The invention relates to a coating system for sustained release of a beneficial agent from a dosage form, and particularly to a dosage form unit having a latex coating for sustained release of a beneficial agent such as a marker dye into a liquid enteral nutritional product. The invention further relates to a method of making and using the sustained release dosage form unit.
A variety of devices and methods are known for the enteral, parenteral or oral delivery of beneficial agents, such as nutrients, medicaments, probiotics, diagnostic agents and marker dyes, to a patient. For example, it is well known to feed a fluid, such as a liquid enteral nutritional product, by gravitational or positive flow from a hangable bottle or bag having an outlet connected to a drip chamber which, in turn, is connected to a flexible tubing or lumen leading to a nasogastric tube or a feeding tube inserted through a gastrostomy or a jejunostomy to a patient. The liquid enteral nutritional product may be aseptically processed or terminally retorted, and may be supplied in a pre-filled, ready-to-hang container, or placed in such a container by a caregiver. However, the selection of diets, particularly special diets, from amongst the rather modest number of typically available liquid enteral nutritional products that are currently available is rather limited.
Moreover, it is often desirable to administer simultaneously a variety of beneficial agents, such as nutrients, medicaments, probiotics, diagnostic agents and marker dyes. These various ingredients, however, often are not stable during heat sterilization and may not be mutually compatible with other desired ingredients for an extended period of time, such as days or even months until used. As such, the combination of these beneficial agents are not readily amenable to large scale preparation and consequent storage as the product moves through commerce.
It also is beneficial to make the liquid enteral nutritional product more detectable in a patient after delivery, such as for diagnostic purposes and to identify when the enteral nutritional product is improperly fed to an area external to the stomach or intestines. One such method of making the liquid enteral nutritional product more detectable is to dissolve a suitable physiologically acceptable marker dye into the liquid product. Because compatibility of such marker dyes with other beneficial agents must be considered, it is advisable not to introduce the marker dye prior to heat sterilization or extended storage.
For these reasons, it therefore has been desirable to alter, modify or mark nutritional products during enteral tube feeding into the gastrointestinal tract of a patient. Certain new apparatus and methods have been developed to address these needs, and are the subject of several recent patents, including U.S. Pat. No. 5,531,681, U.S. Pat. No. 5,531,682, U.S. Pat. No. 5,531,734, U.S. Pat. No. 5,533,973, U.S. Pat. No. 5,549,550, U.S. Pat. No. 5,738,651, U.S. Pat. No. 5,741,243, U.S. Pat. No. 5,746,715, U.S. Pat. No. 5,755,688, and U.S. Pat. No. 5,755,689. Generally, these patents are directed to various aspects of apparatus and methods, which use a formulation chamber joined in fluid communication with a feeding device, and a dosage form unit placed within the formulation chamber. The dosage form unit contains the desired beneficial agents to be added to the liquid enteral nutritional product. As noted by the identified patents, a variety of dosage form units are available for use with these apparatus and methods, including conventional osmotically-driven delivery devices for sustained delivery of a beneficial agent.
One such osmotic delivery device is disclosed in U.S. Pat. No. 5,318,558, which is directed to a pump-type, controlled-release dosage form unit, or delivery device. Generally, the device includes a cylindrical enclosure containing the beneficial agent at one end portion and a piston driven by an osmotic engine at the other end portion. A small orifice is formed in the enclosure, preferably by a laser beam drill, at the end opposite the osmotic engine. In this manner, the beneficial agent is forced from the enclosure through the orifice upon activation of the osmotic piston.
An alternative osmotic dosage system with a sustained release dosage is disclosed by U.S. Pat. No. 5,324,280, wherein the beneficial agent is enclosed within an inner wall surrounded by a layer of hydro-active material that is entirely confined within an outer wall. Osmotic pressure resulting from expansion of the hydro-active material forces the beneficial agent out through a passageway formed in the outer wall by a laser drill or the like.
As noted, each of these conventional osmotic drug delivery devices requires that an orifice or similar passage be drilled or otherwise preformed in an outer membrane. Such precision manufacturing techniques, however, can be both difficult and expensive to perform. Additionally, it has been found that such conventional osmotic drug delivery devices are not particularly efficient, especially when used for the delivery of a marker dye or the like.
Furthermore, it is often desirable to provide an immediate release of beneficial agent upon initial exposure to the liquid enteral nutritional product. To accomplish this immediate release, conventional osmotic delivery systems typically require that an outer layer or film of the desired beneficial agent be provided. In this manner, an initial amount of the beneficial agent can be released quickly upon dispersion within the liquid nutritional product, followed by a sustained release of the beneficial agent from the dosage form unit. The provision of an additional outer film of beneficial agent, however, increases the manufacturing and material costs of the drug delivery device.
As such, there remains a need for an improved dosage form unit capable of sustained delivery of the beneficial agent(s) contained therein.
