CN1155837A - Pharmaceutical compositions containing triclosan or derivatives thereof and EDTA or EGTA - Google Patents
Pharmaceutical compositions containing triclosan or derivatives thereof and EDTA or EGTA Download PDFInfo
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- CN1155837A CN1155837A CN 95194683 CN95194683A CN1155837A CN 1155837 A CN1155837 A CN 1155837A CN 95194683 CN95194683 CN 95194683 CN 95194683 A CN95194683 A CN 95194683A CN 1155837 A CN1155837 A CN 1155837A
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Abstract
A pharmaceutical composition in oral unit dosage form for the treatment of gastrointestinal disorders associated with Helicobacter pylori infestions wherein each unit comprises from 0.1 to 300 mg of triclosan or a derivative thereof, or an amount of an ester of triclosan or a derivative thereof, a cationic salt of an ester of triclosan or a derivative thereof, or a cationic salt of triclosan or a derivative thereof, to provide 0.1 to 300 mg of triclosan or a derivative thereof, and from 1 to 600 mg of EDTA or a salt thereof, or from 1 to 3600 mg of EGTA or a salt thereof, the weight ratio of triclosan to the EDTA or a salt thereof in each unit being in the range of from 1:2 to 1:60, or the weight ratio of triclosan to the EGTA or a salt thereof in each unit being in the range of from 1:10 to 1:500.
Description
The present invention relates to pharmaceutical composition, more specifically say, relate to the pharmaceutical composition that is used for the treatment of the gastrointestinal disease relevant with Helicobacter pylori infection.
Helicobacter pylori (being called pylorus in the past becomes the curved bar bacterium or be C.pylori) is a kind of spiral helicine gram-negative micro-organism, and it lives in the lower floor of gastric mucus layer.Some research shows, gets in touch between gastritis, duodenal ulcer and/or the gastric cancer that exists helicobacter pylori and histology to confirm in the mucosa of stomach.
Once the someone thought, this microorganism is a kind of pathogen, and it can cause multiple different gastropathy, or relevant with multiple different gastropathy, and gastritis, gastric ulcer, duodenal ulcer and gastric cancer are arranged specifically.The summary document of relevant this problem is seen Mike's nguktrum (C.A.M.McNulty) in the prior art: " infect and learn magazine " (J.Infection), 1986,13,107-113; Gourde(G) literary composition (C.S.Goodwin) etc.: at " clinical pathology magazine " (J.Clin.Phthol.), 1986,39,353-365 and European gastropathy research group are at " lancet " (Lancet) 1993,341, the article of delivering among the 1359-1362.
Once propose many different therapeutic schemes and treated the infection of helicobacter pylori.The EP-A-0206626 of Marshall (Marshall) and EP-A-0206627 have narrated use bismuth salt, and Marshall (Manshall) EP-A-0206625 and POLO younger brother (Borody) WO-A-86/05981 have narrated bismuth and together make and be used for treating helicobacter pylori with single antibiotics of planting.Yet, use bismuth that helicobacter pylori is shown lower (30～70%) initial clearance rate separately, in back 12 months infection and recurrence rate of treatment near 100%.Bismuth uses with single antibiotics (as amoxicillin) of planting, aspect the short-term mitigation symptoms, show more effective, understand now, bismuth usually uses with single kind antibiotics can't eradicate infection, and higher repeated infection rate is arranged, see Rauns, people such as Erik.A.D " (gastroenterology " (Gastroenterology), 1988, the article of 94:33-40.It is that first antibacterial and second antibacterial use together that WO-A-89/03219 (Borody) has narrated with bismuth.This therapeutic scheme is not only complicated but also expensive, but still unacceptable high relapse rate is arranged.
Second kind of combinational therapeutic methods is to use blocking histamine-H
2The secretion inhibitor agent of receptor, EP-A-0282132 and EP-A-0282131 Procktor (Procter) and sweet primary (Gamble) have narrated H
2Antagonist uses with the antibacterial that bismuth or inhibition pylorus become the curved bar bacterium.This method still can cause having higher recurrent rate, also can cause each treatment target is produced undesirable side effects.
Narrated the use bacteriocin among (Smithkline Beecham) WO-A-92/18143 of Bi Chang,, randomly taken with the slow release thing as nisin, Gramicidin or Tyrothricin.
Narrated the medicine that uses triclosan preparation treatment and the relevant gastrointestinal disease of Helicobacter pylori infection among Lie Jite (Rcckitt) and (Colman) GB-A-2243549.
