Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-05-19
2002-07-16
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S457000, C424S490000, C424S476000, C424S441000, C424S461000
Reexamination Certificate
active
06419954
ABSTRACT:
CROSS-REFERENCES TO RELATED APPLICATIONS
Not Applicable.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not Applicable.
BACKGROUND OF THE INVENTION
A variety of hydrogel-type preparations have been developed to effect the sustained release of orally ingested drugs. For example, Japanese patent application JP-A-62-120315 discloses a preparation obtained by compression-molding a drug, a hydrogel-forming water-soluble polymer and an enteric coating. JP-A-63-215620 discloses a hydrogel-type preparation with a core having a drug and a water-soluble polymer and an outer layer with a water-soluble polymer as a base. JP-B-40-2053 discloses a sustained-release preparation having a mixture of a drug and a high polymer of ethylene oxide and, as an optional component, a hydrophilic substance. However, all of these preparations are designed to release a drug continuously while the administered preparation is still retained in the upper digestive tract, typically in the stomach and small intestine. They were not intended to provide for a release of a drug in the lower digestive tract including the colon, where little water is available.
Hydrophilic gel-forming preparations have been further developed so that they can provide a sustained release of orally ingested drugs throughout the digestive system, including in the lower digestive tract. For example, EP 0 661 045 describes a preparation adapted to absorb water into its core to undergo substantially complete gelation during its stay in the upper digestive tract. As the tablet moves down the digestive system in the form of a gel to the lower digestive tract, the preparation swells and the gelled outer surface of the tablet erodes gradually releasing the drug. This type of oral tablet is capable of providing a sustained release of the drug throughout the digestive tract, including in the colon.
While the gel-forming preparations, such as those described in the EP 0 661 045, have many applications, they may not be suitable for certain types of active agents, particularly when the active agents are unstable in the gel-forming preparations or may be released in a manner that is not desirable. Thus, there exists a continuing need for improved forms of sustained release preparations which can continuously release an active agent throughout the digestive tract, regardless of the physical or chemical properties of the active agent. Moreover, many situations may require that an active agent be delivered to the patient in a non-random or pulsatile manner, or, that the active agent be delivered to a particular anatomic compartment, e.g., the colon. For example, if an easily degradable drug or a drug with a short biological half-life needs to be delivered to the colon, it cannot be released in the upper digestive tract. Thus, there is a need for tablets that are capable of providing delayed and/or pulsatile release of an active agent. The present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
The present invention provides, for the first time, a tablet and methods for making the tablet that comprises a gel-forming material and at least one particle comprising an active agent in contact with a coating material to modify release of the active agent from the tablet. These particles that comprise the active agent and the coating material are also referred to as “active agent-containing particle”, “coated particle” or “coated bead.” The gel-forming material forms a matrix (a “gel-forming matrix”) for the active agent-containing particles. The active agent-containing particle is formulated with a coating material so that it can modify or control the release of the active agent by, for example, slowing or inhibiting the passage of the active agent out of the tablet and into the digestive system. These tablets are also referred to as OCAS™ (oral controlled absorption system) matrix tablets herein.
In some embodiments of the invention, the release of the active agent from the tablet can be modified and controlled by the combination of two systems: 1) the gel-forming matrix; and 2) the coating material in contact with the active agent. In the digestive system, the gel-forming matrix absorbs water to undergo substantially complete gelation during its stay in the upper digestive tract and moves down into the lower digestive tract undergoing constant erosion, continuously releasing the active agent-containing particles from the tablet. This erosion of the gel-forming matrix can control the release of the active agent-containing particles from the tablet. In addition to the gel-forming matrix, the coating material that is on or around the active agent provides another level of control in releasing the active agent from the tablet. For example, the coating material can modify or control the rate of diffusion of the active agent through the gel matrix and out of the tablet. Moreover, since the coating material provides a physical and/or chemical barrier for the active agent, any type of active agents can be included in the tablets of the present invention. The selection of the active agent is not restricted to those which are released from the tablet in a favorable manner.
In one aspect, the invention is particularly useful for an active agent that is hydrophilic. In the case of water insoluble or less hydrophilic active agents, the erosion of the gel-forming matrix of the tablet precedes the diffusion of the active agent through the swollen gel layer of the tablet. Thus, the active agent release rate limiting step is typically the erosion of the gel-forming matrix. Therefore, with these active agents, the gel-forming matrix alone can provide enough control on release of the active agent and can be used to design a sustained release of these active agents over, e.g., 12-24 hours. However, a hydrophilic active agent tends to diffuse out from the gel-forming matrix faster than the erosion of the swollen gel layer of the tablet. Thus, while a tablet comprising a gel-forming matrix may be useful for water insoluble or less hydrophilic active agents, the gel-forming matrix may not provide for sufficient controlled release for the hydrophilic active agent.
FIG. 9
illustrates this diffusion problem for a hydrophilic active agent. As will be described in further detail below in Example 6B, a tablet comprising Cevimeline HCl (having a high water solubility of about 766 mg/ml at 25° C.) and a gel-forming matrix comprising a polyethylene oxide polymer (PEO) and a polyethylene glycol (PEG) was prepared. The active agent Cevimeline HCl as purchased (without further treatment) was mixed with the gel-forming material.
FIG. 9
shows the drug release profile from this conventional Cevimeline HCl matrix tablet. As shown in
FIG. 9
, substantially all of the drug was released in about 6-8 hours from the tablet. The tablet did not provide for sustained release of the drug over, e.g., 12-24 hours.
Thus, in the embodiments of the invention, a hydrophilic active agent, such as Cevimeline HCl, is physically and/or chemically modified to control its release rate from the tablet. Preferred embodiments of the invention provide a tablet comprising a gel-forming material and a particle comprising a hydrophilic active agent, wherein the particle is formulated to modify release of the active agent from the tablet. For example, the particle comprises a hydrophilic active agent in contact with a coating material (e.g., on or around the active agent). The coating material can slow or prevent the diffusion of the hydrophilic active agent out of the gel-forming matrix.
An improvement in the release profiles of a hydrophilic drug from tablets according to embodiments of the invention are described in Example 6C and shown in FIG.
10
. Example 6C describes an embodiment of the present tablet which comprises Cevimeline HCl in contact with a coating material in a gel matrx. As shown in
FIG. 10
, the release profiles of this modified Cevimeline HCl from the gel matrix tablet are much more gradual and linear than the release profile of unm
Chu James S.
Fix Joseph A.
Yang Yisong
Dees Jose′ G.
Haghighatian Mina
Townsend and Townsend / and Crew LLP
Yamanouchi Pharmaceutical Co. Ltd.
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