40 6.05 5.75 | 5.15 3.95 3.30 2.75 4.80 3.90 3.20 4.85 3.50 | -8.0 -29.5 -40.0 -53.4 -12.7 -33.9 -40.7 -19.8 -39.1 |
(2) analgesic activity
1.. the acetylcholine induced mice is turned round body
60 minutes pneumoretroperitoneum 0.5ml of mice administration, the 200mg/ml acetylcholine chloride places respectively in the glass container at once, writes down to turn round the body number of times in 4 minutes.The results are shown in Table 5.The analgesic activity of ibuprofen in turn round the body number in 95% confidence limit for acetysalicylic 28.0 (19.7～39.8) doubly.According to mice platycoria technology, under lumbar injection 200mg/kg dosage, ibuprofen does not have the cholinergic effect yet, so ibuprofen is the performance analgesic activity in this experiment, and according to acetylcholine effect short characteristics incubation period, the ibuprofen effect directly acts on Pain receptor probably, and does not comprise inflammatory factor.
Table 5 aspirin and ibuprofen are turned round the effect of body to lumbar injection acetylcholine chloride induced mice
| Chemical compound | Oral dose mg/kg | Every mice is on average turned round body and counts * | Suppress % |
| The contrast aspirin | / 30 60 | 6.8 5.4 2.1 | 0 20.5 69.1 |
| Ibuprofen | 120 240 0.94 1.88 3.75 7.5 | 0.6 0.4 4.4 3.4 1.4 0.8 | 91.2 94.1 35.3 50.0 79.4 88.2 |
*15 mices of each dosage group
2.. to the inflammation pawl of rat and the analgesic activity of normal pawl
Generally speaking, the analgesic of peripheral action only acts on the speech pawl, and the analgesia of central action had both acted on the inflammation pawl, acted on normal pawl again.Select Mus great and mighty or powerful for use, weigh 100 to 140g, at a rear solid end vola injection of rat 0.1ml, 20% dry yeast suspension is to bring out inflammation.Codeine phosphate after 120 minutes oral or 150 minutes after subcutaneous injection, measure administration or the pressure threshold before the administration not behind the oral administration behind 60 minutes or the subcutaneous administration after 30 minutes, calculate the analgesic degree according to following formula:
Illustrate that ibuprofen and aspirin belong to a class, it is another kind of that codeine phosphate then belongs to.Ibuprofen under all dosage to the effect of inflammation pawl all significantly greater than normal pawl.Therefore, can draw such conclusion: the effect of ibuprofen is a periphery, and also as can be known, the analgesic activity of ibuprofen approaches acetysalicylic 30 times.
3.. the experiment of mice hot plate
50 ℃ of plate temperature, as the experiment terminal point, the front foot reaction is ignored with the metapedes vibration.Reaction surpasses 40 seconds mice employing.Judged the response time of each mice after taking medicine 30 minutes, be 90 seconds deadline.The analgesia degree is calculated according to following formula:
Experimental result shows that this technology can clearly make a distinction the analgesic of the analgesic of 3 central actions and peripheral action.Obviously ibuprofen belongs to the latter.
(3) refrigeration function
Select 150～200g rat for use, by subcutaneous injection yeast suspension pyrogenicity.The result shows that ibuprofen has refrigeration function, and intensity is equivalent to acetysalicylic 20 times.
(4) glucocorticoid sample or property
The liver glycogen that each dosage group uses 10 mices to estimate the non-mice that adrenalectomizes rises.The result shows, compares with matched group, and the standard sugar 17-hydroxy-11-dehydrocorticosterone hydrocortisone sodium succinate of oral 2mg/kg causes remarkable glycogen precipitation (p=＞0.001) in liver, but oral 40 and the 80mg/kg ibuprofen then do not have obvious effect (p＞=0.05).
Ibuprofen is a kind of antiinflammatory, analgesia, antipyretic, and many classical zooperies show that it act as acetysalicylic 16 times to 32 times.It to the arthritic activity of the fixed adjuvant drug of rat slightly a little less than.The dosage of 300mg can reduce the erythema that is caused by nicotine hydrogen bran ester cream.At this on the one hand, ibuprofen more is similar to aspirin and is different from salicylic acid, Phenylbutazone and crovaril.