Bi Chang (Smithkline Beecham) WO-A-92/18111 has narrated and has used various antibacterial to treat helicobacter pylori, and this antibacterial can be chosen wantonly with chelating agen or surfactant and use.Recommendation is used for including triclosan in the antibacterial that chelating agen or surfactant use, but does not all provide special explanation or embodiment to any such compositions.
Although so many suggestions have been arranged in prior art, have still needed more efficiently compositions for the treatment gastrointestinal disease relevant with Helicobacter pylori infection.
We are surprised to find that at present, if with triclosan and ethylenediaminetetraacetic acid (EDTA) or derivatives thereof or its salt, or ethylene glycol bis [beta-aminoethyl ether]-N, N, N ', N '-tetraacethyl (EGTA) or derivatives thereof or its salt are taken simultaneously together, can obviously strengthen the former and treat the activity of Helicobacter pylori infection when dose is in prescribed limit.
Therefore, the invention provides a kind of pharmaceutical composition that is used for the treatment of the oral dosage form of the gastrointestinal disease relevant with Helicobacter pylori infection, wherein each unit contains 0.1～300mg, more preferably 0.1～200mg, 0.1～100mg triclosan or derivatives thereof most preferably, or the ester or derivatives thereof of a certain amount of triclosan, the cationic salts of triclosan ester or derivatives thereof, or the cationic salts of triclosan or derivatives thereof, so that 0.1～300mg triclosan or described its derivant and 1～600mg are provided, preferred 1～200mg EDTA or its salt, or 1～3600mg, preferred 1～1200mg EGTA or its salt, the weight ratio of triclosan and EDTA or its salt is 1: 2～1: 60 in each unit, and perhaps the weight ratio of triclosan and EGTA or its salt is 1: 10～1: 500 in each unit.
In GB-A-1022744, GB-A-1024022 and GB-A-1038185, narrated triclosan (be 2-hydroxyl-4,2 ', 4 '-trichloro biphenyl ether) various prescriptions.
Term used herein " triclosan or derivatives thereof " means and comprises the triclosan ester or derivatives thereof that uses doses, the cationic salts of triclosan ester or derivatives thereof or the cationic salts of triclosan or derivatives thereof, and they all will provide triclosan or its described derivant of dose,equivalent.
The example of the triclosan ester or derivatives thereof ester of Shi Yonging is phosphate ester, phosphonate ester, sulfuric ester, glucosiduronate, succinate and glutamate in the present invention.Particularly preferred phosphate ester be as shown in the formula phosphate ester:
In the formula, R
1And R
2Be hydrogen or pharmaceutically acceptable cation, n is zero or 1～3 integer.Can use in the prior art known method to make the triclosan or derivatives thereof carry out phosphorylated and prepare its phosphate ester.
This ester can exist with the form of its cationic salts, for example sodium salt, potassium salt, calcium salt or magnesium salt.
Also can use the cationic salts of triclosan in the present invention, such as sodium salt or potassium salt.
The derivant of operable triclosan also comprises following chemical compound in the present invention, wherein on phenyl ring except having the chlorine substituent, also can replace on one or two phenyl by one or more substituent groups.The substituent example that is suitable for is the alkyl that contains 1～4 carbon atom, the haloalkyl that contains 1～4 carbon atom, the alkoxyl that contains 1～4 carbon atom, cyano group, pi-allyl, amino and acetyl group.Preferred substituted is methyl, methoxyl group and trifluoromethyl.Should be appreciated that if triclosan has more than a substituent group, these substituent groups can be identical or different so.
The term of Shi Yonging " triclosan derivant " means the analog that also comprises triclosan in this article, such as at the chemical compound described in the GB-1024022 with following structure:
P is 1～5 integer in the formula, and Hal is a halogen atom, when p greater than 1 the time, halogen atom can be identical or different; And some chemical compounds accordingly, contain one or several on one of them or two phenyl ring and be selected from following substituent group: contain the alkyl of 1～4 carbon atom, the haloalkyl that contains 1～4 carbon atom, the alkoxyl that contains 1～4 carbon atom, cyano group, alkyl, amino and acetyl group.Disclosed GB-A-1024022 is quoted at this as a reference.
In pharmaceutical composition of the present invention, triclosan is most preferred effective ingredient.
