Title:  Pharmaceutical oral patch for controlled release of pharmaceutical agents in the oral cavity

United States Patent:  6,197,331

Assignee:  Perio Products Ltd. (Jerusalem, IL)

Filed:  July 24, 1997

The invention is directed to a controlled-release solid composition for the oral cavity or "pharmaceutical oral patch" that adheres to hard dental surfaces, such as teeth and dentures, and releases an active pharmaceutical agent into the oral cavity. Release of the agent is for a predetermined period of time and at a predetermined sustained concentration. The site of action of the agent is local or systemic.

SUMMARY OF THE INVENTION

A general object of the invention is to provide a sustained- or controlled-release composition for the oral cavity that provides release of effective amounts of one or more pharmaceutical agents in the oral cavity.

A specific object of the invention is to provide a composition that avoids necrosis in the oral cavity.

A further specific object of the invention is to provide a composition that delivers a pharmaceutical agent for local treatment of the oral cavity, throat, or esophagus.

A further specific object of the invention is to provide a composition for topical release to sites of attachment, e.g., to the teeth.

A further specific object of the invention is to provide a composition for oral release of a pharmaceutical, allowing for buccal absorption resulting in rapid systemic delivery of the released pharmaceutical.

A further specific object of the invention is to provide a composition whose application and removal is easy and uncomplicated.

A further specific object of the invention is to provide a device that feels comfortable in the mouth and thus provides the minimum possibility of being dislodged by the patient, so that the pharmaceutical agent is released for an effective period of time at the desired concentration.

A further specific object of the invention is to provide a composition for oral release of a pharmaceutical that releases the pharmaceutical by both diffusion and erosion of a matrix.

A further specific object of the invention is to provide a composition that is degradable in the oral cavity.

A further specific object of the invention is to provide a composition for the oral release of a variety of pharmaceuticals, especially for non-, poorly, or intermediately water-soluble pharmaceuticals and particularly, poorly water-soluble pharmaceuticals.

A further specific object of the invention is to provide for oral release of a pharmaceutical with an adhesive composition that will adhere to the teeth, dentures, or other hard structures of the dental cavity.

A further specific object of the invention is to provide a composition for oral release of a pharmaceutical in which the release rate of the pharmaceutical can be controlled by the method of making the composition.

A further specific object of the invention is to provide a composition that can release more than one pharmaceutical agent in the oral cavity.

A further specific object of the invention is to provide a device having advantages over a film formed in situ by providing for better control of the dose administered.

Accordingly, the inventors have designed a composition that achieves all of these objects.

Thus, the inventors have designed a composition for sustained- or controlled-release in the oral cavity of a pharmaceutically active agent contained in the composition.

The invention provides a solid sustained- or controlled-release composition that can be adhesively attached to the surface of a tooth, denture, or other hard dental structure. The composition is referred to as a "pharmaceutical oral patch."

In the pharmaceutical oral patch, an inert (non-drug-containing) adhesive composition can attach a separate drug-containing non-adhesive composition to the teeth or other hard structures, such as dentures.

Alternatively, the drug-containing composition can be self-adhesive.

In other embodiments, where the drug-containing composition in the patch is not adhesive, the adhesive composition can also contain the same or different drugs.

In a preferred embodiment, the controlled-release composition comprises at least one polymer. Whether the drug-containing composition is self-adherent, not self-adherent (requires a non-drug-containing adhesive to adhere it in the oral cavity), or if the drug-containing non-adhesive composition is attached in the oral cavity by means of an adhesive drug-containing composition, in each of these embodiments the compositions can comprise at least one polymer.

In preferred embodiments, both the adhesive and non-adhesive compositions comprise at least one polymer.

In preferred embodiments, the polymer forms a matrix in which the pharmaceutical is dispersed or embedded.

The preferred polymer for both the adhesive layer and non-adhesive layer is a methacrylic polymer and, preferably, a Eudragit.TM. polymer.

In a highly preferred embodiment, Eudragit S.TM. is the attachment adhesive.

In a highly preferred embodiment, Eudragit L-100.TM. is the non-adhesive drug-releasing component.

In the embodiment in which an adhesive composition attaches a separate drug-containing composition, one advantage over a system with a combined adhesive and drug-releasing layer (e.g., U.S. Pat. Nos. 4,772,470, 4,900,554 and 5,446,070) is the ability to form a new adhesive layer when the first one is damaged without the need for a new releasing layer.

In a system in which both the release layer and the adhesive layer contain an active ingredient, the separation between the two layers avoids migration of the active ingredient from the adhesive layer into the release layer and vice versa. This is preferred where the active ingredients differ between the two layers.

Either or both layers can be degradable. Thus, the entire patch can be significantly or completely degradable. This means that no significant residue remains on the tooth after the intended use (desired released active agent) so there is no need to remove a depleted patch. This includes embodiments in which the drug-releasing matrix layer is self-adherent, and also comprises embodiments in which there is more than one layer, as in the case where a non-adhesive layer is adhered to the tooth by means of a separate adhesive layer.

The minimal essential ingredients, for the non-adhesive release layer include at least one pharmaceutically active agent, at least one polymer, and at least one plasticizer. Optional ingredients include release adjusting agents, pH adjusting agents, emulsifiers, and solubility adjusting agents. In the liquid that ultimately forms this solid composition, the minimal essential ingredients include at least one polymer, at least one pharmaceutical, at least one plasticizer, and a pharmaceutically acceptable solvent.

In the adhesive layer, minimal essential components include at least one polymer. However, optional ingredients may be added, for example, plasticizer, release adjusting agent, emulsifier, pH adjusting agent, and solubility adjusting agent. A drug can be included in the adhesive layer as a minimal essential ingredient.

Where the release layer is self-adherent, the minimal essential components include at least one polymer, at least one pharmaceutical, and at least one plasticizer.

The application also provides a method for making the compositions described herein. In general embodiments of the procedure for forming the drug-releasing matrix, for acrylic or methacrylic polymers, the acrylic or methacrylic polymer is dissolved in a mixture of alcohol and water. A base is then optionally added to adjust the pH. A plasticizer is then added to the mixture to plasticize the resulting solid product. A pharmaceutical is then added, and the mixture is stirred until dissolved. The solution is then introduced into an appropriate mold and dried to form the finished product.

An essential feature is a polymer that dissolves in a pharmaceutically acceptable solvent (such as ethanol:water) and that can be plasticized to form a flexible polymer matrix when dried and then inserted in the oral cavity.

Thus, the invention provides a method for controlling the release of a given pharmaceutical from the non-adherent solid compositions described herein, as well as the adhesive drug-releasing compositions described herein.

Claim 1 of 19 Claims

What is claimed is:

1. A dual-component oral composition for providing sustained controlled release of one or more pharmaceutically active agents therefrom, comprising an adhesive component, said adhesive component comprising at least one polymer, said adhesive component being effective for adhering to teeth or dentures, immediately adjacent to and adhered to a non-adhesive component, said non-adhesive component containing at least one polymer, at least one plasticizer, and one or more pharmaceutically active agents, and from which non-adhesive component said one or more agents are released into the oral cavity in therapeutically active amounts when said adhesive component is adhered to teeth, dentures, or other hard surface in said oral cavity, both components being suitable to remain in the oral cavity for a period of time necessary to allow release of a therapeutically effective amount of said one or more agents into the oral cavity, wherein said adhesive component and said non-adhesive component are substantially degradable so that said composition is degradable.

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