AU749509B2 - Use of triclosan for the treatment of helicobacter pylori infections - Google Patents

Description

USE OF TRICLOSAN FOR THE TREATMENT OF HELICOBACTER PYLORI INFECTIONS This invention relates to the use of triclosan for the preparation of medicaments for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections and to medicaments in oral dosage form containing triclosan.

H.pylori infections have now been acknowledged to be associated with a wide range of gastrointestinal disorders, including gastritis and peptic ulcer disease. A wide variety of treatments have been proposed for H.pylori associated gastric disorders, including the use of bismuth salts, antiinfective agents or H2-receptor antagonists; most of which procedures have afforded limited success. Combinations of some or all of these agents have been used and have sometimes demonstrated greater effect. However the problems of using such combination products are well known (eg poor compliance).

.Whilst killing H.pylori is relatively easy in vitro, actual :20 eradication in vivo is very difficult. One approach (suggested in our own earlier patent, GB 2243549) is the use of particular biphenyl ethers, most notably 2-hydroxy 2 4 trichlorodiphenyl ether triclosan).

:25 In GB 2243549 it is suggested that doses of up to 200 mg of triclosan may be suitable for the treatment of H.pylori associated gastrointestinal disorders. Whilst such doses have been shown to be effective in vivo we have now surprisingly found that much higher doses may be significantly more effective.

The major site of H.pylori infections in man is believed to be at the interface of the adherent gastric mucus layer and the gastric mucosa.

It is further believed that the route by which triclosan is primarily delivered to such sites of infection is direct (i.e.

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9 diffusion through the mucus layer) rather than indirectly by WO 99/56738 PCT/GB99/01188 2 systemic delivery (as is believed to be the case for antibiotic treatments). Thus, the amount of triclosan that can reach the site of infection is controlled by the amount that can pass into the mucus layer from the stomach contents.

W095/08332 discloses administering from 50 mg to 2000 mg of a diphenyl ether phosphate ester of triclosan for the treatment of gastrointestineal disorders due to H. pylori infection. The triclosan phosphate is more soluble than triclosan and is thus cable of passing into the mucus layer quicker and to a greater extent than triclosan. However, triclosan phosphate lacks biological efficacy in that it is not active until the ester is hydrolysed off the triclosan, a reaction which is enzyme controlled and occurs within the bacterium.

Triclosan is less soluble than triclosan phosphate in conditions as acidic as those in the stomach (triclosan has a solubility of approximately 10 micrograms/ml at pH's below 7), and high doses were expected to be of little added value because the solubility limit would soon be passed. That is, once the stomach contents were saturated with triclosan any further material would remain in suspension and not be available to pass into the mucus. Such suspended material would not remain in the stomach long because of its regular emptying and so would not contribute to the activity of the dissolved material. Thus the fact that doses well above the solubility limit of triclosan in normal stomach contents show an increase in activity is highly unexpected.

Without wishing to be bound by theory, it is believed that the undissolved triclosan is preferentially taken up into the adherent mucus layer coating the stomach walls and forms depots there, allowing a much higher proportion of the actual triclosan molecules to be delivered directly to the site of infection. The dose which is delivered is biologically active i.e. it does not 3 require any enzyme activity to become activated and is therefore not dependant on prevailing conditions for its efficacy.

There is therefore provided the use of triclosan for the preparation of a medicament for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections, characterised in that the medicament is in oral unit dosage form, each unit dose comprising 400 mg to 800 mg of triclosan.

There is therefore also provided a medicament in oral unit dosage form comprising from 400 mg to 800 mg of triclosan and a pharmaceutically acceptable carrier.

A pharmaceutically acceptable carrier is one which is suitable for oral ingestion and which is capable of delivering the triclosan to the upper gastrointestinal tract, preferably the stomach. Such carriers therefore include carbomer, e.g.

Carbopol (RTM) and microcrystalline cellulose e.g. Avicel (RTM).

The amount of carrier present in the medicament is sufficient to provide an effective quantity for administration of the medicament and is preferably from 50 mg to 2000 mg per S unit dose.

SThere is yet further provided a method for the treatment of gastrointestinal disorders associated with H. pylori infections by the regular administration of 400 mg to 800 mg triclosan in oral unit dosage form once to four times daily.

In terms of molar quantities of triclosan administered, given that triclosan has a molecular weight of 289.53, according to the present invention, from 1.39 x 10 3 M (400 mg) to 2.77 x 4 3 M (800 mg) of triclosan is administered and becomes bioavailable per unit dose.

Dosing frequency will be preferably from once to four times daily, most preferably twice or three times daily. Accordingly, a patient may receive anything from 400 mg to 3200 mg triclosan in a 24 hour period. Duration of the dosing regimen will be preferably from 7 to 56 days, more preferably from 7 to 28, most preferably from 7 to 21 days.

Oral unit dosage forms of triclosan include any forms that can be conveniently administered to a patient to deliver a fixed dose. Such forms include tablets, capsules (both hard and soft), and sachets containing granules, powders or liquids. They also include sustained release forms.