Pharmaceutical composition of the present invention preferably contains 1～60mg in each unit, 2～45mg more preferably, and more preferably 2.5～30mg, preferred again 2.5～25mg most preferably is the triclosan or derivatives thereof of 5～15mg.Pharmaceutical composition of the present invention preferably contains 1～150mg in each unit, preferred 5～100mg, more preferably 10～100mg, preferred again 15～75mg, the most preferably EDTA of 25～50mg or its salt, the weight ratio of triclosan or derivatives thereof and EDTA is in the limit of above-mentioned definition.If pharmaceutical composition of the present invention contains EGTA or its salt, in each unit, preferably contain 40～800mg so, more preferably 100～600mg, most preferably 200～400mg EGTA or its salt, the weight ratio of triclosan or derivatives thereof and EGTA is in the limit of above-mentioned definition.In compositions of the present invention, preferably that the triclosan or derivatives thereof is compatible with the EDTA that is tetrasodium salt, disodium salt, two calcium salts, disodium-calcium salt or di-potassium form.This salt can be hydrate.
Wherein the weight ratio of triclosan or derivatives thereof and EDTA or its salt is 1: 2～1: 60 the present composition, perhaps wherein the weight ratio of triclosan or derivatives thereof and EGTA or its salt is that 1: 10～1: 500 the present composition all demonstrates amazing and unexpected synergism, this effect be the professional of prior art from any data about triclosan or derivatives thereof treatment and helicobacter pylori diseases related, perhaps from use EDTA or the knowledge of EGTA, do not expected as chelating agen the pharmaceutical composition.
The weight ratio of triclosan or derivatives thereof and EDTA or its salt is preferably 1: 3～1: 40 scope, more preferably 1: 5～1: 10 scope.
The weight ratio of triclosan or derivatives thereof and EGTA or its salt is preferably 1: 25～1: 300 scope, more preferably in 1: 40～1: 80 scope.
Should be appreciated that effective oral dose of the present composition will depend on the order of severity of needs treatment disease.Medicining times also will depend on the order of severity and the reaction to treating thereof of disease.This peroral dosage form administration in general a day 3 times.
Pharmaceutical composition of the present invention is to be suitable for oral form, generally is tablet or capsule, or powder, granule or be packaged in spheroid in the medicine bag, or solution or suspension liquor, and the unit dose of this moment generally should contain 5～20ml liquid formulations.
Being granular pharmaceutical composition of the present invention can be by the method preparation of standard, such as wet method or dry granulation (dry pressing).They can be effervescents, perhaps are non-effervescents, treat to mix to do drink-service with an amount of water.They also can be the granules that can chew clothes.
The pharmaceutical composition of the present invention that is spheroid can prepare by the following method.Triclosan or derivatives thereof, EDTA or EGTA and carrier (as microcrystalline Cellulose) are added that any other excipient mixes with the water of q.s to form " mouldable " moistening block.This block is squeezed into all even isometric cylinder of diameter.With balling machine this extrudate is rolled into sphere, is preferably in the fluidized bed dryer dry then.
Be pulverous pharmaceutical composition of the present invention, can be by triclosan or derivatives thereof, EDTA or EGTA and one or more pharmaceutically acceptable excipient (for example extender/diluent) be carried out mixed getting.
The pharmaceutical composition of the present invention that is tablet can be by preparing such as standard methods such as granulation or direct compressions.They can be cushioned and be effervescent tablets, perhaps non-effervescent tablet, and comprise tabletting adjuvant well known in the prior art, as lubricant (for example magnesium stearate) or disintegrating agent (as sodium starch glycolate).
The pharmaceutical composition of the present invention that is capsule; can prepare by standard method; for example pack in hard gelatin capsule powder, granule or spheroid perhaps add triclosan or derivatives thereof and EDTA or EGTA in fused pharmaceutically acceptable excipient, incapsulate then.
The pharmaceutical composition of the present invention that is solution or suspension liquor can pass through each composition and suitable mixed the getting of liquid (as water).In general, liquid formulations can provide 5～20m1 unit dose.It also can contain common pharmaceutically acceptable excipient, as suspending agent or buffer system.In addition, in order to protect the not reason microorganism and corruption is preferably in and wherein also contains antiseptic of this pharmaceutical composition, for example and with methyl parahydroxybenzoate and propyl ester.
Pharmaceutical composition of the present invention if needed also can contain one or more coloring agent, sweeting agent or flavouring agent.The present composition also can contain antacid.The antacid that is suitable for comprises sodium bicarbonate, calcium carbonate, aluminium hydroxide and their mixture.Use these materials, particularly sodium bicarbonate also can cause under the fluid composition viscosity will, therefore when the easy pouring liquid preparation of design, need carry out viscosity control to a certain degree.
