CN1079234C - Triphenyl diamidine enteric coated tablet as vermifuge - Google Patents
Triphenyl diamidine enteric coated tablet as vermifuge Download PDFInfo
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- CN1079234C CN1079234C CN96116469A CN96116469A CN1079234C CN 1079234 C CN1079234 C CN 1079234C CN 96116469 A CN96116469 A CN 96116469A CN 96116469 A CN96116469 A CN 96116469A CN 1079234 C CN1079234 C CN 1079234C
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- enteric coated
- coating
- triphenyl diamidine
- enteric
- tablet
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Abstract
The present invention relates to a triphenyl diamidine enteric coated tablet as vermifuge. The tablet comprises a tablet core which uses medicine triphenyl diamidine and sodium carboxymethyl starch as a quick disintegrating agent as main ingredients. The outer part of the tablet core is coated with a protective coat which contains hypromellose as a main ingredient. The outer part of the protective coat is coated with an enteric coat which uses No. II acrylic resin and No. III acrylic resin as main ingredients, and the tablet is obtained. The enteric coated tablet can ensure that the enteric coated tablet can be disintegrated in the intestinal tract to exert the medicine effect. The enteric coated tablet has the broad spectrum function of expelling worms, and has the advantages of obvious worm killing effect, low toxicity and convenient use.
Description
The present invention relates to a kind of triphenyl diamidine enteric coated tablet as vermifuge.
Because the aminobenzene amidine compound has the effect of driving Enterozoa, [referring to German patent DE 2029293 (1971), DE 2346939 (1975)], the inventor studies the structure activity relationship of this compounds, triphenyl diamidine and derivant thereof have been synthesized, and find that they have the broad-spectrum anthelmintic action, and chemical property is stable.The inventor has applied for Chinese patent [application number is CN 96116360.7 (1996)].Intestinal anthelmintic commonly used both at home and abroad all has in various degree stimulation to digestive tract, experimental result shows that the triphenyl diamidine medicine also has to a certain degree stimulation to gastric mucosa after the animal n of high dose oral, therefore, develop a kind of only disintegrate in intestinal, make it to directly act on the parasite at this position, both can avoid the stimulation to gastric mucosa, and can guarantee that again medicine brings into play drug effect in intestinal, be a research topic highly significant.
For this reason, the object of the invention provides a kind of triphenyl diamidine enteric coated tablet as vermifuge, this tablet not disintegrate in acidic gastric juice, and then disintegrate and release medicine rapidly in intestinal alkalescence intestinal juice, thus act on the parasite that colonizes in this position, produce anthelmintic action.
Triphenyl diamidine enteric coated tablet of the present invention comprises with medicine triphenyl diamidine and speed and collapses the sheet stamen that the agent carboxymethyl Starch Sodium is main composition; wrap earlier to contain the protective clothing that hypromellose is main composition sheet stamen outside; and then bag is the enteric coating of main composition so that II, III acrylic resin to be arranged, only so just make can be in intestinal juice the triphenyl diamidine enteric coated tablet as vermifuge of disintegrate and release medicine.
The sheet stamen, each other prescription of protective clothing and enteric coating is as described below.
The sheet stamen comprises following each component:
Title consumption (weight portion)
Triphenyl diamidine 50-200
Starch 15-60
Hyprolose 7-30
The cool gelatinized corn starch 40-160 of 4-8%
Carboxymethyl starch sodium 2-10
Micropowder silica gel 2-6
Magnesium stearate 0.7-3
Protective clothing comprises following each component:
Title consumption (weight portion)
Hypromellose 10-30
Propylene glycol 4-12
Ethanol 300-1000
Water 100-300 enteric coating comprises following each component
Title consumption (weight portion)
II, III acrylic resin (1: 1) 30-100
Propylene glycol 10-40
PEG400 3-10
Diethyl phthalate 10-50
Ethanol 400-1600
Water 100-400
Principal agent is a triphenyl diamidine in the sheet stamen, and it is water-soluble hardly, in order to improve its disintegration, adds disintegrating agent carboxymethyl base Starch Sodium.Result of the test shows, when need not about 21-23 minute with the disintegration time of disintegrating agent, and disintegration time can narrow down to 3-4 minute after adding disintegrating agent, therefore added carboxymethyl starch sodium, had obviously improved disintegration.
