CN1279066A - Shuangmidamo suppository and its preparing process - Google Patents
Shuangmidamo suppository and its preparing process Download PDFInfo
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- CN1279066A CN1279066A CN 00113017 CN00113017A CN1279066A CN 1279066 A CN1279066 A CN 1279066A CN 00113017 CN00113017 CN 00113017 CN 00113017 A CN00113017 A CN 00113017A CN 1279066 A CN1279066 A CN 1279066A
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- suppository
- dipyridamole
- shuangmidamo
- fat
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Abstract
A dipyridamole suppository for treating rotaviral enteritis is prepared from dipyridamole (5-75mg/pellet) and liposoluble suppository matrix in weight ratio of 1:(40-80) through fusing said matrix, mixing with dipyridamole or slow-releasing polymer coated dipyridamole, strirring, cooling, pouring in suppository mould, cooling, demoulding. Its advantages include correct dosage, high curative effect and low cost.
Description
The invention belongs to technical field of pharmaceuticals, be specially the production method of a kind of dipyridamole suppository and this pharmaceutical dosage form.
The clinical treatment of diseases such as coronary heart disease, angina pectoris and thrombosis that are mainly used in before the dipyridamole, along with the progress to its pharmacological research, its clinical practice is increasingly extensive.Domesticly in recent years be used for the treatment of upper respiratory tract and dye, viral enteritis, chickenpox, hemorrhagic conjunctivitis, kitchen property myringitis greatly, mumps, diseases such as the herpetic parotitis of children's have all obtained good curative effect.And studies show that dipyridamole pair cell immunologic function has the obvious suppression effect.Dipyridamole energy selectivity suppresses uracil riboside/adenosine and the deoxidation pyrimidine enters cell, thereby it is synthetic to have suppressed viral RNA and DNA, and can influence the metabolism of prostaglandin, thereby enterokinesia is slowed down, secretion reduces, increase the absorption of power and water medium, help the recovery of gastrointestinal function, therefore can be used for treating viral diarrhea.
Children's's rotavirus diarrhoea is common clinical, and how in morbidity autumn and winter, distribute summer.At present clinically generally treat with dipyridamole or virazole, but dipyridamole only has tablet and injection, the tablet bitter in the mouth, feed difficulty, medicining times is many, and dosage is (every day 3-5mg/kg) greatly, simultaneously each children's often only uses the amount less than 1, the head of a family is difficult to accurately cut apart, and dosage is inaccurate to cause untoward reaction easily, and oral administration biaavailability is low; Injection must be treated in hospital, and medical expense is higher, and medicine enters back in the body to arrive the concentration of lesions position lower, so these two kinds of dosage forms are when treatment children's rotavirus diarrhoea, uses and curative effect all can not satisfy doctors and patients' needs.
The objective of the invention is to overcome the shortcoming of prior art, a kind of treatment children's rotavirus diarrheal suppository-dipyridamole suppository and production method thereof is provided, this suppository good effect, easy to use, children's is easy to accept during administration, dosage is accurate, expense is low.
Product suppository of the present invention contains the active constituents of medicine dipyridamole in essence, and adjuvant fat-soluble suppository substrate.
The product of the present invention preferably dipyridamole content of every suppository is 5 milligrams-75 milligrams.Dipyridamole content in every suppository is if surpass the upper limit of above-mentioned scope, and then side effect is big after the administration, and if be lower than the lower limit of above-mentioned scope, then the drug effect variation.As for adjuvant fat-soluble suppository substrate, can be semi-synthetic fatty acid ester, semi-synthetic cocos nucifera oil fat etc.
Scheme as further optimization, the weight ratio of dipyridamole and fat-soluble suppository substrate is in the product of the present invention: 1 part of dipyridamole, 20-100 parts of fat-soluble suppository substrate, optimized scheme are that weight ratio is 1 part of a dipyridamole, 40-80 parts of fat-soluble suppository substrate.
Product of the present invention can also contain other non-essential components, if need make slow, controlled release bolt, then may also contain the macromolecular material such as ethyl cellulose, beta cyclodextrin of packaging medicine active component.