The analgesic activity of ibuprofen is a periphery, and it does not possess the stimulation of glucocorticoid or adrenocortical hormone.
Among the present invention pseudoephedrine hydrochloride in state-owned long use history such as Great Britain and Americas, mainly utilize its alpha-receptor agonism, shrink the blood vessel of swelling in the nasal mucosa, make the nasal cavity obstruction remove, breathe unimpeded, pseudoephedrine hydrochloride is compared with ephedrine and phenylpropanolamine etc., has the little advantage of central nervous system's zest and cardiovascular side effects, pretend to oral nasal decongestant and be used widely clinically, its side effect mainly shows as the heart irritability of blood drug level when high, and it also has good absorption at whole gastrointestinal tract.So also be suitable for making slow releasing preparation, to reduce the incidence rate of its side effect.The application of nasal decongestant can be removed the nasal obstruction symptom of flu, also helps to keep pharyngotympanic tube and hole mouth unimpeded, thereby prevents the generation of secondary infection.But similar ordinary preparation needs 6～8h to take medicine once when the treatment flu, and administration number of times is many, and blood concentration fluctuation is big.Because the heart irritability due to the GI irritation of ibuprofen hydrochloric acid pseudoephedrine and the excessive concentrations of pseudoephedrine hydrochloride all is unfavorable for treatment.Given this, this product is according to pharmacy feature in physicochemical property, pharmacological effect characteristic and the body of ibuprofen, pseudoephedrine hydrochloride, utilization pharmaceutics means are prepared into double-layer sustained release tablets, have following characteristics: 1. each layer of double-layer sustained release tablets has different rate of releasing drug, can guarantee the rapid onset of medicine, can keep the sufficiently long time of drug effect again, be beneficial to the raising curative effect.2. by appropriateness control, reduce its zest thereby the local concentration of ibuprofen on gastrointestinal tract mucous surface reduced, thereby also make the medicine blood concentration steadily avoid or reduce the side effect of pseudoephedrine hydrochloride simultaneously drug release rate.3. administration number of times reduces, and makes things convenient for the patient.
8. the preparation of ibuprofen and pseudoephedrine hydrochloride mainly contains flavoring preparation, controlled release preparation and compound preparation.Wherein the purpose of controlled release preparation mainly only reduces side effect, prolongs curative effect, and compound preparation is the medicine that is added other drug effects by ibuprofen or pseudoephedrine hydrochloride, to alleviate multiple and to deposit symptom.Ibuprofen Chang Keyu cough medicine, analgesic, antihistaminic etc. are formed compound recipe, and pseudoephedrine hydrochloride is then main to be cooperated with antihistaminic, antipyretic analgesic and make compound preparation and treat flu.
9. good stability of products of the present invention, from the preliminarily stabilised experimental result, the original packing of compound recipe pseudoephedrine double-layer sustained release tablets was placed three months under 40 ℃ of conditions, changes of contents is in 10%, though release has fluctuation up and down, but still in prescribed limit, other every indexs are all in prescribed limit, it is 2 years that said preparation effect duration can fix tentatively, and the illumination experimental result shows that light is not obvious to the slow releasing tablet influence, and outward appearance, content do not have significant change.This product was 40 ℃, 60 ℃ heating 10 days, and every index does not have significant change.Though the release of slow releasing tablet has fluctuation up and down under these conditions, but still in prescribed limit.Show through thin layer chromatography, all do not detect the impurity speckle, original packing room temperature reserved sample observing 17 months, every index is still in prescribed limit.
10. the present invention is according to pharmacology, toxicological experiment, and it is clinical to advise that this product can be used for, since the discomfort that flu causes, symptoms such as headache, heating, myalgia, throat pain and congestion of nasal sinus.Clinical consumption is secondary every day, each 1～2, but continuous application and do not produce untoward reaction.
