Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2002-05-29
2004-02-03
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S452000, C424S458000, C424S459000, C424S460000, C424S467000, C424S462000, C424S484000, C424S485000, C424S486000, C424S487000, C424S488000, C424S483000, C424S480000, C424S491000, C424S493000, C424S494000, C424S495000
Reexamination Certificate
active
06685962
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical drug delivery systems for the controlled release of active agents having a narrow absorption window in the gastrointestinal tract, i.e. are usually absorbed in the duodenum and/or jejunum. The invention also relates to the uses of these controlled release delivery systems in the treatment of gastrointestinal-associated disorders and diseases in mammals.
BACKGROUND OF THE INVENTION
Pharmaceutical dosage forms which retain in the stomach for a prolonged period of time after oral administration, and release the active ingredient in a controlled manner are important for delivery of a wide variety of drugs. Various pharmaceutical controlled release drug delivery systems with prolonged gastric retention time have been described in the literature, which involve different technologies.
The advantages of using drug delivery systems are many. Of major importance in controlled drug therapy is the improved efficiency in treatment. Controlled drug therapy reduces the required frequency of administration, and single doses at periodic intervals are sufficient, resulting in improved patient compliance.
However, conventional controlled release drug delivery systems have only limited use for (1) drugs having a narrow absorption window in the gastrointestinal tract, i.e. are absorbed in the duodenum and/or jejunum; (2) local treatment of proximal parts of the gastrointestinal tract (stomach and/or duodenum); and (3) drugs which degrade in the colon. To enable the improved therapy in these cases, a gastroretentive pharmaceutical dosage form should be developed. After oral administration, such gastroretentive dosage form should retain in the stomach and release the drug in a controlled and prolonged manner. Examples of gastroretentive dosage forms are floating dosage forms and dosage forms that expand, swell or unfold in the stomach.
The rationale for developing expandable drug delivery systems is based on the nature of the pyloric antrum that, by means of antiperistaltic motion, retropels large bodies away from the pylorus back to the fundus and body of the stomach, thus prolonging their gastric retention time (GRT). Such dosage forms should preferably be designed to undergo biodegradation or disintegration, to enable their evacuation from the stomach.
U.S. Pat. No. 3,574,820 teaches the use of a gelatin matrix which hydrates in the stomach, gels, swells and cross-links with N-acetyl-homocysteine thiolactone to form a matrix too large to pass through the pylorus.
U.S. Pat. No. 4,207,890 discloses a drug dispensing device which comprises a collapsed, expandable imperforate envelope, made of a non-hydratable, body fluid and drug-permeable polymeric film, which contains the drug, and an expanding agent also contained within the polymeric envelope which, when in contact with body fluids, causes the envelope to expand to a volume such that the device is retained in the stomach.
U.S. Pat. No. 4,434,153 describes a device comprised of a matrix formed of a hydrogel that absorbs and imbibes fluid from the stomach, expands and swells, in order to retain in the stomach for an extended period of time, and a plurality of tiny pills dispersed throughout the matrix, having a drug-containing core and a fatty acid and wax wall surrounding the core
A significant disadvantage of the devices of the above publications is that they appear to ignore natural contractions of the stomach which may contribute to a rapid diminishing of size, leading to early removal of the device from the stomach. These devices lack the mechanical strength required to withstand the natural mechanical activity, that includes contractions of the stomach.
U.S. Pat. Nos. 4,767,627, 4,735,804 and 4,758,436 present dosage forms of various geometries: continuous solid stick; tetrahedron; planar disc; multi-lobed flat device; and ring. The devices are compressible to a size suitable for swallowing, and are self-expandable to a size which prevents passage through the pylorus. They are sufficiently resistant to forces of the stomach to prevent rapid passage through the pylorus for a pre-determined period of time and erode in the presence of gastric juices. The devices are homogenous, namely they contain the same polymer constitution in different areas of the device. The tetrahedron presented in U.S. Pat. No. 4,735,804 is homogenous in its four lobes, which are attached to each other by a polymeric matrix.
The medicaments are incorporated into the device as a liquid solution or suspension, which may necessitate the addition of mentioned preservatives or buffering agents. Alternatively, the controlled release drug module may be tethered or glued to the device.
U.S. Pat. Nos. 5,002,772 and 5,443,843 disclose an oral drug delivery system having a delayed gastrointestinal transit, which releases the drug/s contained therein in a controlled manner and which in their expanded form resist gastrointestinal transit. These delivery systems comprise one or more retention arms as a non-continuous compressible element, and an attached controlled release drug-containing device. The preferred configuration is a coil or a spiral. These systems must comprise at least two distinct parts (at least one retention arm and a controlled release device).
U.S. Pat. Nos. 5,047,464 and 5,217,712 describe a system comprising bio-erodible, thermoset, covalently cross-linked, poly(ortho) ester polymers, which expand from a compressed state upon delivery thereof. The acidic environment of the stomach eventually results in the degradation of the polymers within the system, thus permitting its removal from the stomach. The system is characterized by high resiliency.
Finally, U.S. Pat. No. 5,651,985 describes a system devised from a mixture of polyvinyl-lactams and polyacrylates which are characterized by their high degree of swelling in the stomach resulting in its retention in the stomach for a prolonged period of time.
Notwithstanding the developments in gastric retention devices, known devices still suffer many drawbacks, and there is need for yet improved delivery systems. The present invention is aimed at such improved devices, which would overcome the drawbacks of known devices.
It is therefore an object of the invention to provide a controlled-release drug delivery system that would retain in the stomach for a sufficient period of time, while releasing the active drug therefrom.
This and other objects of the invention would become clearer as the description proceeds.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical gastroretentive drug delivery system for the controlled release of an active agent in the gastrointestinal tract, which system comprises:
a) a single- or multi-layered matrix having a two- or three-dimensional geometric configuration comprising a polymer that does not retain in the stomach more than a conventional dosage form, said polymer selected from:
(1) a degradable polymer selected from:
(i) a hydrophilic polymer which is not instantly soluble in gastric fluids;
(ii) an enteric polymer substantially insoluble at pH less than 5.5;
(iii) a hydrophobic polymer; and
(iv) any mixture of at least two polymers as defined in (i), (ii) or (iii);
(2) a non-degradable; and
(3) a mixture of at least one polymer as defined in (1) with at least one polymer as defined in (2);
b) a continuous or non-continuous membrane, that does not retain in the stomach more than a conventional dosage form, affixed or attached to said matrix, said membrane comprising at least one polymer having a substantial mechanical strength; and
c) a drug, which may be in a particulate form or optionally contained within a drug-containing means; said drug or drug contained within said drug-containing means being embedded in a layer of said matrix, or being entrapped between at least two layers of said matrix, or being attached to said delivery system,
wherein said matrix when affixed or attached to said membrane prevents evacuation from the stomach of said delivery system for a period of time of from about 3
Friedman Michael
Hoffman Amnon
Klausner Eytan
Lavy Eran
Dinola-Baron Liliana
Lerner David Littenberg Krumholz & Mentlik LLP
Page Thurman K.
Yissum Research Development Company Of The Hebrew University Of
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