Drug – bio-affecting and body treating compositions – Chewing gum type
Reexamination Certificate
2000-11-16
2003-03-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Chewing gum type
C424S439000, C424S440000, C424S464000, C424S489000
Reexamination Certificate
active
06531114
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention generally relates to medicaments and other agents. More specifically, the present invention relates to the delivery of medicaments or other agents.
It is of course known to provide agents to individuals for various purposes. There are a great variety of such agents. These agents can be used to treat diseases and as such are typically referred to as drugs or medicaments. Likewise, the drugs or medicaments can be used for prophylactic purposes. In addition, some agents are taken on an as needed basis while others must be taken at regular intervals by the individual being treated.
Still, it is known to provide such agents to an individual for a variety of indicated medicinal purposes such as sildenafil citrate for the treatment of male erectile dysfunction. Typically, drugs (medicaments) are administered parenterally or enterally. Of course, parenteral administration is the administration of the drug intravenously directly into the blood stream. Enteral refers to the administration of the drug into the gastrointestinal tract. In either case, the goal of the drug administration is to move the drug from the site of administration towards the systemic circulation. Except when given intravenously, a drug must traverse several semi-permeable cell membranes before reaching general circulation. These membranes act as a biological barrier that inhibits the passage of drug molecules. There are believed to be four processes by which drugs move across a biological barrier: passive diffusion; facilitated diffusion; active transport; and pinocytosis.
Passive diffusion is the transport across the cell membrane wherein the driving force for the movement is the concentration gradient of the solute. In orally administered drugs, this absorption occurs in the small intestines. Facilitated diffusion is believed to be based on a carrier component that combines reversibly with the substrate molecule at the cell membrane exterior. The carrier substrate complex diffuses rapidly across the membrane with release of the substrate at the interior surface. Active transport requires an energy expenditure by the cell and appears to be limited to agents with structural similarities to normal body constituents. These agents are usually absorbed from specific sites in the small intestines. Pinocytosis refers to the engulfing of particles or fluid by a cell. It is believed to play a minor role in drug transport.
Merck Manual,
16th Edition, pp. 2598-2599.
In determining the efficacy of a drug and the effectiveness of the use of a drug to treat a disease, drug absorption is a critical concern. Drug absorption refers to the process of drug movement from the site of administration toward the systemic circulation.
Oral administration of drugs is by far the most common method. When administered orally, drug absorption usually occurs due to the transport of cells across the membranes of the epithelial cells within the gastrointestinal tract. Absorption after oral administration is confounded by numerous factors. These factors include differences down the alimentary cannel in: the luminal pH; surface area per luminal volume; perfusion of tissue, bile, and mucus flow; and the epithelial membranes. See
Merck Manual
at page 2599.
In particular, oral transmucosal administration via the sublingual or buccal routes is generally quite rapid because of the rich vascular supply within the oral mucosa. The oral cavity exhibits a minimal barrier to drug transport and results in a rapid rise in blood concentrations.
In addition, for significant drug absorption to occur across the oral mucosa, the drug must have a prolonged exposure to the mucosal surface. Taste, then, is one of the major determinants of contact time with the oral mucosa. Such is the case with most medicaments. Sildenafil citrate, for example, exhibits a bitter taste.
Physician's Desk Reference,
23
rd
edition, Page 2424.
A further issue effecting the absorption of orally administered drugs is the form of the drug. Most orally administered drugs are in the form of tablets or capsules. This is done primarily for convenience, economy, stability, and patient acceptance. Accordingly, these capsules or tablets must be disintegrated or dissolved before absorption can occur. There are a variety of factors capable of varying or retarding disintegration of solid dosage forms. Further, there are a variety of factors that effect the dissolution rate and therefore determine the availability of the drug for absorption. See
Merck Manual
at page 2600.
Sildenafil citrate, in particular, is the effective ingredient in Viagra® tablets manufactured by Pfizer Inc. Although the tableted dosage form of sildenafil citrate has been proven very effective for male erectile dysfunction, such a dosage form has shown certain side effects. For instance, some patients taking Viagra® tablets experienced gastroesophageal reflux (a regurgitation of food from the stomach). A gradual release dosage form of sildenafil citrate might prove to be gentler to the stomach and enhance the desirability of the drug to a larger patient population requiring its use.
Not only is drug absorption a central issue in drug delivery, but also the bioavailability of the drug as well. Bioavailability is defined as the rate at which and the extent to which the active moiety (drug or metabolite) enters the general circulation, thereby gaining access to the site of action. Bioavailability depends upon a number of factors, including how a drug product is designed and manufactured, its physiochemical properties, and factors that relate to the physiology and pathology of the patient. See
Merck Manual
at page 2602.
When a drug rapidly dissolves from a dosage form and readily passes across membranes, absorption from most administration sites tends to be complete. This is not always the case for drugs given orally. Before reaching the vena cava, the drug must move down the alimentary cannel and pass through the gut wall and liver, which are common sites of drug metabolism. Thus, the drug may be metabolized before it can be measured in the general circulation. This can cause a decrease in the amount of drug available to exert a therapeutic effect called the first pass effect.
A large number of drugs show low bioavailabilities owing to an extensive first pass metabolism. The two other most frequent causes of low bioavailability are insufficient time in the oral cavity, or GI tract and the presence of competing reactions. See
Merck Manual
at page 2602. Bioavailability considerations are most often encountered for orally administered drugs. Differences in bioavailability can have profound clinical significance. Sildenafil citrate, for example, exhibits only a 40% bioavailability after oral administration, of which the active metabolite accounts for about one-half.
Physician's Desk Reference,
at 2425.
Therefore, there is a need for an improved sildenafil or derivative thereof formulation and method of delivering the same to an individual requiring its use, which overcomes the absorption, bioavailability, and gastroesophageal problems noted above as well as other needs.
SUMMARY OF THE INVENTION
The present invention provides improved methods and delivery vehicles, i.e., dosage forms, for delivering sildenafil or derivatives thereof to an individual requiring its use. To this end, chewing gum is provided as a dosage form that contains sildenafil, preferably sildenafil citrate. The sildenafil citrate component is present within the chewing gum composition (the water soluble portion and/or insoluble base portion). It has been found that by chewing the chewing gum composition of the present invention, the drug is gradually released from the chewing gum. Continuing to chew the chewing gum creates a pressure within the oral cavity of the individual to force sildenafil citrate directly into the systemic system of that individual through the oral mucosa of the oral cavity via the buccal or sublingual absorption routes. This gradual release of sildenafil citrate by the che
Gmunder Charlean B.
Li Weisheng
Ream Ronald L
Bell Boyd & Lloyd LLC
Howard S.
Page Thurman K.
Wm. Wrigley Jr. Company
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