11. acute toxicity testing of the present invention:
(1) medicine: Buluoweima slow releasing tablet and raw material are provided by medicament teaching and research room of China Medicine University, are made into suspension with preceding with 0.5%CMC.
(2) animal: Kunming mouse, body weight 19-21g is supplied with by China Medicine University's Animal Lab..(quality certification number: Soviet Union kinoplaszm 91001)
(3) method: get the qualified mice of body weight, random packet, male and female half and half, lumbar injection and gastric infusion.The intraperitoneal administration volume is 0.2ml/10g, between agent than being 1: 0.75, the molten long-pending 0.3ml/10g that is of gastric infusion, between agent than being 1: 0.75.Observed 10 days after the administration, record was observed the dead mouse situation and dead Mus was done postmortem every day, and perusal main organs situation is pressed the Bliss method and calculated median lethal dose(LD 50) (LD and 95% fiducial limit thereof).
(4) result: mouse peritoneal drug administration by injection, the acute toxicity of Buluoweima slow releasing tablet are that (95% crediblely is limited to 773.6～1041.5mg/kg) to 897.6mg/kg; The crude drug acute toxicity is that (95% crediblely is limited to 624.5～787.0mg/kg) to 701.1mg/kg.Mouse stomach administration, the acute toxicity of Buluoweima slow releasing tablet are that (95% crediblely is limited to 2409.5～3245.9mg/kg) to 2796.6mg/kg; The crude drug acute toxicity is that (95% crediblely is limited to 1698.6～2351.3mg/kg) to 1998.5mg/kg.
Medicine and raw material
Buluoweima slow releasing tablet (sheet kind 350mg contains ibuprofen 200mg, pseudoephedrine hydrochloride 30mg, adjuvant 120mg) reference substance be crude drug be in the Buluoweima slow releasing tablet raw material ibuprofen and pseudoephedrine by 200: 30 mixture.To be subjected to test piece agent and reference substance to use 0.5% carboxymethyl cellulose suspendible respectively, the limit edged grinds, and suspension is closely neutral.
Kunming mouse, body weight 19～21g supplies with the (quality certification number: Soviet Union's kinoplaszm 91001) by animal housing of China Medicine University.
Laboratory condition: 18 ℃～20 ℃ of temperature T, relative humidity 65%.
Acute toxicity testing
1. the acute toxicity testing of mouse peritoneal injection Buluoweima slow releasing tablet: get 50 of Kunming mouses, body weight 20 ± 1 grams, male and female half and half are divided into 5 groups at random, every group of 10 mices.On the basis of preliminary experiment, give the mouse peritoneal drug administration by injection, breeding observing 10 days is observed reaction of animals situation and death condition, and dead Mus performs an autopsy on sb.Experimental design, mice poisoning symptom and death condition see Table 1.Experimental data the results are shown in Table 2.
Dead mouse number behind the table 1 Buluoweima slow releasing tablet lumbar injection
| Group | Mus number (only) | Dosage (mg/kg) | Dead mouse number (%) | Toxic reaction and postmortem result |
| 12345 | 10 10 10 10 10 | 1,450 1,088 816 612 459 | 97420 | Show as abnormal motion after the administration, spasm, business concern operating a porters' service is walked, run and jump, ataxia afterwards, dyspnea is twitched, righting reflex loss is until death.Dead Mus is dead in 48 hours, and the postmortem naked eyes show no obvious abnormalities. |
Table 2 is pressed lumbar injection acute toxicity and 95% fiducial limit that the Bliss method is calculated the Buluoweima slow releasing tablet
| Dosage | Log10 dose | Number of animals | Death toll | Mortality rate | Probit |
| (mg/kg) | (x) | (only) | (only) | (％) | (Y) | Acute toxicity and 95% fiducial limit (mg/kg) |
| 1450 1088 816 612 459 | 3.161 3.037 2.912 2.787 2.662 | 10 10 10 10 10 | 9 7 4 2 0 | 90 70 40 20 10 | 6.28 5.52 4.75 4.16 2.60 | 897.6 (773.6～1041.5) |
2. mouse peritoneal is injected the acute toxicity testing of reference substance
