Use of polyalkylamine polymers in controlled release devices

Details Use of polyalkylamine polymers in controlled release devices Use of polyalkylamine polymers in controlled release devices

2002-02-12

2003-11-18

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S464000, C424S473000, C424S479000, C424S480000, C424S489000, C424S078080

Reexamination Certificate

active

06649187

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a controlled release device and in particular to a controlled release device comprising a polyalkylamine polymer for controlling release of an amine drug from the device.
BACKGROUND OF THE INVENTION
Sustained release oral dosage forms of drugs offer the advantages of convenience, improved patient compliance, and reduced peak to trough drug concentration ratio. In addition, they provide lower C
max
levels and longer T
max
times than comparable immediate release devices containing the same amount of drug. As a result, controlled release devices generally provide less side effects typically associated with the high plasma peak levels as provided by immediate release devices.
One of the systems that is useful for the delivery of poorly water soluble compounds is the Controlled Release Drug Dispersion Delivery Device disclosed in U.S. Pat. No. 5,366,738. This device comprises a core containing the drug and a polymer that forms gelatinous microscopic particles upon hydration. The core is surrounded by a water insoluble and impermeable coating that contains apertures and adheres to the core. An aqueous fluid from an environment of use enters the core through the apertures and hydrates the polymer to form a dispersion comprising gelatinous particles and the drug. The polymer is a sodium polyacrylate or a carboxypolymethylene. These polymers possess carboxyl functional groups and are negatively charged at physiological pH.
Formula 2: [S-(R,S)]-2-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide) is a novel, monocyclic &bgr;-lactam amine drug. It is a highly selective and potent inhibitor of human polymorphonuclear leukocytes (PMN) elastase. Experimental data suggests that [S-(R,S)]-2-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide) may be useful for the treatment of rheumatoid arthritis, among other diseases and disorders. The pharmacokinetic profile of [S-(R,S)]-2-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide) suggests that a controlled release device would be well suited for delivering the drug to a patient.
Cation and anion exchange resins have been used for delivering drugs. Generally, these resins are coupled with active agents to form ion pairs. For example, a conventional polyamine resin would be coupled with an acidic drug to form an amine-acid ion pair, which would then be included in a pharmaceutical dosage form. In other words, prior to the present invention, a polyamine resin would not be combined with an amine drug to form a pharmaceutical composition that provides a controlled release of the amine drug.
To date, no formulations that provide the controlled release of [S-(R,S)]-2-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide) or its related analogues have contained a polyalkylamine polymer matrix for controlling the delivery of the drug.
SUMMARY OF THE INVENTION
The present inventors have evaluated the device disclosed in the '738 patent and determined that it is not suitable for the controlled delivery of amine drugs, such as [S-(R,S)]-2-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide), due to the formation of ion pairs or the related incompatibility between the drug and the negatively charged polymer. In addition, the gelatinous particles clog the apertures resulting in incomplete release of drug from the dosage form.
The present invention provides a controlled release device that delivers an amine drug, such as [S-(R,S)]-2-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide). The controlled release device contains a core prepared from an admixture of [S-(R,S)]-2-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide) and a polyalkylamine polymer, such as DMP 504, which is a hydrogel. The core is surrounded by an impermeable water insoluble coat comprising a polymer and a plasticizer. The coat adheres to the core and also includes plural apertures through which hydrated gelatinous particles of polymer containing the amine drug are released into an environment of use.
One aspect of the invention includes a controlled release solid dosage form comprising:
a pharmaceutical composition comprising an amine drug and a polyalkylamine polymer that forms gelatinous particles when hydrated;
a coat surrounding the pharmaceutical composition and comprising a film-forming polymer and plasticizer; and
plural apertures in the coat;
wherein the amine drug and polyalkylamine polymer are released through the apertures when the dosage form is placed into an aqueous environment of use, and the dosage form provides a controlled release of the amine drug.
Another aspect of the invention provides a pharmaceutical composition comprising:
an amine drug;
a gel-forming polyalkylamine polymer; and
at least one pharmaceutical excipient;
wherein the polyalkylamine polymer controls the release of the amine drug when the pharmaceutical composition is included in a dosage form and exposed to an aqueous environment of use.
Yet another aspect of the invention provides a method of treating a disorder or disease with an amine drug comprising the step of administering to a subject a controlled release dosage form comprising:
a core comprising an amine drug and a polyalkylamine polymer that forms gelatinous particles when hydrated;
a coat surrounding the core and comprising a film-forming polymer and plasticizer; and
plural apertures in the coat;
wherein the amine drug and polyalkylamine polymer are released through the apertures when the dosage form is placed into an aqueous environment of use, and the dosage form provides a controlled release of the amine drug.
Embodiments of the Invention
[1] A first embodiment of the invention provides a controlled release solid dosage form comprising:
a pharmaceutical composition comprising an amine drug and a polyalkylamine polymer that forms gelatinous particles when hydrated;
a coat surrounding the pharmaceutical composition and comprising a film-forming polymer and plasticizer; and
plural apertures in the coat;
wherein the amine drug and polyalkylamine polymer are released through the apertures when the dosage form is placed into an aqueous environment of use, and the dosage form provides a controlled release of the amine drug.
[2] Another embodiment of the invention provides a controlled release solid dosage form of embodiment [1], wherein the amine drug is the free base or salt form of [S—(R,S)]-2-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-N-[1-(3,4-methylenedioxyphenyl)butyl]-4-oxo-1-azetidinecarboxamide).
[3] Another embodiment of the invention provides a controlled release solid dosage form of any one of embodiments [1] to [2], wherein the polyalkylamine polymer is cross-linked polymeric ammonium salt and comprises groups that link ammonium nitrogen atoms wherein:
about 25% or more of the groups which link ammonium nitrogen atoms are group Y, wherein each Y is independently —C(R
1
R
2
)
b
—; b is an integer of 7 to about 20; and each R
1
and each R
2
is independently alkylene of about 1 to 20 carbon atoms;
zero to about 75% of the groups which link ammonium nitrogen atoms are group Z wherein Z is

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