PHARMACEUTICAL COMPOSITIONS CONTAINING TRICLOSAN OR DERIVATIVES
THEREOF AND EDTA OR EGTA
The present invention relates to pharmaceutical compositions and, in particular, to pharmaceutical compositions for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections. Helicobacter pylori (formerly Campylobacter pyloridis or C. pylori) is a spiral-shaped Gram negative microorganism which appears to live beneath the mucus layer of the stomach. An association between the presence of H. pylori in the gastric mucosa and histologically confirmed gastritis, duodenal ulceration and/or gastric cancer has been shown in several studies.
It has been suggested that the organism is a pathogen which causes or is implicated in a number of different gastric diseases and in particular gastritis, gastric ulcers, duodenal ulcers and gastric carcinoma. Reviews on the state of the art include those by C.A.M. McNulty in J. Infection. 1986, 3_3, 107-113, CS. Goodwin et al. in J. Clin. Pathol.. 1986, 3_9, 353-365 and the Eurogast Study Group, Lancet. 1993, 341. 1359-1362. A number of different treatment regimens have been proposed to treat Helicobacter pylori infections. EP-A-0206626 and EP-A-0206627 (Marshall) describe the use of bismuth salts whilst EP-A-0206625 (Marshall) and WO-A-86/05981 (Borody) describe the use of a combination of bismuth with a single antibiotic for the treatment of Helicobacter pylori. However, bismuth alone achieves low (30 to 70%) initial clearance rates for Helicobacter pylori and recurrence of the infection approaches 100% by twelve months post therapy. Bismuth together with a single antibiotic, namely amoxicillin, appears to be relatively effective as a short term means of reducing the symptoms but it is now clear that the use of bismuth
together with a single antibiotic frequently fails to eradicate the infection and has a high rate of reinfection (Rauwε, Erik A.D. et al. Gastroenterology, 1988, 94: 33-40) . WO-A-89/03219 (Borody) describes the use of a combination of bismuth, a first antimicrobial agent and a second antimicrobial agent. This treatment regimen is not only complicated and expensive but still has unacceptably high relapse rates.
A second approach to combination therapy uses histamine-H2 receptor blocking anti-secretary agents. EP-A-0282132 and EP-A-0282131 (Procter and Gamble) describe the use of H2 antagonists in combination with bismuth or Campylobacter inhibiting antimicrobial agents. This approach has still led to high relapse rates and may lead to many of the undesirable side effects of the individual treatment components.
WO-A-92/18143 (S ithKline Beecham) describes the use of a bacteriocin antimicrobial agent, such as nisin, gramicidin or tyrothricin, optionally co-administered with a release delaying substance.
GB-A-2243549 (Reckitt & Colman) describes the use of triclosan for the preparation of medicaments for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections. WO-A-92/18111 (SmithKline Beecham) describes the use of various antimicrobial agents for the treatment of Helicobacter pylori, the antimicrobial agent being optionally combined with a chelating agent or a surfactant. Triclosan is included amongst the list of antimicrobial agents which are suggested for use in combination with a chelating agent or a surfactant, but no specific teaching is given or exemplification provided of any such compositions.
Despite all of the prior art proposals there is still a need for a more effective composition for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections.
We have now surprisingly found that the activity of triclosan in the treatment of Helicobacter pylori infections is significantly enhanced if it is co-administered with ethylenediamine tetraacetic acid (EDTA) or a derivative or salt thereof, or ethylene glycol bis [β-aminoethyl ether]-N,N,N' ,N'-tetraacetic acid (EGTA) or a derivative or salt thereof, within specific ranges.
Accordingly, the present invention provides a pharmaceutical composition in oral unit dosage form for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections wherein each unit comprises from 0.1 to 300mg, more preferably 0.1 to 200mg, still more preferably 0.1 to lOOmg 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 the said derivative thereof, and from 1 to 600mg, preferably 1 to 200mg, of EDTA or a salt thereof, or from 1 to 3600mg, preferably 1 to 1200mg 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.
Triclosan (2-hydroxy- , 2' , 4 '-trichlorodiphenyl ether) is described in various formulations in GB-A-1022744, GB-A-1024022 and GB-A-1038185.
