Oral pharmaceutical extended release dosage form

Details Oral pharmaceutical extended release dosage form Oral pharmaceutical extended release dosage form

2000-01-15

2003-08-12

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S470000, C424S464000, C424S468000, C424S469000, C424S451000, C424S497000, C424S480000, C424S494000, C424S474000

Reexamination Certificate

active

06605303

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to new pharmaceutical dosage forms which comprise a proton pump inhibitor, i.e. a H
+
,K
+
-ATPase inhibitor. The new dosage forms are enteric coated formulations which provide an extended and continuous release of the H
+
,K
+
-ATPase inhibitor in the small and/or large intestines resulting in an extended blood plasma profile. The formulations comprise a hydrophilic or hydrophobic matrix resulting in an extended release of the H
+
,K
+
-ATPase inhibitor preferably for a minimum of 2 and a maximum of 12 hours. Furthermore, the present invention refers to the manufacture of such extended release pharmaceutical formulations, and their use in medicine.
BACKGROUND OF THE INVENTION AND PRIOR ART
Acid labile H
+
,K
+
-ATPase inhibitors also named as gastric proton pump inhibitors are for instance compounds known under the generic names omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole. Some of these compounds are disclosed in EP-A1-0005129, EP-A1-124495, WO 94/27988, EP-A1-174726, EP-A1-166287 and GB 2163747.
These pharmaceutical substances are useful for inhibiting gastric acid secretion in mammals including man by controlling gastric acid secretion at the final step of the acid secretory pathway and thus reduce basal and stimulated gastric acid secretion irrespective of stimulus. In a more general sense, they may be used for prevention and treatment of gastric-acid related diseases in mammals and man, including e.g. reflux oesophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger-Ellison syndrome. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, and in patients with symptomatic gastro-oesophageal reflux disease (GORD). They may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre-and postoperatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, they may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and diseases related to these.
Therapeutic control of gastric acid secretion is fundamental in all theses diseases, but the degree and duration of acid inhibition required for optimal clinical effect is not fully understood.
It has been proposed by the Applicant in WO97/48380 (published Dec. 24, 1997, i.e. after the priority date of the present application) that an administration regimen that gives blood plasma levels extending from 2 to 2 hours (by any of several means) will result in a larger fraction of the proton pumps being inhibited. Thus, an extended blood plasma level should result in more effective inhibition of acid secretion resulting in improved efficacy in GORD, more rapid healing of gastric ulcer and improved eradication of
H. Pylori
. The present invention provides pharmaceutical dosage forms which achieve such extended plasma levels by an extended release of the drug.
A pharmaceutical dosage form comprising omeprazole or any other proton pump inhibitor is best protected from contact with acidic gastric juice by an enteric coating layer. In U.S. Pat. No. 4,786,505 and U.S. Pat. No. 4,853,230 such enteric coated preparations are described. These preparations have a core comprising an alkaline salt of the drug or a core comprising the drug together with an alkaline reacting compound. The core is coated with a water soluble or in water rapidly disintegrating separating layer and then with an enteric coating layer. WO 96/01623 and WO 96/01624 describe tableted dosage forms of omeprazole and other proton pump inhibitors, wherein enteric coating layered pellets are compressed into a multiple unit tableted dosage form. It is essential in these tableted formulations that the enteric coating layer can withstand the compression forces. None of these by the Applicant previously described formulations gave an extended release of the drug which resulted in an extended blood plasma profile.
WO 97/02020 describes a dosage form for pantoprazol together with an antibiotic substance, which dosage form has a release-slowing membrane positioned as a intermediate layer. Said membrane comprises a water-insoluble film-forming agent as an important feature of the dosage forms. WO 97/02021 describes the same type of dosage form for a reversible proton pump inhibitor in combination with an antibiotic substance.
A facilitated way to produce extended release dosage forms compared to applying a semipermeable membrane, is to make a dosage form comprising a matrix unit. Some advantages of such matrices are for instance easier processing methods mainly by the use of common granulating and tableting equipment, and sometimes also with regard to solvents handling, energy and production time gain etc.
The use of hydrophilic matrix tablets as a principle for extended drug release was first A described in the early 60's, see for instance U.S. Pat. No. 3,065,143. Also the hydrophobic matrix tablet principle for extended release originates from the 60's, for instance quinidine dureles were on the market in 1963.
Extended release dosage forms comprising different drugs in a matrix have been described in prior art. However, none of these matrix dosage forms as such is suitable for a H
+
,K
+
-ATPase inhibitor.
Some extended release hydrophilic matrix dosage forms are described in the literature for instance: In Journal of Pharmaceutical Sciences vol. 84, No. 3, March 1995, in which Kim describes dosage forms comprising theophylline or diltiazem hydrochloride. U.S. Pat. No. 5,273,758 describes dosage forms comprising for instance clemastine fumarate. EP 0249587 discusses felodipine formulations. Dosage forms comprising a benzodiazepine derivative are described by Franz et al in Journal of Controlled Release 1987, 5, 159-72.
Dosage forms comprising an extended release hydrophobic matrix have been described for instance by Romero et al in International Journal of Pharmacy 1991, 73, 239-48.
Extended release tablets with an additional coating layer have also been described, for instance by Sangalli et al in International Journal of Pharmaceutics, 91(1993), 151-6. The drugs exemplified are metoprolol tartrate and benfluorex. The described dosage form has an impermeable coating which is perforated to achieve a hole in the middle of the tablet, exposing a starting surface area for the dissolution of the inner core, i.e. dissolution of the active drug.
A rather complicated dosage form was described in U.S. Pat. No. 5,178,867. The dosage forms had a core comprising a drug which core was coated with a semipermeable wall (maintaining its physical integrity during the life-time of the dosage form) having at least one hole drilled through it as an exit port for the dissolved drug. It is also mentioned that an enteric coating layer may be applied for restricting drug delivery in the stomach and for providing drug release in the small intestine. This dosage form is much more complicated to manufacture than a matrix unit. There is no detailed description of a prepared dosage form comprising a proton pump inhibitor compound and testing of such a dosage form to assure that no acidic gastric fluid is penetrating the semipermeable membrane, and that the active substance is delivered intact to the site of absorption.
None of these dosage forms provides an easy-to-produce matrix dosage form which protect an acidic susceptible substance such as a proton pump inhibitor against degradation which occurs in contact with an acidic milieu such as the one found in the stomach.
SUMMARY OF THE INVENTION
Thus, the present invention relates to an enteric coated formulation with extended release properties comprising a hydrophilic or hydrophobic matrix, in which a H
+
,K
+
-ATPase inhibitor or one single enantiomer thereof, or an alkaline salt of the H
+
,K
+
-ATPase

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