CN1596878A - Oral medicine possessing colon orientation medicine releasing function - Google Patents
Oral medicine possessing colon orientation medicine releasing function Download PDFInfo
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- CN1596878A CN1596878A CN 200410040254 CN200410040254A CN1596878A CN 1596878 A CN1596878 A CN 1596878A CN 200410040254 CN200410040254 CN 200410040254 CN 200410040254 A CN200410040254 A CN 200410040254A CN 1596878 A CN1596878 A CN 1596878A
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Abstract
An orally taken medicine with the function of locating in colon and releasing medicine is composed of the core prepared from active medicine and pharmacologically acceptible auxiliary, the internal coated layer prepared from hydrophilic gel or water-expansive high-molecular material, and the external coated layer prepared from enteric high-molecular material.
Description
Technical field
The present invention relates to a kind of oral drugs, except that being specially adapted to, also applicable to the colon positioning release that contains other active drug composition with the colon positioning release of nitro glyoxaline antibiotic as the active drug composition with colon positioning release function.
Background technology
Metronidazole (Metronidazole), tinidazole (Tinidazole), ornidazole (Ornidazole), secnidazole nitro glyoxaline antibiotic derivatives such as (Secnidazole), in oxygen-free environment, be reduced into amino or the formation by free radical by the nitro in the molecule, interact with cell component, thereby cause the death of microorganism, can have good anaerobe resistant and anti-protoplasm (as infusorian etc.) infection effect, antimicrobial spectrum is wider, be widely used in treatment by anaerobe, ameba, the merchant infusorian, the various diseases that infection such as trichomonacide cause, especially colitis, the treatment of prevention infection and operation back anaerobe before the operation.Oral formulations commonly used has tablet, capsule, granule etc., and specification mostly is 0.25g.Because its The book of Changes gastrointestinal absorption, the period in a medicine patient stomach discomfort can occur, feels sick, headache, symptom such as drowsiness; When carrying out the disease treatment of colon position,, cause therapeutic effect not good, and the whole body toxic and side effects is bigger simultaneously owing to arrive colon fraction medicine amount seldom.
In the local disease that is used for the treatment of the colon position, be the whole body toxic and side effects that reduces even avoid medicine to cause because of oral absorption, or for reducing even avoiding medicine to degrade, improve bioavailability, the oral colon-specific drug release technology that can adopt existing report and use at gastrointestinal.According to the physiological and pathological feature of gastrointestinal tract and colon, present colon-specific drug delivery system mainly can be divided three classes:
(1) medicine-releasing system that utilizes time-lag effect to design: oral drugs arrive about 6 hours of the time of colon through stomach, small intestinal, it is so-called time lag, utilize suitable packaging technique control drug coating layer in the time lag time range, can not dissolve fully, the dissolving of clothing layer finishes after arriving colon, medicine begins to discharge, and this medicine-releasing system is a time lag type medicine-releasing system.Because the emptying time of small intestinal is comparatively constant, there is the research report to be about (3 ± 1) h; But because the emptying time of stomach is subjected to factor affecting such as food, age, individual physiological pathological characters obvious, individual variation is big, therefore adopts time lag type medicine-releasing system need carry out individual administration, be difficult to for suitability for industrialized production used.
(2) utilize the pH of gastrointestinal tract pH value difference design to rely on medicine-releasing system: according to the physiological feature of gastrointestinal tract pH value variation, the pH value that is common stomach is 0.9～1.5, small intestinal is 6.0～6.8, and colon is 6.5～7.5, and employing coated technology of dissolved macromolecular material under colon pH environment forms.The colon positioning release reliability of this medicine-releasing system is higher.Tinidazole colon positioning enteric soluble tablet and slow-releasing Metronidazole preparation for position of colon are provided as publication number respectively for the Chinese patent literature of CN1364462A and CN1398587A.But because colitis, especially patients of ulcerative colitis, the pH value at its colon place may calibration often reduce a 1-2 pH unit, when therefore adopting the pH dependent colon-specific drug delivery to treat colitis, its Release Performance instability, even may not release occur and cause treatment failure.
