CN1853655A - Oral colon target preparation for treating colitis ulcerativa and its making method - Google Patents
Oral colon target preparation for treating colitis ulcerativa and its making method Download PDFInfo
- Publication number
- CN1853655A CN1853655A CNA2005100208072A CN200510020807A CN1853655A CN 1853655 A CN1853655 A CN 1853655A CN A2005100208072 A CNA2005100208072 A CN A2005100208072A CN 200510020807 A CN200510020807 A CN 200510020807A CN 1853655 A CN1853655 A CN 1853655A
- Authority
- CN
- China
- Prior art keywords
- preparation
- oral colon
- targeting preparation
- colon targeting
- oral
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
An orally taken target medicine for treating the ulcerative colitis with high curative effect and low dosage is prepared from the extract of American periplaneta. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of oral colon targeting preparation for the treatment of ulcerative colitis, specifically, is to be medicine of feedstock production and its production and use with the Chinese crude drug, belongs to the field of Chinese medicines.
Background technology
Ulcerative colitis is a kind of former, non-specific colon chronic disease.As seen colonoscope only invades the mucosa and the tela submucosa of colon down, and rotten to the corn and shallow table ulcer are arranged.
At present, the western medical treatment ulcerative colitis mainly contains following a few class medicine: sulfonamides, antibiotics, metronidazole, hormone therapy, oral 17-hydroxy-11-dehydrocorticosterone, topical, immunosuppressant; Above-mentioned Western medicine all proves to have reliable therapeutic effect by the long-term test of pesticide effectiveness and clinical trial, but toxicity is big mostly, and side effect is many, such as: nausea and vomiting, headache, general malaise are often arranged after sulfonamides is oral, or cause leukopenia, arthralgia, erythra, albuminuria etc.; The oral gastrointestinal irritation that easily causes of antibiotic; The intravenous administration toxic and side effects is big; Immunosuppressant is big to the hemopoietic function of bone marrow influence, answers the periodic review bone marrow smear in the medication process; The position restriction of external-use lotion medication, the patient uses inconvenience.
Theory of Chinese medical science with ulcerative colitis adhere to diarrhea, dysentery separately, have blood in stool, category such as hemorrhoidal hamorrhage, dysentery.Its pathogenesis has internal organs weakness, being invaded by exogenous pathogen, injury due to diet and disorder of emotion etc., and its basic pathogenesis is that deficiency of spleen-QI and stomach-QI, damp and hot heresy are pented up in large intestine, pyrogenicity fulminant dysentery disease, stomachache tenesmus, dysentery pus and blood.Compare with Western medicine, the Chinese medicine primary disease have dialectical flexibly, advantage such as method of treatment is various, curative effect is considerable, toxic and side effects is few, and more can be at the cause of disease of ulcerative colitis.
At present, the existing new liquid of American-cockroach-extract preparation rehabilitation uses separately or unites the relevant report of using the treatment ulcerative colitis with other medicines: with the new liquid retention-enema treatment of rehabilitation ulcerative colitis, totally 21 examples, produce effects 13 examples, effective 7 examples, part is alleviated 1 example, obvious effective rate 62.5% (the new liquid retention-enema treatment of rehabilitation ulcerative colitis 21 routine Lv Wen, Chinese combination of Chinese and Western medicine digestion such as Mei Qinna magazine 2003,11 (2) .-107-108); Oral medicinal herb adds rehabilitation and newly treats chronic non-specific ulcerative colitis 120 examples, produce effects 92 examples, effective 28 examples, total effective rate 100%, cure in the case and follow up a case by regular visits to 21 examples, drug withdrawal does not all have recurrence (oral medicinal herb adds the new liquid enema treatment of rehabilitation chronic non-specific ulcerative colitis 120 routine Wang Meng Dong Hua English Jilin Chinese medicine 2003,23 (12) .-24-24) more than 1 year.The new liquid of rehabilitation has promoting blood circulation, nourishing yin and promoting granulation, anti-inflammation detumescence, improves local microcirculation, promotes revascularization, promotes that slough comes off, promotes effects such as granulation tissue hyperplasia and epithelial growth, be usually used in treating ulcer, burn etc., oral administration, washout, external application.Colon hydrotherapy dominant mechanism is to utilize colonic mucosa, enteraden potential function, and the antibacterial on eliminating enteric cavity and the intestinal mucosa and toxin, the noxious substance of generation thereof, local coloclysis are easy to absorb the body utility, reach therapeutical effect.At present adopt oral or coloclysis or both all use administration, because contained main component is an amino acids, in easily molten, the easy decomposition of gastrointestinal tract epimere, poor stability can't orally be scattered in site of action with high concentration, brings into play curative effect to greatest extent in the new liquid of rehabilitation more; Though the coloclysis administration can better overcome the above problems, medicine is at the colon skewness, and individual variation is big, and uses inconvenience, patient to be difficult for accepting, and this method is not recorded by the legal national drug standards.From above-mentioned report as can be known, extract of the present invention only has the report of external curing, does not have the report of oral medication ulcerative colitis.