Protective clothing adopts hypromellose as the protective clothing material, is because triphenyl diamidine is an alkaline matter, and II, III acrylic resin are acidic materials, and the two contact can change, for addressing this problem, in sheet stamen outside earlier bag with protective clothing.Hypromellose is to acid, and alkali is stable, is good filmogen.When the sheet stamen increases weight approximately 0.5%, promptly play a protective role, disintegration time only prolongs 2-3 minute.
Therefore the drug effect position of triphenyl diamidine also should wrap with enteric coating at intestinal.The present invention adopts 1: 1 mixture of II, III acrylic resin as enteric materials.II, III acrylic resin are relatively stricter to the requirement of pH value, dissolve in intestinal juice, and the two are at film property, have complementarity in appearance.
For the dissolution velocity that improves enteric coating and improve the inherent fragility of resin, adopt diethyl phthalate to make plasticizer, propylene glycol is made porogen.For increasing the fineness of enteric coating, added Polyethylene Glycol simultaneously, Polyethylene Glycol has the effect of porogen concurrently.After the sheet stamen is wrapped enteric coating, sheet stamen weightening finish 2.5-3.5%, the disintegration of casing sheet is within 30 minutes.
Used starch in the above-mentioned prescription, carboxymethyl starch sodium, hypromellose, II, III acrylic resin, adjuvants such as propylene glycol all conform to the standard of Chinese Pharmacopoeia (90 editions) or American Pharmacopeia (XXIII version).
The manufacture method of triphenyl diamidine enteric coated tablet as vermifuge of the present invention is as described below:
1, the manufacturing of sheet stamen, triphenyl diamidine is ground into 100 order fine powders, takes by weighing the cool gelatinized corn starch of triphenyl diamidine, starch, hyprolose and 4-8% by above-mentioned prescription then, behind the mix homogeneously, granulate with 18 order nylon wires, 60 ℃ of dryings, with dried granule again with carboxymethyl starch sodium, micropowder silica gel, the magnesium stearate mixing, with 16 order wire gauze granulate, heavy by recording content conversion slice, carry out tabletting.2, protective clothing preparation and coating are got hypromellose by above-mentioned prescription, propylene glycol, and it is stand-by that ethanol and water are mixed into protective clothing liquid.Get the sheet stamen and put in the coating pan, rotation at a slow speed, pre-backing stamen to 40 ℃.Then with the protective clothing liquid spray coating for preparing, wrap in that temperature is controlled between 35-40 ℃ in the process, rotating speed is 13-17 rev/min, has wrapped intensive drying slice, thin piece behind the protective clothing, and is stand-by.The sheet stamen increases weight about 0.5%.
3, enteric coating preparation and coating II, III acrylic resin (1: 1) and ethanol mixing, are treated resin all after the dissolving by above-mentioned prescription, the adding propylene glycol, and PEG400, diethyl phthalate and water are mixed into casing liquid, and is stand-by.Get the sheet stamen of bag overprotection clothing, be preheating to 40 ℃, with the casing liquid spray coating for preparing, temperature is controlled at 30-45 ℃ in the coating process then, and rotating speed is 20-25 rev/min, and the slice, thin piece that contracts out is at 40 ℃ of dryings 4 hours, sheet stamen weightening finish 2.5-3.5%.Detect slice, thin piece, should be in simulated gastric fluid 2 hours insoluble, disintegrate within 30 minutes in simulated intestinal fluid.
Triphenyl diamidine enteric coated tablet of the present invention has the broad-spectrum anthelmintic action, can find out that from the following test of pesticide effectiveness it has splendid insecticidal effect.
1, Brazilian Nippostrongylus is had tangible anthelminthic effect, infected rats is once irritated the deworming rates that stomach gives 10mg/kg and 20mg/kg and is respectively 99.9% and 100%, and intramuscular injection 75mg/kg and 100mg/kg deworming rates then respectively are 99.4% and 99.9%.