The term "triclosan or a derivative thereof" as used herein is intended to encompass the use of 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 which will provide the equivalent amount of triclosan or the said derivative thereof.
Examples of esters of triclosan or esters of the derivatives thereof for use in the present invention are the phosphate, phosphonate, sulfate, glucuronide, succinate and glutamate esters. Particularly preferred phosphate esters are the phosphate esters of the formula:
where R, and R2 are hydrogen or a pharmaceutically acceptable cation; and n is 0 or an integer of from 1 to 3. The phosphate esters may be prepared by the phosphorylation of triclosan or a derivative thereof, using methods well known in the art.
The esters may be present in the form of the cationic salts thereof, for example the sodium, potassium, calcium or magnesium salts.
The cationic salts of triclosan may also be used in the present invention, for example, the sodium or potassium salts.
Derivatives of triclosan which may be used in the present invention further include those compounds in which one or both of the phenyl groups is/are substituted by one or more substituent groups in addition to the chloro substituents already present on the phenyl rings. Examples of suitable substituents are alkyl groups containing 1 to 4 carbon atoms, haloalkyl groups containing 1 to 4 carbon atoms, alkoxy groups
. -
containing 1 to 4 carbon atoms, cyano, allyl, amino and acetyl groups. Preferred substituents are methyl, methoxy and trifluoromethyl groups. It will be understood that if triclosan is substituted by more than one substituent, then the substituents may be the same or different.
The term "derivatives of triclosan" as used herein is intended also to include the analogues of triclosan, for example those as described in GB-1024022 having the general formula:
where p is a whole number of from 1 to 5, Hal is a halogen atom and when p is greater than 1 the halogen atoms may be the same or different, and the corresponding compounds in which one or both of the benzene groups contain one or more substituent groups selected from alkyl groups containing from 1 to 4 carbon atoms, haloalkyl groups containing from 1 to 4 carbon atoms, alkoxy groups containing 1 to 4 carbon atoms, cyano, alkyl, amino and acetyl groups. The disclosure of GB-A-1024022 is incorporated herein by reference.
In the compositions according to the invention triclosan is the most preferred active ingredient.
The pharmaceutical compositions of the present invention preferably comprise, in each unit, triclosan or a derivative thereof in an amount of from 1 to 60mg, more preferably from 2 to 45mg, still more preferably from 2.5 to 30mg, yet more preferably from 2.5 to 25mg, and most preferably from 5 to 15mg. The pharmaceutical compositions of the present invention preferably comprise, in each unit, EDTA or a salt thereof in an amount of from 1 to 150mg, more preferably 5 to lOOmg,
still more preferably 10 to lOO g, yet more preferably 15 to 75mg, and even more preferably from 25 to 50mg, with the weight ratio of triclosan or a derivative thereof to EDTA being within the above-defined limits. Where the pharmaceutical compositions of the present invention comprise EGTA or a salt thereof they preferably comprise, in each unit, 40 to 800mg, more preferably 100 to 600mg, and still more preferably 200 to 400mg, with the weight ratio of triclosan or a derivative thereof to EGTA being within the above defined limits. The triclosan or a derivative thereof is preferably formulated in the compositions of the present invention with EDTA in the form of its tetra-sodium, di-sodium, di-calcium, disodium-calcium or dipotassium salt. The salts may be hydrated.
The compositions of the present invention in which the weight ratio of triclosan or a derivative thereof to EDTA or a salt thereof is within the range of from 1:2 to 1:60, or those compositions in which the weight ratio of triclosan or a derivative thereof to EGTA or a salt thereof is within the range of from 1:10 to 1:500, show a surprising and unexpected synergism which could not have been predicted by a person skilled in the art from any data relating to the effect of triclosan or its derivatives in the treatment of gastrointestinal disorders associated with Helicobacter pylori, or from a knowledge of the use in pharmaceutical compositions of EDTA or EGTA as a chelating agent.
The weight ratio of triclosan or a derivative thereof to EDTA or a salt thereof is preferably within the range of from 1:3 to 1:40, more preferably within the range of from 1:5 to 1:10.
The weight ratio of triclosan or a derivative thereof to EGTA or a salt thereof is preferably within the range of from 1:25 to 1:300, more preferably 1:40 to 1:80.