Experimental technique is with 1.Body weight 20 ± 1g.Experimental design, poisoning symptom and death condition see Table 3.Experimental data calculates acute toxicity and fiducial limit with the Bliss statistic law, the results are shown in Table 4
Dead mouse number behind the table 3 reference substance lumbar injection
| Group | Mus number (only) | Dosage (mg/kg) | Dead mouse number (%) | Toxic reaction and postmortem |
| 12345 | 10 10 10 10 10 | 1,308 981 736 552 414 | 10 9620 | Show as abnormal motion after the administration, spasm is run and is jumped, last ataxia, dyspnea, righting reflex loss causes death.Dead Mus is dead in 48 hours, and the postmortem naked eyes show no obvious abnormalities. |
Table 4 is pressed the Bliss method and is calculated acute toxicity and 95% fiducial limit behind the reference substance lumbar injection
| Dosage (mg/kg) | Log10 dose (x) | Number of animals (only) | Death toll (only) | Mortality rate (%) | Probit (Y) | Acute toxicity and 95% fiducial limit (mg/kg) |
| 1308 981 736 552 414 | 3.117 2.992 2.867 2.742 2.617 | 10 10 10 10 10 | 10 9 6 2 0 | 100 90 60 20 0 | 7.40 6.28 5.25 4.16 2.60 | 701.1 (624.5～787.0) |
3. the acute toxicity testing of mouse stomach Buluoweima slow releasing tablet
Get 50 of Kunming mouses, body weight 20 ± 1g, male and female half and half are divided into 5 groups at random, and every group of 10 mices are given the mouse stomach administration on the basis of preliminary experiment.Administration after the fasting, breeding observing 10 days is observed reaction of animals situation and death toll, and dead Mus performs an autopsy on sb.Experimental design, poisoning symptom and death condition see Table 5.Experimental data calculates with the Bliss statistic law, and acute toxicity and fiducial limit see Table 6
Dead mouse number after the administration of table 5 Buluoweima slow releasing tablet mouse stomach
| Group | Mus number (only) | Dosage (mg/kg) | Dead mouse number (%) | Toxic reaction and postmortem |
| 12345 | 10 10 10 10 10 | 5,333 4,000 3,000 2,250 1688 | 10 8531 | Mice is movable unusual, runs and jumps, the toe walking.Last dyspnea, ataxia, righting reflex loss is until death.Dead mice is dead in three days, and the postmortem naked eyes show no obvious abnormalities. |
Table 6 is pressed the Bliss method and is calculated acute toxicity and 95% fiducial limit that the Buluoweima slow releasing tablet is irritated stomach
| Dosage (mg/kg) | Log10 dose (x) | Number of animals (only) | Death toll (only) | Mortality rate (%) | Probit (Y) | Acute toxicity and 95% fiducial limit (mg/kg) |
| 5333 4000 3000 2250 1688 | 3.727 3.602 3.477 3.352 3.227 | 10 10 10 10 10 | 10 8 5 3 1 | 100 80 50 30 10 | 7.40 5.84 5.00 4.48 3.72 | 2796.6 (2409.5～3245.9) |
The specific embodiment:
Embodiment 1:
Buluoweima slow releasing tablet and preparation method, its composition comprises: nonferrous layer granule and white layer granule, the ratio of weight and number of raw material stype Lip river sweet smell is 80 grams in the described nonferrous layer granule, the ratio of weight and number of pseudoephedrine hydrochloride is 30 grams, acrylic resin II number ratio of weight and number is 40 grams, the ratio of weight and number of hypromellose is 10 grams, the ratio of weight and number of lactose is 10 grams, the ratio of weight and number of ferrum oxide is 2 grams, the Pulvis Talci ratio of weight and number that contains 1% ferrum oxide is 6.66 grams, binding agent is to contain 2% polyacrylic resin II number and the ratio of weight and number of 80% alcoholic solution of 2% hypromellose is 28 grams in the nonferrous layer, the ratio of weight and number of ibuprofen is 120 grams in the described white layer granule, acrylic resin II number ratio of weight and number is 30 grams, the ratio of weight and number of hypromellose is 5 grams, the Pulvis Talci ratio of weight and number is 6.66 grams, and wetting agent is that 80% ethanol ratio of weight and number is 30 grams.