The anthelmintic action of triphenyl diamidine is rapid, and infected rats promptly began parasite removing in 8 hours after administration, and the borer population of discharging in 24 hours has reached 99%.
2, American hookworm there is tangible anthelminthic effect.The deworming rates that 1 filling of infection hamster stomach gives triphenyl diamidine 50mg/kg and 100mg/kg is respectively 86.8 and 99.7%.Intramuscular injection triphenyl diamidine 50mg/kg and 75mg/kg deworming rates respectively are 95.8% and 100%.
3, the dog ancylostome there is obvious curative effects.The deworming rates that infected dogs gavages triphenyl diamidine 25mg/kg for 1 time is 94.6%.
4, ascaris alata there is obvious curative effects.After 3 infected dogs gavaged triphenyl diamidine 25mg/kg 1 time, deworming rates was 100%.
Triphenyl diamidine all has various nematicides and cestode and kills effect significantly in addition.
The toxicity of triphenyl diamidine is very little, and the result is as follows for its toxicity test:
1, acute toxicity: 1 gastric infusion of triphenyl diamidine is respectively 947mg/kg and 2262mg/kg to the LD50 of mice and rat.The LD50 of mouse peritoneal injection triphenyl diamidine is 277mg/kg.
2, subacute toxicity: rat gavage every day triphenyl diamidine dosage be 30,150 or 300mg/kg (be respectively 5,25 and 50 times that intend recommending clinical dosage, the administration phase be 14 days (accumulated dose respectively for recommend clinical dosage 70,350 and 700).To the hematological examination of the rat of taking medicine, serum biochemistry and routine urinalysis detect, and do not see that every index has unusually.Histopathologic observed result shows, digestive system, particularly gastrointestinal tract triphenyl diamidine cause the main target organ of pathological lesion, but infringement is lighter, is reversibility, can recover normal after the drug withdrawal.
And all experimental mouse is all dead in rat oral albendazole 168mg/kg2-3 week.
3, triphenyl diamidine mutagenicity test feminine gender.
4, the general reproduction poison of triphenyl diamidine test, dosage are that 60mg/kg/ day (clinical plan is with 10 times of dosage), the result was negative, and albendazole dosage only has tangible teratogenesis for 7.5mg/kg/ during day.
5, rat embryo teratogenesis sensitivity tests, triphenyl diamidine dosage are that oral 250mg/kg/ day (clinical plan is with 48 times of dosage), even 10 days results of administration were negative.And matched group albendazole dosage only is 15mg/kg/ day, and connecting administration just has obvious teratogenesis after 6 days.
Triphenyl diamidine enteric coated tablet using dosage of the present invention is 6-12mg/kg/ day, and every in tablet contains triphenyl diamidine 5-100mg.
Dog ancylostome and human body Ancylostoma duodenale belong to Ancylostoma together, and both biological characteristicses are close, so make insect esexpeling test (seeing real examination example 4) to confirm the anthelmintic action of triphenyl diamidine enteric coated tablet to the Ancylostoma ancylostome with dog ancylostome one dog model.
In addition, Toxocara canis and ascariasis are with being under the jurisdiction of ascarid superfamily.The present invention selects the Canis familiaris L. of natural infection Toxocara canis for use, gives triphenyl diamidine enteric coated tablet with the anthelminthic effect (see real examination example 5) of oral confirmation triphenyl diamidine enteric coated tablet to Toxocara canis
Triphenyl diamidine enteric coated tablet as vermifuge advantage of the present invention, it is that disintegrate produces anthelmintic action after directly acting on the polypide that colonizes in this position in intestinal, so both can avoid the stimulation of medicine to gastric mucosa, can guarantee that again medicine brings into play drug effect in intestinal.Owing to adopt suitable prescription, make the tablet that the outside is surrounded by the casing sheet can be in simulated intestinal fluid in disintegrate within 30 fens kinds, this tablet toxicity is little, has the broad-spectrum anthelmintic action, and insecticidal effect is obvious, and easy to use.