The purpose and advantages of the present invention will be set forth in and apparent from the description that follows, as well as will be learned by practice of the invention. Additional advantages of the invention will be realized and attained by the methods and systems particularly pointed out in the written description and claims hereof, as well as from the appended drawings.
To achieve these and other advantages and in accordance with the purpose of the invention, as embodied and broadly described, the invention includes a dosage form unit to deliver a beneficial agent into a fluid. Particularly, and as embodied herein, an intended use of the dosage form unit is for delivering one or more beneficial agents into a liquid enteral nutritional product to be fed to the gastrointestinal tract of a patient.
The dosage form unit of the invention includes a core containing at least one beneficial agent, which is dispersible in a fluid, such as liquid enteral nutritional product. As embodied herein, the beneficial agent is selected from a group consisting of nutrients, medicaments, probiotics, diagnostic agents and, in the preferred embodiment, marker dyes. Particularly, F.D.and C. Blue Dye #1 and methyl anthranilate are two such preferred markers.
The core also contains a compatible binding agent to bind the beneficial agent together. Although a variety of binding agents may be used, cellulose acetate is preferred. In the preferred embodiment, a plasticizer or cold solvent such as triacetin is used to soften the cellulose acetate and thus enhance binding to establish a stronger core. If desired or necessary, a conventional lubricant and a standard flow agent also can be provided for construction of the core. Other known tableting aids also may be used, such as dicalcium phosphate, to enhance the core construction. The core embodied herein also includes at lease one hydrophilic agent, such as hydroxypropyl methylcellulose, and one or more osmotically effective compounds if desired, to create an osmotic system for delivery of the beneficial agent.
Further in accordance with the present invention, the dosage form unit also includes a latex coating encasing the core. The latex coating includes a mixture containing a substantially hydrophobic base material capable of defining a semi-porous matrix-type membrane and at least one hydrophilic component being dispersible in the fluid. Preferably, the base material of the latex coating is formed from an emulsion of cellulose acetate microspheres.
A variety of hydrophilic components can be used for the latex coating, provided such components are dispersible in the fluid of interest, so as to create or open passages in the matrix-type membrane defined by the base material of the latex coating. A preferred hydrophilic component is polyethylene glycol, which not only facilitates the formation of passages, but also increases the flexibility of the wall formed by the latex coating and increases fluid-flux therethrough. If the immediate release of a beneficial agent is desired upon contact of the dosage form unit with a fluid, it is further preferred that the beneficial agent be provided as a component of the latex coating. This beneficial agent of the latex coating preferably is selected from a group consisting of nutrients, medicaments, probiotics, diagnostic agents and marker dyes.
In this manner, the dosage form unit may be configured to be placed within the formulation chamber of an enteral feeding system. Preferably, the dosage form unit is shaped so as to inhibit blockage of the enteral feeding system, such as in the shape of a square tablet.
The present invention also is directed to a method of forming a dosage unit to deliver a beneficial agent into a fluid, such as a liquid enteral nutritional product. The method includes the step of forming a core containing at least one beneficial agent dispersible in a fluid and a compatible binding agent to bind the beneficial agent together. As previously noted, the beneficial agent is selected from a group consisting of nutrients, medicaments, probiotics, diagnostic agents and, preferably, marker dyes, whereas the binding agent is cellulose acetate softened with triacetin. Likewise, the forming step can include adding a standard flow agent, a lubricant, or other tableting aids to the core. The method further includes, in the preferred embodiment, adding at least one hydrophilic agent, such as hydroxypropyl methylcellulose, and one or more osmotically effective compounds if desired to the core.
Further in accordance with the invention, the method also includes the step of preparing a latex formulation including a mixture containing an emulsion of a substantially hydrophobic base material capable of defining a matrix-type membrane and at least one hydrophilic component dispersible in the fluid. This step preferably includes mixing an emulsion of cellulose acetate as the base material with the hydrophilic component. Although other hydrophilic components may be provided, an additional aspect of the invention includes providing a beneficial agent dispersible in the fluid as a component of the latex formulation, so as to facilitate immediate release of the beneficial agent upon exposure of the dosage form unit to the fluid. This beneficial agent for the latex formulation is preferably selected from a group consisting of nutrients, medicaments, probiotics, diagnostic agents and marker dyes.
Finally, the method of the invention includes applying the latex formulation onto the core to form a latex coating thereon. Preferably, this step is performed by spraying the latex formulation onto the core using a conventional pan coater or a Wurster column in a batch fluid bed coater as is known in the art, and then drying the applied coating to define an outer wall.
Other features and advantages of the present invention will become readily apparent from the following detailed description, the accompanying drawings, and the appended claims.
The accompanying drawings, which are incorporated in and constitute part of this specification, are included to illustrate and provide a further understanding of the method and system of the invention. Together with the description, the drawings serve to explain the principles of the invention.
USPTO Backgrounds
USPTO Backgrounds