Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-11-18
2001-03-27
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S493000, C424S495000
Reexamination Certificate
active
06207197
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel method for retaining pharmaceutical agents in the stomach of a mammal, in order to provide local treatment of diseases of the stomach, or to improve the intestinal absorption of drugs which have a limited absorption capacity in the small intestine of such a mammal.
BACKGROUND
The preferred route for the administration of most drugs is via the gastrointestinal tract Most drugs are well absorbed from throughout the entire intestinal tract, but some compounds, usually those which are polar in nature, are poorly absorbed from the large intestine. For such drugs, the main area from which absorption occurs is the small intestine. Some drugs may exploit a natural pathway, such as receptor-mediated transport, active transport or other specific transport mechanisms, and are known to have socalled “absorption windows” in the small intestine. The term “absorption windows” describes the fact that a drug will be absorbed from a limited region of the intestine rather than the whole of the small and large intestines. The “window” could represent the duodenum, the jejunum or the ileum or parts thereof. Examples of such drugs include methyldopa and captopril. It would be advantageous to hold these drugs, which may display less than ideal absorption behaviour from the small intestine, in the stomach above their main absorption site for extended time periods, for example by way of a gastroretentive drug formulation.
A gastroretentive system would also be of value in the administration of a drug which is intended to produce a local effect in the stomach. A good example of this type of therapy is provided by way of the w ell known use of antibiotics in the local treatment of
Helicobacter pylori
(
H. pylori
) Furthermore, the use of antimicrobial substances for the treatment of
Camplobacter pylori
(with the additional treatment with other substances sach as H
2
-receptor blockers) is suggested in an article by Hirsche and Pletschelte (1989) (
Campylobacter pylori
and
Gastroduodenal Ulcers
Rathbone and Heatley, eds.), Blackwell (1989) p. 217). More particularly, these authors also suggest that, if retention in the stomach could be achieved, drugs which demonstrate topical activity could be readily administered orally for local treatment.
Various methods have been proposed in the prior art to achieve gastroretention, including dosage forms which display extended residence in the stomach due to their density or size, or through the use of mechanisms based on a putative bioadhesion concept.
The topic of gastroretentive dosage forms has been well reviewed by Moes (
Crit. Rev. Ther. Drug Carrier Syst
., 10, 143 (1993)) and Deshpande el al (
Drug Devel. Ind. Pharm
., 22, 531 (1996)). Proposed methods described in these review articles for prolonging the gastric residence time of drug delivery systems include agents such as fatty acids, pharmacological agents which delay the passage of material from the stomach to the small intestine, and devices such as unfolding polymer sheets and balloon hydrogels (Park, K. and Park, H., Proc.
Int. Symp. Control. Rel. Bioact. Mater
., 14, 41 (1987) and Cargill R., Caldwell, I. J., Engle, K., Fix, J. A., Porter, P. A., and Gardner, C. R.,
Pharm. Res
., 5, 533, 1988). While the concept of using large single unit dosage forms for gastric retention is attractive at first sight, potential problems, including blockage of the oesophagus or small itesine in certain patient groups, are known to be associated.
A further way to retain a drug delivery system in the stomach for an extended time period is to administer a nondisintegrating tablet or capsule, of a size greater than about 7 mm, and less than 20 mm, together with a large meal. The nature processes of gastric motility ensure that a delivery system of this size does not normally exit from the stomach until the stomach is empty of food. Thereafter the delivery system is cleared into the intestine through the action of a physiological process known as the migrating myoelectric complex (Phase III activity). However, in many instances, where drug absorption is affected by food, it would be advantageous to dose therapeutic agents to an empty, fasted stomach.
In the case of local treatment of gastric disorders, it would also be beneficial to achieve close adherence of a drug delivery system to the mucosal surface of the stomach, once the stomach has been emptied of liquid/food. Previous attempts to achieve this effect have not been successful, and no beneficial increase in residence time in man has been reported. By “beneficial increase in residence time” in this context, we mean that the residence time in the stomach for patients in the fasted state is at least three times greater than that for a control solution formulation.
The use of bioadhesive polymers as gastroretentive materials has been well reviewed in the pharmaceutical literature and is the subject of patent applications (see, for example, Ch'ng, H. S., Park, H., Kelly, P., and Robinson, J. R.,
J. Pharm. Sci
., 74, 399 (1985); Longer, M. A., Ch'ng, H. S., and Robinson, J. R.,
J. Pharm. Sci
., 74, 406 (1985); and Gurney and Junginger (Eds.)
Bioadhesion Possibilities and Future Trends
, Wissenschafliche Verlaggeschelchaft (1990)).
Tablets and pellets with increased gastric retention and bioadhesive properties have been described in international patent application WO 94/00112. The specific use of microadherent formulations in the treatment of gastric disorders (including
H. pylori
) has been described in international patent application WO 92/18143. Natural gums, plant extracts, sucralfate, acrylic acid or methacrylic acid derivatives are suggested as means to give sustained release and/or prolonged retention in the stomach.
Controlled release mucoadhesive microgranules for the oral administration is of furosemide are described in U.S. Pat. No. 5,571,533. The granules are made from lipophilic excipients and are coated with mucoadhesive anionic polymers selected from the group: carbomer, polycarbophil, hydrodroxypropyl methyl cellulose, hydroxypropyl cellulose or admixtures thereof.
Moes (1993) (see reference above) reports that the use of bioadhesive polymers to modify gastrointestinal transit has been abandoned since such mucoadhesive polymers are not able to control or slow down significantly the gastrointestinal transit of solid delivery systems, such as pellets and tablets
Pellets and other single units with a high density have also been investigated for gastroretention in Bechgaard, H. and Ladefoged, K.,
J. Pharm. Pharmacol
., 30, 690 (1978) and Clarke, G. M.
Gastrointestinal Transit of Spherical Granules of Differing Size and Density
, PhD Thesis (1989), University of London), but the approach has not led to significant advantage in man unless the specific gravity is greater than 2.0. The skilled person will appreciate that such a high density presents a considerable disadvantage in a conventional pharmaceutical product from the standpoint of processing and weight.
Low density (floating systems) in the form of pellets and tablets have also been reported (Babu et al,
Pharmazie
, 45, 268 (1990); Mazer et al,
J. Pharm. Sci
. 77, 647 (1988)). Whilst some small benefits can be demonstrated, such systems in their own right do not appear to provide extended periods of residence in the stomach. However, they do offer some protection against early and random gastric emptying, though, in order to do this, need to be administered immediately after a meal
Floating minicapsules, having a size 0.1 to 2 mm, containing sodium bicarbonate, and which are coated by conventional water soluble film coating agents are described in U.S. Pat. No. 4,106,120. Similar floating granules based on gas generation have been described in U.S. Pat. No. 4,844,905. Floating capsules have also been described in U.S. Pat. No. 5,198,229. Atyabi et al, (
J. Control. Rel
., 42, 105 (1996)) have described ion exchange systems containing bicarbonate that release CO
2
on contact with hydrochloric acid in the stomach, whic
Illum Lisbeth
Ping He
Arnall Golden & Gregory LLP
Di Nola-Baron Liliana
Page Thurman K.
West Pharmaceutical Services Drug Delivery & Clinical Research C
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