The present invention is further elaborated by following examples, but does not place restrictions on scope of the present invention
The manufacturing of embodiment 1, triphenyl diamidine enteric coated tablet
1, the manufacturing of sheet stamen, triphenyl diamidine is ground into 100 order fine powders, take by weighing triphenyl diamidine 500 grams, starch 150 grams, granulate with 18 order nylon wires behind hyprolose 70 grams and the 8% cool gelatinized corn starch 400 gram mix homogeneously, 60 ℃ of dryings, dried granule is restrained with carboxymethyl starch sodium 20 again, and micropowder silica gel 20 grams and magnesium stearate 7 gram mixings are with 16 order wire gauze granulate, record content 97.5%, carry out tabletting, every tablet contains triphenyl diamidine amount 100mg, and average sheet heavily is 150mg, 20 sheet differences are within ± 5%, and the sheet difference is qualified.
2, protective clothing preparation and coating are got hypromellose 10 grams, propylene glycol 4 grams, and it is stand-by that ethylene glycol 300 grams and water 100 grams are mixed into protective clothing liquid.Getting above-mentioned stamen puts in the coating pan; rotate pre-backing stamen to 40 ℃ at a slow speed; then with the protective clothing liquid spray coating for preparing; temperature is controlled between 35-40 ℃ in the coating process; rotating speed 13-17 rev/min; wrapped slice, thin piece behind the protective clothing 40 ℃ of dryings 4 hours, stand-by, record the sheet stamen and increase weight about 0.5%.
3, enteric coating preparation and coating, get II, III acrylic resin (1: 1) 30 grams and ethanol 400 gram mix homogeneously, treat that resin all after the dissolving, adds propylene glycol 10 and restrains, PEG400 3 grams, it is stand-by that diethyl phthalate 10 grams and water 100 grams are mixed into enteric coating.The sheet stamen of getting above-mentioned bag overprotection clothing is preheating to 40 ℃, and with the casing liquid spray coating for preparing, temperature is controlled at 30-35 ℃ in the coating process then, and rotating speed is 20-25 rev/min, and the slice, thin piece that contracts out records sheet stamen weightening finish 3% 40 ℃ of dryings 4 hours.
The detection of tablet, in simulated gastric fluid 2 hours insoluble, disintegrate in 17 minutes in simulated intestinal fluid.
The manufacturing of embodiment 2, triphenyl diamidine enteric coated tablet
1, the manufacturing of sheet stamen takes by weighing triphenyl diamidine 200 grams, starch 60 grams, and hyprolose 30 grams, 4% cool gelatinized corn starch 160 grams, carboxymethyl starch sodium 10 grams, micropowder silica gel 6 grams, and magnesium stearate 3 grams, operating procedure is with embodiment 1.Record content 99.6%, carry out tabletting, every tablet contains triphenyl diamidine amount 100mg, and 20 sheet differences are within ± 5%, and the sheet difference is qualified.
2, the protective clothing preparation is got hypromellose 30 grams with coating, propylene glycol 12 grams, and ethanol 1000 grams and water 300 grams, operating procedure is with embodiment 1.
3, enteric coating preparation and coating, get II, III acrylic resin (1: 1) 100 grams, ethanol 1600 grams, propylene glycol 40 grams, PEG400 10 grams, diethyl phthalate 50 grams and water 400 grams, temperature is controlled at 35-40 ℃ in the coating process, operating procedure records sheet stamen weightening finish 3.5% with embodiment 1.
The detection of slice, thin piece, in simulated gastric fluid 2 hours insoluble, disintegrate in 25 minutes in simulated intestinal fluid.
The manufacturing of embodiment 3, triphenyl diamidine enteric coated tablet
1, the manufacturing of sheet stamen takes by weighing triphenyl diamidine 100 grams, starch 30 grams, hyprolose 15 grams, 6% cool gelatinized corn starch 80 grams, carboxymethyl starch sodium 5 grams, micropowder silica gel 3 grams, and magnesium stearate 3 grams, operating procedure with embodiment 1, record content 98.7%, carry out tabletting, every tablet contains triphenyl diamidine amount 100mg, and average sheet heavily is 160mg, 20 sheet differences are within ± 5%, and the sheet difference is qualified.