Below be the report that the new liquid of rehabilitation is used for other treatment for diseases:
1, the new liquid of rehabilitation is in the clinical practice Yao Chun sea of condyloma acuminatum postoperative wound surface, the refined civilian West China of Lee pharmaceutical journal 2004,19 (2) .-160-160
2, the new liquid treatment of rehabilitation II degree burn observation of curative effect Yang Xin flower bud, Zhang Xin closes Chinese Chinese and western medical science magazine 2004,2 (1) .-49-50
3, new liquid of rehabilitation and QINGRE JIEDU KOUFUYE treatment Hand-Food-Mouth Disease 58 routine Deng Ying China combination of Chinese and Western medicine magazine 2004,24 (2) .-164-164
4, the clinical observation seat Xiao Yan of " the new liquid of rehabilitation " treatment decubital ulcer 30 examples, Sichuan medical science 2004,25 (2) .-249-249 such as easy Fructus Mume
5, the military peace of the new liquid treatment of rehabilitation erosive type gastritis 112 routine efficacy analysis, Li Ping, Zheng Yu journal of shanghai Chinese medicine 2004,38 (2) .-28-29
6, oral cavity reaction Zhu is imitated two doctor's magazines, 2003,1 (11) .-964-964 in diligent China's modern times behind the new liquid treatment of the rehabilitation nasopharyngeal carcinoma radiotherapy
7, the new liquid rinsing the mouth treatment of rehabilitation chemotherapy stomatitis 27 routine Chen Xu beacons, Zhu Yuejiao, Li Jie China Pharmaceutical 2003,12 (12) .-72-72
8, the new liquid treatment of rehabilitation erosive gastritis 60 routine observation of curative effect Peng shower medicine clinical research 2003,20 (10) .-788-790
9, the new liquid wound surface of hemorrhoid postoperative rehabilitation change dressings the observation of curative effect gold build charming, fourth Yunlong modern combination of Chinese and Western medicine magazine 2003,12 (18) .-1984-1984
10, application clock intelligent sweet smell Chinese basic unit medicine 2003,10 (3) .-275-275s of the new liquid of rehabilitation in malignant hematologic disease patient's mouth ulcer
11, it is gorgeous that the new liquid associating of rehabilitation famotidine treatment peptic ulcer 82 examples are closed cloud, Chinese combination of Chinese and Western medicine digestion such as Liu Wanli magazine 2003,11 (2) .-83-84
12, the new liquid of rehabilitation application Yao Xiuqin in the mucocutaneous injury nursing after radiotherapy, south such as Zhao Haijian nursing journal 2002.9 (6)-6-6
13, the few face U.S. of the new liquid treatment of rehabilitation decubital ulcer 10 routine woodss China clinical medicine magazine 2002,4 (4) .-303-303
14, new liquid of Chinese medicine rehabilitation and Chinese medicine Leader, the phthisical prorogation Xiao Jie of Western medicine short-course chemotherapy therapeutic alliance Hunan 2002,8 (7) .-401-401.406
15, ultrashort wave closes the new liquid treatment of rehabilitation diabetic skin ulcer and looks into astronomy, Nie Mei folks of china therapy 2002,10 (5) .-52-53
16, the new liquid treatment of rehabilitation peptic ulcer short term effect is observed Mei Jian Hebei medical science 2002,8 (3) .-255-255
17, outer fistula 1 routine Zhou Ruitang external treatment with Chinese medicine magazine 2002,11 (2) .-54-54 of the new external treatment small intestinal of rehabilitation
18, clinical observation Tan Lin Chengdu medicine 2002,28 (2) .-89-89 of the new liquid treatment of oral rehabilitation digestive tract ulcer
19, the research woods green grass or young crops of the new liquid anti-experimental character of rehabilitation gastric ulcer effect, Chinese patent medicines such as Cao Dong 2001,23 (2) .-122-124
Though the existing report that uses American-cockroach-extract treatment ulcerative colitis does not still have the relevant report that this medication preparation oral colon targeting preparation is used for the treatment of ulcerative colitis at present.
Summary of the invention
At above problem, purpose of the present invention just provides a kind of oral colon targeting preparation for the treatment of ulcerative colitis, and it is a kind of new dosage form.
Another object of the present invention provides the oral colon targeting preparation used targeting coating adjuvant and the formulation preparation method of this treatment ulcerative colitis.
Periplaneta americana is the Scorpio of Blattidae Periplaneta animal periplaneta americana; Nature and flavor are salty, cold, have removing blood stasis with potent drugs, eliminate indigestion, detumescence, diuresis, antidotal effect.
The invention provides a kind of oral colon targeting preparation for the treatment of ulcerative colitis, it is the oral colon targeting preparation that the adjuvant by extract of periplaneta americana (Peripleneta americana (Linnaeus)) and pharmaceutically acceptable colon targeting preparation is mixed and made into.The adjuvant of described pharmaceutically acceptable colon targeting preparation is: the mixture of any one or a few in acrylic resin III or EUDRAGIT S100, triethyl citrate, pectin, the hydroxypropyl emthylcellulose (HPMC)..The principle of these segmented intestine targeted adjuvants is: acrylic resin III or EUDRAGIT S100 are insoluble in the pH value less stomach and intestinal fluid, but be dissolved in the bigger colonic fluid of pH value, so consider with a certain amount of acrylic resin III or EUDRAGIT S100 and add a certain amount of plasticizer triethyl citrate preparation is carried out coating, preparation pH relies on oral colon targeting preparation; Pectin at stomach, intestinal since the shortage of corresponding enzyme can not be degraded, but can be decomposed by the peculiar pectase of colon, after HPMC mixes by a certain percentage, can improve the hydrophilic of pectin, both couplings are carried out coating to preparation, can prepare enzyme and rely on oral colon targeting preparation.
Particularly, the adjuvant of described pharmaceutically acceptable oral colon targeting preparation is respectively: acrylic resin III or EUDRAGIT S100, triethyl citrate, pectin and HPMC, the content that wherein mixes HPMC in the use is 10% ~ 90%, and it is 20: 1～2: 1 that acrylic resin III or EUDRAGIT S100, triethyl citrate mix the ratio range that uses.
Described oral colon targeting preparation is oral colon-target tablet, oral colon-target capsule, oral colon-target pill, oral colon-target capsule specifically.
The oral colon targeting preparation of described treatment ulcerative colitis contains 18 seed amino acids, is benchmark with crude drug weight, and total amino acids content is not less than and connects.
The present invention also provides the preparation method of the oral colon targeting preparation of this treatment ulcerative colitis, and it comprises following steps:
A, preparation contain the semi-finished product of periplaneta americana (Peripleneta americana (Linnaeus)) extract
B, a step gained semi-finished product and acceptable accessories or complementary composition are prepared into oral colon targeting preparation.
