Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-06
2004-03-16
Webman, Edward J. (Department: 1617)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S269000, C544S372000, C546S093000, C546S208000, C548S520000, C514S254020, C514S290000, C514S422000, C514S423000, C514S265100, C514S326000, C514S776000, C424S045000, C424S489000, C424S078170, C424S078370
Reexamination Certificate
active
06706892
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the therapeutic and diagnostic agents in medicine. In particular, this invention relates to the field of delivery, in particular, pulmonary delivery, of therapeutic and diagnostic agents wherein the agents are capable of covalently bonding to a site of interest in vivo, to provide increased bioavailability and pharmacodynamic duration of therapeutic and diagnostic benefit for the given agent.
BACKGROUND OF THE INVENTION
Peptide and protein drugs are being used increasingly in major research and development programs in the pharmaceutical industry and are also an important class of therapeutic agents due to advances in genetic engineering and biotechnology. Systemic delivery of these macromolecular drugs and other therapeutic and diagnostic agents,however, has been limited to the parenteral route largely because of their extensive presystemic elimination when taken orally. Faced with this dilemma concerning the systemic delivery of these macromolecules with their unique conformational complexity for therapeutic activity, pharmaceutical scientists are continually evaluating the potential of various non-oral routes of administration as alternatives.
Despite the tremendous efforts that have been devoted to this problem, only limited success has been achieved—mostly with small peptides. An alternative, non-invasive means for systemic delivery of therapeutic and diagnostic agents is via the pulmonary system. Delivery via the pulmonary system is advantageous because the lungs provide a large but extremely thin absorptive mucosal membrane for increased absorption and delivery to the blood stream. However, pulmonary delivery of therapeutic and diagnostic agents is complicated by the complexity of the anatomic structure of the human respiratory system; the effect of respiration on drug deposition and an instability of the drugs resulting from degradation in either the lungs or plasma.
There is thus a need to improve and enhance delivery of therapeutic and diagnostic agents, especially pulmonary delivery of therapeutic and diagnostic agents through increasing the stability and blood absorption of the agents.
SUMMARY OF THE INVENTION
In order to meet these needs, the present invention is directed to therapeutic and diagnostic agents capable of forming covalent bonds to blood and pulmonary fluid proteins or other components ex vivo or in vivo. The therapeutic agents of this invention have a long duration of action for the management of disease. The invention relates to ex vivo and in vivo bioconjugation of therapeutic agents to protein (e.g. albumin), as well as an intrapulmonary in vivo bioconjugation of therapeutic agents to endogenous pulmonary fluid proteins or other components to dramatically increase the half life of the therapeutic agents and avoid the need for parenteral administration.
The present invention reflects the ability to bioconjugate selected therapeutic agents to blood and pulmonary pulmonary fluid proteins, including albumin, for processing as a particulate for intrapulmonary drug delivery. The pulmonary fluid protein conjugate is targeted to provide a stable drug substance that retains biological activity for prolonged periods of time. This invention provides prolonged local retention of therapeutic agent activity in the airways for use with selected therapeutic agents in managing pulmonary disease.
The invention is further directed to methods of facilitating systemic drug delivery of protein-therapeutic agent bioconjugates and to agents capable of forming bioconjugates to protein in vivo via pulmonary delivery with subsequent transcytosis across the alveolar and pulmonary mucosa. The invention is further directed to methods of facilitating systemic drug delivery of protein-therapeutic agent bioconjugates via pulmonary delivery of agents capable of forming bioconjugates in vivo, the agents crossing the epithelium of the alveolar or pulmonary mucosa, either through diffusion or receptor mediated transport, to conjugate with blood proteins. The methods of this invention result in long acting, systemic therapeutics that are stabilized by ex vivo or in vivo conjugation to pulmonary fluid proteins and/or blood proteins.
This invention is further directed to site-specific and protein-specific bioconjugation of a therapeutic agent to albumin. Albumin possesses a unique nucleophilic moiety, specifically, the thiol functionality on cysteine 34 that is capable of undergoing a nucleophilic attack on an electrophile present on a therapeutic agent modified according to the invention. This selective covalent bonding enables bioconjugation to extracellular as well as intracellular albumin for prolonged retention and bioavailabilty of the therapeutic agent.
This invention is further directed to the use of reactive chemistries including: N-hydroxy sulfosuccinimide, maleimide-benzoyl-succinimide, gamma-maleimido-butyryloxy succinimide ester, maleimidopropionic acid, isocyanate, thiolester, thionocarboxylic acid ester, imino ester, and carbodiimide anhydride. Maleimidopropionic acid is the preferred reactive chemistry, but the invention also contemplates the selection of the above and like reactive chemistries as an electrophilic moeity for bioconjugations with albumin or other proteins.
This invention is further directed to the use of a composition for the manufacture of a medicament where the composition comprises a derivative of an antihistamine and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an an histamine effect.
The modified antihistamine may be cetirizine, loratidine and analogs thereof.
This invention is further directed to the use of a composition for for the manufacture of a medicament where the composition comprises a derivative of an anti-angina agent and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-angina effect.
The modifed anti-angina agent may be tirofiban or analogs thereof.
This invention is further directed to the use of a composition for the manufacture of a medicament where the composition comprises a derivative of an anti-hypertensive agent and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-hypertensive effect.
The anti-hypetensive agent may be enalapril or analogs thereof.
This invention is further directed to the use of a composition for the manufacture of a medicament where the composition comprising a derivative of an anti-arrhythmic agent and analogs thereof wherein the derivative includes a reactive functional group which reacts with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds, said reactive functional group being selected from N-hydroxysuccinimide, N-hydroxy-sulfosuccinimide and a maleimide group for use in the treatment of the human body to provide an anti-arrhythmic effect.
The anti-arrhythmic agent may be capobenic acid or analogs thereof. This invention is further directed to the use of a composition for the manufacture of a medicament where the composition comprising a derivative of an anti-depressant agent and analogs thereof wherein the derivative includes a reactive functional group w
Bridon Dominique P.
Ezrin Alan M.
Fleser Angelica
Milner Peter G.
Robitaille Martin
Conjuchem, Inc.
Morrison & Foerster / LLP
Webman Edward J.
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