Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – Coated – impregnated – or colloidal particulate
Reexamination Certificate
1999-07-26
2003-05-13
Jones, Dameron L. (Department: 1616)
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
Coated, impregnated, or colloidal particulate
C424S001110, C424S001370
Reexamination Certificate
active
06562318
ABSTRACT:
This invention relates to novel particulate agents for use in diagnostics and therapy, especially in diagnostic imaging, and more particularly diagnostic imaging or therapeutic treatment via the neural system.
In the living body, pain, paralysis and neural dysfunction can be inferred from electrical studies such as EMG, NCV and SSEP, but these kinds of assessment have continued to prove awkward and imprecise. While CT and MRI have made it possible to diagnose a wide variety of structural problems affecting the brain and spinal chord, and while studies on excised tissue and post mortem studies have enabled neuronal pathways to be traced, there is currently virtually no effective means by which diagnostic functional imaging of the neural system, and especially the peripheral nervous system, can be achieved in vivo.
Diagnostic imaging of nervous system function has a multitude of potential applications which will readily be apparent to the physician or neurosurgeon and many of these are discussed further below. Thus for example the possibilities would exist to visualize the impact of neurofibrillary tangles as they develop, to locate and assess nerve compressions, to verify the effectiveness of surgical vagotomy and to measure the response of the injured spinal cord to attempts at treatment.
It has now been realized that particulate agents suitable for use as contrast agents in diagnostic imaging modalities, especially MRI and PET, may be conjugated to nerve adhesion molecules and that following administration into body tissue, especially muscle, such agents are endocytosed by neurons having axon termini in that tissue and carried along the axons by axoplasmic flow thus allowing imaging of the axons and of the nerves of which they form part.
The endocytosis of nerve adhesion molecule (NAM) labelled agents can also clearly be utilized for the remote delivery of therapeutic agents, i.e. axoplasmic flow can serve to transport a therapeutically active agent comprising a nerve adhesion moiety from its administration site in tissue such as muscle to a remote site where it exerts its pharmacological effect. This is of particular interest where the sensitivity or accessibility of the remote site is such as to prevent direct administration of the pharmaceutical.
Thus viewed from one aspect the invention provides a method of treatment of the living human or non-human (preferably mammalian) body to effect a desired therapeutic or prophylactic treatment or assist diagnostic investigation or surgical treatment thereof, said method comprising administering into a vascularized peripherally innervated tissue site (preferably a muscle although possibly also other tissue sites innervated by cranial, peripheral or autonomic nerves) or into other tissue sites innervated by a spinal root a particulate pharmaceutical agent comprising a nerve adhesion moiety serving to promote neuronal endocytosis of said agent and a physiologically active or diagnostic marker moiety capable of axonal transport from said tissue site, and, where said method is to assist diagnostic investigation or surgical treatment, detecting axonal transport within said living body of a said agent having a diagnostic marker moiety, preferably by generating an image of at least part of said body.
Viewed from another aspect the invention provides the use of a particulate pharmaceutical agent comprising a nerve adhesion moiety serving to promote neuronal endocytosis of said agent and a physiologically active or diagnostic marker moiety capable of axonal transport following neuronal endocytosis of said agent for the preparation of a therapeutic, prophylactic or diagnostic composition for use on administration into vascularized peripherally innervated tissue or into other tissue sites innervated by a spinal root in a method of treatment of the living human or non-human body to effect a desired therapeutic or prophylactic treatment or assist diagnostic investigation or surgical treatment thereof.
Especially in the case of therapeutic or prophylactic Treatment, the pharmaceutical agent is preferably administered into a tissue site, such as a muscle, having a volume of at least about ten times that of the group of nerve cells which are to transport the agent.
The term pharmaceutical agent is used herein Lo designate a substance capable of exerting a desired therapeutic or prophylactic effect and/or acting as a tracer, label, contrast agent or other diagnostic marker detectable in the intact living mammal. This substance may be a single compound but more generally will comprise a NAM coupled directly or indirectly to a physiologically active or diagnostically marked compound. Diagnostic marking may for example be with radiolabels, chromophores, fluorophores, by virtue of magnetic properties, or with atoms or structures capable of higher or lower radiation (e.g. X-ray or sound) absorbance or reflectance than surrounding body tissue. Particulate NAM-coupled moieties may be coated or uncoated and if coated the coating may be selected to be broken down within the neuron after endocytosis, either slowly or more rapidly, or to be maintained during axonal transport.
For the purposes of the present invention it should be appreciated that while natural or synthetic, essentially inert, organic polymer particles (such as dextran coated microspheres or latex nanospheres) are capable of being endocytosed, these organic polymers unlike more specific and complicated molecules such as proteins, antibodies and antibody fragments are not considered to be nerve adhesion molecules.
The mean particle size for the particulate pharmaceutical agents used in the invention is conveniently in the range 5 to 100 nm, especially 8-70 nm, more particularly 10 to 50 nm and preferably about 20-30 nm.
Many of the pharmaceutical agents that may be used in the method of invention are themselves novel and viewed from a further aspect the invention provides a pharmaceutical agent comprising a nerve adhesion molecule coupled (directly or indirectly) to an optionally-coated, particulate, physiologically active or diagnostically marked substance, with the proviso that for diagnostically marked substances the substance is a metal oxide, metal sulphide or alloy.
For use to assist diagnosis, the pharmaceutical agent preferably has a diagnostic marker that can be detected non-invasively, e.g. by virtue of its radiation emission or absorption characteristics or by virtue of its magnetic characteristics. For use in assisting surgery, for example to enable important nerve pathways passing through or near a wound site or other site undergoing surgical intervention, chromophores and fluorophores can also be used as diagnostic markers and in this instance in particular the use of non-particulate as well as of particulate pharmaceutical agents might be contemplated.
One especially important group of pharmaceutical agents for use according to the invention is that of NAM-coupled particulate inorganic compounds, for example metal oxides, sulphides or alloys, where the inorganic material is selected for its magnetic properties, in particular ferri- and ferromagnetism and more particularly superparamagnetism, or includes within an otherwise essentially inert matrix atoms or molecules which are released gradually from the matrix to exert a therapeutic or prophylactic effect or which function as diagnostic markers, e.g. radioisotopes or nuclides detectable upon MR spectroscopy. Many metal oxide structures may be utilized as the inorganic particles, and spinels and garnets have been found to be particularly useful in this regard. It should however be stressed that other well known inert and Preferably essentially water insoluble metal compounds may be used, especially those having or capable of being doped to exhibit cooperative magnetic properties and those having lattices such as permit desired radioisotopes to be included. By alloys, mixed metals are of course included. Organic particulate matrices may also be used to accommodate a therapeutic compound or a diagnostic marker.
As is clear from the
Fish & Neave
Haley Jr. James F.
Jones Dameron L.
Ruskin Barbara A.
Syngenix Limited
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