Wherein the concrete steps of a are:
I, get periplaneta americana and add alcohol reflux, filter filtrate for later use
Ii, with the filtrate defat that the i step obtains, be condensed into extractum, drying, semi-finished product
Used concentration of alcohol is 70%～90% in the step I.
Oral colon-target capsule pH wherein of the present invention relies on the concrete preparation method of preparation: get the semi-finished product powder, add equivalent starch and a small amount of Pulvis Talci and sodium carboxymethyl cellulose mixing, by general ball prepared micropill, get the plain ball of medicine of the present invention; Preparation contains acrylic resin III or EUDRAGIT S100 and triethyl citrate ethanol coating solution, makes 18%, 40 ℃ of oven dry of micropill weightening finish, and micropill divides encapsulated, promptly gets colon target medicine pH of the present invention and relies on capsule.
Oral colon-target capsule enzyme of the present invention relies on the concrete preparation method of preparation: get semi-finished product extractum, add equivalent starch and a small amount of Pulvis Talci and sodium carboxymethyl cellulose mixing, by general ball prepared micropill, get the plain ball of medicine of the present invention; The pectin and HPMC mixing coating adjuvant that will contain HPMC25% are mixed with 5% water coating solution; Spray into coating solution and carry out coating, make 110%, 40 ℃ of oven dry of micropill weightening finish, micropill divides encapsulated, promptly gets colon target medicine enzyme of the present invention and relies on capsule.
The present invention also provides the purposes of said preparation compositions in the medicine of preparation treatment ulcerative colitis.
Preparation of the present invention has promoting blood circulation, nourishing yin and promoting granulation, anti-inflammation detumescence, improves local microcirculation, promotes revascularization, promotes that slough comes off, promotes effects such as granulation tissue hyperplasia and epithelial growth, treatment dominant mechanism is to utilize colonic mucosa, enteraden potential function, the antibacterial on eliminating enteric cavity and the intestinal mucosa and toxin, the noxious substance of generation thereof, local coloclysis is easy to absorb the body utility, reaches therapeutical effect.
Oral colon targeting preparation of the present invention has dosage form novelty, medicine and directly is positioned target area (colon), make the target area drug level be higher than other normal structure, reduce systemic side effects, and taking convenience, dose is littler, material base is clear and definite, curative effect is more remarkable.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
Example 1 pH relies on the screening of preparation coating adjuvant
Get periplaneta americana, add alcohol reflux three times, determining alcohol 70% ~ 90%, merge extractive liquid,, defat, drying gets medicine dry powder.Add appropriate amount of starch and Pulvis Talci, sodium carboxymethyl cellulose, agitation procedure prepares micropill, gets plain ball; Getting the EUDRAGIT S100 of different proportionings and triethyl citrate is dissolved in 95% ethanol and makes coating solution and carry out coating.The spray coating sprays into coating solution with 4g/ minute speed micropill is carried out coating, whiff pressure 0.8kg/cm at the bottom of the fluid bed
2, 34 ℃ of inlet temperature, drying is 2 hours in 40 ℃ of baking ovens, and micropill is encapsulated, gets finished product.
| EUDRAGIT S100: triethyl citrate (g: g) | Coating weightening finish (%) | |
| 1 2 3 4 5 6 | 8∶1 8∶1 10∶1 10∶1 12∶1 12∶1 | 12 18 12 18 12 18 |
Second method is carried out the release evaluation to above sample in the employing pharmacopeia appendix XC dissolution method, i.e. the oar method; Dissolution medium: simulated gastric fluid (0.1mol/l hydrochloric acid solution) 750ml, simulated intestinal fluid (phosphate buffer of pH6.8) 1000ml, artificial colonic fluid (phosphate buffers of pH.7.8～8.0) 900ml; Rotating speed of agitator: 150rpm; Temperature: 37 ± 0.5 ℃.
The segmented intestine targeted capsule of preparation drops in the cup, puts into simulated gastric fluid respectively, and the 5ml that takes a sample after 2 hours (adding the dissolution medium of equivalent simultaneously) crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.Add 0.2mol/L sodium radio-phosphate,P-32 solution 250ml, regulate pH=6.8, the 5ml that takes a sample after 4 hours (adding the dissolution medium of equivalent simultaneously) crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.The dissolution fluid that inclines adds the artificial colonic fluid of 900ml, respectively at the 5ml (adding the dissolution medium of equivalent simultaneously) that takes a sample after 1,2 hour, crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.
Measurement result:
Concrete measurement result sees the following form:
The external total release percentage of segmented intestine targeted capsule total amino acids (%)
| Release medium | 1 | 2 | 3 | 4 | 5 | 6 |
| The artificial colonic fluid (behind the 2h) of the artificial colonic fluid (behind the 1h) of simulated gastric fluid (behind the 2h) simulated intestinal fluid (behind the 4h) | 0 18.6 86.5 99.9 | 0 15.3 85.0 100 | 0 12.8 81.3 99.8 | 0 7.3 76.8 100 | 0 13.2 81.6 99.7 | 0 12.1 88.4 100 |
The result shows: aminoacid only discharges 7.3% of total amount behind sample 4 process simulated gastric fluids, the simulated intestinal fluid; After 1 hour, the burst size of total amino acids reaches 76.8% to Swertia Tablet in artificial colonic fluid, and after 2 hours, medicine discharges fully substantially in colonic fluid, and so the conlon targeting best results is this coating proportioning the best.