(3) utilize the triggering medicine-releasing system of the specific enzymes design that colonic microflora produces: utilize special azo reductase that colonic microflora produces, polyase, various glycosidase etc., act on coating material or blocker, make the macromolecular material degraded and discharge medicine.Because nitro glyoxaline antibiotic has a broad antifungal spectrum in case enter the colon release, will act on flora, enzyme produces and reduces, and causes release incomplete.
Summary of the invention
In view of the foregoing, for further improving the reliability of its conlon targeting, make medicine arrive lesions position and discharge rapidly, the performance therapeutical effect, to improve curative effect, to reduce toxic and side effects, the present invention will provide a kind of colon released Types of Medicine medicine that fully utilizes time-lag effect and gastrointestinal tract pH value difference.
Active drug composition in the said colon released Types of Medicine medicine of the present invention, except that being specially adapted to the above-mentioned nitro imidazole derivatives antibiotic that comprises metronidazole, tinidazole, ornidazole, secnidazole, also being applicable to other or also containing the colon released Types of Medicine medicine of other types active drug composition.
The present invention has the oral drugs of colon positioning release function, be to become medicated core with the auxiliary element mutual group that allows in active drug composition and the medicine to accept, it is coated with by at least a interior coatings that constitutes in hydrophilic gel or the imbibition type macromolecular material, and outermost layer is coated with the outer coatings layer of enteric solubility macromolecular material.
In the above-mentioned oral drugs with colon positioning release function, the auxiliary element that allows in the medicine that uses in the said medicated core to accept includes disintegrating agent and filler at least, and other complementary compositions can also have binding agent, lubricant etc.For example:
Disintegrating agent wherein can (molar substitution MS) be at least a in the low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium, dried starch, microcrystalline Cellulose of 0.2-0.4 for the molar substitution of hydroxypropyl; Serve as preferred wherein with low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium.The amount of disintegrating agent generally can be preferably 4%～8% for 1%～15% of medicated core weight.
Said filler can be in lactose, starch, microcrystalline Cellulose, dextrin, Icing Sugar, partially pregelatinized starch, Polyethylene Glycol, calcium hydrogen phosphate, the polyvinylpyrrolidone at least a; Wherein preferably lactose, microcrystalline Cellulose, partially pregelatinized starch and starch etc.The consumption of filler generally can be 10%～80%, preferred 25%～50% of medicine medicated core amount.
In other auxiliary elements that can also use, what said binding agent can be in starch, polyvinylpyrrolidone, syrup, hypromellose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, the hydroxyethylmethyl-cellulose etc. is at least a; But preferably polyethylene ketopyrrolidine wherein.The general concentration of binder dosage can be 5%～10%, is preferably 5%.
Said lubricant can be in Pulvis Talci, magnesium stearate, stearic acid, hydrogenated vegetable oil (as hydrogenated groundnut, hydrogenated cottonseed oil, hydrogenated coconut wet goods), Polyethylene Glycol, sodium lauryl sulphate, Stepanol MG, the micropowder silica gel etc. at least a; Preferred magnesium stearate wherein.The consumption of lubricant generally can be preferably 0.3%～1.0% for 0.1%～3% of medicated core weight.
In above-mentioned oral drugs with colon positioning release function, coatings hydrophilic gel or imbibition type macromolecular material in said can adopt the currently reported and methylcellulose that uses, carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, carbopol, polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone, poloxamer, natural or synthetic rubber, polysaccharide and as chitosan. at least a in its derivant such as alginate; Wherein preferably hypromellose, carbopol.The consumption of this coatings composition can be controlled in the 1.0%-50.0% of coating solution total amount, wherein is preferably 2%-20%.
Said outermost layer enteric solubility macromolecular material coatings can be selected at least a as in methacrylic acid-acrylate interpolymer constituents, polyvinyl acetate phthalic acid ester (PVAP), phthalic acid hypromellose ester (HMCP), succinic acid acetic acid hypromellose (HPMCAS), the cellulose acetate phthalate ester (CAP) for use.Wherein said methacrylic acid-acrylate interpolymer constituents can comprise as methacrylic acid/butyl acrylate (35/65) copolymer (trade name polyacrylic resin I number), methacrylic acid/methyl methacrylate (50/50) copolymer (trade name polyacrylic resin II number), methacrylic acid/methyl methacrylate (35/65) copolymer (trade name polyacrylic resin III number), the medicinal resin series of the Eudragit of Rohm company as Eudragit L, at least a among the Eudragit S etc., but preferable methyl acrylic acid-methacrylate copolymer (I number wherein, the II acrylic resin), polyvinyl acetate phthalic acid ester (PVAP), phthalic acid hypromellose ester (HPMCP), succinic acid acetic acid hypromellose (HPMCAS).The consumption of enteric solubility macromolecular material generally can be the 1.0%-50.0% of coating solution gross weight, wherein is preferably 2%-20%.