In another aspect of this invention, this pharmaceutical composition can be mixed with the stomach slow releasing composition, it can prolong the time of staying at gastric, and continues to discharge the triclosan or derivatives thereof during this period.In this respect, said composition can be prepared, make it produce buoyant alginate floating thing under one's belt, perhaps make sticking to mould sticker coated granules or sphere with method well known in the prior art.
Can mucoadhesive coated granules or sphere be arranged with following method preparation: make earlier granule or the sphere that contains triclosan or derivatives thereof and EDTA/EGTA as mentioned above, they are carried out coating with one or more known mucoadhesive polymer (as carboxymethyl cellulose, sodium carboxymethyl cellulose, carbopol, polymerization parent Organic substance material (polycarbophil), tragakanta, sodium alginate or potassium alginate, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl emthylcellulose, Pelvetia siliquosa Tseng et C. F. Chang polysaccharide or chitosan).Can carry out coating with any traditional technology (for example spraying coating).In case after coating and the drying, just granule or spheroid can be packed into medicine bag or gelatine capsule, if used the sufficiently solid fine coating that adheres to, so just can be repressed to form tablet.In addition, when the present composition is tablet, in tablet matrix, can include the mucoadhesive polymer.
The preferred in the present invention mucoadhesive polymer that uses is the carbopol of narrating in British Pharmacopoeia and American National formulary, and this is a kind of crosslinked acrylate copolymer of synthetic high polymer amount that contains 56～68% carboxylic acid groups.The British Pharmacopoeia regulation is crosslinked with allyl sucrose.In for oral administration and external medicine preparation, carbopol is used as suspending agent with the form of neutral gel.
The example of the commerical grade carbopol that is suitable for is the product of being sold by B.F.Goodrich company, and commodity are called Carbopol 910,934,934P, 940,941,971P, 974P, 980,981 and 1342.The molecular weight of these carbopol is about 750,000～4,000,000.Other example has the Junlon PW110 of Nihon Junyaku company, Junlon PW150 and Junlon PW111, and the Acrisint 400 of Italian Sigma company (Sigma).The private-use class carbopol that the present invention preferably uses is Carbopol 934P and 974P.
The compositions that produces the floating thing of buoyant alginate under one's belt of carrying out compatibility as tablet, powder or granule is the solid single dose, or is liquid form.
In the solid single dose form, the stomach slow releasing composition of the present invention that contains alginate is except containing the triclosan or derivatives thereof and EDTA/EGTA of narrating scope in the above, usually also contain 200～600mg alginic acid and/or its salt, particular certain cancers, potassium salt or magnesium salt; 50～250mg sodium carbonate or potassium, or bicarbonate are chosen wantonly and are contained the calcium carbonate until 100mg.Said composition also can contain the film-making excipient of standard well known in the prior art, as solubility filler, binding agent, lubricant and flavouring agent.Can produce tablet with standardization program, for example direct compression or first with wet method or dry granulation, tabletting then.
In liquid dosage form, the stomach slow releasing composition of the present invention that contains alginate generally contains 0.1～2% (w/v) triclosan or derivatives thereof; 0.2～4% (w/v) EDTA or its salt, perhaps 1～35% (w/v) EGTA or its salt; 1～8% (w/v) sodium alginate or potassium alginate; 1.3～6.5% (w/v) sodium carbonate or potassium carbonate, or bicarbonate; 0.5～4% calcium carbonate and randomly contain 0.3～1.7% (w/v) suspending agent, preferred carbopol, the ratio of triclosan or derivatives thereof and EDTA or EGTA is within above-mentioned scope.Described fluid composition also can contain standard excipients commonly known in the art, for example antiseptic, flavouring agent and coloring agent.The liquid that contains alginate can make by will all compositions except carbopol being dispersed in the water.If the use carbopol, it will add in the above-mentioned dispersion liquid as the water slurry that neutralized.
When above-mentioned alginate compositions when contacting with the acid condition of stomach under the normal condition, carbonate or bicarbonate generation effervescent so, this makes the floating structure that is formed by alginate loose, the result swims on the gastric content it.
Further specify the present invention with reference to following embodiment.
Embodiment 1
Use (Reeves based on people such as Li Wosi, D., Phillip, I., Williams, J.D. and Wise, R): " (laboratory method of antibiotic chemistry therapy " (Laboratory Methods inAntimierobial Chemotherapy), (London Churchill Livingstone publishing house version in 1978) described method is measured the external activity of the various compositionss of triclosan, EDTA disodium salt dihydrate and triclosan/EDTA disodium salt dihydrate to different helicobacter pylori bacterial strains.