Example 2 enzymes rely on the screening of preparation coating adjuvant
Get periplaneta americana, add alcohol reflux three times, determining alcohol 70% ~ 90%, merge extractive liquid,, defat, drying gets medicine dry powder.Add appropriate amount of starch and Pulvis Talci, sodium carboxymethyl cellulose, agitation procedure prepares micropill, gets plain ball; Get the pectin of different proportionings and HPMC 5% the coating solution of making soluble in water and carry out coating.The spray coating sprays into coating solution with the speed of 30ml/h and micropill is carried out coating, whiff pressure 1kg/cm at the bottom of the fluid bed
2, 70 ℃ of inlet temperature make micropill weightening finish certain proportion, and drying is 3 hours in 40 ℃ of baking ovens, and micropill is encapsulated, gets finished product.
| HPMC accounts for the proportion (g/g) of adjuvant | Coating weightening finish (%) | |
| 1 2 3 4 5 6 7 8 9 | 15％ 15％ 15％ 25％ 25％ 25％ 35％ 35％ 35％ | 60 90 110 60 90 110 60 90 110 |
Second method is carried out the release evaluation to above sample in the employing pharmacopeia appendix XC dissolution method, i.e. the oar method; Dissolution medium: simulated gastric fluid (0.1mol/l hydrochloric acid solution) 750ml, simulated intestinal fluid (phosphate buffer of pH6.8) 1000ml, artificial colonic fluid (phosphate buffers of pH.7.8～8.0) 900ml, and pectase solution (pH 4); Rotating speed of agitator: 150rpm; Temperature: 37 ± 0.5 ℃.
The segmented intestine targeted capsule of preparation drops in the cup, puts into simulated gastric fluid respectively, and the 5ml that takes a sample after 2 hours (adding the dissolution medium of equivalent simultaneously) crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.Add 0.2mol/L sodium radio-phosphate,P-32 solution 250ml, regulate pH=6.8, the 5ml that takes a sample after 4 hours (adding the dissolution medium of equivalent simultaneously) crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.The dissolution fluid that inclines adds the artificial colonic fluid of 900ml, and the 5ml that took a sample after 1 hour (adding the dissolution medium of equivalent simultaneously) crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.The dissolution fluid that inclines adds 900ml pectase solution (pH 4), respectively at the 5ml (adding the dissolution medium of equivalent simultaneously) that takes a sample after 1,2 hour, crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.
Measurement result:
Concrete measurement result sees the following form:
The external total release percentage of segmented intestine targeted capsule total amino acids (%)
| Release medium | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
| Artificial colonic fluid (behind the 1h) pectase solution (behind the 1h) the pectase solution (behind the 2h) of simulated gastric fluid (behind the 2h) simulated intestinal fluid (behind the 4h) | 5.6 38.6 44.9 95.6 100 | 1.8 36.5 43.6 98.6 100 | 1.3 30.5 46.3 99.8 100 | 0.9 19.5 32.7 96.6 100 | 0.8 15.4 21.8 90.7 100 | 0.2 9.7 15.6 86.2 98.9 | 2.6 26.7 38.4 91.4 99.6 | 2.1 20.6 34.9 89.7 97.2 | 1.9 20.1 33.5 86.8 96.3 |
The result shows: aminoacid only discharges 9.7% of total amount behind sample 6 process simulated gastric fluids, the simulated intestinal fluid; Swertia Tablet in artificial colonic fluid after 1 hour, the burst size 15.6% of total amino acids, add enzyme after drug release rapid, after 2 hours, medicine discharges fully substantially, so the conlon targeting best results is this coating proportioning the best.
Example 3 oral colon-target capsules preparation techniques
Get periplaneta americana 1000g, add alcohol reflux three times, determining alcohol 70% ~ 90%, merge extractive liquid,, defat, drying gets medicine dry powder 178g.Add starch 178g, Pulvis Talci 5g, sodium carboxymethyl cellulose 5g, agitation procedure prepares micropill, gets plain ball 330g; Get 100g acrylic resin III or EUDRAGIT S100, triethyl citrate 10g adds 95% ethanol to 1250g, gets coating solution.The spray coating sprays into coating solution with 4g/ minute speed micropill is carried out coating, whiff pressure 0.8kg/cm at the bottom of the fluid bed
2, 34 ℃ of inlet temperature make micropill weightening finish 18%, and drying is 2 hours in 40 ℃ of baking ovens, and micropill is encapsulated, gets finished product.
Specification: the 0.42g/ grain, every is equivalent to crude drug 1g.
Example 4 oral colon-target capsules preparation techniques
Get periplaneta americana 1000g, add alcohol reflux three times, determining alcohol 70% ~ 90%, merge extractive liquid,, defat, drying gets medicine dry powder 181g.Add starch 181g, Pulvis Talci 5g, sodium carboxymethyl cellulose 5g, agitation procedure prepares micropill, gets plain ball 330g; Get pectin 75g, HPMC25g, compound concentration are 5% water coating solution.The spray coating sprays into coating solution with the speed of 30ml/h and micropill is carried out coating, whiff pressure 1kg/cm at the bottom of the fluid bed
2, 70 ℃ of inlet temperature make micropill weightening finish 110%, and drying is 3 hours in 40 ℃ of baking ovens, and micropill is encapsulated, gets finished product.
Specification: the 0.43g/ grain, every is equivalent to crude drug 0.667g.
Example 5 oral colon-target tablet producing technologies
Get periplaneta americana 1000g, add alcohol reflux three times, determining alcohol 70% ~ 90%, merge extractive liquid,, defat, drying gets medicine dry powder 164g.Add starch 295g, Pulvis Talci 5g, sodium carboxymethyl cellulose 5g presses tablet general technology pelletizing press sheet, gets 938 of plain sheets; Get 100g acrylic resin III or EUDRAGIT S100, triethyl citrate 10g adds 95% ethanol to 1250g, gets coating solution.The coating pan coating sprays into the speed of coating solution with 5g/min, and the coating pan rotating speed is 20r/min, and inlet temperature is 70 ℃, and leaving air temp is 30～35 ℃, makes tablet weightening finish 12% promptly get segmented intestine targeted.
Specification: the 0.58g/ sheet, every is equivalent to crude drug 1g.