2, the protective clothing preparation is got hypromellose 15 grams with coating, propylene glycol 6 grams, and ethanol 50 grams and water 150 grams, operating procedure is with embodiment 1.
3, enteric coating preparation and coating, get II, III acrylic resin (1: 1) 50 grams, ethanol 800 grams, propylene glycol 20 grams, PEG400 5 grams, diethyl phthalate 25 grams and water 200 grams, temperature is controlled at 40-45 ℃ in the coating process, operating procedure records sheet stamen weightening finish 2.5% with embodiment 1.
The detection of slice, thin piece, in simulated gastric fluid 2 hours insoluble, disintegrate in 15 minutes in simulated intestinal fluid.
Embodiment 4 triphenyl diamidine enteric coated tablets are to the insect esexpeling test of dog ancylostome
The Canis familiaris L. of 10 infected dogs ancylostomes (male and female dual-purpose, body weight 5-10kg) 1 oral triphenyl diamidine enteric coated tablet, (being subjected to the reagent thing is triphenyl diamidine enteric coated tablet, every 25mg or 5mg), dosage is established two dosage groups, be 6mg/kg and 12mg/kg, and make the blank group with 5 Canis familiaris L.s, result of the test sees the following form 1:
Table 1 infects the anthelminthic effect of 1 oral triphenyl diamidine enteric coated tablet of Canis familiaris L. to the dog ancylostome
| Group dosage Canis familiaris L. count the total deworming rates of anthelminthic effect deworming rates (mg/kg) (%) (%) seize the total borer population of borer population (bar) feces small intestinal large intestine |
| 4 668 00 668 100.0 6 97.6 6 1,160 48 0 1,208 96.0 are subjected to reagent 9 1,673 00 1,673 100.0 12 99.9 1 36 20 38 94.7 |
| Blank 50 736 0 736 00 |
As seen from the above table, the deworming rates 10 Canis familiaris L.s treating with triphenyl diamidine enteric coated tablet 6mg/kg is 97.6%.When the dosage of triphenyl diamidine enteric coated tablet was 12mg/kg, the deworming rates of 10 Canis familiaris L.s being controlled was 99.9%.Therefore triphenyl diamidine enteric coated tablet has significant anthelminthic effect to the dog ancylostome.And the Canis familiaris L. of 2 dosage groups was observed after administration 24 hours, there is no untoward reaction, and food-intake and feces are all normal.
Embodiment 5 triphenyl diamidine enteric coated tablets are to the insect esexpeling test of Toxocara canis
6 Canis familiaris L. (male and female dual-purposes of natural infection Toxocara canis, body weight 5-10kg) (be subjected to the reagent thing is triphenyl diamidine enteric coated tablet to 1 oral triphenyl diamidine 12mg/kg, every 25mg or 5mg) back 14 days, faecal egg is all turned out cloudy, do not seize Toxocara canis in the small intestinal when cuing open inspection, so triphenyl diamidine enteric coated tablet there is tangible anthelminthic effect to Toxocara canis.