Minimal inhibitory concentration (MIC) with each compositions of agar dilution technical measurement.The definition of MIC is in this concentration (mg/1) following 10
5Individual visible bacterium colony only is less than 1 antibacterial after cultivating.
Obtain helicobacter pylori bacterial strain NCTC 11637,11916,12384,12386,12455 and 12823 by National Collection of Type Cultures (London).Helicobacter pylori bacterial strain HP34 is the clinical isolates that obtains from the living tissue of taking out when doing splanchnoscopy from the patient in Nottingham medical college queen medical centre.Helicobacter pylori bacterial strain Chapman, Brown, Ahmed, 4467 and Calder also be the clinical isolates that living tissue that patient from the Harmer Randy Smyth hospital in London takes out when doing splanchnoscopy obtains.
The glandular cell spirillum (Helicobacter) of puncturing is the strain of spirillum, and it can cause the gastritis of cheetah (acinonyx).
Description preparation according to manufacturer contains the inferior blood agar (OXOID, Britain) of 5% horse blood taxi driver brother rival, and prepares the serial dilution sample of each test compounds or compositions with it.Be distributed on the plate with the inoculum of multiple spot inoculator with 1～5 μ l, it is fixed that its consumption comes according to the contact area of experimental compound or compositions and each pylori strain culture.Various pylori inoculation things can be pressed method preparation: scrape the culture inoculation circle of 2 10 μ l from the plate of each bacterial strain, this culture is suspended in again in the 600 μ l tryptone soy broth (TSB-Difco, the U.S.) again.
The little aerobic environment that is produced by the gas bag that provides at Bake Dun Dijinxun company limited (Becton Dickinson Limited) is provided plate, cultivated 3 days at 37 ℃.Each test is all carried out with double.
Below table 1 expression only with triclosan, with EDTA disodium salt dihydrate and contain the EDTA disodium salt dihydrate of 0.05mM, 0.125mM or 0.20mM and the compositions of the triclosan of various variable concentrations to helicobacter pylori bacterial strain test for data, glandular cell's spirillum bacterial strain that punctures is organized in contrast.
Table 1
| Microorganism | EDTA(E) mg/l | Triclosan (T) (mg/l) | E?19mg/l ＋(T) | E?47mg/l ＋(T) | E?76mg/l ＋(T) |
| Helicobacter pylori HP34 | 186 | 2 | 0.5 | 0.25 | 0.25 |
| Helicobacter pylori NCTC11637 | 93 | 0.25 | ＜0.06 | ＜0.03 | ＜0.01 |
| Helicobacter pylori NCTC11916 | 93 | 0.25 | ＜0.06 | ＜0.03 | ＜0.01 |
| Helicobacter pylori NCTC12386 | 47 | 0.25 | ＜0.06 | ＜0.03 | ＜0.01 |
| Helicobacter pylori NCTC12823 | 93 | 0.5 | 0.25 | 0.125 | ＜0.01 |
| Helicobacter pylori NCTC12455 | 93 | 0.25 | ＜0.06 | ＜0.06 | ＜0.01 |
| Helicobacter pylori NCTC12384 | 93 | 0.5 | ＜0.06 | ＜0.06 | ＜0.01 |
| Brown | 93 | 0.5 | 0.5 | 0.25 | ＜0.01 |
| Ahmed | 93 | 4.0 | 0.25 | 0.06 | ＜0.01 |
| 4467 | 93 | 0.5 | ＞1 | 0.5 | ＜0.01 |
| Calder | 93 | 4.0 | ＜0.06 | ＜0.06 | ＜0.01 |
| Glandular cell's pylori that punctures | 47 | 0.5 | 2.0 | 0.5 | ＜0.01 |
Embodiment 2
According to the general operation procedure of embodiment 1, the effect when measuring EDTA disodium salt dihydrate and triclosan, ampicillin and CPC and share with the agar dilution technology.Helicobacter pylori bacterial strain 12385 is to obtain from National Collection of Type Cultures (London).Working concentration is the EDTA disodium salt dihydrate (E) of 22mg/l in the research share at every turn.The results are shown in as in the following table 2.