Example 6 oral colon-target tablet producing technologies
Get periplaneta americana 1000g, add alcohol reflux three times, determining alcohol 70% ~ 90%, merge extractive liquid,, defat, drying gets medicine dry powder 173g.Add starch 192g, Pulvis Talci 5g, sodium carboxymethyl cellulose 5g press technology pelletizing press sheet as the tablet, must plain sheet 1000; Get pectin 75g, HPMC25g, compound concentration are 5% water coating solution.The coating pan coating sprays into the speed of coating solution with 30ml/h, and the coating pan rotating speed is 25r/min, and inlet temperature is 70 ℃, and leaving air temp is 30～35 ℃, makes tablet weightening finish 100% promptly get segmented intestine targeted.
Specification: the 0.6g/ sheet, every is equivalent to crude drug 0.667g.
Example 7 oral colon-target pill preparation technologies
Get periplaneta americana 1000g, add alcohol reflux three times, determining alcohol 70% ~ 90%, merge extractive liquid,, defat, drying gets medicine dry powder 171g.Add starch 171g, Pulvis Talci 5g, sodium carboxymethyl cellulose 5g, agitation procedure prepares micropill, gets plain ball 342g; Get 100g acrylic resin III or EUDRAGIT S100, triethyl citrate 10g adds 95% ethanol to 1250g, gets coating solution.The coating pan coating sprays into the speed of coating solution with 5g/min, and the coating pan rotating speed is 26r/min, and inlet temperature is 70 ℃, and leaving air temp is 30～35 ℃, makes pill weightening finish 15%, promptly gets the oral colon-target pill.
Specification: the 2g/15 ball, every ball contains crude drug 0.32g.
Example 8 oral colon-target pill preparation technologies
Get periplaneta americana 1000g, add alcohol reflux three times, determining alcohol 70% ~ 90%, merge extractive liquid,, defat, drying gets medicine dry powder 180g.Add starch 180g, Pulvis Talci 5g, sodium carboxymethyl cellulose 5g, agitation procedure prepares micropill, gets plain ball 360g; Get pectin 75g, HPMC25g, compound concentration are 5% water coating solution.The coating pan coating sprays into the speed of coating solution with 30ml/h, and the coating pan rotating speed is 28r/min, and inlet temperature is 70 ℃, and leaving air temp is 30～35 ℃, makes pill weightening finish 100%, promptly gets the oral colon-target pill.
Specification: the 2g/15 ball, every ball contains crude drug 0.21g.
Below be example explanation quality of the pharmaceutical preparations control method of the present invention with example 3 prepared capsule preparations
Example 9 examples 3 quality of the pharmaceutical preparations control methods
1, qualitative identification
The preparation of reference substance solution: get glycine and alanine 0.005g respectively, put in the 5ml volumetric flask, use 75% dissolve with ethanol, be settled to scale.
The preparation of sample solution: take out capsule 's content, pulverize, get the 0.1g powder, add 75% ethanol 2ml dissolving, filter, get filtrate.
Developing solvent: n-butyl alcohol: formic acid: water (75: 15: 10)
Lamellae: silica gel G plate
Expansion mode: pre-equilibration 15 minutes; Ascending development; Exhibition distance: 10 ~ 13cm
Colour developing: 0.5% 1,2,3-indantrione monohydrate acetone soln
Chromatograph identification: daylight is inspected the visible speckle in the relevant position after the colour developing down.
2, assay:
American-cockroach-extract contains several amino acids.Primary standard adopts determined by ultraviolet spectrophotometry total amino acids content.The present invention uses automatic amino acid analyzer that each main aminoacid and total amino acids content are measured
2.1 instrument
The 835-50 of Hitachi type automatic amino acid analyzer
2.2 analysis condition
Ion exchange column: 2.6mm * 150mm
Visible light detector wavelength: 570nm; 440nm (Pro, Hypro)
Mobile phase: the buffer that citric acid and citric acid are received
Flow velocity: post pump: 0.225ml/min
1,2,3-indantrione monohydrate pump: 0.3ml/min
2.3 sample preparation
With the sample pulverize, accurately take by weighing the about 100mg of sample powder, add 6mol/L hydrochloric acid and put in the 15ml peace bottle, the vacuum sealing tube acid hydrolysis places 110 ℃ of baking oven hydrolysis 24 hours.The cooling back moves in the 25ml measuring bottle, and is diluted to scale with 6mol/L hydrochloric acid.Boil off hydrochloric acid then,, use for test with the dissolving with hydrochloric acid of 0.02mol/L.
2.4 assay method
Accurately draw 0.200ml kilnitamin standard, be diluted to 5ml with the buffer of pH2.2, measure the aminoacid standard of usefulness as last machine, the usefulness automatic amino acid analyzer is with the amino acid content of external standard method working sample liquid.Measurement result sees Table:
The segmented intestine targeted capsule amino acid content of table 1 periplaneta americana is measured (%)
| Aminoacid | Content |
| Asparatate threonine serine glutamic acid glycine alanine cystine valine methionine isoleucine leucine tyrosine phenylalanine arginine lysine histidine amino proline acid total amount | 0.27 0.25 0.34 0.52 1.10 1.93 0.26 1.66 1.04 0.36 0.60 0.22 0.31 0.28 0.03 1.01 0.61 1.79 |
Below prove beneficial effect of the present invention by the pharmacodynamics contrast test.
The pharmacodynamics contrast test of experimental example 1 medicine different modes of administration of the present invention
1, laboratory animal: SD rat, male and female half and half, body weight 200～250g;
2, the modeling method of the animal model of ulcerative colitis: with the laboratory animal fasting after 24 hours, the emptying stool, use the etherization animal, adopting internal diameter is that the tube for transfusion of 3mm is that 30% alcoholic solution 0.6ml of 33.33mg/ml trinitro-benzene-sulfonic acid imports apart from anus 8cm place with concentration, make animal keep lying low, clear-headed naturally.