In addition, in above-mentioned coatings material, can also use in the usual way comprise be mainly used in the porogen of coatings and the plasticizer that mainly in outer enteric coat layer, uses, lubricant, opacifier etc. at other interior adjunct ingredients.For example, said porogen can comprise polymeric amino acid constituents, polyvinyl alcohol, polyethylene glycols, polyvinylpyrrolidone classes such as gelatin for comprising the polysaccharide composition of sucrose, sorbitol, mannitol, comprise at least a in the water soluble film-forming material of water soluble film-forming materials such as hypromellose, hydroxypropyl cellulose, methylcellulose.Wherein preferably polyethylene glycols and/or water soluble film-forming material.The consumption of porogen generally can be the 0%-30% of coating solution weight, is preferably 0%-10%.Constituents such as polyvinyl alcohol, Polyethylene Glycol and polyvinylpyrrolidone be need not too much restrictive requirement generally speaking.
Said plasticizer generally can be selected at least a in glycerol, propylene glycol, polyethylene glycols, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, last of the ten Heavenly stems dibutyl carboxylic acid, triethyl citrate, tributyl citrate, acetyl group triethyl citrate, acetyl group tributyl citrate, triglycerin acetate, the Semen Ricini wet goods composition.Wherein preferably diethyl phthalate, polyethylene glycols, triethyl citrate etc.Plasticizer dosage generally can be the 0%-30% of coating solution gross weight, wherein is preferably 0%-20%.
Said lubricant can be in the compositions such as Pulvis Talci commonly used, magnesium stearate, stearic acid, hydrogenated vegetable oil, Polyethylene Glycol, sodium lauryl sulphate, Stepanol MG, micropowder silica gel at least a.But preferably talc powder, magnesium stearate etc.The consumption of lubricant generally can be the 0%-30% of coating solution gross weight, is preferably 0%-20%.
Said opacifier can adopt titanium dioxide (titanium dioxide) the most commonly used, and consumption generally can be the 2%-30% of coating solution gross weight, is preferably 2.5%-15%.
The used solvent of preparation coating can be in the usual way, selects at least a as in the solvents commonly used such as water, ethanol, acetone, isopropyl alcohol, ethyl acetate, but preferred alcohol-water mixed solution wherein.Coating preparation technology can adopt usual manners such as comprising spray coating, pan coating, various automatizatioies coating or pressed coated.
Above-mentioned oral drugs with colon positioning release function of the present invention are by becoming medicated core with the auxiliary element mutual group that allows in active drug composition and the medicine to accept, being coated on its outer being made up of at least a interior coatings that constitutes in hydrophilic gel or the imbibition type macromolecular material and the outer coatings layer that is coated on outermost enteric solubility macromolecular material.By aforesaid positioning release medicine mechanism and process as can be known,, can suitably adjust the coatings thickness in the said medicine of the present invention, to reach satisfied and best release effect according to desirable release position.Result of the test shows that wherein making the weight of said interior coatings with employing is 2.0%～50.0% of medicated core weight, preferably can be 2%～25%; And/or the weight of outermost coatings is 1.0%～50.0% of medicated core weight, preferably can be at 2%～25% o'clock, can have the quick release function of ideal conlon targeting.
