Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2001-04-13
2003-05-06
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S422000, C424S423000, C424S486000, C424S489000, C424S499000, C424S501000, C514S002600, C514S021800, C514S04400A, C514S089000, C514S107000, C514S108000, C514S964000
Reexamination Certificate
active
06558702
ABSTRACT:
BACKGROUND OF THE INVENTION
Many illnesses or conditions require administration of a constant or sustained level of a medicament or biologically active agent to provide the most effective prophylactic or therapeutic. This may be accomplished through a multiple dosing regimen or by employing a system that releases the medicament in a sustained fashion.
Attempts to sustain medication levels include the use of biodegradable materials, such as polymeric matrices, containing the medicament. The use of these matrices, for example, in the form of microparticles or microcarriers, provides sustained release of medicaments by utilizing the inherent biodegradability of the polymer. The ability to provide a sustained level of medicament can result in improved patient compliance.
However, these sustained release devices can exhibit high release of active agent over the first twenty-four hours, often referred to as a burst. In some instances this burst can result in an undesirable increase in the levels of biologically active agent and minimal release of agent thereafter. In addition, due to the high solution concentration of medicament within and localized around these sustained release devices, the medicament can aggregate thereby increasing immunogenicity in vivo and interfering with the desired release profile for the medicament.
Therefore, a need exists to exert additional control over the release profile of sustained release compositions by, for example, reducing the burst of agent and/or providing an improved release such as a longer period of release.
SUMMARY OF THE INVENTION
The present invention is based upon the unexpected discovery that the release profile of a biologically active agent from a sustained release composition comprising a biocompatible polymer and the biologically active agent incorporated therein can be modified such as by prolonging the period of release of agent when a bisphosphonate compound is co-administered.
Accordingly, the present invention relates to a method for the sustained release in vivo of a biologically active agent comprising administering to a subject in need of treatment an effective amount of a sustained release composition comprising a biocompatible polymer having the biologically active agent incorporated therein, and a bisphosphonate wherein the bisphosphonate is present in an amount sufficient to modify the release profile of the biologically active agent from the sustained release composition.
In one embodiment, the bisphosphonate compound can be co-incorporated into the sustained release composition comprising the biocompatible polymer and the biologically active agent incorporated therein.
In another embodiment, the bisphosphonate compound can be separately incorporated into a second biocompatible polymer. The biocompatible polymer can be the same or different from the first biocompatible polymer which has the biologically active agent incorporated therein.
In yet another embodiment, the bisphosphonate compound can be present in an unencapsulated state but comingled with the sustained release composition. For example, the bisphosphonate can be solubilized in the vehicle used to deliver the sustained release composition. Alternatively, the bisphosphonate compound can be present as a solid suspended in an appropriate vehicle. Further, the bisphosphonate can be present as a powder which is comingled with the sustained release composition.
The invention described herein also relates to pharmaceutical compositions suitable for use in the invention. In one embodiment, the pharmaceutical composition comprises a sustained release composition comprising a biocompatible polymer having an effective amount of a biologically active agent incorporated therein, and an amount of bisphosphonate compound sufficient to modify the release profile of the biologically active agent from the sustained release composition.
In one embodiment, the bisphosphonate compound can be co-incorporated into the sustained release composition comprising the biocompatible polymer and the biologically active agent incorporated therein.
In another embodiment, the pharmaceutical composition comprises the sustained release composition comprising a first biocompatible polymer having incorporated therein an effective amount of a biologically active agent and a second biocompatible polymer having incorporated therein an amount of bisphosphonate which modifies the release profile of the biologically active agent from the first polymer. In a particular embodiment, the first and second polymers are the same type of polymer. In another embodiment, the first and second polymers are different.
In yet another embodiment, the bisphosphonate compound can be present in the pharmaceutical composition in an unencapsulated state. For example, the bisphosphonate compound can be comingled with the sustained release composition. In one embodiment, the bisphosphonate can be solubilized in the vehicle used to deliver the pharmaceutical composition. Alternatively, the bisphosphonate compound can be present as a solid suspended in an appropriate vehicle useful for delivering the pharmaceutical composition. Further, the bisphosphonate can be present as a powder which is comingled with the sustained release composition.
Without being bound by a particular theory, it is believed that at least in part the effects of the bisphosphonates can be related to a reduction in the amount of inflammatory cellular reaction which can occur in the area of administration of the sustained release composition. This reaction, although clinically insignificant, is well characterized as a foreign body response, and can be realized with most foreign materials.
The present invention also relates to a composition for the sustained release of bisphosphonates. The sustained release composition comprises a biocompatible polymer matrix having a therapeutically effective amount of bisphosphonate incorporated therein. Further, the invention relates to a method for the sustained release in vivo of a bisphosphonate compound comprising administering to a subject in need of treatment a therapeutically effective amount of a sustained release composition comprising a biocompatible polymer and a bisphosphonate compound.
In a particular embodiment, administration of the sustained release composition comprising a biocompatible polymer and a bisphosphonate can be to a joint, for example, the articular space of a joint. For example, the sustained release composition can be administered to the articular space of the knee, shoulder, ankle, hip etc . . .
The sustained release composition of the invention comprising a biocompatible polymer and a bisphosphonate compound can be used for the treatment of diseases associated with bone resorption or joint inflammation. For example, the sustained release composition having a biocompatible polymer and a bisphosphonate compound incorporated therein can be suitable for use as a treatment for rheumatoid arthritis, osteoporosis or Paget's disease.
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p
Dasch James R.
Riley M. Gary I.
Alkermes Controlled Therapeutics Inc.
Hamilton Brook Smith & Reynolds P.C.
Russel Jeffrey E.
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