Its preparation method is: get ibuprofen, pseudoephedrine hydrochloride by above ratio of weight and number, ground 120 mesh sieves respectively, other crude drug are also crossed 120 mesh sieves earlier,
A: feed intake by described nonferrous layer granule prescription, mix homogeneously adds binding agent, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 50 ℃ of dryings 10 minutes, be chilled to room temperature, cross 18 mesh sieve granulate, what add corresponding parts by weight grinds the Pulvis Talci that contains ferrum oxide 1% that mixing is crossed 120 mesh sieves in advance, and mixing is made for the nonferrous layer granule.
B: throw grain by white layer granule prescription, mix homogeneously adds the wetting agent of corresponding parts by weight, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 50 ℃ of dryings 10 minutes, be chilled to room temperature, cross 18 mesh sieve granulate, add the Pulvis Talci of corresponding parts by weight, mixing is made for white particle.
C: nonferrous layer granule and white layer granule are placed on the tablet machine, are pressed into double-layer tablet with the 10mm punch die.
The clinical consumption of this product is secondary every day, each 1～2.
Embodiment 2:
Buluoweima slow releasing tablet and preparation method, its composition comprises: nonferrous layer granule and white layer granule, the ratio of weight and number of raw material stype Lip river sweet smell is 80 grams in the described nonferrous layer granule, the ratio of weight and number of pseudoephedrine hydrochloride is 30 grams, acrylic resin II number ratio of weight and number is 40 grams, the ratio of weight and number of hypromellose is 10 grams, the ratio of weight and number of lactose is 10 grams, the ratio of weight and number of ferrum oxide is 2.5 grams, the Pulvis Talci ratio of weight and number that contains 1% ferrum oxide is 6.66 grams, binding agent is to contain 2% polyacrylic resin II number and the ratio of weight and number of 80% alcoholic solution of 2% hypromellose is 28 grams in the nonferrous layer, the ratio of weight and number of ibuprofen is 120 grams in the described white layer granule, acrylic resin II number ratio of weight and number is 30 grams, the ratio of weight and number of hypromellose is 5 grams, the Pulvis Talci ratio of weight and number is 6.66 grams, and wetting agent is that 80% ethanol ratio of weight and number is 30 grams.
Its preparation method is: get ibuprofen, pseudoephedrine hydrochloride by above ratio of weight and number, ground 120 mesh sieves respectively, other crude drug are also crossed 120 mesh sieves earlier,
A: feed intake by described nonferrous layer granule prescription, mix homogeneously adds binding agent, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 55 ℃ of dryings 13 minutes, be chilled to room temperature, cross 18 mesh sieve granulate, what add corresponding parts by weight grinds the Pulvis Talci that contains ferrum oxide 1% that mixing is crossed 120 mesh sieves in advance, and mixing is made for the nonferrous layer granule.
B: throw grain by white layer granule prescription, mix homogeneously adds the wetting agent of corresponding parts by weight, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 55 ℃ of dryings 13 minutes, be chilled to room temperature, cross 18 mesh sieve granulate, add the Pulvis Talci of corresponding parts by weight, mixing is made for white particle.
C: nonferrous layer granule and white layer granule are placed on the tablet machine, are pressed into double-layer tablet with the 10mm punch die.
The clinical consumption of this product is secondary every day, each 1～2.
