Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-04-04
2002-02-19
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06348502
ABSTRACT:
This is a 371 of PCT/GB99/01717 filed Jun. 1, 1999.
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical compositions suitable for oral delivery and, in particular, to pharmaceutical compositions for the treatment of reflux oesophagitis, gastritis, dyspepsia or peptic ulceration, or for use as sustained release or targeted delivery compositions.
Reflux oesophagitis occurs when small amounts of gastric juices, food and/or bile acids pass into the lower part of the oesophagus and cause oesophageal inflammation (oesophagitis) accompanied by pain which may manifest itself in the form of heartburn.
One approach to the problem of reflux oesophagitis has been to administer a preparation which, on contact with gastric acid, generates a carbonated gelatinous foam or raft which floats on the stomach contents. When gastric reflux occurs, this raft precedes the stomach contents into the oesophagus, thus protecting the mucosa from further irritation.
Known preparations of this type include solid preparations in the form of powder or tablets containing alginic acid, sodium bicarbonate and antacid materials; or liquid preparations containing sodium alginate, sodium bicarbonate and calcium carbonate which are marketed under the name of GAVISCON (Registered Trade Mark—Reckitt & Colman Products Ltd). In our British Patent No. 1524740 we describe such preparations, which are in liquid form.
Suppressants of gastric acid secretion are known to increase the healing of gastric ulcers and the effect of capsaicin and/or cimetidine on gastric acid secretion was therefore investigated in a recent study. It was found that capsaicin protects the gastric mucosa against experimental injury, such as acetic-acid induced gastric ulceration in rats (J. Y. Kang, C. H. Teng and F. C. Chen; Gut 1996, 38, 832).
The capsaicin and/or cimetidine was introduced directly into an ex vivo chamber prepared by surgery in order to establish the efficacy of the treatment. The effect of capsaicin on the healing of such gastric ulcers was compared with the effects of cimetidine (a histamine 2-receptor antagonist) which is widely used for the treatment of peptic ulcers, and with a combination of cimetidine and capsaicin.
It was concluded that capsaicin promotes the healing of acetic-acid induced gastric ulcers, but that this effect is blunted by the prior administration of cimetidine. In addition, it appears that capsaicin has no effect on gastric acid secretion.
It has also been established that capsaicin provides mucosal protection in white rabbits against topical injury by noxious agents such as ethanol (B. L. Bass, K. S. Trad, J. W. Harman and F. Z. Hakki; Surgery August 1991, 419). The capsaicin was administered directly to the white rabbits at the gastro-oesophageal junction via cannulae and the blood flow was monitored through catheters positioned in the left ventricle and iliac artery.
It is believed that mucosal protection arises because capsaicin stimulates the chemosensitive afferent neurones of the mucosa and submucosa, thereby causing local release of vasoactive and permeability-altering peptides resulting in increased blood flow. The specific protective factors associated with augmentation of blood flow remain unknown however.
Further studies have indicated that chilli has a protective effect on acute aspirin-induced gastroduodenal mucosal injury in humans (K. G. Yeoh, J. Y. Kang, I. Yap, R. Guan, C. C. Tan, A. Wee and C. H. Teng; Diseases and Sciences 1995, 40(3), 580).
Healthy volunteers took 20 g of chill powder (containing 9.56 mg of capsaicin) orally with 200 mls of water, followed by 600 mg of asprin with 200 mls of water. The resulting lesions were observed by gastroduodenoscopy both in this group and in a control group.
The chilli powder exhibited a gastroprotective effect against aspirin-induced injury. The mechanism of action is unclear, but is thought to be due to increased gastric mucosal blood flow.
Capsaicin-sensitive nerves contribute to the maintenance of tissue integrity, and also influence healing of acute and chronic lesions. Ablation of capsaicin-sensitive nerves increases the degree of gastric lesions induced by a number of mechanical and chemical stimuli, including NSAIDs, alcohol and acid. In contrast, intragastric administration of a low concentration of capsaicin appears to protect the gastric mucosa against these agents and aids lesion-healing.
The efficacy of capsaicin has been explained by the local release of neuoropeptides from afferent nerve endings, such as Substance P, CGRP and sonatostatin, which in turn acts to increase local blood flow. In vivo, capsaicin-sensitive neurones are suggested to be stimulated by the reduction in pH presented to the gastric mucosa, which signifies an injurious situation. Similarly, stimulation of capsaicin-sensitive neurones by both acid and capsaicin in rats has been shown to increase duodenal bicarbonate secretion (Inada and Satoh). Thus, capsaicin may act to support natural defensive pathways both prophylactically, and in the face of injury.
However, for the general treatment of gastric disorders in patients the administration of capsaicin by any of the above methods is unsuitable and could not be used as a means of treating the general population. The prior art treatments are particularly unsuitable for use in human patients and do not allow for selective treatment of the affected area using an acceptable dosage form. Indeed, it is probable that patients may be unwilling or unable to consume a large amount of chilli orally in the manner suggested by Yeoh et al.
The prior art thus does not disclose a generally applicable method of administering capsaicin to patients, nor does it provide a suitable vehicle for the administration of capsaicin to the oesophageal region. Thus, there remains a need for an active agent which can be delivered to the oesophageal region and hence for a suitable vehicle for the active agent. In the case of the present invention, the active agent can be directed to the oesophaagus to provide relief from oesophageal inflammation and lesions, such as those sustained during periods of heartburn and indigestion. Alternatively, it can function as a prophylactic prior to the addition of agents likely to be harmful to the gastric mucosa, for example asprin, perhaps after damage due to overindulgence of alcohol.
Ideally, the active ingredient should be delivered to the site of sensitive neurones located throughout the gastrointestinal tract (including the oesophagus and stomach) which provide a gastroprotective function and which are sensitive to capsaicin and other gastroprotective agents.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a pharmaceutical composition for the treatment of gastro-oesophageal reflux disease which comprises a carrier vehicle which is capable of producing a floating barrier layer on contact with gastric acid, or is capable of forming a bioadhesive film which binds to the oesophageal region and at least one active ingredient which is selected from capsaicin ((E)-(N)-[(4-hydroxy-3-methoxphenyl)-methyl]-8-methyl-6-nonenamide), zingerone (4-(4-hydroxy-3-methoxyphenyl)-2-butanone),curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione), piperine (1-[5-1,3-benzodioxol-5-yl)-1-oxo-2,4-pentadienyl]piperidine), resiniferatoxin (daphnetoxin 6,7-deepoxy-6,7-didehydro-5-deoxy-21-dephenyl-21-(phenylmethyl)-20-(4-hydroxy-3-methoxybenzeneacetate), pharmaceutically acceptable derivatives and salts thereof.
For the purposes of the present invention, gastro-oesophageal reflux disease includes reflux oesophagitis, gastritis, dyspepsia, peptic ulceration and/or Barrett's oesophagus.
DETAILED DISCLOSURE
Thus it will be seen that protection of the oesophageal region in accordance with the invention by delivering the required dosage to the required site can be achieved in two ways. The oesophagus can be protected by coating on reflux with the carrier vehicle which has formed a carbonated raft, mucoadhesive granules or an oil or wax film
Dettmar Peter William
Gardiner Fiona Kate
Jolliffe Ian Gordon
Fish & Richardson P.C.
Henley III Raymond
Reckitt & Colman Products Limited
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