The production method of product of the present invention is: after fat-soluble suppository substrate heat fused, add dipyridamole or add with the dipyridamole behind slow, the controlled release high molecular material parcel, stir and make its suspendible even, be poured in the bolt mould after cold slightly, take out promptly the cooling back.Products obtained therefrom is a glassy yellow bullet shaped suppository.
Experiment material and instrument: dipyridamole raw material (Shanghai No.6 Pharmaceutical Factory); Dipyridamole contrast (Nat'l Pharmaceutical ﹠ Biological Products Control Institute); Semi-synthetic fatty acid ester (Jiangling, Hubei Province pharmaceutical factory); Used chemical reagent is analytical pure.With 2401-PC type ultraviolet spectrophotometer (day island proper Tianjin); Low speed autobalancing centrifuge (Beijing Medical Centrifugal Machine Factory).
Differentiate:
1, get 1 of product of the present invention, add the vibration of ethanol 5ml post-heating, make abundant dissolving, cooling, centrifugal, supernatant promptly shows green fluorescence, adds acid back fluorescence and disappears.
2, get 1 of product of the present invention, add the vibration of ethanol 5ml post-heating, make abundant dissolving, cooling, centrifugal, to get supernatant and volatilize, residue adds dilute hydrochloric acid 2ml makes dissolving, drips 1% potassium chromate solution, promptly show reddish violet, reddish violet disappears after the jolting, adds excessive test solution reddish violet and does not reappear.
Assay:
1, standard curve: precision takes by weighing the about 10mg of the dipyridamole that is dried to weight and puts in the 100ml measuring bottle, adds the dissolving with hydrochloric acid of 0.01N/L and be diluted to scale to shake up.Accurate respectively absorption 0.5,1.0,1.5,2.0,2.5,3.0ml puts in the 25ml capacity, and the hydrochloric acid that adds 0.01N/L is diluted to scale, shakes up, and measures trap in the 283nm place.A returns concentration with trap, dipyridamole at 2-12 μ g/ml scope internal regression equations: C=15.997A+0.0092, n=6, r=0.9999.
2, assay: precision takes by weighing 1 Shuangmidamo suppository, and the hydrochloric acid heating for dissolving of using 0.01N/L shakes up to the 100ml volumetric flask, gets subsequent filtrate 2.0ml and places the 25ml volumetric flask, and the hydrochloric acid that adds 0.01N/L shakes up to scale.As blank, measure trap in the 283nm place with substrate, bring regression equation into according to spectrophotography, calculation sample content, content is 98.34% of labelled amount as a result, RSD is 2.34%.
The response rate: simulation prescription ratio takes by weighing substrate and dipyridamole, presses operation under the assay item, calculate recovery rate, and the response rate is 99.21% as a result, RSD is 1.78%.
Study on the stability: the sample of getting the room temperature placement is in 0,2, and to its face shaping, content is observed mensuration in the time of 6,12 months, and the result there is no significant change.
Determination of plasma concentration in the rabbit body:
The preparation of blood plasma standard curve: precision takes by weighing about 4 dipyridamole standard crystalline substance, and (the 250mg sodium dihydrogen phosphate is dissolved in the 250ml water, transfers pH4.6 with phosphoric acid,diluted, adds methanol 750ml with flowing.) being diluted to 25ml, accurate absorption 0.5,1.0,2.0,3.0,4.0,5.0ml place the 10ml volumetric flask, are diluted to scale with mobile phase.Get above-mentioned titer 0.2ml respectively and add in the 0.8ml blood plasma, vortex mixing 10s, it is fine to add 3.0ml second then, vortex 1 minute, centrifugal 10 minutes (4000r/min) gets supernatant 20 μ l sample introductions.Chromatographic condition is: carbon 18 silicagel columns, and wavelength 288nm, flow velocity 1ml/min, 40 ℃ of temperature return to such an extent that equation is: C=0.032825+0.00003275H, r=09926, n=6.942 with peak height to concentration.
Precision: get each 5 parts of the titers of high, medium and low concentration respectively, according to the down operation of standard curve item, the precision of the high, medium and low concentration of result is respectively 2.89%, 2.78%, 2.59%.
Extraction recovery: accurate two parts of No. 3 0.2ml of titer that draw, add the fine 3.0ml of second, vortex 1 minute, centrifugal 10 minutes, get supernatant 20 μ l sample introductions, calculating concentration, extraction recovery is 75.29% as a result.