Claims (2)
1, a kind of enteric coated tablet as vermifuge; it is characterized in that it comprises with medicine triphenyl diamidine and speed collapses the sheet stamen that the agent carboxymethyl Starch Sodium is main composition; wrap earlier to contain the protective clothing that hypromellose is main composition sheet stamen outside; and then to be surrounded by with II, III acrylic resin be that the enteric coating of main composition forms
The sheet stamen comprises following each component:
Title consumption (weight portion)
Triphenyl diamidine 50-200
Starch 15-60
Hyprolose 7-30
The cool gelatinized corn starch 40-160 of 4-8%
Sodium Hydroxymethyl Stalcs 2-10
Micropowder silica gel 2-6
Magnesium stearate 0.7-3 protective clothing comprises following each component:
Title consumption (weight portion)
Hypromellose 10-30
Propylene glycol 4-12
Ethanol 300-1000
Water 100-300 enteric coating comprises following each component:
Title consumption (weight portion)
II, each 50% 30-100 of III acrylic resin
Propylene glycol 10-40
PEG400 3-10
Diethyl phthalate 10-50
Ethanol 400-1600
Water 100-400
2, the manufacture method of enteric coated tablet as vermifuge according to claim 1 is characterized in that:
A. the manufacturing of sheet stamen takes by weighing the cool gelatinized corn starch mixing of triphenyl diamidine, starch, hyprolose and 4-8% by above-mentioned prescription, and it is dry to granulate, again with carboxymethyl starch sodium, and micropowder silica gel, magnesium stearate mixing, tabletting;
B. protective clothing preparation and coating take by weighing hypromellose, propylene glycol, second alcohol and water by above-mentioned prescription and are mixed into protective clothing liquid, get the sheet stamen and are preheating to 40 ℃, and with protective clothing liquid spray coating, temperature is 35-40 ℃ during coating, and rotating speed is 13-17 rev/min;
C. the enteric coating preparation is pressed above-mentioned prescription with each II of 50%, III acrylic resin and ethanol mixing with coating; after treating that resin all dissolves; add propylene glycol, PEG400, O-phthalic ester diethylester and water and be mixed into casing liquid; get the sheet stamen of bag overprotection clothing; be preheating to 40 ℃; use casing liquid spray coating then, temperature is 30-45 ℃ when enteric coated, and rotating speed is 20-25 rev/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96116469A CN1079234C (en) | 1996-08-19 | 1996-08-19 | Triphenyl diamidine enteric coated tablet as vermifuge |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96116469A CN1079234C (en) | 1996-08-19 | 1996-08-19 | Triphenyl diamidine enteric coated tablet as vermifuge |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1174030A CN1174030A (en) | 1998-02-25 |
| CN1079234C true CN1079234C (en) | 2002-02-20 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96116469A Expired - Lifetime CN1079234C (en) | 1996-08-19 | 1996-08-19 | Triphenyl diamidine enteric coated tablet as vermifuge |
Country Status (1)
| Country | Link |
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| CN (1) | CN1079234C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103060426A (en) * | 2008-04-01 | 2013-04-24 | 北京九强生物技术股份有限公司 | Low density lipoprotein cholesterin quantifying method |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103054827A (en) * | 2011-11-29 | 2013-04-24 | 成都盛尔嘉科技有限公司 | Parasite expelling medicament with no irritation to gastric mucosa and method for preparing same |
| CN112159338A (en) * | 2020-10-15 | 2021-01-01 | 山东新华制药股份有限公司 | Preparation of triphenyldiamidine impurity |
-
1996
- 1996-08-19 CN CN96116469A patent/CN1079234C/en not_active Expired - Lifetime
Non-Patent Citations (4)
| Title |
|---|
| 中国寄生虫学与寄生虫病杂志，5(4) 1987.1.1 任海南等，"驱钩虫新药三苯双脒的实验治疗研究" * |
| 医药工业，19(3) 1988.1.1 邵葆若等，"驱钩新化合物三苯双脒的诱变性和致畸性检测" * |
| 药学学报，23(10) 1988.1.1 姚润华，陈耀清"驱肠虫新药三苯双脒的研究简报";医药工业，19(3) 1988.1.1 邵葆若等，"驱钩新化合物三苯双脒的诱变性和致畸性检测";中国寄生虫学与寄生虫病杂志，5(4) 1987.1.1 任海南等，"驱钩虫新药三苯双脒的实验治疗研究" * |
| 药学学报，23(10) 1988.1.1 姚润华，陈耀清"驱肠虫新药三苯双脒的研究简报" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103060426A (en) * | 2008-04-01 | 2013-04-24 | 北京九强生物技术股份有限公司 | Low density lipoprotein cholesterin quantifying method |
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| Publication number | Publication date |
|---|---|
| CN1174030A (en) | 1998-02-25 |
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