Table 2
| Microorganism | Triclosan | Triclosan+E | Ampicillin | Ampicillin+E | CPC | CPC＋E |
| Helicobacter pylori NCTC11637 | ?0.125 | ?0.06 | ?0.125 | ?0.125 | 2.0 | 2.0 |
| Helicobacter pylori NCTC12385 | ?0.06 | ?0.005 | ?0.06 | ?0.01 | 1.0 | 0.5 |
| Helicobacter pylori NCTC12386 | ?0.125 | ?0.005 | ?0.06 | ?0.06 | 0.5 | 0.5 |
| Helicobacter pylori NCTC12455 | ?0.06 | ?0.005 | ?0.06 | ?1.0 | 1.0 | 0.5 |
| Helicobacter pylori NCTC12384 | ?0.125 | ?0.06 | ?0.125 | ?0.125 | ＜2.0 | 2.0 |
| Helicobacter pylori NCTC12823 | ?0.125 | ?0.005 | ?0.25 | ?0.25 | 1.0 | 0.5 |
No matter it should be noted that, be the influence of the low-concentration EDTA disodium salt dihydrate that do not added basically of ampicillin or CPC.
Embodiment 3
Carry out the research of inhibition zone so that measure the diffusance of triclosan/EDTA disodium salt dihydrate by the mucin bolt.In this experiment, the big more then inhibitory action to helicobacter pylori in inhibition zone is high more.
All research all uses the helicobacter pylori NCTC11638 that is obtained by National Collection of Type Cultures (London) to carry out.Having inoculated the cave that cuts out many 9mm diameters on the inferior blood agar plate of helicobacter pylori bacterial strain taxi driver brother rival in advance, in each cave, add the sterile solution of the hog gastric mucin (Sigma) of 5% (w/v) or 10% (w/v) purification, so that form bolt.The granule (10mg) that only contains the 0.25mg triclosan or contain 0.25mg triclosan/1.28mg EDTA disodium salt dihydrate is put on the mucin bolt surface, but does not contact agar.In order to produce the inhibition zone, reactive compound must diffuse through mucin.The results are shown in the following table 3.
Table 3
Inhibition zone diameter (mm)
| Granule | 5%w/v mucin bolt | 10%w/v mucin bolt |
| Triclosan | ??????26 | ??????26 |
| Triclosan+EDTA | ??????37 | ??????38 |
Embodiment 4
The inoculum that will contain helicobacter pylori NCTC11638 is added in the buffer solution that contains triclosan/EDTA disodium salt dihydrate.37 ℃ expose a period of time after, take out aliquot, in and active component, measure the microbe number of survival with the method for plate count.The result represents with the logarithm subtrahend between exposure period with following formula:
Microbicidel effect (ME)=Log N
c-N
t
N
c-no the colony-forming units that obtains by the matched group suspension
N
t-no the colony-forming units that obtains by test group suspension
Target is that microbicidel effect in 5 minutes is greater than 5 logarithm subtrahends.
Use above-mentioned technology to measure the effect of triclosan and EDTA disodium salt dihydrate and usefulness under typical stomach concentration 300mg/l and 1530mg/l respectively.(should be noted that the capacity of typical fasting descendant stomach is approximately 50ml).The results are shown among the following table 4A, by this table as can be seen, even after 5 minutes, just reached 5 logarithm subtrahends.
Table 4A
| Time (branch) | Matched group survival logarithm | Experimental group survival logarithm | The ME value |
| ????5 | ????7.2 | ????＜1.7 | ???＞5.5 |
| ????30 | ????7.1 | ????＜1.7 | ???＞5.4 |
| ????60 | ????5.9 | ????＜1.7 | ???＞4.2 |
| ????120 | ????4.9 | ????＜1.7 | ???＞3.2 |
Also detected in 5 minutes the concentration that produces the required triclosan/EDTA disodium salt dihydrate of 5 logarithm subtrahends, the result lists in following table 4B.
Table 4B
| Triclosan/EDTA mg/l | Matched group survival logarithm | Experimental group survival logarithm | The ME value |
| ???300/1530 | ????7.4 | ????＜1.7 | ????＞5.7 |
| ???200/1020 | ????7.4 | ????＜1.7 | ????＞5.7 |
| ???100/510 | ????7.4 | ????＜1.7 | ????＞5.7 |
| ???50/255 | ????7.4 | ????＜1.7 | ????＞5.7 |
| ???25/128 | ????7.4 | ????＜1.7 | ????＞5.7 |
| ???10/51 | ????7.4 | ????3.4 | ????4.0 |
Should be noted that, when every liter of concentration is low to moderate 25mg triclosan/128mg EDTA disodium salt dihydrate, can in 5 minutes, obtain 5 logarithm subtrahends.
Embodiment 5
Use technology as described in example 4 above, in 5 minute contact time, under various stomach concentration, measure pH value the also influence of the triclosan/EDTA disodium salt dihydrate effect of usefulness.
The results are shown in the following table 5.
