Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-05
2003-04-22
Dees, Jose' G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C424S400000, C424S443000, C424S444000, C424S484000, C424S485000, C424S486000, C424S487000, C424S488000, C514S182000, C514S258100, C514S289000, C514S343000, C514S534000
Reexamination Certificate
active
06552024
ABSTRACT:
TECHNICAL DESCRIPTION
The present invention is directed to a device and method for administering agents in a dissolving film configuration.
BACKGROUND TO THE INVENTION
Many pharmaceutical dosage forms are administrated orally in the form of solid shaped articles such as tablets, pills, caplets and capsules that retain their shape under moderate pressure. Generally these dosage forms are designed to be swallowed whole or chewed to deliver the medication with adequate amounts of liquid. Some patients, particularly pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms. Certain patients such as children or animals resist taking medication, and may try to hide a solid pill in order to spit it out later. In addition, many pediatric and geriatric patients are unwilling to take a solid dosage form because the active agent is difficult to swallow or is retained in the pharynx or gullet even when liquids are consumed with the dosage unit. Furthermore, the availability of liquids at the time of administering medications may be limited for certain patients and may be restricted for certain diseases and/or treatments. Chewable tablets provide some advantages over the conventional tablets. However, they are not suitable for children wearing braces and the taste of the medication may be unpleasant and difficult to mask in a chewable tablet. At the same time, water may be still required for the administration of chewable tablets.
In addition, the standard oral dosage forms, such as tablets, pills, caplets, and capsules, are designed for short residence time in the mouth. Absorption of the agent from these dosage forms occurs in the gastrointestinal (GI) tract, after the agent has separated from the dosage form and dissolved in the gastric fluids. For some active agents, it is desirable to achieve absorption through the oral mucosal tissues in order to accelerate onset of the therapeutic effect.
Many active agents are poorly absorbed, even after they are dispersed in the stomach, because of low solubility or slow dissolution rate in the gastric fluids. Tablets may be formulated so as to be quick dissolving. These tablets are commonly placed on the tongue and disintegrate rapidly in the oral cavity. However, these dosage units are not fixed to a mucosal surface and may move around in the mouth. Consequently, they do not overcome a risk associated with choking or gagging that occurs with subjects having limited control of their swallowing reflexes. However, once placed in the mouth, these tablets dissolve rapidly in the saliva to provide a liquid formulation which is then swallowed. Quick dissolving tablets may be formed from a particulate support matrix containing the therapeutic agent, where the particulate support matrix is a protein (U.S. Pat. Nos. 5,807,576, 5,635,210, 5,595,761). Alternatively, the tablet may be formed from a laminate with several layers and an outer coating (JP 100535518). Tablets have also been manufactured from shearform matrices which are substantially amorphous sugar formed when crystalline sugar is subjected to heat and shear (WO 95/07194; WO 95/35293). Other methods of forming quick dissolving tablets include wet granulation methods (EP 0627 218) and dry granulation methods (EP 0124027A1) and by freeze-drying techniques (EP 0084705A2). Generally, quick dissolving tablets are formed using complex multi-step manufacturing processes. In addition, these tablets may have poor mechanical strength, are fragile and friable and have insufficient holding capacity for active ingredients (U.S. Pat. No. 5,720,974) and may be difficult to store and handle.
Therapeutic compounds are sometimes provided as powders or granules which may be difficult to swallow and cause unpleasant sensations in the mouth. Furthermore, many quick dissolving tablets contain particulates (>25 microns) which leave a “gritty” and unpleasant taste in the mouth. In the elderly, powders may cause choking and discomfort associated with trapping of granules in dentures. Powders and granules are generally packaged in a sealed pouch which requires tearing before use. This causes problems for geriatric patients and those suffering from arthritis in the fingers as well as for children. Consequently, problems of spillage of the contents arise in this group of patients. Furthermore, these oral preparations should be taken with water which for certain patients are inconvenient and may cause reduced patient compliance.
Liquid, syrups or suspensions are an alternative to solid dosage forms and are considered desirable for pediatric and geriatric patients who have problems in swallowing tablets. However, these dosage forms are often difficult to measure accurately and administer easily. Liquid formulations deteriorate rapidly upon exposure to heat or atmosphere and consequently have a relatively short shelf life. Furthermore, liquid formulations require a relatively large volume and are bulky to store.
In addition to solid and liquid dosage forms, rapidly dissolving buccal/oral delivery systems have been developed. These systems are commonly freeze dried preparations which are more expensive to manufacture as compared to tablets (U.S. Pat. No. 5,648,093). Furthermore, freeze dried preparations are brittle and fragile when handled and must be kept in dry conditions to avoid disintegration. The instability of freeze-dried preparations has been reduced somewhat by the addition of mannitol (U.S. Pat. No. 4,946,684). WO 9820862 reports a film that is formed according to a method that does not utilize freeze drying and avoids problems described in the art such as rigidity of the films, delayed softening and poor solubility in the mouth (U.S. Pat. No. 4,876,092; EP 0200508; EPO 381194; CA-PS 1-26331; DE 2449865.5; DE 3630603; EP 0452446 and EP 0219762). However, the film described in WO 9820862 relies on the use of at least two different non-ionic surfactants to achieve immediate wettability.
It is desirable that a dosage unit should provide a non-invasive, effective and economic means to deliver an active agent to the target site. Where the target site is the plasma, additional issues arise concerning the rate of delivery of the active agent to that site as measured by bioavailability. For many types of active agent, fast onset of the therapeutic effect is desirable. Traditional oral dosages, such as tablets, are limited in onset time by the rate of absorption in the gastro-intestinal tract. Formulations have been developed which, when applied in the mouth, lead to faster onset that the traditional oral dosages because they target the oral mucosa. These formulations include dosage units containing 75%-90% polyethylene glycol that melt at body temperature, in the mouth.(U.S. Pat. No. 5,004,601 and 5,135,752) Other formulations include liquid forms, lozenges or tablets that are administered sublingually or by a sweetened matrix on a stick. (U.S. Pat. No. 5,770,606, Streisand et al. and Zhang et al., Christie et al., Sasaki et al.). Whereas the above references address the delivery route, they do not address the problems of bioavailability that arise from poor solubility or low dissolution rate.
A delivery device that addresses the above limitations would represent a desirable improvement on existing delivery systems.
SUMMARY OF THE INVENTION
A novel dosage unit and its method of manufacture and use is provided. In an embodiment, the dosage unit includes a water-soluble hydrocolloid, mucosal surface-coat-forming film, such film including an effective dose of an active agent. In an embodiment of the invention, the hydrocolloid includes a polymer selected from the group consisting of a natural, semi-natural and synthetic biopolymer being exemplified by a polysaccharide and a polypeptide. In addition to the hydrocolloid, the film may further include one or more of an emulsifier, a plasticizer, a taste modifying agent, a water soluble inert filler, a preservative, a buffering agent, a coloring agent, a permeation enhancer, and a stabilizer. The film may further include an active agent selecte
Buranachokpaisan Thitiwan
Chen Li-Lan H.
Osborne James
Pfister William R.
Renn Donald W.
Choi Frank
Dechert
Dees Jose' G.
Deibert Thomas S.
Lavipharm Laboratories Inc.
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