Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Coated – impregnated – or colloidal particulate
Reexamination Certificate
2000-08-01
2003-02-11
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Coated, impregnated, or colloidal particulate
C424S001290, C424S001250, C424S001330, C424S001810
Reexamination Certificate
active
06517809
ABSTRACT:
BACKGROUND OF THE INVENTION
Brief Description of the Prior Art
Factors adversely affecting the function of the gastrointestinal system in humans are exceedingly varied in their nature. Such disorders may arise in the upper or lower gastrointestinal tracts or both. There is a broad range of causes of gastrointestinal disorders, including genetic, physiological, environmental and psychogenic factors. Accordingly, the diagnosis and management of these disorders can be exceptionally difficult.
Among the chronic disorders of the upper gastrointestinal tract are those which fall under the general categories of gastritis and peptic ulcer disease. The gastrointestinal tract is generally defined as including the esophagus, the stomach, the duodenum, the jejunum and ileum. Peptic ulcers are lesions of the gastrointestinal tract lining, characterized by the loss of tissue due to the action of digestive acids and pepsin. It has generally been held that peptic ulcers are caused by gastric hypersecretion, decreased resistance of the gastric lining to digestive acids and pepsin or both. Gastritis is, by definition, an inflammation of the stomach mucosa. In practice, though, the disorder is manifested by a broad range of poorly defined, and heretofore inadequately treated, symptoms such as indigestion, “heart burn”, dyspepsia and excessive eructation.
However, the diagnostic methods typically employed in the art are often slow, cumbersome, costly and may yield equivocal or inaccurate results. Such patients may simply be treated with conventional therapies, such as with antacids or drugs which inhibit stomach acid secretion. While such therapies might provide temporal symptomatic relief, a cure is often not effected. In particular, it has been discovered that many such gastrointestinal disorders are mediated by infection of the gastric mucosa by bacteria. Thus treatment of the bacterial infection may be required in order to effectively treat the manifested gastrointestinal disorder.
Accordingly, a simple diagnostic test for gastrointestinal disorders could afford substantial advantages in the proper end effective treatment of patients having gastrointestinal disorders. Such a test should be easily performed, allowing definitive interpretation, and yield a result with a high degree of correlation to the presence or absence of the gastrointestinal disorder.
It was disclosed in U.S. Pat. No. 4,830,010, the subject matter of which is incorporated herein by reference, that gastrointestinal disorders of the upper gastrointestinal tract may be detected and diagnosed by methods involving the administration of urea to a human or lower animal subject followed by analyzing the breath of the subject to detect the presence of products of urea hydrolysis. The methods disclosed in U.S. Pat. No. 4,830,010 provided a rapid, inexpensive, non-invasive diagnosis, however, accuracy was compromised by several factors.
The
14
C-urea was administered in liquid form and caused contamination of the mouth and generation of labelled carbon dioxide from the oropharynx. When the solution of
14
C-urea contacts the oropharynx, a small amount of
14
CO
2
is generated by the hydrolysis of the urea as a result of urease from mouth bacteria contaminating the mouth. This contamination results in the generation of
14
CO
2
, which peaks approximately one minute after swallowing the solution and is generally detectable for 12 minutes. In some cases, excessive mouth hydrolysis results in continuation of this peak for up to 20 minutes, producing a possible false positive result. The liquid also was likely to empty quickly from the stomach through the pylorus. This prevented adequate contact between the
14
C-urea and the gastric mucosa, where the bacterial urease of
Helicobacter pylori
is located. Therefore, urea hydrolysis tended to be slowed and larger doses of isotope or breath volume collection bottles greater than 1.5 liters were necessary. The liquid additionally increased the possibility of spillage and safe transport of the isotope was difficult.
The shelf life of isotope in the solution was short leaving a possibility that contamination of the isotope with microorganisms could result in hydrolysis of the urea. To prevent the contamination, refrigeration and/or the addition of a preservative was necessary.
The breath samples were collected by blowing through a tube into a collecting bottle. Patients exhaled at a different rates, thereby introducing an unwanted variability into the test result. Because of this variability, several samples were necessary and the collection bottles were relative large to prevent spillage of bubbles and solution. It was found that the slow transit of lung air through the mouth caused heavy contamination of breath by labelled
14
CO
2
arising in the oropharynx.
Vászquez and others U.S. Pat. No. 4,851,209 describe in-vivo procedure of in-vivo diagnostics for the clinical evaluation of gastrointestinal ulcer illness that uses radioactive isotopes. The procedure involves the previous administration of a pharmaceutical followed by cintigraphic imagery of the gastrointestinal area of interest, with equipment of cintigraphic imagery.
Even when the use of urease or other indicators have been used in combination with pH indicators, all except Vászquez are conducted in-vitro.
It has now been found that the problems of the prior art relating to the diagnosis in a human or lower animal subject of a gastrointestinal disorder of the upper gastrointestinal tract caused or mediated by bacteria which result in the gastric materials of the subject to contain relatively large quantities of urease, can be overcome through the use of a novel method of detection of urease that uses a reactive encapsulated product for the detection of urease by breath and a device (kit) specially designed for quick tests.
It is therefore an object of this invention to provide a procedure for preparing a reactive product for pharmaceutical use for detecting urease caused by gastrointestinal disorders.
Another object of the present invention is to provide an encapsulated reactive product for pharmaceutical use comprising a safe amount of isotope-labelled urea, that is orally administered, and allows by breath analysis of the subject to determine the presence of the product of the hydrolysis of urea.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to with a procedure for obtaining a pharmaceutical product useful to detect a gastrointestinal disorder of the upper gastrointestinal tract in a human or lower animal, as well as the pharmaceutical product thereof.
Accordingly in a first aspect the present invention provides a process for the preparation of a reactive pharmaceutical product for the detection of gastrointestinal disorder caused by bacteria in the superior gastrointestinal tract, characterized by the preparation of a dense powdered vehicle or granules of sugar, or granules of Nu-pareil seeds, of a diameter from 0.12 to 3.0 mm and soluble in gastric fluids; dispersing in or coating on the vehicle a micro dose of
14
C-urea; and coating or encapsulating the resulting blend with a gelatin substance that dissolves rapidly, thereby obtaining a capsule, wherein the density of the vehicle is such that it allows deposition of the isotope contained in the capsule onto the gastrointestinal tract mucosa.
In a second aspect the invention provides a pharmaceutical product for breath tests for the detection of gastrointestinal disorder that comprises an isotope of
14
C-urea dispersed in or coated on a dense powdered or granulated vehicle of sugar, or Nu-pareil seeds, the resulting blend being coated with or enclosed in gelatin substance that dissolves rapidly in the presence of gastric juice, wherein the vehicle has a density sufficient to allow the capsule contents to be deposited onto the gastrointestinal tract mucosa, and wherein the granules have a diameter of from 0.12 and 3.0 mm.
Urea has the formula H
2
NCONH
2
and is a product that occurs naturally in the metabolism of proteins. The gastric materials of huma
Dority & Manning P.A.
Hartley Michael G.
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