Table 5
| ????pH | At [triclosan/Na 2EDTA mg/l] under the ME value | ||
| ????50/255 | ????100/510 | ????300/1530 | |
| ????4 | ????＞5.3 | ????＞5.3 | ????＞4.1 |
| ????5 | ????＞5.5 | ????＞5.5 | ????＞5.1 |
| ????7 | ????＞5.5 | ????＞5.5 | ????＞5.0 |
Embodiment 6
According to following formulation tablet: triclosan 150gEDTA disodium salt dihydrate 765g calcium carbonate 1000g microcrystalline Cellulose (Avicel PH101) 2705g magnesium stearate 30g sodium bicarbonate 200g
Sodium carbonate, EDTA disodium salt dihydrate and microcrystalline Cellulose are mixed, in this mixture, add the triclosan that is dissolved in isopropyl alcohol.In high-speed mixer, the mixture that obtains mixed be incorporated in the forced ventilation drying machine dry, by the sieve of 840 μ m.In mixture, add sodium bicarbonate and water then, in high-speed mixer with low amounts of water with this granulating mixture.In the thermopnore exsiccator,, by the sieve of 840 μ m, in granule, add magnesium stearate, and in drum mixer, mix then as the tabletting adjuvant with particle drying.Mixture is pressed into tablet, and every final weight is 470mg.Contain triclosan 15mg and EDTA disodium salt dihydrate 76.5mg in every.
Also can add other optional composition and prepare similar tablet, such as adding mucoadhesive polymer such as carbopol (in above-mentioned composition, for example adding 1000g), or tablet disintegrant, as sodium starch glycolate (in above-mentioned composition, for example adding 300g).
Embodiment 7
Prepare capsule by following each composition:
Triclosan 150g
EDTA disodium salt dihydrate 765g
Calcium carbonate 2000g
Polyethylene Glycol (400) 4356g
Water 229g
Each uniform ingredients must be mixed No. 0 also sealing of hard gelatin capsule of packing into, the heavy 750mg of capsule charge thing.Each capsule contains triclosan 15mg, EDTA disodium salt dihydrate 76.5mg.
Embodiment 8
According to the operational approach of embodiment 6, preparation contains triclosan 7.5mg and EDTA disodium salt dihydrate 38.25mg, or the such tablets of triclosan 3.75mg and EDTA disodium salt dihydrate 19.125mg.
Embodiment 9
Repeat embodiment 6, just replace EDTA with 4800g EGTA.Mixture is pressed into tablet, and every final weight is 888mg, contains triclosan 15mg and EGTA 400mg.
Embodiment 10
Repeat embodiment 7, just replace EDTA with 4800g EGTA.With mixture pack into No. 0 hard gelatin capsule and sealing, heavy 288mg, every capsules contains triclosan 3.75mg and EGTA 120mg.
Embodiment 11
According to the operational approach of embodiment 6, preparation contains triclosan 7.5mg, and EGTA240mg perhaps contains the such tablets of triclosan 3.75mg and EGTA 120mg.
Embodiment 12
Operational approach according to embodiment 6, preparation contains the such tablets of a certain amount of triclosan phosplate, make it that dosage that is equivalent to 7.5mg triclosan and 38.25mg EDTA disodium salt dihydrate is provided, perhaps be equivalent to the dosage of 3.75mg triclosan and 19.125mgEDTA disodium salt dihydrate.
Embodiment 13
According to the operational approach of embodiment 11, preparation contains the such tablets of a certain amount of triclosan phosplate, makes it provide the dosage that is equivalent to the 7.5mg triclosan to replace the 7.5mg triclosan.
Claims (21)
1. the pharmaceutical composition that is used for the treatment of the gastroenteropathy relevant with the oral dosage form with Helicobacter pylori infection, wherein each unit contains 0.1～300mg triclosan or derivatives thereof, or the triclosan ester or derivatives thereof of doses, or the cationic salts or derivatives thereof of triclosan ester, or the cationic salts or derivatives thereof of triclosan, they can provide and be equivalent to 0.1～300mg triclosan or derivatives thereof, and 1～600mg EDTA or its salt, perhaps 1～3600mg EGTA or its salt, the weight ratio of triclosan and EDTA or its salt is 1: 2～1: 60 in each unit, and perhaps the weight ratio of triclosan and EGTA or its salt is 1: 10～1: 500 in each unit.
2. pharmaceutical composition as claimed in claim 1, wherein the triclosan derivant is the form of its phosphate ester, phosphonate ester, sulfuric ester, glucosiduronate, succinate or glutamate.
