Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-10-24
2003-03-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S468000, C424S471000, C424S473000, C424S474000, C424S900000, C424S479000, C424S482000, C424S489000
Reexamination Certificate
active
06531152
ABSTRACT:
FIELD OF THE INVENTION
The invention is directed to a drug delivery system for delivery of enterally-administered pharmaceuticals to specific locations along the gastrointestinal tract by immediate release (not sustained) of all or most of the drug at the specific location. The drug delivery system has the capability of complete loss of integrity in a very short space of time allowing delivery of virtually all of the drug contained therein at the location of disintegration. The features that allow this capability are a channel-forming coating allowing the controlled entry of liquid into a core and a core capable of absorbing liquid and swelling enough to cause breakage of a coating surrounding the core, the core disintegrating rapidly after the integrity of the coating is breached.
BACKGROUND OF THE INVENTION
Specific delivery of drugs to a selected target in the gastrointestinal tract is desired for the treatment of a wide variety of diseases and conditions. It is especially desirable to be able to deliver drugs so that they are targeted to, and absorbed at, specific regions of the gastrointestinal tract. Targeting drugs to specific regions along the gastrointestinal tract provides the ability to locally treat gastrointestinal diseases, thus avoiding systemic side effects of drugs or inconvenient and painful direct delivery of drugs. Such specific delivery also potentially increases the efficiency of the drug and enables a reduction of the minimum effective dose of the drug.
Delivery systems based on coatings exist in the art. Some systems have been reported to target particular parts of the body. For example, U.S. Pat. No. 5,593,697 describes a pharmaceutical implant containing a biologically active material, an excipient comprised of at least one water soluble material and at least one water insoluble material, and a polymer film coating adapted to rupture at a predetermined period of time after implantation. In one form, a bilayer film coating forms an impermeable barrier to the drug. An insoluble outer film controls the degree of access of physiological fluid to an inner film that is soluble at physiological pH. By varying the thickness of the outer film, access of the physiological fluid to the inner film, and thus the time before the failure of the inner film occurs, is said to be controlled. Failure of the inner film then permits a swellable excipient (disintegrant) to exert a force on the outer film which then ruptures releasing the core content. In another embodiment, a monolayer film is used. A film coating comprising a mixture of ethylcellulose and a copolymer of glycolic and lactic acid is used. Ethylcellulose is an insoluble polymer and thus when the PLGA polymer in the film hydrolyzes, the film becomes porous and allows release of the drug. The rate of hydrolysis of the PLGA depends on the ratio of lactic-to-glycolic acid in the polymer.
U.S. Pat. No. 4,252,786 describes a controlled release tablet for the administration of medicinal agents over a prolonged period of time. It involves the application of a film comprising a combination of hydrophobic and hydrophilic polymers to an insoluble swelling type delayed release matrix to modify the drug release rate. Initially when the film is intact, the release of the drug contained in the matrix is primarily controlled by diffusion of solvent and solute molecules through the film. As water or gastric fluid permeates through the film, the gummy complex forms in the core and the slight swelling of the complex causes the film to rupture or erode. The release rate is then controlled by the gummy complex. The application of a relatively water-insoluble water-permeable film primarily controls the drug release rate while the matrix gel is being generated and it is reported that this generates a smoother, gradual, more uniform, release rate during the period of about 8-12 hours, approaching a zero order release pattern.
U.S. Pat. Nos. 5,260,069 and 5,472,708 describe a dosage form for delivering drugs, and particularly drugs that cannot be released by diffusion through a porous coating, such as water insoluble drugs. Pellets are provided in a unit dosage form such as a capsule or tablet. The pellets are composed of a core containing the drug and swelling agent which expands in volume when exposed to water. The core is enclosed within a membrane or coating that is permeable to water. The membrane is composed of a water insoluble but permeable film forming polymer, a water soluble film forming polymer and a permeability reducing agent. Water diffuses through the coating and into the core. As water is taken up by the swelling agent the core expands, exerting force on the coating until it bursts, releasing the drug. The permeability reducing agent reduces the rate at which water reaches the swelling agent, thereby delaying release time. The water soluble polymer dissolves, weakening the coating so that it bursts sooner. By varying the proportions of the three coating ingredients and/or coating thickness, the release timing is reported to be effectively controlled.
U.S. Pat. No. 4,897,270 describes a pharmaceutical tablet comprising a tablet core and a film coat to mask the taste of the core. The core disintegrates immediately following rupture of the film coat. The film coat allows a permeation of moisture to the core which ruptures very rapidly upon contact with gastrointestinal fluid. Thus the core immediately disintegrates, allowing dispersion and dissolution of the drug.
U.S. Pat. No. 5,204,121 describes a drug release system in pellet form where the pellets consist of a core containing the active compound. The core is surrounded by a polymer-containing jacket and a undigestible lacquer layer that is permeable to water. The outer lacquer layer does not dissolve but carries water to the migration controlling jacket layer which then brings the liquid in contact with the drug containing core.
U.S. Pat. No. 4,891,223 describes compositions for the sustained release of a pharmaceutical, comprising a drug-containing core, a first coating containing a polymer swellable upon penetration of the surrounding media, and a second coating, enveloping the first coating, comprising a polymer that is water-soluble and that forms a semi-permeable barrier. The outer coating permits diffusion of the media, into the first coating and then diffusion of the dissolved drug into the surrounding media. The second coating must have requisite stretchability to prevent rupture of a second coating due the swelling of the first coating until a specific time in the release pattern.
U.S. Pat. No. 4,327,725 describes a variation of a basic osmotic device for drug release. The structure of the device is an active agent enclosed in a hydrogel layer that is enclosed in a semi-permeable membrane. The semi-permeable membrane allows diffusion of external fluid but does not allow diffusion of the solution of active agent to the surrounding environment. The hydrogel swells with absorption of external fluid and exerts pressure on the solution of active agent in the external fluid. The solution of the active agent in the external fluid is then delivered to the surrounding media through a single specially constructed passageway through the hydrogel layer and the membrane.
Delivery of Drugs in the Alimentary Canal
The targeting of drugs to desired locations in the alimentary canal can be complicated. Various factors must be taken into consideration for delivery to desirable areas of the alimentary canal. Each segment of the alimentary canal has distinct features which may hinder or favor permeation of drugs across the membrane. The following characteristics are to be taken into account:
1. Anatomic—Surface area, epithelium, presence of mucus cells, venous drainage, lymphatic drainage;
2. Physiologic features—absorption pathways, pH, motility and transit time, enzymes;
3. Biochemical features—endogenous secretion, pH, gut flora, enzymes;
4. Mechanical features—mucus and water coating layers and their turnover rate;
5. Immunological features—antigenic stimulation at the e
Flashner Moshe
Lerner E. Itzhak
Penhasi Adel
Channavajjah Lakshmi
Dexcel Pharma Technologies Ltd.
Graeser D'vorah
Page Thurman K.
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