Surgery – Controlled release therapeutic device or system
Reexamination Certificate
2001-01-22
2004-03-09
Page, Thurman K. (Department: 1615)
Surgery
Controlled release therapeutic device or system
C424S472000, C424S473000, C424S400000, C424S464000, C424S465000, C424S468000
Reexamination Certificate
active
06702803
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to controlled-delivery drug dosage forms. More specifically, the invention relates to multi-step drug dosage forms having an extended release component.
BACKGROUND OF THE INVENTION
First order release of a drug results from administration of medication as a single dose with the immediate release of a single dose unit. First order release is often undesirable, as in the case of drugs that have a wide therapeutic window or whose duration of action is shorter than the desired therapeutic duration. Zero order release, where the drug plasma concentration is nearly constant for an extended time, frequently requires continuous administration of the drug.
In many cases, the ideal release profile for an extended release dosage form is zero order drug release (i.e., the release of drug is independent of time, over a certain length of time). In the case of most extended release dosage forms, however, as the drug level inside the dosage form decreases, the rate of release also decreases. Consequently, dosage forms often show two phases of drug release: an initial phase, which may or may not be linear, and a second phase, which reflects the rapid depletion of the drug from the device. It would be advantageous to have a dosage form that exhibits a zero order release over substantially the entire period of drug release. Multi-step release systems have been proposed to achieve such profiles in that multi-step drug release permits an approximation to zero order drug delivery using a series of small doses.
Several U.S. patents describe multi-step, extended release oral dosage forms. Many of these patents rely on a mechanical release mechanism, wherein a driving means slidably moves dosage units within a housing until each is released from one end of the housing into the environment. The driving means is typically a fluid activated driving means such as a material in one end of the dosage form that swells upon contact with fluid. The release of drug is thus osmotically driven. One disadvantage of these types of devices is that they are essentially mechanical devices and can malfunction. Another disadvantage is that the device design is fairly inflexible because, among any other reasons, the choice of materials that can be used for the fluid activated swelling means is limited. Still another disadvantage is that such devices typically include a semi-permeable membrane through which fluid enters the device. On the other end of the device is an orifice or a larger opening. Blockage or other impediment of this opening would restrict the drug release and have a negative impact on drug delivery.
Many prior art multi-step devices include the drug in a conventional format (e.g., in a matrix or tablet form) and so have the disadvantages inherent in such formats. In particular, conventional processes for manufacturing tablets or capsules typically have many independent steps and often require several days or weeks to produce a product. The traditional processes for manufacturing tablets typically involve blending the bulk drug substance with excipients such as bulking agents, disintegrants, solubilizers, and flavors. After blending, the mixture is usually granulated, which frequently involves the addition of a liquid, before it is dried, milled, blended with lubricant, and compressed into a tablet prior to coating and packaging. Each step in these traditional processes requires investment in equipment, facilities, and labor. Process controls for each step must be established, dictating numerous in-process quality control checks. Because conventional quality control involves destructive testing of the product, only a small sample of the lot can be tested.
The art would therefore benefit from improved multi-step drug dosage forms, and a method for making them.
SUMMARY OF THE INVENTION
The illustrative embodiments of the present invention are directed to controlled release drug dosage forms that can be designed to deliver a drug at a desired pharmacokinetic profile. Some dosage forms in accordance with the illustrative embodiment of the present invention employ a plurality of dose units. In one embodiment, a dose unit is a single dosage amount of a drug that is disposed on a substrate, referred to herein as a “deposit”. The dose units are assembled into controlled release multi-step dosage forms. In some embodiments, controlled release is achieved through the use of various structural elements such as substrates and separators, having various dissolution and/or drug release characteristics. A release profile desired for a particular drug can be achieved using a dosage form incorporating structural elements having dissolution and/or release characteristics to achieve the desired profile.
In some embodiments, a plurality of dose units are assembled into a dosage form. One or more separators are included to controllably and sequentially expose the dose units to the environment and allow release of drug from the dosage form. Release of drug can also be controlled by selection of the substrate for the dose unit, if one is used, and by the use of one or more overwrappings. The multi-layer construction of the dosage form and the manner in which the different layers are assembled allows the incorporation of multiple release-determining factors into the dosage form, such as different amounts of a drug, different drugs, and/or different materials that can impart different properties. Controlled release dosage forms can be assembled having the desired drug release profile, including immediate release as well as extended release from a single dosage form, to obtain a desired pharmacokinetic profile. The dosage form can be designed to exhibit a zero order release profile. Furthermore, the dosage form is advantageously designed to exhibit desired characteristics such as stability, reproducibility, precision, and safety, offering significant improvements over existing products that require multiple administrations per day to achieve similar profiles.
In some embodiments, the deposits are made using an electrostatic deposition process, which permits the manufacture of small, precisely controlled dose units. Electrostatic deposition can rapidly and accurately deposit pure drug on a substrate, which can greatly reduce the amount of time required to produce a batch. Less equipment and fewer operators are necessary, which can lower manufacturing cost. Each dose can be inspected with a non-destructive technique so that 100% inspection can be achieved. The elimination of off-line in-process quality checks can reduce product and lab material consumption.
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patent: 4723958 (1988-02-01), Pope et al.
patent: 4891223 (1990-01-01), Ambegaonkar et al.
patent: 5017381 (1991-05-01), Maruyama et al.
patent: 5938654 (1999-08-01), Wong et al.
patent: WO 01/12103 (2001-02-01), None
Chrai Suggy S.
Karetny Marc S.
Kupperblatt Gary
Murari Ramaswamy
Dechert LLP
Delsys Pharmaceutical Corporation
Oh Simon J.
Page Thurman K.
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