The dosage forms may further comprise any conventional :20 suitable excipients depending upon their form; for example, fillers, binding agents, flavours, lubricants, mucoadhesive polymers etc.

The dosage forms may be produced by any conventional means, with the proviso that the process does not result in significant Striclosan losses.

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The invention will now be illustrated by reference to the following Examples: 55

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S 6 Example 1 Tablets containing 500 mg triclosan mg/tablet g/batch Triclosan 500 250 Avicel PH200 (FMC Company) 445 222.5 Sodium starch glycolate 50 Magnesium stearate 5 1000 500 All the ingredients except the magnesium stearate are blended for 10 minutes in a high speed food processor. The magnesium Sstearate is added and blended in for 2 minutes using a tumble mixer.

•20 The blended powders are compressed into 1000 mg caplet shaped b l tablets.

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e Example 2 Cultures of different strains and clinical isolates of Helicobacter pylori were initially prepared on agar plates and then formed into suspensions. Small aliquots of each suspension

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WO 99/56738 PCT/GB99/01188 8 were spotted onto agar plates containing two fold serial dilutions of triclosan and triclosan monophosphate at different pHs. The plates were incubated for 4 days at 37 0 C and the presence or absence of growth noted after this time. In so doing the Minimum Inhibitory Concentration (MIC) of triclosan and triclosan monophosphate was determined for each pH on two separate dates (tests) in each instance.

The results are set out in Tables 1 and 2 below.

It can clearly be seen from the tables that triclosan has a significantly lower MIC than triclosan monophosphate in inhibiting the growth of H.pylori.

Table 1 Triclosan MIC (pg/ml) for H.plyori Strain pH 5.7 pH 6.0 pH 6.5 pH Test Test Test Test Test Test Table Test #1 #2 #1 #2 #1 #2 #1 #2 Helix IIa 003/24495 4 2 0.5 2 <0.125 8 8 8 Helix IIa 005/18495 2 C 0.5 C <0.125 C 4 C Helix IIa 006/18495 8 4 0.5 8 <0.125 4 8 4 Helix IIa 007/18495 4 0.5 0.5 1 <0.125 1 1 Helix IIa 033/24495 1 1 0.5 0.5 <0.125 1 2 NG Patient 1 4 0.25 1 2 <0.125 0.5 8 NG Patient 2 4 1 0.5 1 <0.125 4 1 NG Patient 3 0.25 0.5 0.5 0.25 <0.125 4 0.125 1 Patient 4 NT NT NT NT NT NT NT NT Patient 5 2 1 0.5 8 <0.125 1 8 0.25 Patient 6 2 1 0.5 8 <0.125 1 8 NG Patient 7 NT NT NT NT NT NT NT NT Patient 8 8 8 0.5 8 8 8 8 8 NT, Not tested; NG, No growth at that pH; C, contaminated Table 2 Triclosan Monophosphate MIC (pg/ml) for H.pylori Strain pH 5.7 pH 6.0 pH 6.5 pH Test Test Test Test Test Test Test Test Test #1 #2 #1 #2 #1 #2 #1 #2 #3 Helix IIa 003/24495 >32 >32 16 8 16 16 16 8 16 Helix IIa 005/18495 1 >32 1 4 2 4 C NG 0.25 Helix IIa 006/18495 0.5 >32 16 16 32 16 16 16 8 Helix IIa 007/18495 >32 32 8 4 4 8 16 0.5 8 Helix IIa 033/24495 >32 >32 8 16 8 16 NG NG NG Patient 1 1 4 16 1 0.5 16 8 NG 4 Patient 2 >32 >32 8 16 16 16 2 0.25 Patient 3 NG >32 4 2 16 8 16 NG Patient 4 2 16 8 8 4 16 16 8 16 Patient 5 0.25 16 NG 1 NG 0.5 NT NG NG Patient 6 C >32 C 4 C 8 2 C 8 Patient 7 >32 >32 32 16 32 16 32 16 16 NT, Not tested; NG, No growth at that pH; C, contaminated

Claims (6)

1. The use of triclosan for the preparation of a medicament for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections, characterized in that the medicament is in oral unit dosage form, each unit dose comprising from 400 mg to 800 mg of triclosan.

2. A medicament in oral unit dosage form comprising from 400 mg to 800 mg of triclosan and a pharmaceutically acceptable carrier.

3. A method for the treatment of gastrointestinal disorders associated with H.pylori infections by the regular 15 administration of 400 mg to 800 mg of triclosan in oral unit dosage form once to four times daily.

4. The use of triclosan for the prepration of a medicament for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections substantially as described in Example 1.

5. The use of triclosan according to the invention, substantially as herein before described.

6. A medicament accordinc to the invention substantially as .*o herein before described. DATED this sixth day of May 2002 Reckitt Benckiser Healthcare (UK) Limited Patent Attorneys for the Applicant: F B RICE CO