Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-08-16
2003-07-01
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S435000, C424S448000, C424S449000
Reexamination Certificate
active
06585997
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a bioerodable pharmaceutical carrier device that adheres to mucosal surfaces for the localized, controlled delivery of pharmaceuticals or other active compounds and/or the protection of the underlying treatment site.
BACKGROUND OF THE INVENTION
The localized treatment of body tissues, diseases and wounds requires that a particular pharmaceutical be administered and maintained at the treatment site for a therapeutically effective period of time. The topical treatment of wet, mucosal surfaces has been problematic, since natural bodily fluids can rapidly wash away a topically applied active compound before the appropriate therapeutic action to the underlying surface can occur. In the mouth, saliva, the natural replacement of the mucosal tissue, and the actions of eating, speaking and drinking are just some of the problems that have limited the usefulness of pharmaceutical carrier devices.
Gels, pastes, tablets and films have been developed as bioadhesive carriers and are well known in the art. These types of products, however, do not exhibit all of the major characteristics required for an efficient and commercially acceptable pharmaceutical delivery device for mucosal treatment. The important characteristics include, water erodability, ease of handling and application to the treatment site, comfort with minimal foreign body sensation, rapid adhesion, prolonged residence time for the protection of the treatment site and/or the delivery of a pharmaceutical or other active compound, and ease of removal from the underlying mucosal surface by natural erosion or dissolution of the delivery device at the treatment site.
Bioadhesive gels used especially in the oral mucosal cavity are known in the art. For example, U.S. Pat. No. 5,192,802 describes a bioadhesive teething gel composed of a mixture of sodium carboxymethyl cellulose and xanthan gum. This gel composition may have potential use in the treatment of canker sores, fever blisters and hemorrhoids. However, these types of gel systems have limited residence times, since bodily fluids such as saliva will quickly wash gels away from the treatment site. Other bioadhesive gels described in U.S. Pat. Nos. 5,314,915; 5,298,258 and 5,642,749 use an aqueous or oily medium and different types of bioadhesive and gelling materials, but still suffer from the inherent limitation of all gel products. Another type of bioadhesive products known in the art is denture adhesive pastes. These products, however, were developed primarily for their adhesive properties only, and not to protect tissue or deliver pharmaceuticals to the underlying mucosal surface. However, active compounds such as local anesthetics may be formulated with the paste for the relief of sore gums. Denture adhesive pastes are described in U.S. Pat. Nos. 4,894,232 and 4,5518,721. In the '721 patent, the combination of sodium carboxymethyl cellulose and polyethylene oxide in polyethylene glycol is used to provide a bioadhesive composition. Mucoadhesive pastes have also been used as protective films and drug delivery systems. Orabase®-B, a commercialized paste product that has both film forming and adhesive properties, is used for the relief of mouth sores. This product does provide numbing of the treatment site, but the residence time is small due to the quick dissolution by saliva. This product contains guar gum, sodium carboxymethyl cellulose, tragacanth gum and pectin.
Bioadhesive tablets are described in U.S. Pat. No. 4,915,948. A xanthan gum or a pectin in combination with an adhesion enhancing material such as polyol is the water-soluble bioadhesive used in this device. Although the residence time is greatly enhanced, these tablets are not user friendly, especially when used in the oral cavity, due to their unpleasant feeling, solidity, bulkiness and slow dissolution time. Also, solid devices cannot readily adhere to curved surfaces, especially crevices within the oral cavity. Bioadhesive tablets described in U.S. Pat. Nos. 4,226,848; 4,292,299, and 4,250,163 are single or bilayer devices having an average thickness of 0.2 to 2.5 mm. These devices are less bulky, but have limited residence times. They are composed of a non-adhesive material such as cellulose ether, a bioadhesive ingredient such as polyacrylic acid, sodium carboxymethyl cellulose, or polyvinylpyrrolidone, and a binder for tableting purposes. The cellulose derivatives used in these devices may or may not be water-soluble. The bilayer devices described in the '299 patent contain methyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose. Bandages and bioadhesive laminated films are also known in the art. The films as described in U.S. Pat. Nos. 3,996,934 and 4,286,592 are thinner, more flexible and therefore elicit a decreased foreign body sensation. The laminated films are usually composed of an adhesive layer, a reservoir layer and a backing layer and are designed to deliver drugs through the skin or mucosa. These films are typically not water soluble, thus they are not dissolved or washed away by bodily fluids and must be removed after the prescribed treatment time.
Film delivery systems for use on mucosal surfaces are also known in the art. These types of systems, which are water-insoluble and usually in the form of a laminated, extruded or composite film, are described in U.S. Pat. Nos. 4,517,173; 4,572,832; 4,713,243; 4,900,554 and 5,137,729. The '173 patent relates to a membrane-adhering film composed of at least three layers, including a layer containing a pharmaceutical, a layer with limited water solubility, and an intermediate layer. The pharmaceutical layer contains a drug and a cellulose derivative selected from hydroxypropyl cellulose, methyl cellulose, and hydroxypropylmethyl cellulose. The layer having limited water solubility consists of a combination of one or more cellulose derivatives and a hydrophobic fatty acid, and the intermediate layer is made of cellulose derivatives. The '832 patent describes a\soft film for buccal delivery. The film is composed of a water soluble protein, a polyol, and a polyhydric alcohol such as cellulose and polysaccharides and coloring and flavoring agents. The '243 patent relates to a single or multi-layered bioadhesive thin film made from 40-95% water soluble hydroxypropyl cellulose, 5-0% water-insoluble ethylene oxide, 0-10% water-insoluble ethyl cellulose, propyl cellulose, polyethylene or polypropylene and a medicament. These films are three-layered laminates and are composed of a bioadhesive layer, a reservoir layer, and a non water-soluble outer protective layer. The '729 patent teaches a soft, adhesive film for use on oral mucosa. The film is comprised of a mixture of vinyl acetate non water-soluble homopolymer, an acrylic acid polymer, a cellulose derivative and a systemic drug.
In the '554 patent, the device is designed for use in the oral cavity and is composed of an adhesive layer including a mixture of an acrylic acid polymer, a water-insoluble cellulose derivative, a water-insoluble or sparingly soluble backing layer, and a pharmaceutical. The adhesive layer contains the active ingredient and upon application to the treatment site, the drug is delivered to the underlying mucosal surface. This patent also teaches that all three of the aforementioned components are required to attain an appropriate adhesive device suitable for mucosal treatment and drug delivery.
Finally, bioerodable films for the delivery of pharmaceutical compounds are also known in the art. U.S. Pat. Nos. 5,800,832 and 6,159,498 describe a bioerodable, water soluble pharmaceutical device to treat mucosal surfaces. These bilayer devices are composed of an adhesive layer and a non-adhesive backing layer, and the pharmaceutical may be contained in either or both layers.
The composition of the adhesive layer comprises polyacrylic acid, sodium carboxymethyl cellulose, and polyvinyl pyrrolidone, alone or in combination thereof. In addition to these mucoadhesive polymers, film fo
Callahan Howard
Moro Daniel G.
Nowotnik David
Access Pharmaceuticals Inc.
Azpuru Carlos A.
Jackson & Walker, LLP
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