3, experimental program: drug extract is mixed with contains the prescription three days that primary filling stomach gives tentatively to work out, modeling in the 4th day, successive administration is seven days again, put to death animal on the 8th day, take from the above 8cm colon of anus, vertical profile is opened, with contents such as ice normal saline flush away enteral feces, use 10% formaldehyde fixed, paraffin embedding, the 4 μ m that cut into slices, HE dyeing, light microscopic is observed pathological changes such as colonic ulcer, inflammation situation, the pathological changes degree of depth and fibrosis down, to represent that colonic pathological change and medicine are to its influence;
4, grouping situation: be divided into model group, positive controls, be subjected to reagent thing group, each 10 of every treated animals.
Be subjected to the reagent thing: the aqueous solution that contains crude drug 1g/ml
Model group gives the normal saline of same amount every day except that modeling;
Positive controls gives 0.3g sulfasalazine/kg (sulfasalazine tablet, Hainan Hong Hui pharmaceutical Co. Ltd, lot number: 030101) every day except that modeling;
Be subjected to reagent thing group except that modeling, give medicine decocting liquid of the present invention every day, dosage is 0.66ml/kg;
Experimental result sees the following form:
The different modes of administration experimental result
| Group | The ulcer situation | The inflammation situation | The pathological changes degree of depth | Fibrosis | |||||||||
| Do not have | ＜3mm | ＞3mm | Do not have | Gently | Heavy | Do not have | Under the mucosa | The flesh layer | Serous coat | Do not have | Gently | Heavy | |
| I II III IV | 1 6 5 8 | 2 4 ★ 2 2 ★★ | 7 - 3 - | 1 7 5 8 | 2 2 2 2 ★★ | 7 1 ★ 3 - | 1 7 4 9 | 2 3 ★ 3 1 ★★ | 2 - 3 - | 5 - - - | 1 7 5 8 | 4 2 3 2 ★★ | 5 1 ★ 2 - |
Annotate: I is a model group, and the positive matched group of II, III are the gastric infusion group, and IV is a coloclysis administration group, compares with model group:
★P＜0.05
★ ★P＜0.01.
The result shows, gastric infusion has and can reduce colonic ulcer, alleviates its inflammation, reduces the trend of its pathological changes degree of depth and fibrosis; And the more every index of coloclysis administration group and model group has significant difference, and therapeutic effect is better than gastric infusion.
The pharmacodynamics contrast experiment of experimental example 2 colon target medicine preparations of the present invention and common oral preparation
1, the modeling method of laboratory animal, Animal Model of Ulcerative Colitis is with experimental example 1;
2, grouping situation: be divided into model group, positive controls, ordinary preparation administration group, colon targeting drug administration group 1, each 10 of colon targeting drug administration group 2, every treated animals;
3, experimental program: directly the medicine piller is filled in the rat stomach except that administering mode adopts, all the other are with experimental example 1;
4, dosage regimen: model group gives the normal saline of same amount every day except that modeling;
Positive controls gives 0.3g sulfasalazine/kg (sulfasalazine tablet, Hainan Hong Hui pharmaceutical Co. Ltd, lot number: 030101) every day except that modeling;
Ordinary preparation administration group, give common drug preparation from stomach every day, and dosage is counted 0.66g/kg by crude drug:
Colon targeting preparation administration group is pressed the preparation of example 3 methods, and give colon targeting preparation from stomach every day, and dosage is counted 0.66g/kg by crude drug.
Experimental result sees the following form:
Ordinary preparation and colon targeting preparation drug effect contrast and experiment
| Group | The ulcer situation | The inflammation situation | The pathological changes degree of depth | Fibrosis | |||||||||
| Do not have | ＜3mm | ＞3mm | Do not have | Gently | Heavy | Do not have | Under the mucosa | The flesh layer | Serous coat | Do not have | Gently | Heavy | |
| I II III IV | 0 7 4 9 | 4 3 4 1 ★★ | 6 0 ★ 2 - | 0 6 5 9 | 3 4 3 1 ★★ | 7 0 ★ 2 - | 0 7 4 9 | 2 3 1 1 ★★ | 4 0 5 - | 4 0 ★ - - | 0 6 5 9 | 4 4 2 1 ★★ | 6 0 ★ 3 - |
Annotate: I is a model group, and the positive matched group of II, III are ordinary preparation administration group, and IV is the colon targeting drug administration group, compares with model group:
★P＜0.05
★ ★P＜0.01.
The result shows: behind medicine ordinary preparation of the present invention, the colon targeting preparation drug treatment, every index and model group more all improve, colon targeting preparation better effects if wherein, and every index and model group relatively have utmost point significant difference.
Below be the superiority of example explanation colon targeting preparation of the present invention with segmented intestine targeted capsule preparations in the example 3.
The inside and outside release of experimental example 3 colon targeting preparation targeting is estimated
1, colon targeting preparation release in vitro degree test of the present invention
1.1 release in vitro degree condition determination
Adopt second method, i.e. oar method in the pharmacopeia appendix XC dissolution method; Dissolution medium: simulated gastric fluid (0.1mol/l hydrochloric acid solution) 750ml, simulated intestinal fluid (phosphate buffer of pH6.8) 1000ml, artificial colonic fluid (phosphate buffers of pH.7.8～8.0) 900ml; Rotating speed of agitator: 150rpm; Temperature: 37 ± 0.5 ℃.
1.2 release in vitro degree content assaying method:
Selecting total amino acids for use is index, adopts automatic amino acid analyzer to measure.
1.3 the release in vitro degree is measured:
The segmented intestine targeted capsule of example 3 preparations is dropped in the cup, put into simulated gastric fluid respectively, the 5ml that takes a sample after 2 hours (adding the dissolution medium of equivalent simultaneously) crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.Add 0.2mol/L sodium radio-phosphate,P-32 solution 250ml, regulate pH=6.8, the 5ml that takes a sample after 4 hours (adding the dissolution medium of equivalent simultaneously) crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.The dissolution fluid that inclines adds the artificial colonic fluid of 900ml, respectively at the 5ml (adding the dissolution medium of equivalent simultaneously) that takes a sample after 1,2 hour, crosses 0.46 μ m micro-filtration membrane, and sample introduction is measured.
