EP1075257A1 - Use of triclosan for the treatment of helicobacter pylori infections - Google Patents
Use of triclosan for the treatment of helicobacter pylori infectionsInfo
- Publication number
- EP1075257A1 EP1075257A1 EP99919357A EP99919357A EP1075257A1 EP 1075257 A1 EP1075257 A1 EP 1075257A1 EP 99919357 A EP99919357 A EP 99919357A EP 99919357 A EP99919357 A EP 99919357A EP 1075257 A1 EP1075257 A1 EP 1075257A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- triclosan
- medicament
- treatment
- pylori infections
- patient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
- A61K31/055—Phenols the aromatic ring being substituted by halogen
Definitions
- This invention relates to the preparation of medicaments for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections.
- 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.
- the problems of using such combination products are well known (eg poor compliance) .
- 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.
- H. pylori infections 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 .
- triclosan is primarily delivered to such sites of infection is direct (i.e. by diffusion through the mucus layer) rather than indirectly by systemic delivery (as is believed to be the case for antibiotic treatments) .
- 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.
- WO95/08332 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.
- 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.
- 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 require any enzyme activity to become activated and is therefore not dependant on prevailing conditions for its efficacy.
- 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 300 mg to 2000 mg of triclosan.
- a medicament in oral unit dosage form comprising from 300 mg to 2000 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 unit dose .
- each unit dose will comprise from 300 mg to 1000 mg and most preferably 400 mg to 800 mg of triclosan.
- 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 300 mg to 8000 mg triclosan in a 24 hour period. Duration of the dosing regimen will be preferably from about 7 to about 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 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 triclosan losses .
- Carbopol 974P (Goodrich) 100 66.7 Avicel PH200 (FMC Company) 210 140 Calcium carbonate 100 66.7 Sodium Crosscarmellose 36 24 Magnesium stearate 4 2.6
- magnesium stearate All the ingredients except the magnesium stearate are blended for 10 minutes in a high speed food processor.
- the magnesium stearate is added and blended in for 2 minutes using a tumble mixer.
- the blended powders are compressed into 750 mg caplet shaped tablets .
- Tablets are prepared as in Example 1 .
- Example 4 Tablets are prepared as in Example 1 but are compressed into 1000 mg caplets .
- Example 4
- the polyethylene glycol 1000 is melted at 60°C and the triclosan is stirred in and dispersed.
- the liquid mixture is filled into hard gelatin capsules (size 0) to a fill weight of 750 mg and solidified by cooling.
- Tablets are prepared as in Example 1 but are compressed into 1000 mg caplets.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
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 300 mg to 2000 mg of triclosan.
Description
USE OF TRICLOSAN FOR THE TREATMENT OF HEL1COBACTER PYLORI INFECTIONS
This invention relates to the preparation of medicaments for the treatment of gastrointestinal disorders associated with Helicobacter pylori infections.
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 vi tro, actual eradication in vivo is very difficult. One approach (suggested in our own earlier patent, GB 2243549) is the use of particular bbiipphheennyyll eetthheerrss,, mmoosstt nnoottably 2-hydroxy -4, 2 , 4 - trichloro- diphenyl ether triclosan)
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. by diffusion through the mucus layer) rather than indirectly by
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.
WO95/08332 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
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 300 mg to 2000 mg of triclosan.
There is therefore also provided a medicament in oral unit dosage form comprising from 300 mg to 2000 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 unit dose .
There is yet further provided a method for the treatment of gastrointestinal orders associated with H. pylori infections by the regular administration of at least 300 mg triclosan in oral unit dosage form.
Preferably each unit dose will comprise from 300 mg to 1000 mg and most preferably 400 mg to 800 mg of triclosan.
In terms of molar quantities of triclosan administered, given that triclosan has a molecular weight of 289.53, according to the present invention, from 1.04 x 10"3 (300 mg) to 6.91 x
10"3 M (2000 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 300 mg to 8000 mg triclosan in a 24 hour period. Duration of the dosing regimen will be preferably from about 7 to about 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 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 triclosan losses .