It will be understood that the effective oral dose of the compositions of the present invention will depend upon the severity of the condition which is to be treated. The frequency of the dosing regime will also depend upon the severity of the condition and its response to the treatment. Typically the oral dosage form will be taken up to three times a day.
The pharmaceutical compositions of the present invention are in a form suitable for oral administration and will generally be in the form of tablets or capsules; or in the form of powders, granules or spheroids packed into sachets; or in the form of solutions or suspensions in which case a unit dose will generally comprise from 5 to 20ml of the liquid formulation.
The pharmaceutical compositions of the present invention when presented in the form of granules may be prepared by standard methods such as wet or dry granulation (slugging) . They may be effervescent or non-effervescent to be mixed with a suitable quantity of water for administration as a drink. They may also be chewable granules.
The pharmaceutical compositions of the present invention when presented in the form of spheroids may be prepared by the following method. The triclosan or a derivative thereof, EDTA or EGTA and a carrier (for example microcrystalline cellulose) plus any other excipients are mixed with a sufficient quantity of water to form a 'plastic' wet mass. The mass is extruded into cylinders of uniform diameter and equal length. The extrudates are rolled into spheres using a spheroniser and then dried, preferably in a fluid bed dryer.
The pharmaceutical compositions of the present invention when presented in the form of powders may be prepared by blending triclosan or a derivative thereof, EDTA or EGTA and one or more pharmaceutically acceptable excipients such as bulking agents/diluents.
The pharmaceutical compositions of the present invention when presented in the form of tablets may be prepared by standard methods such as granulation or direct compression. They may be buffered and effervescent, or non-effervescent, and include tableting aids known in the art such as a lubricant, for example magnesium stearate, or a disintegrating agent, such as sodium starch glycolate.
The pharmaceutical compositions of the present invention when presented in the form of capsules may be prepared by standard methods such as filling powders, granules or spheroids into hard gelatine capsules, or adding the triclosan or a derivative thereof and EDTA or EGTA to melted pharmaceutically acceptable excipients before filling into capsules.
The pharmaceutical compositions of the present invention when presented in the form of solutions or suspensions may be prepared by mixing the components with a suitable liquid, such as water. Generally the liquid formulations will be formulated to provide the unit dosage in 5 to 20ml. They may include pharmaceutically acceptable conventional excipients such as suspending agents or buffer systems. Furthermore, to protect the pharmaceutical compositions against microbial deterioration it is preferred to include a preservative therein, for example a combination of methyl- and propyl-para-hydroxybenzoate (methyl and propyl parabens) .
The pharmaceutical compositions may also include one or more colouring, sweetening or flavouring agents, if desired. The composition of the present invention may also include an antacid. Suitable materials include sodium bicarbonate, calcium carbonate, aluminium hydroxide and mixtures thereof. Use of these materials, in particular sodium bicarbonate, also results in a reduction in the viscosity of the liquid compositions,
thereby providing some degree of viscosity control in the design of readily pourable liquid preparations. In another aspect of the present invention the pharmaceutical compositions may be formulated as gastric sustained release compositions, having a prolonged residence time within the stomach and continuously releasing the triclosan or a derivative thereof during that time. In this aspect the compositions may be formulated so as to produce floating alginate rafts within the stomach, or as ucoadherent-coated granules or spheroids, by techniques known in the art.
Mucoadherent-coated granules or spheroids may be produced by forming triclosan or a derivative thereof and EDTA/EGTA containing granules or spheroids as described above, and coating them with one or more known mucoadherent polymers such as carboxymethylcellulose, sodium carboxymethyl-cellulose, carbomer, polycarbophil, tragacanth, sodium or potassium alginate, methyl- cellulose,hydroxyethylcellulose, hydroxypropylmethyl- cellulose, carageenan or chitosan. The coating may be carried out by any conventional technique, for example spray coating. Once coated and dried the granules or spheroids may be filled into sachets or gelatine capsules or, if sufficiently robust microadherent coatings have been used, compressed to form tablets.
Alternatively, the compositions of the present invention when presented in tablet form may comprise a mucoadherent polymer in the tablet matrix.
