Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1997-02-13
2001-02-06
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S469000, C424S472000, C424S474000
Reexamination Certificate
active
06183776
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to new oral pharmaceutical preparations especially for use in the prevention and treatment of dyspeptic symptoms like upper abdominal pain/discomfort and heartburn. The present preparations comprise a combination of different gastric acid suppressing agents, such as an acid susceptible proton pump inhibitor and antacid agent(s) and/or an alginate in a new fixed unit dosage form, especially a tableted dosage form. Furthermore, the present invention refers to a method for the manufacture of such preparations and the use of such preparations in medicine, especially in the treatment of dyspeptic symtoms.
BACKGROUND OF THE INVENTION
Dyspepsia is a common disorders and patients are seeing both gastroenterologists and general practicians because of it. Heartburn is a symptom of dyspepsia, and it is estimated that 44% of Americans have heartburn at least monthly and some has to contact a doctor about the problem, but only around 25% of the patients are seeing the doctor because of their dyspepsia problem. Symtoms associated with dyspepsia symtom are for instance upper abdominal pain/discomform and heartburn, indigestion, sour stomach, heartburn and other gastrointestinal disorders including gastro oesophageal reflux. The wide diversity of symptoms and disease severity produced by gastro oesophageal reflux has led to the need for more individualized treatment strategies.
Therapeutic agents effective in the treatment of dyspepsia include gastric acid suppressing agents, such as H
2
receptor antagonists, proton pump inhibitors, other agents of interest are antacids/alginates and prokinetic agents. These agents can be distinguished by their mechanisms of action, safety profile, pharmacokinetics and indications. WO 95/017080 describes a composition for use in the treatment of for instance heartburn, the composition comprises a H
2
receptor antagonist, such as famotidine, and an alginate and optionally simethicone.
Antacid agents and alginates may be used alone in the treatment of heartburn. They have a short duration of action but are seen as inexpensive and safe. Antacid agents work locally through a neutralisation of gastric acid. Alginates further give some mechanical protection against reflux or gastric acid into the oesophagasus. The main advantages of antacid agents and alginates are, that they provide fast relief of symtoms. The main disadvantage of antacid agents and alginates is that, dosing has to be repeated frequently to keep the patients free of symtoms, further that antacids in many cases do not provide symtom resolution, i.e. complete relief of symtoms.
H
2
receptor antagonists are widely prescribed for reducing gastric acid secretion systemically. Proton pump inhibitors, such as omeprazole, are rapidly taking share from H
2
receptor antagonists. Omeprazole is known to offer significant gain over H
2
receptor antagonists in terms of symptom resolution, healing and prevention of relapse. Proton pump inhibitors provide symtom resolution, but normally not immediately.
Proton pump inhibitors have in clinical studies been proven to be very effective in providing symtom resolution (usually within 24-48 hours) in patients with dyspepsia associated with gastric ulcers, duodenal ulcers, reflux oesophagitis and gastro oesophageal reflux without oesophagitis. It is for instance established that omeprazole is superior to H
2
receptor antagonists regarding healing of gastroduodenal and oesophageal lesions as well as providing dyspeptic symtom resolution in these conditions, See Eriksson S., Euro Journ of Gastroenterology & Hepatology 1995, 7:465.
EP 338861 describes a solid pharmaceutical preparation of an antacid and excipients. It is proposed to use this preparation in combination with a proton pump inhibitor or any other substance inhibit gastric acid secretion. There is no suggestion to combine these substances in one fixed unit dosage form.
U.S. Pat. No. 5,244,670 describes an ingestible pharmaceutical composition comprising a substance selected from the group consisting of antacid agents, acid secretion prevention agents, bismuth-containing agents, and mixtures thereof, and the excipient 3-1-menthoxy propane 1,2-diol. There are no specific arrangements discussed in neither of these references, to solve the problem with one of the component being an acid susceptible proton pump inhibitor.
A combination therapy of a proton pump inhibitor and an antacid or an alginate would provide immediate symtom relief, provided by the local effect of the antacid agent or the alginate, combined with a long-lasting symtom resolution provided by the systemically acting proton pump inhibitor. Such a combination would be ideal for “on-demand treatment ” of dyspepsia as well as for symtom resolution. The combination therapy comprising an acid suppressing agent, for instance a proton pump inhibitor, together with an antacid agent or an alginate could also be an alternative to each of them separately in case of failure. It is well known that patient compliance is a main factor in receiving good results in medical treatments. Administration of two or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results. The present invention now provides new oral dosage forms comprising two or more active substances combined in one fixed unit dosage form, preferably a tablet.
Some gastric acid suppressing agents, such as proton pump inhibitors, are susceptible to degradation/transformation in acid reacting and neutral media. In respect of the stability properties, it is obvious that the one of the active substances being a proton pump inhibitor must be protected from contact with acidic gastric juice by an enteric coating layer. There are different enteric coating layered preparations of proton pump inhibitors described in the prior art, see for example U.S. Pat. No. 4,786,505 (AB Hässle) describing a preparation comprising omeprazole.
There are problems to produce a fixed unit dosage form comprising a rather high amount of active substance. Different active substances in the same preparation give further problems. Preparation of a multiple unit tableted dosage form arises specific problems when enteric coating layered pellets comprising an acid susceptible proton pump inhibitor as active substance are compressed into tablets. If the enteric coating layer does not withstand the compression of the pellets into a tablet the susceptible active substance will be destroyed upon administration by penetrating acidic gastric juice, i.e. the acid resistance of the enteric coating layer of the pellets will not be sufficient in the tablet after compression.
SUMMARY OF THE INVENTION
The present invention provides oral, fixed unit dosage forms, i.e. multiple unit tableted dosage forms, layered formulations comprising an enteric coating layered tablet core, multilayered tablets or a sachet filled with more than one pharmaceutically active compound. The active compounds present in the dosage form are preferably an acid susceptible proton pump inhibitor and antacid agents. Alternatively, in some of the formulations the antacid agents may be replaced by an alginate. These new dosage forms will simplify the regimen and improve the patient compliance.
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Depui Helene
Hallgren Agneta
Astra Aktiebolag
Spear James M.
White & Case LLP
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