Said medicine of the present invention is to design according to the difference that fully utilizes time-lag effect and gastrointestinal tract pH value.The uniqueness of its colon released Department of Pharmacy system is, earlier will as active drug compositions such as nitro glyoxaline antibiotic and suitable adjunct ingredient be prepared in the colon medium release fast as medicated core such as label (plain sheet), ball core, granule, capsules, select hydrophilic gel or imbibition type film forming macromolecular material or the two to mix the coating membrane of forming again, to guarantee that medicine arrives site of action and discharges; The enteric film forming macromolecular material that adopts again that continues carries out coating, to guarantee medicine not release under one's belt.After this medicine oral administration, can disintegrate and release under gastric pH environment; Entering small intestinal under intestinal pH environment, the enteric coating film dissolves gradually, by regulating the thickness of the expanding layer that hydrophilic gel layer or expanding material form, make gel layer can wrap up label (plain sheet), ball core, granule, capsule all the time in the small intestinal section, medicine is not discharged at small intestinal; After entering colon; the gel layer corrosion finishes; label (plain sheet), ball core, granule or capsule Chinese medicine rapid release; concentrate and play a role in the colon position; to improve therapeutic effect; and reduce as nitro glyoxaline antibiotic etc. can be avoided the generation of bacterial drug resistance to the zest and/or the systemic toxic side effect of stomach generation.Colon locating administrated system compares with single pH dependent form, and this system's conlon targeting or targeting are higher, and selectable coating material is more, and the suitability is wider.The result of the test that the release in vitro degree of the above-mentioned colon positioning release medicine of the present invention is measured shows not disintegrate in the 0.1mol/L hydrochloric acid solution, not release; 2～4 hours outer enteric coating films dissolve gradually in the pH6.0 phosphate buffer, and the middle level suction forms gel layer, not release; Release is complete in 1 hour afterwards.
The dosage form that above-mentioned colon released medicine of the present invention can be suitable for includes tablet commonly used, small pieces, piller, granule, soft capsule and hard capsule etc.To comprise that nitro glyoxaline antibiotic such as metronidazole, tinidazole, ornidazole or secnidazole are that the colon released medicine of the present invention of active drug composition is an example, active constituent content in its unit label, ball core, granule, the capsule 's content generally can be 10mg～1000mg, serves as preferred with 100mg～500mg wherein.
Below in conjunction with by the specific embodiment shown in the drawings as embodiment, foregoing of the present invention is described in further detail again.Each routine medicine is the treatment that can be mainly used in prevention infection and operation back anaerobic infection before the colitis, colonic operation and with the colon released medicine of nitro imidazole derivatives antibiotic as the active drug composition.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made include within the scope of the invention.
Description of drawings
Fig. 1 is the release in vitro curve of the colon released tablet of ornidazole of the present invention.
Fig. 2 is a metronidazole colon positioning release piller release in vitro curve of the present invention.
The specific embodiment
The colon released tablet of embodiment 1 nitro glyoxaline antibiotic
Label forms label by effective ingredient, lactose, partially pregelatinized starch, carboxymethyl starch sodium, polyvinylpyrrolidone and the magnesium stearate of 250mg through wet granulation or direct compression.Dissolution test, this label in water, pH6.0 or pH7.5 phosphate buffer in the 1h medicine all can dissolve fully.
Selecting the low viscosity hypromellose for use is hydrogel coating macromolecular material, and PEG6000 is a porogen, is mixed with the solution that contains hypromellose 2%, carries out coating, increases weight to be 5.0% of label; Selecting I enteric acrylic resin again is that enteric macromolecular material, triethyl citrate are that plasticizer, titanium dioxide are that opacifier etc. is mixed with that to contain I enteric acrylic resin be 7% solution, carries out coating, and increasing weight is 10.0% of label.
Release in vitro degree measurement result shows, according to said method the colon released tablet of Zhi Bei metronidazole, tinidazole, ornidazole and secnidazole equals all not releases more than 2 hours in 1 the medium at pH, not release in 4 hours in pH5.0,6.0,6.5,6.8 phosphate buffers, drug release is complete in the 5th hour.Wherein the release in vitro degree measurement result of the colon released tablet of ornidazole is respectively as table 1 and shown in Figure 1.