The mucoadherent polymer which is preferred for use in the present invention is carbomer which is described in the British Pharmacopeia and the United States National Formulary as being a synthetic high molecular weight cross-linked polymer of acrylic acid containing 56 to 68% of carboxylic acid groups. The British Pharmacopeia specifies cross-linking with allylsucrose. Carbomer is used in the form of neutralised gel as a
suspending agent in pharmaceutical preparation for internal and external uses.
Examples of suitable commercial grades of carbomer are those sold by B.F. Goodrich under the Registered Trade Marks Carbopol 910, 934, 934P, 940, 941, 971P, 974P, 980, 981 and 1342. These carbomer grades have molecular weights between approximately 750,000 and 4,000,000. Others examples are those sold by Nihon Junyaku as Junlon PW110, Junlon PW150 and Junlon PWlll, and Acrisint 400 (Sigma, Italy) . Specific grades of carbomer which are preferred for use in the present invention are Carbopol 934P and Carbopol 974P.
Compositions formulated so as to produce floating alginate rafts within the stomach may be in solid single dosage form as tablets, powders or granules, or in liquid form.
In solid single dosage form the alginate containing gastric sustained release compositions of the present invention will generally comprise, in addition to the triclosan or a derivative thereof and EDTA/EGTA within the above stated ranges, from 200 to 600mg of alginic acid and/or a salt thereof, preferably a sodium, potassium or magnesium salt; 50 to 250mg of a sodium or potassium carbonate or bicarbonate salt; and optionally up to lOOmg calcium carbonate. The compositions may also contain standard tableting excipients known in the art, such as soluble fillers, binders, lubricants and flavours. The tablets may be produced by standard procedures such as direct compression, or by wet or dry granulation followed by tablet compression.
In the form of liquids the alginate containing gastric sustained release compositions of the present invention will generally comprise, 0.1 to 2% w/v triclosan or a derivative thereof; 0.2 to 4% w/v EDTA or a salt thereof, or 1 to 35% w/v EGTA or a salt thereof; 1 to 8% w/v sodium or potassium alginate; 1.3 to 6.5% w/v sodium or potassium carbonate or bicarbonate salt;
0.5 to 4% calcium carbonate and optionally 0.3 to 1.7% w/v of a suspending agent, preferably carbomer, with the ratio of triclosan or a derivative thereof to EDTA or EGTA being within the above stated ranges. These liquid compositions may also contain standard excipients known in the art such as preservatives, flavouring and colouring agents. The alginate containing liquids may be produced by dispersing all of the ingredients, except carbomer in water. If carbomer is used it will be added to the dispersion as a neutralised suspension in water. When the alginate compositions described above come into contact with the, normally, acid conditions of the stomach the carbonate or bicarbonate salts effervesce, which aerates the raft structure formed by the alginates, thereby causing it to float on the stomach contents.
The present invention will be further described with reference to the following Examples.
EXAMPLE 1
The in vitro activities of triclosan, EDTA-disodium salt dihydrate and various combinations of triclosan/ EDTA-disodium salt dihydrate versus different strains of Helicobacter pylori were determined by methods based on those described in Reeves, D. , Phillip, I., Williams, J.D. and Wise, R. , Laboratory Methods in Antimicrobial Chemotherapy, Churchill Livingstone, London, 1978.
The Minimum Inhibitory Concentrations (MIC) of each composition were determined using an agar dilution technique. The MIC was defined as that concentration mg/1 at which less than 1 in 105 organisms produced visible colonies after incubation.
Helicobacter pylori strains NCTC 11637, 11916, 12384, 12386, 12455 and 12823 were obtained from the National Collection of Type Cultures, London. Helicobacter pylori strain HP34 was a clinical isolate
1 7 -
from a biopsy taken during endoscopy of a patient at Queen's Medical Centre, The University Hospital, Nottingham. Helicobacter pylori strains Chapman, Brown, Ahmed, 4467 and Calder were also clinical isolates from biopsies taken during endoscopy of patients at The Hammersmith Hospital, London.
Helicobacter acinonvx is a Helicobacter species which causes gastritis in cheetahs.
