Solid oral pharmaceutical formulation of modified release...

Details Solid oral pharmaceutical formulation of modified release... Solid oral pharmaceutical formulation of modified release...

2000-09-12

2004-08-24

Tran, Susan T. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S457000, C424S458000, C424S459000, C424S461000, C424S462000, C424S472000, C424S480000, C424S482000, C424S489000, C424S490000, C424S493000, C424S494000, C424S495000

Reexamination Certificate

active

06780436

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to new pharmaceutical formulations that contain an acid labile benzimidazole compound, suitable for oral administration, constituted of a number of pellets that comprise the active ingredient, one or more intermediate layers that comprise, at least, a system of modified release, and an external enteric coating. The invention also refers to the procedure for the production of said pellets and pharmaceutical formulations and to the use thereof in Medicine.
BACKGROUND OF THE INVENTION
The compound, 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulphinyl]-1H-benzimidazole, is a benzimidazole compound suitable for inhibiting the gastric secretion in mammals. In particular, it is suitable for the prevention and treatment of disorders related with the secretion of gastric acid, for example, gastric ulcer, duodenal ulcer, reflux esophagitis, Zollinger-Ellison syndrome, etc. Other benzimidazole compounds with anti-ulcer activity are pantoprazole, lansoprazole and rabeprazole.
Omeprazole, just as is the case with other benzimidazole compounds that have therapeutic interest, is an acid labile compound. This causes numerous problems when it comes to developing a pharmaceutical formulation for oral administration due to the fact that when said compound comes into contact with the stomach content, which is a strongly acidic environment, degradation occurs. This lability may be responsible for the variability of the intra- and inter-individual therapeutic response of omeprazole.
To avoid contact between acid labile compounds and gastric juice after oral administration of said compounds, solid pharmaceutical formulations have been developed that comprise a nucleus that contains the acid labile compound and an external layer that constitutes a gastro-resistant coating that may be separated by one or more intermediate layers. In some cases, conventional enteric coatings of acidic nature cannot be used because the active compound would decompose on contact, either direct or indirect, with this coating. This would be evidenced by a colour change and by a reduction in the amount of active compound after a time.
There are several ways of solving the problem related to the stability of the active compound. One of these consists of creating an alkaline environment around the acid labile benzimidazole compound, which is achieved using alkaline salts of the benzimidazole compound and/or incorporating a compound of alkaline reaction in the pharmaceutical gastro-resistant preparation [see, for example, European patent application EP 0 244 380 and the U.S. Pat. No. 4,786,505]. Another way of solving the problem of stability of the active compound is based on the creation of a physical barrier that manages a complete separation between the active compound and the enteric layer, thus avoiding any degradation of the active compound, and comprises the use of acceptable pharmaceutical excipients except those that give an alkaline reaction [see, for example, European patent EP 0 773 025].
The European patent application EP 0 244 380 describes pharmaceutical formulations suitable for oral administration of acid labile substances that comprise (a) a nucleus that contains the active substance along with a compound of alkaline reaction, (b) one or several inert intermediate layers that contain the excipients for the tablets that are soluble in water and which disintegrate quickly in water, a polymer forming a film soluble in water optionally along with compounds of alkaline reaction that act as regulators of pH between the nucleus and the external layer, and (c) an external layer consisting of an enteric coating.
The U.S. Pat. No. 4,786,505 describes pharmaceutical formulations suitable for oral administration of omeprazole that comprise (a) a nucleus that comprises omeprazole and a compound of alkaline reaction, an alkaline salt of omeprazole and a compound of alkaline reaction, or only an alkaline salt of omeprazole, (b) one or several inert intermediate layers soluble in water or that disintegrate quickly in water, and (c) an external layer consisting of an enteric coating.
The U.S. Pat. No. 5,626,875 describes pharmaceutical formulations suitable for the oral administration of acid labile benzimidazole compounds that comprise (a) a nucleus formed of inert granules, the active compound, an inert polymer soluble in water and excipients that do not exhibit alkaline reactions, (b) an inert layer coating the aforementioned nucleus, formed from a polymer soluble in water and non-alkaline excipients, and (c) an external layer consisting of an enteric coating.
Other pharmaceutical formulations of benzimidazole compounds are described in the PCT patent applications: WO 96/01623, which describes a form of dosing comprised of multiple units that contain omeprazole or an alkaline salt thereof, and that is composed of units deployed in the form of layers, individually covered with an enteric coating, that contain the active compound. These units deployed in the form of enterically covered layers are mixed with excipients for tablets that are then compressed together; and WO 96/01624, that describes a form dosing comprised of multiple units similar to that described in the application PCT WO 96/01623 that contains, by way of the active ingredient, an inhibitor of H
+
K
+
-ATPase [proton pump], labile in acid medium, for example, omeprazole, lansoprazole or pantoprazole.
One problem associated with some pharmaceutical formulations for oral administration of acid labile benzimidazole compounds is related to the plasma half life of the active ingredient. In general, the plasma concentration of omeprazole, administered by means of hard gelatin capsules that contain omeprazole pellets with enteric coating, is at peak 2 hours after administration, with a gradual tailing off at later times. This leads to large fluctuations in the concentration of the active ingredient in blood and tissues that in turn leads to the need to carry out frequent administrations of the medicament to maintain a suitable therapeutically effective concentration.
As is known, in order that a certain active ingredient can act in a therapeutically effective manner it is necessary to reach a concentration in blood lying within the range known as the “effective concentration”. The concentration in blood of the active ingredient at levels greater than the effective concentration tends to increase the incidence of secondary effects, while concentrations below the effective concentration level would result in a weak or null pharmacological response. With a target to obtain an active ingredient blood concentration level lying within the effective concentration range, different solid pharmaceutical formulations have been developed with modified release that allow the release and absorption of the active ingredient to be adjusted with respect to biotransformation thereof and elimination thereof from the organism, thus allowing the secondary effects to be reduced and prolonging the action of the active ingredient. Despite the numerous advantages that solid pharmaceutical formulations of modified release enjoy not many such pharmaceutical formulations have been described for the administration of omeprazole or other acid labile benzimidazole compounds.
The patent application PCT WO 98/52547 describes a pharmaceutical formulation of an active ingredient, for example, an inhibitor of the proton pump such as omeprazole, suitable for oral administration thereof, that comprises a composition for the controlled release of an active ingredient in the gastric environment during a prolonged period of time consisting of microspheres that comprise an active ingredient in the interior nucleus of the microsphere, a layer controlling the rate of release of the active ingredient consisting of a polymer insoluble in water, and an external layer of a bioadhesive agent in the form of a cationic polymer. In general, these formulations act by releasing the active ingredient i

Affiliated with

Also associated with

Rating

Solid oral pharmaceutical formulation of modified release... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Solid oral pharmaceutical formulation of modified release..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Solid oral pharmaceutical formulation of modified release... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3358040