The invention will now be illustrated by reference to the following Examples:
Example 1
Tablets containing 300 mg triclosan.
mg/tablet g/ba
Triclosan 300 200
Carbopol 974P (Goodrich) 100 66.7 Avicel PH200 (FMC Company) 210 140 Calcium carbonate 100 66.7 Sodium Crosscarmellose 36 24 Magnesium stearate
4 2.6
750 500
All the ingredients except the magnesium stearate are blended for 10 minutes in a high speed food processor. The magnesium stearate is added and blended in for 2 minutes using a tumble mixer.
The blended powders are compressed into 750 mg caplet shaped tablets .
Example 2
Tablets containing 300 mg triclosan .
mg/tablet g/bat
Triclosan 300 200
Avicel PH200 (FMC Company) 310 206.7 Calcium carbonate 100 66.7 Sodium starch glycolate 36 24 Magnesium stearate
4 2.6
750 500
Tablets are prepared as in Example 1 .
Example 3
Tablets containing 500 mg triclosan
mg/tablet g/batch
Triclosan 500 250
Avicel PH200 (FMC Company) 445 222.5 Sodium starch glycolate 50 25
Magnesium stearate 5 2.5
1000 500
Tablets are prepared as in Example 1 but are compressed into 1000 mg caplets .
Example 4
Capsule containing 300 mg triclosan.
mg/capsule
Triclosan 300
Polyethylene glycol 1000 450
The polyethylene glycol 1000 is melted at 60°C and the triclosan is stirred in and dispersed. The liquid mixture is filled into hard gelatin capsules (size 0) to a fill weight of 750 mg and solidified by cooling.
Example 5
Tablets containing 300 mg triclosan.
mg/capsule g/bat
Triclosan 300 150
Carbopol 974 300 150
Avicel PH200 (FMC Company) 345 172.5
Sodium starch glycolate 50 25 Magnesium stearate 5 2.5
1000 500
Tablets are prepared as in Example 1 but are compressed into 1000 mg caplets.
Example 6
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
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°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 (μg/ml) for H.plyori
Di
Strain pH 5.7 pH 6.0 pH 6.5 pH 7.0 00
w Test Test Test Test Test Test Table Test c
CD #1 #2 #1 #2 #1 #2 #1 #2 </>
H Helix Ila 003/24495 4 2 0.5 2 <0.125 8 8 8
H C H Helix Ila 005/18495 2 C 0.5 C <0.125 C 4 C m
(0 Helix Ila 006/18495 8 4 0.5 8 <0.125 4 8 4 x m Helix Ila 007/18495 4 0.5 0.5 1 <0.125 1 1 0.5 m Helix Ila 033/24495 1 1 0.5 0.5 <0.125 1 2 NG
3D c r- m r Patient 1 4 0.25 1 2 <0.125 0.5 8 NG σ> 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 o ■o
H
60 so so
NT, Not tested; NG, No growth at that pH; C, contaminated 00 oe
SO
Table 2 Triclosan Monophosphate MIC (μg/ml) for H. pylori SO
(Λ
(*»
00
Strain pH 5.7 pH 6.0 pH 6.5 pH 7.0
CΛ
C Test Test Test Test Test Test Test Test Test CD (0
H #1 #2 #1 #2 #1 #2 #1 #2 #3
H C mH
Helix Ila 003/24495 >32 >32 16 8 16 16 16 8 16
0) x m Helix Ila 005/18495 1 >32 1 4 2 4 C NG 0.25 H Helix Ila 006/18495 0.5 >32 16 16 32 16 16 16 8 c Helix Ila 007/18495 >32 32 8 4 4 8 16 0.5 8 mi- Helix Ila 033/24495 >32 >32 8 16 8 16 NG NG NG σ N3>
Patient 1 1 4 16 1 0.5 16 8 NG 4 Patient 2 >32 >32 8 16 16 16 2 0.25 0.5 Patient 3 NG >32 4 2 16 8 16 NG 0.5 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 O
H Patient 7 >32 >32 32 16 32 16 32 16 16 O cα so
so
©
NT, Not tested; NG, No growth at that pH; C, contaminated 00 OS
Claims
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 300 mg to 2000 mg of triclosan.
2. The use as claimed in Claim 1 wherein each unit dose comprises from 300 mg .to 1000 mg, preferably 400 to 800 mg of triclosan.
