Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-10-25
2004-04-20
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S486000, C424S488000
Reexamination Certificate
active
06723340
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention arises in the technology of pharmaceutical dosage forms, and relates in particular to formulations for drugs that benefit from a prolonged time of controlled release in the stomach and upper gastrointestinal (GI) tract, and from an enhanced opportunity for absorption in the stomach and upper GI tract rather than the lower portions of the GI tract.
2. Description of the Prior Art
Many drugs have their greatest therapeutic effect when released in the stomach, particularly when the release is prolonged in a continuous, controlled manner. Drugs delivered in this manner have fewer side effects and produce their therapeutic effect without the need for repeated or frequent dosing. Localization of the drug delivery in the stomach is an advantage for the treatment of local disorders of the stomach such as esophageal reflux disease, for the eradication of ulcer-causing bacteria in the gastric mucosa, and for the treatment of disorders that require sustained antacid action. Sustained release in the stomach is also useful for therapeutic agents that the stomach does not readily absorb, since sustained release prolongs the contact time of the agent in the stomach or in the upper part of the small intestine, which is where absorption occurs and contact time is limited.
In the normal digestive process, the passage of matter through the stomach is delayed by a physiological condition that is variously referred to as the digestive mode, the postprandial mode, or the “fed mode.” Between fed modes, the stomach is in the interdigestive or “fasting” mode. The difference between the two modes lies in the pattern of gastroduodenal motor activity.
In the fasting mode, the stomach exhibits a cyclic activity called the interdigestive migrating motor complex (IMMC). This activity occurs in four phases:
Phase I, which lasts 45 to 60 minutes, is the most quiescent, with the stomach experiencing few or no contractions.
Phase II is characterized by sweeping contractions occurring in a irregular intermittent pattern and gradually increasing in magnitude.
Phase III consists of intense bursts of peristaltic waves in both the stomach and the small bowel. This lasts for 5 to 15 minutes.
Phase IV is a transition period of decreasing activity which lasts until the next cycle begins.
The total cycle time for all four phases is approximately 90 minutes. The greatest activity occurs in Phase III whose powerful peristaltic waves sweep the swallowed saliva, gastric secretions, food particles, and particulate debris, out of the stomach and into the small intestine and colon. Phase III thus serves as an intestinal housekeeper, preparing the upper tract for the next meal and preventing bacterial overgrowth.
The fed mode is initiated by nutritive materials entering the stomach upon the ingestion of food. Initiation is accompanied by a rapid and profound change in the motor pattern of the upper gastrointestinal (GI) tract, over a period of 30 seconds to one minute. The change is observed almost simultaneously at all sites along the GI tract and occurs before the stomach contents have reached the distal small intestine. Once the fed mode is established, the stomach generates 3-4 continuous and regular contractions per minute, similar to those of the fasting mode but with about half the amplitude. The pylorus is partially open, causing a sieving effect in which liquids and small particles flow continuously from the stomach into the intestine while indigestible particles greater in size than the pyloric opening are retropelled and retained in the stomach. This sieving effect thus causes the stomach to retain particles exceeding about 1 cm in size for approximately 4 to 6 hours.
The particle size required for gastric retention during the fasting mode is substantially larger than the particle size required for gastric retention in the fed mode. Particles large enough to be retained in the fasting mode are too large for practical administration in most patients. Particles of a smaller particle size can be retained in the stomach if they are administered to a patient who is in the fed mode, and this offers a means of prolonging the amount of time that the particles spend in the stomach.
The prior art of dosage forms for gastric retention also teaches that the residence time of drug formulation particles in the stomach can be prolonged by using particles that are small enough to be swallowed comfortably but swell to a larger size upon contact with the gastric fluid in the stomach. With a great enough degree of swelling, particles of this type achieve gastric retention regardless of whether the subject is in the fed mode or the fasting mode. One means of achieving a swellable particle is to disperse the drug in a solid matrix formed of a substance that absorbs the gastric fluid and swells as a result of the absorbed fluid. Disclosures of this type of particle are found in U.S. Pat. No. 5,007,790 (“Sustained-Release Oral Drug Dosage Form;” Shell, inventor; Apr. 16, 1991), U.S. Pat. No. 5,582,837 (“Alkyl-Substituted Cellulose-Based Sustained-Release Oral Drug Dosage Forms;” Shell, inventor: Dec. 10, 1996): U.S. Pat. No. 5,972,389 (“Gastric-Retentive Oral Drug Dosage Forms for the Controlled Release of Sparingly Soluble Drugs and Insoluble Matter;” Shell et al., inventors; Oct. 26, 1999); and International (PCT) Patent Application WO 98/55107 (“Gastric-Retentive Oral Drug Dosage Forms for Controlled Release of Highly Soluble Drugs;” Shell et al., inventors; publication date Dec. 10, 1998).
Polymer matrices have also been used to achieve controlled release of the drug over a prolonged period of time. Such sustained or controlled release is achieved either by limiting the rate by which the surrounding gastric fluid can diffuse through the matrix and reach the drug, dissolve the drug and diffuse out again with the dissolved drug, or by using a matrix that slowly erodes, continuously exposing fresh drug to the surrounding fluid. Disclosures of polymer matrices that function by either of these two methods are found in U.S. Patent No. 6,210,710, (“Sustained release polymer blend for pharmaceutical applications,” Skinner, inventor, Apr. 3, 2001); U.S. Pat. No. 6,217,903, (“Sustained release polymer blend for pharmaceutical applications,” Skinner, inventor, Apr. 17, 2001); International (PCT) Patent Application WO 97/18814 (Pharmaceutical Formulations,” MacRae et al., inventors, publication date May 29, 1997); U.S. Pat. No. 5,451,409, (“Sustained release matrix system using hydroxyethyl cellulose and hydroxypropyl cellulose polymer blends,” Rencher et al., inventors, Sep. 19, 1995); U.S. Patent No. 5,945,125, (“Controlled release tablet,” Kim, inventor, Aug. 31, 1999); International (PCT) Patent Application WO 96/26718 (“Controlled Release Tablet,” Kim, inventor: publication date Sep. 6, 1996); U.S. Pat. No. 4,915,952, (“Composition comprising drug, HPC, HPMC, and PEO,” Ayer et al., inventors, Apr. 10, 1990); U.S. Pat. No. 5,328,942, (“Seed film compositions,” Akhtar et al., inventors, Jul. 12, 1994); U.S. Pat. No. 5,783,212, (“Controlled release drug delivery system,” Fassihi et al., inventors, Jul. 21, 1998); U.S. Pat. No. 6,120,803, (“Prolonged release active agent dosage form for gastric retention,” Wong et al., inventors, Sep. 19, 2000); U.S. Pat. No. 6,090,411, (“Monolithic tablet for controlled drug release,” Pillay et al., inventors, Jul. 18, 2000).
The goals of gastric retention and controlled release are not always compatible. Poly(ethylene oxide) is a matrix material that possesses both swelling and controlled release properties, but at the amounts needed for high drug dosage, and particularly the amounts needed for sufficient swelling to achieve gastric retention, the use of poly(ethylene oxide) raises regulatory concerns, since the United States Food and Drug Administration lists poly(ethylene oxide) as a substance with undefined toxicology considerations when used at sufficiently high doses on a long-term basis. Other matrix materials swell but also offer the b
Berner Bret
Chau Mei
Gusler Gloria
Padua Aimee
DepoMed, Inc.
Heines M. Henry
Townsend and Townsend / and Crew LLP
Webman Edward J.
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