The release in vitro degree measurement result of the colon released tablet of table 1 ornidazole
Release amount (%)
The medium time
1 2 3 4 5 6 Mean±SD
0.1mol/L hydrochloric acid solution＞2h clothing film is intact, not disintegrate of label
The phosphate buffer 2h of PH6.8～4h enteric coating film dissolves gradually, and the hydrophilic gel suction forms gel layer, not disintegrate of label
PH6.8 phosphate buffer 4h 15min 10.2 16.5 11.5 8.5 18.7 13.7 13.2 ± 3.9
After
30min 40.8 43.5 38.7 39.6 46.5 48.2 42.9±3.8
45min 79.7 82 83.6 78.4 74.2 80.6 79.8±3.3
60min 96.5 95.4 97.5 98.6 95.4 97.8 96.9±1.3
Embodiment 2 nitro glyoxaline antibiotic colon positioning release small pieces
The molding adjuvant of label comprises lactose, starch, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate etc., through the small pieces of granulating, tablet forming technique is made the about 3mm of diameter.Dissolution test, this label in water, pH6.0 or pH7.5 phosphate buffer in the 1h medicine all can dissolve fully.
Adopting the coating macromolecular material of embodiment 1 to carry out coating, is 7.0% when the hydrophilic gel layer increases weight, and the enteric coat layer weightening finish is 14.0% o'clock, and the release in vitro curve is with embodiment 1.
Embodiment 3 nitro glyoxaline antibiotic colon positioning release piller or granules
The ball core is by effective ingredient, partially pregelatinized starch, Icing Sugar, polyvinylpyrrolidone, (rotating speed is 20r/min through extruder, sieve aperture is 0.8～1.2mm) to extrude, extrudate put in the spheronizator that rotating speed is 950r/min roll 5min, the wet ball of balling-up is in 50 ℃ of dry 4h, get the ball core, every bag contains effective composition 500mg.Ball core dissolution test, this ball core in water, pH6.0 or pH7.5 phosphate buffer in the 1h medicine all can dissolve fully.
Selecting methylcellulose and carbopol for use is hydrogel coating macromolecular material, and hydroxypropyl cellulose is a porogen, is mixed with the solution that contains carbopol 5.0%, carries out coating, increases weight to be 10.0% of ball core; Selecting phthalic acid hypromellose ester (HPMCP) again is that plasticizer, titanium dioxide are that opacifier etc. is mixed with that to contain phthalic acid hypromellose ester (HPMCP) be 5.0% solution for enteric macromolecular material, triethyl citrate, carry out coating, increasing weight is 18.0% of ball core.
Release in vitro degree measurement result shows, according to said method Zhi Bei metronidazole, tinidazole, ornidazole and secnidazole colon positioning release piller equal all not releases more than 2 hours in 1 the medium at pH, not release in 4 hours in pH5.0,6.0,6.5,6.8 phosphate buffers, drug release is complete in the 5th hour.The release in vitro degree measurement result of the colon released tablet of metronidazole is respectively as table 2 and shown in Figure 2.
Table 2 metronidazole colon positioning release piller release in vitro degree measurement result
Release amount/%
The medium time
1 2 3 4 5 6 Mean±SD
0.1mol/L hydrochloric acid solution 2h clothing film is intact, not release
The phosphate buffer 4h enteric coating film of PH6.8 dissolves gradually, and the hydrophilic gel suction forms gel layer, not release
15min 15.4 17.5 14.8 13.6 18.7 14.5 15.8 ± 1.9 behind the PH6.8 phosphate buffer 4h
30min?45.7 48.6 46.2 44.6 49.8 45.5 46.7±2.0
45min?80.8 84.5 83.6 87.4 89.2 83.7 84.9±3.0
60min?98.5 99.4 100.4?97.5 98.5 97.4 98.6±1.1
The colon released Drug Capsule of embodiment 4 nitro glyoxaline antibiotic
With adjuvants such as effective ingredient 200mg and microcrystalline Cellulose, lactose, behind wet granulation, insert in the hard capsule; Or, be prepared into soft capsule with adjuvant effects such as effective ingredient and PEG.This capsule shells is made up of gelatin.This conventional capsule dissolution test, medicine all can dissolve fully in the 1h in water, pH6.0 or pH7.5 phosphate buffer.
Selecting Eudragit L outside capsule shells for use is that enteric-coating material, Oleum Ricini are plasticizer, are mixed with 8% solution, carries out coating, obtains colon released Drug Capsule when the coating weightening finish is 12.0%, and external release is identical with the release pattern of embodiment 1.