Columbia Blood Agar (OXOID, U.K.) containing 5% horse blood was prepared according to the manufacturer's instructions and used to prepare a dilution series of each compound or composition under test. A multipoint innoculator was used to deliver to the plates, an innoculum of 1 to 5μl, depending on the contact surface, of a culture of each Helicobacter strain against which the compound or composition was being tested. The innoculum of each Helicobacter strain was prepared by scraping two lOμl innoculating loops of culture from plates of each strain and resuspending the culture in 600μl of Tryptone Soya Broth (TSB-Difco, U.S.A.)
The plates were incubated for three days at 37°C in a microaerophilic environment produced from a gas pack supplied by Becton Dickinson Limited. Each test was carried out in duplicate. Table 1 below presents data for the testing of triclosan alone, EDTA-disodium salt dihydrate alone, and compositions comprising 0.05mM, 0.125mM or 0.20mM EDTA-disodium salt dihydrate with varying concentrations of triclosan against the Helicobacter pylori strains and the Helicobacter acinonvx strain as a comparison.
o
EXAMPLE 2
Following the general procedures of Example 1 using agar dilution techniques, the effect of EDTA-disodium salt dihydrate combination with triclosan, ampicillin and CPC was examined. Helicobacter pylori strain 12385 was obtained from the National Collection of Type Cultures, London. The EDTA-disodium salt dihydrate (E) was used at a concentration of 22mg/l in each combined study. The results are given in Table 2 below.
TABLE 2
Microorganism Trie Tric+E AMP AMP+E CPC CPC+E
H.Pylori 0.125 0.06 0.125 0.125 2.0 2.0 NCTC11637
H.Pylori 0.06 0.005 0.06 0.01 1.0 0.5 NCTC12385
H.Pylori 0.125 0.005 0.06 0.06 0.5 0.5 NCTC12386
H.Pylori 0.06 0.005 0.06 1.0 1.0 0.5 NCTC12455
H.Pylori 0.125 0.06 0.125 0.125 <2. 2.0 NCTC12384 0
H.Pylori 0.125 0.005 0.25 0.25 0.5 NCTC12823 1.0
It will be noted that the activity of both ampicillin and CPC were essentially unaffected by the inclusion of a low level of EDTA-disodium salt dihydrate.
EXAMPLE 3
Zone of inhibition studies were carried out to determine the degree of diffusion of triclosan/EDTA- disodium salt dihydrate through a mucin plug. In these experiments, the greater the zone of inhibition, the higher the Helicobacter pylori inhibition.
All studies were performed with Helicobacter pylori NCTC 11638 obtained from the National Collection of Type Cultures, London. Wells 9mm in diameter were cut into Columbia blood agar plates which had previously been inoculated with the Helicobactoer pylori strain. The wells were filled with 5% w/v or 10% w/v sterile solutions of purified pig gastric mucin (Sigma) to form a plug. Granules (lOmg) comprising either 0.25mg triclosan alone or 0.25mg triclosan/l.28mg EDTA-disodium salt dihydrate were placed on the surface of the mucin plug, but not touching the agar. In order for zones of inhibition to occur, diffusion of the active components must take place through the mucin. The results are given in Table 3 below.
TABLE 3
Inhibition Zone Diameter (mm)
Granules 5% w/v Mucin plug 10% w/v Mucin plug
Triclosan 26 26
Triclosan + EDTA 37 38
EXAMPLE 4
An inoculum containing Helicobacter pylori NCTC 11638 was added to a buffered solution containing triclosan/EDTA-disodium salt dihydrate. After a certain exposure period at 37°C, an aliquot was removed, the active agents neutralised and the number of surviving
organis s determined by plate count. The results are expressed as the number of log reductions achieved within the exposure period using the formula given below:-
Microbicidal effect (ME) = Log N.-Nt
N. No colony forming units from control suspension
N. No colony forming units from test suspension
The aim is to achieve a microbicidal effect of greater than 5 Log reductions within 5 minutes.
Using the above technique the effect of triclosan in combination with EDTA-disodium salt dihydrate at typical stomach concentrations of 300mg/l and 1530mg/l, respectively, was examined. (It should be noted that a typical fasted human stomach contains a volume of about 50 ml) . The results are given in Table 4A below from which it can be seen that even after 5 minutes, a 5 Log reduction could be achieved.