1.4 measurement result:
Concrete measurement result sees the following form:
The external total release percentage of segmented intestine targeted capsule total amino acids (%)
| Release medium | 1 | 2 | 3 | 4 | 5 | 6 | Meansigma methods |
| The artificial colonic fluid (behind the 2h) of the artificial colonic fluid (behind the 1h) of simulated gastric fluid (behind the 2h) simulated intestinal fluid (behind the 4h) | 0 8.9 79.5 99.9 | 0 9.3 85.0 100 | 0 7.6 81.3 99.8 | 0 7.3 76.8 100 | 0 8.2 81.6 99.7 | 0 10.1 88.4 100 | 0 8.6 85.5 99.9 |
The result shows: colon target medicine capsule of the present invention only discharges 8.6% of total amount through aminoacid behind simulated gastric fluid, the simulated intestinal fluid; After 1 hour, the burst size of total amino acids reaches 85.5% to Swertia Tablet in artificial colonic fluid, and after 2 hours, medicine discharges substantially fully in colonic fluid.
1.5 conclusion:
Show that by above-mentioned experimental result said preparation is in the external purpose that can reach good segmented intestine targeted release.
2. release research in the body
2.1 be subjected to the reagent thing
The medicinal barium sulfate micropill that wraps identical clothing layer is encapsulated.
2.2 test method
Test and took 3g Folium Sennae decocting liquid in preceding 12 hours, waiting diarrhoea to empty the intestine after, take 5 of barium sulfate capsules, every 0.5～1 hour, observing position and the disintegrate situation of barium sulfate capsule in intestinal on the X-ray machine.
2.3 subjects
Adult normally each 3 people of men and women volunteer experimenter of gastrointestinal function.
2.4 result of the test
Concrete experimental result sees the following form:
Discharge the result in the colon target medicine capsule body of the present invention
| Experimenter's sequence number | Gastric emptying time (h) | The small intestinal transhipment time (h) | Arrive the ileocecus time (h) | The disintegrate position | Disintegration time (h) |
| 1 2 3 4 5 6 | 1.0 1.5 1.0 1.5 2.0 0.5 | 2.5 4.0 3.5 2.5 2.5 3.5 | 3.5 5.5 4.5 3.5 4.5 4.5 | Ascending colon ileocecus ascending colon ascending colon ascending colon ileocecus | 1.0 1.5 2.5 2.0 1.5 1.5 |
As can be seen from the above table: there are big individual variation in gastric emptying time 0.5～2.0h of each experimenter, small intestinal transhipment time 2.5～4.0h, arrival ileocecus time 3.5～5.5h; The release position of medicine is not subjected to the influence of gastrointestinal tract transhipment time difference, begins all to concentrate on ileocecus disintegrate release the release after having an example to reach ascending colon; Be subjected to the disintegration time of reagent thing more stable between Different Individual, concentrate on 1.0～2.5h.
2.5 conclusion
Can reach a conclusion from the in vivo test result: this pharmaceutical preparation can reach the purpose of colon targeting drug administration.
By the explanation of above-mentioned effect experiment, oral colon targeting preparation treatment ulcerative colitis of the present invention can significantly reduce colonic ulcer, alleviates its inflammation, reduce the trend of its pathological changes degree of depth and fibrosis, has curative effect preferably.Select colon target medicine preparation of the present invention administration, better effects if, selection, use by the targeting preparation adjuvant have reached the targeting effect, and taking convenience, dose is little, material base is clear and definite, determined curative effect.
Claims (11)
1, a kind of oral colon targeting preparation for the treatment of ulcerative colitis is characterized in that it is the oral colon targeting preparation that the adjuvant by extract that contains periplaneta americana (Peripleneta americana (Linnaeus)) and pharmaceutically acceptable colon targeting preparation is mixed and made into.
2, according to the oral colon targeting preparation of the described treatment ulcerative colitis of claim 1, it is characterized in that the adjuvant of described pharmaceutically acceptable colon targeting preparation is: the mixture of any one or a few in acrylic resin III or EUDRAGIT S100, triethyl citrate, pectin, the hydroxypropyl emthylcellulose (HPMC).
3, according to the oral colon targeting preparation of the described treatment ulcerative colitis of claim 2, the adjuvant that it is characterized in that described pharmaceutically acceptable colon targeting preparation is: acrylic resin III or EUDRAGIT S100, triethyl citrate, the weight ratio scope of wherein mixing use is: 20: 1～2: 1.
4, according to the oral colon targeting preparation of the described treatment ulcerative colitis of claim 2, the adjuvant that it is characterized in that described pharmaceutically acceptable colon targeting preparation is: pectin, hydroxypropyl emthylcellulose (HPMC), the weight content that wherein mixes HPMC in the use is 10% ~ 90%.
5,, it is characterized in that described oral colon targeting preparation is oral colon-target tablet, oral colon-target capsule, oral colon-target pill according to the oral colon targeting preparation of the described treatment ulcerative colitis of claim 1.
6,, it is characterized in that described oral colon targeting preparation is the oral colon-target capsule according to the oral colon targeting preparation of the described treatment ulcerative colitis of claim 5.
7, according to the oral colon targeting preparation of claim 5,6 described treatment ulcerative colitiss, it is characterized in that it contains 18 seed amino acids, be benchmark with crude drug weight, total amino acids content is not less than 0.1mg/g.
8, the preparation method of the oral colon targeting preparation of the described treatment ulcerative colitis of claim 1, it comprises following steps:
A, preparation contain the semi-finished product of periplaneta americana (Peripleneta americana (Linnaeus)) extract
B, a step gained semi-finished product and acceptable accessories or complementary composition are prepared into oral colon targeting preparation.
9, according to the preparation method of the oral colon targeting preparation of right 8 described treatment ulcerative colitiss, it is characterized in that the concrete steps of step a are:
I, get periplaneta americana and add alcohol reflux, filter filtrate for later use
Ii, with the filtrate defat that the i step obtains, be condensed into extractum, semi-finished product.