By above-mentioned table 1 and table 2; and the result of the test of Fig. 1 and Fig. 2 as seen; the oral drugs of the several formulations form that comprises tablet, small pieces, piller, granule or capsule for preparing by mode of the present invention; all can reach the satisfied quick release purpose of conlon targeting; improved the reliability of its conlon targeting; can discharge rapidly after making medicine arrive lesions position, the performance therapeutical effect helps the generation that improves curative effect and/or reduce toxic and side effects.
Claims (9)
1. the oral drugs that have the colon positioning release function, it is characterized in that becoming medicated core with the auxiliary element mutual group that allows in active drug composition and the medicine to accept, it is coated with by at least a interior coatings that constitutes in hydrophilic gel or the imbibition type macromolecular material, and outermost layer is coated with the outer coatings layer of enteric solubility macromolecular material.
2. the oral drugs with colon positioning release function as claimed in claim 1, the auxiliary element that allows in the medicine that it is characterized in that using in the said medicated core to accept includes disintegrating agent and filler at least.
3. the oral drugs with colon positioning release function as claimed in claim 2 is characterized in that said disintegrating agent is that molar substitution is at least a in the hydroxypropyl substituted cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, crosslinked carboxymethyl fecula sodium, dried starch, microcrystalline Cellulose of 0.2-0.4; Said filler is at least a in lactose, starch, microcrystalline Cellulose, dextrin, Icing Sugar, partially pregelatinized starch, Polyethylene Glycol, calcium hydrogen phosphate, the polyvinylpyrrolidone.
4. the oral drugs with colon positioning release function as claimed in claim 1, it is characterized in that said in coatings hydrophilic gel or imbibition type macromolecular material be at least a in methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hypromellose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, carbopol, polyvinyl alcohol, Polyethylene Glycol, polyvinylpyrrolidone, poloxamer, natural or synthetic rubber, polysaccharide and the derivant thereof.
5. the oral drugs with colon positioning release function as claimed in claim 1 is characterized in that said outermost layer enteric solubility macromolecular material coatings is at least a in methacrylic acid-acrylate interpolymer constituents, polyvinyl acetate phthalic acid ester, phthalic acid hypromellose ester, succinic acid acetic acid hypromellose, the cellulose acetate phthalate ester.
6. the oral drugs with colon positioning release function as claimed in claim 5, it is characterized in that methacrylic acid-acrylate interpolymer constituents in the said outermost layer enteric solubility macromolecular material coatings be methacrylic acid-methacrylate copolymer, methacrylic acid/butyl acrylate copolymer, methacrylic acid/and methylmethacrylate copolymer, the medicinal resin series of Eudragit at least a.
Oral drugs with colon positioning release function as claimed in claim 1 is characterized in that also including porogen, plasticizer, lubricant, opacifier in the said coatings material.
7. as the described oral drugs of one of claim 1 to 8, it is characterized in that the weight of said interior coatings is 2.0%～50.0% of medicated core weight with colon positioning release function.
8. as the described oral drugs with colon positioning release function of one of claim 1 to 8, the weight that it is characterized in that said outermost coatings is 1.0%～50.0% of medicated core weight.
9. as the described oral drugs of one of claim 1 to 8, it is characterized in that said active drug composition is the nitro imidazole derivatives that comprises metronidazole, tinidazole, ornidazole, secnidazole with colon positioning release function.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410040254 CN1596878A (en) | 2004-07-19 | 2004-07-19 | Oral medicine possessing colon orientation medicine releasing function |
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| CN 200410040254 CN1596878A (en) | 2004-07-19 | 2004-07-19 | Oral medicine possessing colon orientation medicine releasing function |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832695A (en) * | 2016-03-28 | 2016-08-10 | 祝云琴 | Tizol-series medicine capsule |
| CN107174572A (en) * | 2016-03-11 | 2017-09-19 | 天路药业有限公司 | The pharmaceutical composition delivered for colon-specific |
-
2004
- 2004-07-19 CN CN 200410040254 patent/CN1596878A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107174572A (en) * | 2016-03-11 | 2017-09-19 | 天路药业有限公司 | The pharmaceutical composition delivered for colon-specific |
| CN105832695A (en) * | 2016-03-28 | 2016-08-10 | 祝云琴 | Tizol-series medicine capsule |
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