TABLE 4A
Time Log Log ME (Mins) Control Test Value
Survivors Survivors
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
The levels of triclosan EDTA-disodium salt dihydrate required to produce a 5 Log reduction in 5 minutes were also examined and the results are given in Table 4B below.
TABLE B
Triclosan/ Log Log ME EDTAmgl"1 Control Test Value
Survivors Survivors
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
It will be noted that a 5 Log reduction in 5 minutes was obtained at concentrations as low as 25mg triclosan/128mg EDTA-disodium salt dihydrate per litre.
EXAMPLE 5
The effect of pH on the efficacy of triclosan and EDTA-disodium salt dihydrate in combination at various stomach concentrations was also examined using the procedures as described in Example 4 with a 5 minute contact time.
The results are given in Table 5 below:
TABLE 5
pH ME values at [tric/Na2EDTAmgl 1]
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
EXAMPLE 6
A preparation in the form of tablets was prepared from the following ingredients:
Triclosan 150g
EDTA-disodium salt dihydrate 765g
Calcium carbonate lOOOg
Microcrystalline Cellulose 2705g (Avicel PH101)
Magnesium stearate 30g
Sodium bicarbonate 200g
The sodium carbonate, EDTA-disodium salt dihydrate, and microcrystalline cellulose were mixed and to the mixture was added triclosan in isopropanol. The resulting mixture was blended in a high speed blender, dried in a forced air drier and sieved through an 840 μ mesh sieve. Sodium bicarbonate and water was then added to the mixture and the mixture granulated with a small amount of water in a high speed blender. The granules were dried in a fluid bed dryer and then passed through an 840 μ mesh sieve. The magnesium sterate as a tableting aid was added to the granules and the mixture blended in a tumble blender. The mixture was compressed into tablets each having a final weight of 470mg. Each tablet contained 15mg of triclosan and 76.5mg of EDTA- disodium salt dihydrate.
Similar tablets may also be prepared with the addition of other optional ingredients such as a mucoadherent polymer for example carbomer (e.g. lOOOg in the above composition) , or tablet disintegrants, for example sodium starch glycolate (e.g. 300g in the above composition) .
EXAMPLE 7
A preparation in the form of capsules was prepared from the following ingredients:
Triclosan - 150g
EDTA-disodium salt dihydrate - 765g
Calcium carbonate - 2000g
Polyethylene glycol (400) - 4356g Water - 229g
The ingredients were uniformly mixed together and filled and sealed into size 0 hard gelatin capsules with a capsule fill weight of 750mg. Each capsule contained 15mg triclosan and 76.5mg EDTA-disodium salt dihydrate.
EXAMPLE 8
Following the procedure of Example 6, similar tablets were prepared containing 7.5mg triclosan and 38.25mg of EDTA-disodium salt dihydrate, or 3.75mg triclosan and 19.125mg of EDTA-disodium salt dihydrate.
EXAMPLE 9
Example 6 was repeated replacing the EDTA by 4800g of EGTA. The mixture was compressed into tablets each having a final weight of 888mg and containing I5mg triclosan and 400mg of EGTA.
EXAMPLE 10
Example 7 was repeated replacing the EDTA by 4800g of EGTA. The mixture was filled and sealed into size 0 hard gelatin capsules with a full weight of 288mg. Each capsule contained 3.75mg triclosan and 120mg of EGTA.
EXAMPLE 11
Following the procedure of Example 6, similar tablets were prepared containing 7.5mg of triclosan and 240mg of EGTA, or 3.75mg triclosan and 120mg of EGTA.
EXAMPLE 12
Following the procedure of Example 6, similar tablets were prepared containing an amount of triclosan monophosphate to provide the equivalent of an amount of 7.5 mg of triclosan and 38.25 mg of EDTA-disodium salt dihydrate, or 3.75 mg of triclosan and 19.125 mg of EDTA-disodium salt dihydrate.
EXAMPLE 13
Following the procedure of Example 11, similar tablets were prepared containing an amount of triclosan monophoshate to provide the equivalent of an amount of 7.5mg triclosan in place of the 7.5mg of triclosan.