Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-09-28
2003-05-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S443000, C424S448000, C514S772500
Reexamination Certificate
active
06562363
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Background of the Invention
This invention relates generally to bioadhesive compositions and methods for the topical administration of active agents to a mammal. More particularly, this invention relates to compositions capable of being used in wet or moist environments, especially on mucous membranes, for a prolonged period of time. There is no limitation on the type of drug that can be used in the present invention, provided that it can be topically administered. Thus, the active agent includes both drugs that are topically applied for local effects and those which can be administered topically for systemic effects.
2. Description of Related Art
Mucous membranes such as the mucosa of the buccal cavity have several physical attributes, such as a rich blood supply, that makes it a desirable site for topical administration of active agents for systemic delivery. Transmucosal delivery of active agents further avoids first-pass metabolism by the liver as well as poor uptake or inactivation via the gastrointestinal pathway. Examples of such agents include steroids such as estrogens, progestins and related compounds; androgens and anabolic steroids; non-steroidal anti-inflammatory agents such as ketoprofen; diclofenac; propranolol; thyroid hormones; pH sensitive peptides and small proteins such as insulin and ACTH; physostigmine; scopolamine; verapamil; and gallopamil.
Moreover, it is often desirable or necessary to deliver pharmaceutical agents locally, such as to alleviate pain in the buccal cavity.
Buccal and/or mucosal delivery compositions, devices and methods re disclosed, for example, in U.S. Pat. No. 3,972,995 to Tsuk, et al., U.S. Pat. No. 4,755,396 to Hsiao et al., U.S. Pat. No. 4,764,378 to Keith et al., U.S. Pat. No. 4,740,365 to Yukimatsu et al., U.S. Pat. No. 4,889,720 to Konishi et al U.S. Pat. No. 5,047,244 to Sanvordeker et al., and RE 33,093 to Schiraldi et al.
The use of bioadhesives in the administration of active agents to mucous membranes has been known for some time. The most commonly used bioadhesive compositions have “non-finite”, (i.e., spreading substances which do not retain their form) and liquid or semi-liquid carriers such as pastes, gels, lotions, emulsions, creams, sprays, drops or ointments. Increasing use has been recently made of “finite” carriers (i.e., non-spreading substances which retain their form) such as films, dressings and bandages, or which start as finite then dissolve such as lozenges and tablets. Such compositions and devices have been less than satisfactory in achieving controlled release of such agents, and in maintaining adhesion (i.e., simply staying in place) or efficacy for prolonged periods of time. Moreover, they often leave unacceptable tacky residues upon removal.
It is disclosed in U.S. Pat. No. 5,446,070 to Mantelle, that concentrations of substantially dissolved anesthetic agents and other drugs as high as 50% by weight can be achieved in a system containing a bioadhesive carrier in which the adhesion of the carrier is not hindered. However, a need exists to increase the amount of time such compositions can be maintained at the site of administration in order to achieve maximum prolongation of therapeutic effects, both systemically and locally.
A successful bioadhesive device for topical administration of active agents for prolonged periods of time needs to satisfy a number of physical characteristics. For instance, the release liner should be easily peelable from the bioadhesive portion, yet the latter must be both sufficiently adhesive and cohesive to maintain close or intimate contact with the site of application for prolonged periods of time, typically between 1 to 2 hours, and up to even 24 hours with certain active agents. The bioadhesive composition must further retain the active agent at an appropriate rate for sustained or controlled delivery under the conditions prevailing in wet and moist environments associated with mucosa. In addition, the bioadhesive composition must be non-toxic, not cause chemical irritation and, must be easily removable with minimal mechanical irritation or damage to the application site.
In this regard, compositions according to the present invention are capable of adhering for prolonged periods of time, such as, for example, greater than 1 hour, preferably 2 hours, more preferably 4 hours, even more preferably greater than 8 hours, up to even 24 hours, to moist tissue such as mucosa and thus the desired therapeutic effects are ensured by the high degree of adhesion provided by the compositions of this invention.
SUMMARY OF THE INVENTION
This invention provides a bioadhesive composition comprising a mixture of at least two bioadhesive materials, especially comprising at least one soluble polyvinylpyrrolidone (“PVP”) polymer, optionally in an admixture with a pharmaceutically acceptable solvent suitable for use with an active agent, the solvent optionally including a plasticizer for the bioadhesives. The bioadhesive compositions of this invention either include at least one active agent solubilized within the composition or, alternately, are used together with the topical administration of at least one active agent at the site of application, such as the means to adhere a drug reservoir to the application site.
In accordance with one aspect of the invention, an improved bioadhesive composition of a type which is suitable for prolonged adherence to wet or moist surfaces for controlled release of an active agent therefrom comprises a mixture of a polysaccharide, preferably a natural gum such as karaya gum, and a soluble PVP.
Optionally, the bioadhesive composition may further comprise a pressure-sensitive adhesive, preferably a solvent-based acrylic polymer.
In accordance with another aspect of the invention, the bioadhesive compositions provide for topical administration of two or more active agents of differing flux rates, in order to achieve prolonged and/or multiple therapeutic effects.
In accordance with yet another aspect of the invention, the bioadhesive composition also serves as a pressure-sensitive adhesive suitable for prolonged adherence to either wet/moist surfaces or dry surfaces, such as skin, for controlled release of an active agent therefrom.
This invention also relates to methods of administering the foregoing compositions.
In particular, the invention is directed to a bioadhesive composition in a flexible, finite form for topical application comprising:
(a) a mixture of two or more bioadhesives wherein at least one bioadhesive is a soluble PVP polymer;
(b) optionally a pharmaceutically acceptable solvent suitable for use with an active agent, the solvent optionally including a plasticizer for the bioadhesives;
(c) optionally, a pressure-sensitive adhesive;
wherein the composition is substantially free of water and substantially water insoluble; and wherein the composition either includes at least one active agent or, alternately, is used together with an active agent.
The invention further relates to a bioadhesive composition in a flexible, finite form for topical application comprising:
(a) a mixture of two or more bioadhesives wherein at least one bioadhesive is a soluble PVP polymer;
(b) optionally a pharmaceutically acceptable solvent suitable for use with an active agent, the solvent optionally including a plasticizer for the bioadhesives;
(c) in an admixture with at least two active agents, the at least two active agents comprising
(i) combinations of the same active agent in free acid, free base and salt forms, or
(ii) combinations of different active agents, each being delivered to a subject at a different flux rate;
(d) optionally, a pressure-sensitive adhesive; and
wherein the composition is substantially free of water and substantially water insoluble.
The invention further relates to a composition in a flexible, finite form for topical application comprising:
(a) a mixture of two or more bioadhesives wherein at least one bioadhesive is a soluble PVP polymer;
(b) optionally a pharmaceutically acceptable solvent suitable for use
Houze David
Kanios David
Mantelle Juan
Noven Pharmaceuticals Inc.,
Page Thurman K.
Sheikh Humera N.
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