10, according to the preparation method of the oral colon targeting preparation of right 9 described treatment ulcerative colitiss, it is characterized in that concentration of alcohol used in the concrete steps of step a is 70%～90%.
11, the application of each described oral colon targeting preparation of claim 1～7 in preparation treatment ulcerative colitis medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100208072A CN1853655A (en) | 2005-04-28 | 2005-04-28 | Oral colon target preparation for treating colitis ulcerativa and its making method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100208072A CN1853655A (en) | 2005-04-28 | 2005-04-28 | Oral colon target preparation for treating colitis ulcerativa and its making method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1853655A true CN1853655A (en) | 2006-11-01 |
Family
ID=37194309
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005100208072A Pending CN1853655A (en) | 2005-04-28 | 2005-04-28 | Oral colon target preparation for treating colitis ulcerativa and its making method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1853655A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784214A (en) * | 2014-12-21 | 2015-07-22 | 昆明赛诺制药有限公司 | A periplaneta americana extract micropore osmotic pump tablet and a preparing method thereof |
| WO2018086550A1 (en) * | 2016-11-11 | 2018-05-17 | 南京希尔寿生物科技有限公司 | Biological active component colon-targeted composition and application thereof |
| CN109718252A (en) * | 2017-10-25 | 2019-05-07 | 浙江京新药业股份有限公司 | American-cockroach-extract treats and prevents the application in chemotherapy cause intestinal mucosa inflammation drug in preparation |
| CN111374962A (en) * | 2018-12-28 | 2020-07-07 | 内蒙古京新药业有限公司 | Enteric coated preparation of periplaneta americana extract and preparation method thereof |
-
2005
- 2005-04-28 CN CNA2005100208072A patent/CN1853655A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784214A (en) * | 2014-12-21 | 2015-07-22 | 昆明赛诺制药有限公司 | A periplaneta americana extract micropore osmotic pump tablet and a preparing method thereof |
| CN104784214B (en) * | 2014-12-21 | 2019-05-31 | 昆明赛诺制药股份有限公司 | A kind of American-cockroach-extract micro hole seep irrigation and preparation method thereof |
| WO2018086550A1 (en) * | 2016-11-11 | 2018-05-17 | 南京希尔寿生物科技有限公司 | Biological active component colon-targeted composition and application thereof |
| US11337926B2 (en) | 2016-11-11 | 2022-05-24 | Nanjing Healsoul Life Science And Technology Co., Ltd. | Colon-targeted composition of biological active component and application thereof |
| CN109718252A (en) * | 2017-10-25 | 2019-05-07 | 浙江京新药业股份有限公司 | American-cockroach-extract treats and prevents the application in chemotherapy cause intestinal mucosa inflammation drug in preparation |
| CN111374962A (en) * | 2018-12-28 | 2020-07-07 | 内蒙古京新药业有限公司 | Enteric coated preparation of periplaneta americana extract and preparation method thereof |
| CN111374962B (en) * | 2018-12-28 | 2022-08-23 | 内蒙古京新药业有限公司 | Enteric coated preparation of periplaneta americana extract and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6656316B2 (en) | How to use cucumbers, how to use cucumbers extract and how to use drug mixtures | |
| CN1566124A (en) | Cornel extract and use thereof | |
| CN1939298A (en) | Schuqindin sulfate solid and target preparation and their making method | |
| JP6389958B2 (en) | Medicinal use of anti-tumor for rutile pentacyclic triterpene saponins | |
| CN1853655A (en) | Oral colon target preparation for treating colitis ulcerativa and its making method | |
| JP2012509909A (en) | Five crystal forms of nicosamide compound, its production method and its drug combination and use | |
| CN1316990C (en) | Chinese medicinal composition, preparation method and quality control method thereof | |
| CN1709341A (en) | Medicinal composition for nourishing qi to invigorate spleen, and its preparing method and use | |
| WO2019134159A1 (en) | Rectal mucosal administration preparation of pulsatilla chinensis (bge.) regel saponin b4 and preparation method therefor | |
| CN1305512C (en) | Traditional Chinese medicine compound recipe for treating hyperplasia of mammary glands and preparation method thereof | |
| CN111840425A (en) | Traditional Chinese medicine composition for treating diabetic nephropathy and application thereof | |
| CN1582952A (en) | Use of asiaticoside in preparation of medicines for diseases of cardio-cerebral blood vessels | |
| CN1682969A (en) | Medicinal composition and its preparing method and quality control method | |
| CN1810284A (en) | Yunnan Rhizoma Paridis extract and its prepn, medicinal use and medicine composition | |
| CN1323662C (en) | Pharmaceutical composition containing ambroxol and erdosteine or acetylcysteine and application thereof | |
| CN1120708C (en) | Medicine prepared from bolostemmatoside B for preventing and curing tumor | |
| CN105147709A (en) | Novel application of tenofovir disoproxil fumarate or medicinal salt thereof | |
| CN1202832C (en) | High-activity ginkgo leaf extract preparation and application | |
| CN107865828B (en) | Oral colon positioning preparation for preventing and treating colon cancer metastasis, preparation method and application thereof | |
| CN1281238C (en) | External-applied medicine for treating terminal neuritis and preparation thereof | |
| CN1965879A (en) | Chinese medicinal effective parts for treating nasal inflammation and preparation process thereof | |
| CN1660865A (en) | Saponin compound, general saponin of cynanchum bunaei and application in medication for treating disease of gstrointestinal tract | |
| CN110833550B (en) | Application of pyrazolopyrimidine derivative in treatment of liver injury caused by acute pancreatitis | |
| CN101190245B (en) | Medicine for treating chronic gastritis | |
| CN1754554A (en) | Traditional Chinese medicine compositions |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Qiu Xuelan Document name: the First Notification of an Office Action |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20061101 |