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.

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• 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)

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• 1998
  • 1998-05-05 GB GBGB9809347.9A patent/GB9809347D0/en not_active Ceased
• 1999
  • 1999-05-05 GB GB9910316A patent/GB2336999A/en not_active Withdrawn
  • 1999-05-05 AU AU37162/99A patent/AU749509B2/en not_active Ceased
  • 1999-05-05 EP EP99919357A patent/EP1075257A1/de not_active Ceased
  • 1999-05-05 WO PCT/GB1999/001188 patent/WO1999056738A1/en active IP Right Grant

Non-Patent Citations (1)

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