Plasma drug level is measured in the rabbit body: 3 of the rabbit (male and female limit) that do not feed the next day of getting, rectum is filled in 1 of Shuangmidamo suppository, and blood plasma 1.0ml is got in sampling in 0,0.25,0.5,1,2,3,4,6,8,10,12 hour then after administration, sighting target directrix curve item is operation down, the results are shown in Table 1.
Plasma drug level time (h) 0.25 0.5 123468 10 12 numbering 1 0.39 0.68 0.81 0.69 1.14 1.03 1.62 1.90 1.74 1.432 0.35 1.24 1.36 1.46 1.28 1.65 1.50 2.07 1.70 1.453 00 1.38 2.94 2.80 2.29 2.76 2.01 2.95 2.39 in the table 1 rabbit body
Clinical practice:
Include the case standard in: the infantile diarrhea patient who meets the rotavirus infection diagnosis: stool routine examination is normal or have little fat to drip and leukocyte; stool routine examination has detected leukocyte or hemocyte person to carry out feces and cultivates and all do not detect pathogen; the routine urianlysis feminine gender; numeration of leukocyte and classification are normal substantially, and rotavirus detects positive.
Get rid of case: the infantile diarrhea patient of non-rotavirus infection, do not take medicine in accordance with regulations and be not carried out in accordance with regulations the infant of inspection.
Parameters for observation on effect: general health check-up project, stool routine examination, rotavirus detects.
Curative effect determinate standard:
Recovery from illness: treated 3 days, times of defecation and character are recovered normally fully, and unusual physical and chemical index recovers normal, and rotavirus detects negative.
Produce effects: treated 3 days, times of defecation be reduced to before the treatment below 1/3, character takes a turn for the better, unusual physical and chemical index obviously improves, rotavirus detects negative.
Effectively: 1/2 before times of defecation is reduced to and treats, character takes a turn for the better, and unusual physical and chemical index makes moderate progress, and rotavirus detects feminine gender.
Invalid: as not meet above standard person.
Therapeutic Method: meet the infant of including the case standard in and be divided into treatment at random and organize 32 examples, matched group 34 examples.The treatment group is divided 2-3 times anum administration by 3-5mg/kg/ day administration, and dehydrator gives fluid infusion and handles.The oral Zantine of matched group, by 3-5mg/kg/ day oral administration, dehydrator gives fluid infusion and handles.
Result: treatment group cure rate 56.25%, obvious effective rate 37.5%, effective percentage 3.125%, inefficiency 3.125%, total effective rate 96.875%, virus sweep rate 96.875%, average rotavirus clearance time 2.8 days, is not seen untoward reaction at the average 23 days antidiarrheal time.Matched group cure rate 14.71%, obvious effective rate 38.24%, effective percentage 32.35%, inefficiency 14.70%, total effective rate 85.30%, virus sweep rate 85.30%, average rotavirus clearance time 4 days, the average 35 days antidiarrheal time, flush appears in 1 example.See Table 2.
The several 32 matched groups recovery from illness of the total example of the several 34 treatment groups of the total example of table 2 therapeutic outcome matched group treatment groups fully recover 5 examples, 18 routine matched group produce effects treatment group produce effects 13 examples 12 routine matched groups effectively treatment organize the average rotavirus clearance time of effective 11 examples, 1 routine matched group futile treatment group invalid 5 examples 1 routine matched group, (my god) treatment organizes average rotavirus and turn out cloudy, (my god)
The average antidiarrheal natural law of 4 2.8 matched groups (my god) treatment organize average antidiarrheal natural law (my god)
The natural law 3.5 2.3 matched groups are on average brought down a fever (my god) the treatment group on average bring down a fever natural law (my god)
3．1 2．1
The main proximal small bowel mucosa of rotavirus, it is present in the Epithelium of intestinal villus cell, causes cytopathy and comes off, and the basal cell that is positioned at crypts portion quickens to divide a word with a hyphen at the end of a line to replace it to the top.Overrun owing to divide a word with a hyphen at the end of a line, basal cell fails to reach full growth, and except that still keeping original secretory function, absorbability is then obviously not enough, owing to contain abundant Na
+, K
+, the top cell of ATP enzyme is impaired, and cell is to Na
+Absorption and transport generation obstacle, cause a large amount of moisture and electrolyte to assemble at enteral, cause malabsorption diarrhoea.