3. A medicament in oral unit dosage form comprising from 300 mg to 2000 mg of triclosan and a pharmaceutically acceptable carrier.
4. A medicament as claimed in Claim 3 wherein each unit dose comprises from 300 mg to 1000 mg, preferably 400 to 800 mg of triclosan.
5. A method for the treatment of gastrointestinal orders associated with H. pylori infections by the regular administration of at least 300 mg of triclosan in oral unit dosage form.
6. A method as claimed in Claim 5 wherein each unit dose comprises from 300 mg to 2000 mg (preferably 300 mg to 1000 mg and most preferably 400 to 800 mg) of triclosan.
7. The use of triclosan for the preparation of a medicament for the treatment of gastrointestinal disorders associated with
Helicobacter pylori infections substantially as described in any of the Examples.
8. The use of triclosan according to the invention, substantially as herein before described. 12
9. A medicament according to the invention substantially as herein before described.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9809347.9A GB9809347D0 (en) | 1998-05-05 | 1998-05-05 | Compositions |
| GB9809347 | 1998-05-05 | ||
| PCT/GB1999/001188 WO1999056738A1 (en) | 1998-05-05 | 1999-05-05 | Use of triclosan for the treatment of helicobacter pylori infections |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1075257A1 true EP1075257A1 (en) | 2001-02-14 |
Family
ID=10831308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP99919357A Ceased EP1075257A1 (en) | 1998-05-05 | 1999-05-05 | Use of triclosan for the treatment of helicobacter pylori infections |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1075257A1 (en) |
| AU (1) | AU749509B2 (en) |
| GB (2) | GB9809347D0 (en) |
| WO (1) | WO1999056738A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9816837D0 (en) | 1998-08-04 | 1998-09-30 | Zeneca Ltd | Amide derivatives |
| US7772432B2 (en) | 1991-09-19 | 2010-08-10 | Astrazeneca Ab | Amidobenzamide derivatives which are useful as cytokine inhibitors |
| CN1271279A (en) | 1997-09-23 | 2000-10-25 | 普尼卡有限公司 | Amide derivatives for the treatment of diseases mediated by cytokines |
| KR100628284B1 (en) | 1998-05-15 | 2006-09-27 | 아스트라제네카 아베 | Benzamide derivatives for the treatment of diseases mediated by cytokines |
| HUP0103019A3 (en) | 1998-08-04 | 2002-01-28 | Astrazeneca Ab | Amide derivatives useful as inhibitors of the production of cytokines, process for producing them and pharmaceutical compositions containing them |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3629477A (en) * | 1966-08-08 | 1971-12-21 | Geigy Chem Corp | Halogenated diphenyether-containing compositions and control of pests therewith |
| GB9010039D0 (en) * | 1990-05-03 | 1990-06-27 | Reckitt & Colmann Prod Ltd | Medicament preparation |
| WO1995008332A1 (en) * | 1993-09-20 | 1995-03-30 | The Procter & Gamble Company | Use of triclosan phosphates for the treatment of gastrointestinal disorders due to heliobacter infection |
| GB9505032D0 (en) * | 1995-03-13 | 1995-05-03 | Westminster Lab Ltd | Improvements in or relating to organic compositions |
| EP0768874A1 (en) * | 1994-06-29 | 1997-04-23 | RECKITT & COLMAN PRODUCTS LIMITED | Pharmaceutical compositions containing Triclosan or derivates thereof and Edta or Egta |
-
1998
- 1998-05-05 GB GBGB9809347.9A patent/GB9809347D0/en not_active Ceased
-
1999
- 1999-05-05 WO PCT/GB1999/001188 patent/WO1999056738A1/en active IP Right Grant
- 1999-05-05 EP EP99919357A patent/EP1075257A1/en not_active Ceased
- 1999-05-05 GB GB9910316A patent/GB2336999A/en not_active Withdrawn
- 1999-05-05 AU AU37162/99A patent/AU749509B2/en not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9956738A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2336999A (en) | 1999-11-10 |
| WO1999056738A1 (en) | 1999-11-11 |
| AU3716299A (en) | 1999-11-23 |
| GB9910316D0 (en) | 1999-06-30 |
| GB9809347D0 (en) | 1998-07-01 |
| AU749509B2 (en) | 2002-06-27 |
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