3. pharmaceutical composition as claimed in claim 2, wherein phosphate ester is the chemical compound with following formula:
R wherein
1And R
2Be hydrogen or pharmaceutically acceptable cation, n is 0 or integer 1～3.
4. as pharmaceutical composition any in the claim 1～3, wherein each unit dose contains 0.1～100mg triclosan or derivatives thereof and 1～200mg EDTA or its salt, perhaps 1～1200mg EGTA or its salt.
5. any one pharmaceutical composition in each claim as described above, wherein each unit dose contains 2.5～25mg triclosan or derivatives thereof.
6. pharmaceutical composition as claimed in claim 5, wherein each unit dose contains 5～15mg triclosan or derivatives thereof.
7. any one pharmaceutical composition in each claim as described above, wherein each unit dose contains 10～100mg EDTA or its salt, perhaps 40～800mg EGTA or its salt.
8. pharmaceutical composition as claimed in claim 7, wherein each unit dose contains 15～75mgEDTA.
9. any one pharmaceutical composition in each claim as described above, wherein the weight ratio of triclosan or derivatives thereof and EDTA or its salt is 1: 3～1: 40, and perhaps the weight ratio of triclosan or derivatives thereof and EGTA or its salt is 1: 25～1: 300.
10. pharmaceutical composition as claimed in claim 9, wherein the weight ratio of triclosan or derivatives thereof and EDTA or its salt is 1: 5～1: 10.
11. any one pharmaceutical composition in each claim as described above, wherein said composition is tablet or capsule, or is packaged in powder, granule or sphere in the wafer.
12. as the pharmaceutical composition of any described liquid form in the claim 1～10, one of them unit dose is 5～20ml liquid preparation.
13. pharmaceutical composition as solid unit dose forms as described in the claim 1～11 any, it also includes the mucoadhesive polymer in addition, such as carboxymethyl cellulose, sodium carboxymethyl cellulose, carbopol, tragakanta, sodium alginate or potassium alginate, methylcellulose, hydroxyethyl-cellulose, poly(ethylene oxide), hydroxypropyl emthylcellulose, chondrus ocellatus Holmes polysaccharide, chitin or chitosan.
14. as the pharmaceutical composition of claim 13, mucoadhesive polymer wherein is a carbopol.
15. as the pharmaceutical composition of claim 13 or 14, it comprises graininess or spherical compositions with the mucoadhesive polymer coating.
16., in this tablet base material, contain the mucoadhesive polymer as tablet medicine compositions as described in claim 13 or 14.
17. pharmaceutical composition as stomach slow releasing composition as described in the claim 1～10 any.
18. pharmaceutical composition as solid unit dose forms as described in the claim 17, wherein each unit also comprises 200～600mg alginic acid and/or its sodium, potassium or magnesium salt, 50～250mg sodium carbonate or potassium carbonate, perhaps sodium bicarbonate or potassium bicarbonate also can be chosen wantonly and contain the calcium carbonate until 100mg.
19. as the compositions of liquid form as described in the claim 17, it contains 0.1～2% (w/v) triclosan or derivatives thereof; 0.2～4% (w/v) EDTA or its salt, or 1～35% (w/v) EGTA or its salt; 1～8% (w/v) sodium alginate or potassium alginate; 1.3～6.5% (w/v) sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate; 0.5～4% calcium carbonate and optional 0.3～1.7% (w/v) suspending agent that contains.
20. as the compositions of claim 19, suspending agent wherein is a carbopol.
21. any one compositions in every as described above claim, wherein the triclosan or derivatives thereof is exactly a triclosan.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95194683 CN1155837A (en) | 1994-06-29 | 1995-06-29 | Pharmaceutical compositions containing triclosan or derivatives thereof and EDTA or EGTA |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| WOPCT/GB95/00540 | 1995-03-13 | ||
| GB9413072.1 | 1995-03-13 | ||
| GB9505032.4 | 1995-03-13 | ||
| CN 95194683 CN1155837A (en) | 1994-06-29 | 1995-06-29 | Pharmaceutical compositions containing triclosan or derivatives thereof and EDTA or EGTA |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1155837A true CN1155837A (en) | 1997-07-30 |
Family
ID=5082802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95194683 Pending CN1155837A (en) | 1994-06-29 | 1995-06-29 | Pharmaceutical compositions containing triclosan or derivatives thereof and EDTA or EGTA |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1155837A (en) |
-
1995
- 1995-06-29 CN CN 95194683 patent/CN1155837A/en active Pending
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