Advantage of the present invention and beneficial effect: oral dipyridamole treatment infant rotavirus enteritis, medicining times is many, and dosage is big, and (every days 3-5mg/kg), infant was difficult for accepting, and dosage is inaccurate, causes untoward reaction easily.Product Shuangmidamo suppository dosage of the present invention is little, and children's is easy to acceptance during administration, dosage is accurate, easy to use, good effect, and steady quality, expense is low.
Embodiment 1: claim semi-synthetic fatty acid ester 45 grams, after 70 ℃ of heating in water bath fusings, add dipyridamole 1 gram, stirring makes its suspendible even, is poured into after cold slightly to have scribbled in the bolt mould of liquid paraffin in advance, scrapes off after the cooling to overflow partly, take out, be made as 60 suppositorys.
Embodiment 2: proportioning is semi-synthetic fatty acid ester 100 grams, and dipyridamole 1 gram is made as 200 suppositorys, and all the other are with embodiment 1.
Embodiment 3: proportioning is semi-synthetic fatty acid ester 40 grams, dipyridamole 1 gram, be made as 15 suppositorys all the other with embodiment 1.
Embodiment 4: dipyridamole 1 gram, and with saturated solution method parcel ethyl cellulose 0.2 gram.Claim semi-synthetic fatty acid ester 50 grams, after 70 ℃ of heating in water bath fusings, add the dipyridamole after wrapping up, stirring makes its suspendible even, is poured into after cold slightly to have scribbled in the bolt mould of liquid paraffin in advance, scrapes off after the cooling to overflow partly, take out, promptly get delay, 35 of controlled-release suppositories.
Embodiment 1-4 products obtained therefroms all can be realized purpose of the present invention.
Above embodiment is only for the present invention is further illustrated, and scope of the present invention is not subjected to the limitation of illustrated embodiment.
Claims (5)
1, a kind of Shuangmidamo suppository is characterized in that suppository contains the active constituents of medicine dipyridamole in essence, and adjuvant fat-soluble suppository substrate.
2, as the said Shuangmidamo suppository of claim 1, the dipyridamole content that it is characterized in that every suppository is 5 milligrams-75 milligrams.
3,, it is characterized in that the weight ratio of dipyridamole and fat-soluble suppository substrate is: 1 part of dipyridamole, 20-100 parts of fat-soluble suppository substrate as the said Shuangmidamo suppository of claim 2.
4,, it is characterized in that said weight ratio is 1 part of a dipyridamole, 40-80 parts of fat-soluble suppository substrate as the said Shuangmidamo suppository of claim 3.
5, a kind of production method of Shuangmidamo suppository, it is characterized in that after the fat-soluble suppository substrate heat fused, the dipyridamole after adding dipyridamole or adding are wrapped up with slow, controlled release high molecular material, stirring makes its suspendible even, be poured into after cold slightly in the bolt mould, take out promptly the cooling back.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00113017 CN1126544C (en) | 2000-06-12 | 2000-06-12 | Shuangmidamo suppository and its preparing process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 00113017 CN1126544C (en) | 2000-06-12 | 2000-06-12 | Shuangmidamo suppository and its preparing process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1279066A true CN1279066A (en) | 2001-01-10 |
| CN1126544C CN1126544C (en) | 2003-11-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00113017 Expired - Fee Related CN1126544C (en) | 2000-06-12 | 2000-06-12 | Shuangmidamo suppository and its preparing process |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3362047A4 (en) * | 2015-10-15 | 2019-06-26 | Moshe Rogosnitzky | Low dose oral dipyridamole compositions and uses thereof |
-
2000
- 2000-06-12 CN CN 00113017 patent/CN1126544C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3362047A4 (en) * | 2015-10-15 | 2019-06-26 | Moshe Rogosnitzky | Low dose oral dipyridamole compositions and uses thereof |
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| Publication number | Publication date |
|---|---|
| CN1126544C (en) | 2003-11-05 |
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