Embodiment 3:
Buluoweima slow releasing tablet and preparation method, its composition comprises: nonferrous layer granule and white layer granule, the ratio of weight and number of raw material stype Lip river sweet smell is 80 grams in the described nonferrous layer granule, the ratio of weight and number of pseudoephedrine hydrochloride is 30 grams, acrylic resin II number ratio of weight and number is 40 grams, the ratio of weight and number of hypromellose is 10 grams, the ratio of weight and number of lactose is 10 grams, the ratio of weight and number of ferrum oxide is 3 grams, the Pulvis Talci ratio of weight and number that contains 1% ferrum oxide is 6.66 grams, binding agent is to contain 2% polyacrylic resin II number and the ratio of weight and number of 80% alcoholic solution of 2% hypromellose is 28 grams in the nonferrous layer, the ratio of weight and number of ibuprofen is 120 grams in the described white layer granule, acrylic resin II number ratio of weight and number is 30 grams, the ratio of weight and number of hypromellose is 5 grams, the Pulvis Talci ratio of weight and number that contains 1% ferrum oxide is 6.66 grams, and wetting agent is that 80% ethanol ratio of weight and number is 30 grams.
Its preparation method is: get ibuprofen, pseudoephedrine hydrochloride by above ratio of weight and number, ground 120 mesh sieves respectively, other crude drug are also crossed 120 mesh sieves earlier,
A: feed intake by described nonferrous layer granule prescription, mix homogeneously adds binding agent, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 60 ℃ of dryings 15 minutes, be chilled to room temperature, cross 18 mesh sieve granulate, what add corresponding parts by weight grinds the Pulvis Talci that contains ferrum oxide 1% that mixing is crossed 120 mesh sieves in advance, and mixing is made for the nonferrous layer granule.
B: throw grain by white layer granule prescription, mix homogeneously adds the wetting agent of corresponding parts by weight, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 60 ℃ of dryings 15 minutes, be chilled to room temperature, cross 18 mesh sieve granulate, add the Pulvis Talci of corresponding parts by weight, mixing is made for white particle.
C: nonferrous layer granule and white layer granule are placed on the tablet machine, are pressed into double-layer tablet with the 10mm punch die.The clinical consumption of this product is secondary every day, each 1～2.
Embodiment 4:
The Buluoweima slow releasing tablet, 1.. get this product a slice, pulverize and grind, be transferred in the volumetric flask, add water and wait in right amount to dissolve, the about 410min of jolting, make pseudoephedrine fully dissolving in water, be settled to 10ml, filter, discard filtrate, get the about 10ml of subsequent filtrate, add 2 of blue vitriol test solutions, with 20% caustic lye of soda 1ml, promptly show blue, about 1ml adds diethyl ether, place a moment after the jolting, ether layer is a displaing amaranth, and water layer is blue.
2.. release is measured according to Chinese Pharmacopoeia nineteen ninety-five version appendix XD first method well.Ibuprofen has great absorption to disturb in the entire ultraviolet uptake zone of pseudoephedrine hydrochloride, and pseudoephedrine hydrochloride is at the strong absorbing wavelength of ibuprofen 222 ± 1nm place, in the absorption and faint down of corresponding extension rate (25 times), thereby can adopt ultraviolet spectrophotometry ibuprofen to be carried out quantitatively in 222 ± 1nm place, pseudoephedrine hydrochloride then can utilize its alkaloidal character, carry out quantitatively with acid stain (BTB, bromothymol blue) colorimetry (in 420nm wavelength place).
Ibuprofen in simulated gastric fluid (pH1.2) because dissolubility is very little, so carry out quantitatively i.e. Ci=Ci0Ai/AiO, Ci0=10.0 μ g/ml in the formula, Ai0=0.421 with the absorbance ratio method.
Ibuprofen carries out quantitatively with standard curve method in simulated intestinal fluid, and the standard curve equation is:
Ci＝24.95Ai-0.1498(r＝0.9999)。
Pseudoephedrine hydrochloride carries out quantitatively with standard curve method in simulated gastric fluid (Ph1.2) and simulated intestinal fluid, and the standard curve equation is respectively:
In simulated gastric fluid: Cp=138.89Ap-0.6452 (r=0.9999)
In simulated intestinal fluid: Cp=138.22Ap-0.4600 (r=0.9999)
3.. the assay ibuprofen can carry out quantitatively pseudoephedrine hydrochloride usable highly effective liquid chromatography for measuring content with the standard curve method of ultraviolet spectrophotometry in the trap at 222nm wavelength place to ibuprofen.The clinical consumption of this product is secondary every day, each 1～2.
Claims (2)
1. Buluoweima slow releasing tablet, its composition comprises: nonferrous layer granule and white layer granule, it is characterized in that: the ratio of weight and number of raw material stype Lip river sweet smell is 80 in the described nonferrous layer granule, the ratio of weight and number of pseudoephedrine hydrochloride is 30, acrylic resin II number ratio of weight and number is 40, the ratio of weight and number of hypromellose is 10, the ratio of weight and number of lactose is 10, the ratio of weight and number of ferrum oxide is 2～3, the Pulvis Talci ratio of weight and number that contains 1% ferrum oxide is 6.66, binding agent is to contain 2% polyacrylic resin II number and the ratio of weight and number of 80% alcoholic solution of 2% hypromellose is 28 in the nonferrous layer, the ratio of weight and number of ibuprofen is 120 in the described white layer granule, acrylic resin II number ratio of weight and number is 30, the ratio of weight and number of hypromellose is 5, the Pulvis Talci ratio of weight and number is 6.66, and wetting agent is that 80% ethanol ratio of weight and number is 30.
2. the preparation method of the described Buluoweima slow releasing tablet of claim 1 is characterized in that: get ibuprofen, pseudoephedrine hydrochloride by above ratio of weight and number, ground 120 mesh sieves respectively, other crude drug are also crossed 120 mesh sieves earlier;
A: feed intake by described nonferrous layer granule prescription, mix homogeneously adds binding agent, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 50 ℃～60 ℃ dryings 10～15 minutes, be chilled to room temperature, cross 18 mesh sieve granulate, what add corresponding parts by weight grinds the Pulvis Talci that contains ferrum oxide 1% that mixing is crossed 120 mesh sieves in advance, and mixing is made for the nonferrous layer granule;
B: throw grain by white layer granule prescription, mix homogeneously adds the wetting agent of corresponding parts by weight, makes suitable soft material, cross 20 mesh sieves, make wet granular,, take out in 50 ℃～60 ℃ dryings 10～15 minutes, be chilled to room temperature, cross 18 mesh sieve granulate, add the Pulvis Talci of corresponding parts by weight, mixing is made for white particle;
C: nonferrous layer granule and white layer granule are placed on the tablet machine, are pressed into double-layer tablet with the 10mm punch die.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101700245B (en) * | 2009-10-10 | 2012-03-21 | 天圣制药集团股份有限公司 | Compound drug for curing colds and preparation technology thereof |
| CN102349900B (en) * | 2009-10-10 | 2013-01-02 | 天圣制药集团股份有限公司 | Preparation method of compound capsule for treating cold |
| CN107007564A (en) * | 2017-04-12 | 2017-08-04 | 南京康川济医药科技有限公司 | A kind of medicinal composition of the double-layer sustained release containing brufen and PHENYLEPHRINE HYDROCHLORIDE and preparation method thereof |
| CN107233325A (en) * | 2017-06-23 | 2017-10-10 | 南京优科生物医药研究有限公司 | A kind of composition containing Imatinib and preparation method thereof |
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2005
- 2005-05-26 CN CNB2005100100284A patent/CN100500143C/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101700245B (en) * | 2009-10-10 | 2012-03-21 | 天圣制药集团股份有限公司 | Compound drug for curing colds and preparation technology thereof |
| CN102349900B (en) * | 2009-10-10 | 2013-01-02 | 天圣制药集团股份有限公司 | Preparation method of compound capsule for treating cold |
| CN107007564A (en) * | 2017-04-12 | 2017-08-04 | 南京康川济医药科技有限公司 | A kind of medicinal composition of the double-layer sustained release containing brufen and PHENYLEPHRINE HYDROCHLORIDE and preparation method thereof |
| CN107233325A (en) * | 2017-06-23 | 2017-10-10 | 南京优科生物医药研究有限公司 | A kind of composition containing Imatinib and preparation method thereof |
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