Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1998-11-20
2002-06-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C424S427000, C424S428000, C514S853000, C514S854000, C514S912000
Reexamination Certificate
active
06410046
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
FIELD OF THE INVENTION
The present invention relates to a device for the combined use of electrotransport or phonophoresis with a chemical permeation enhancer in order to facilitate transnasal or transocular drug delivery to the nervous system of a mammal.
BACKGROUND OF THE INVENTION
A variety of routes currently exist for delivering drugs with a therapeutic and/or diagnostic effect on a mammalian organism, herein termed “drugs”, to the nervous system of a mammal. Examples of such routes include, among possible others, oral administration, transcutaneous or transmucosal absorption, as Ill as intravenous, subcutaneous or intramuscular injections. All of these routes of drug delivery are based on the administration of a drug into the general bloodstream, wherein the drug is delivered by the bloodstream systemically to all organs and tissues. Because all of the body organs are exposed to relatively high concentrations of a drug during systemic delivery, there is a potential for adverse effects and iatrogenic complications that may be quite severe with
It is very important to consider the anatomy of the olfactory region of a mammal including human. The olfactory area is quite different between primates and lower animals. The anatomy of the nasal passages is quite complex (human nasal cavity is illustrated in
FIG. 1
; Anthony Wexler, personal communications). The olfactory fissure leading to the cribriform plate at the roof of the nose is very narrow; ranging from complete closureto 3-4 mm when a decongesting agent is used (Guilmette, R. A., Wicks, J. D. and Wolff, R. K., Morphometry of Human Nasal Airways In Vivo Using Magnetic Resonance Imaging, J. Aerosol Med., Vol. 2, No. 4, pp. 365-377, 1989). It is obvious that a drug-containing device in a liquid or semi-liquid form will be preferred to enter such a difficult to access region and to make an intimate contact with the olfactory mucosa in every part of the olfactory region including the olfactory fissure and the cribriform plate. certain drugs. This problem of systemic side effects can be particularly aggravated when drugs must be given relatively frequently and/or few therapeutic alternatives exist.
When a drug has to be delivered to the central nervous system (CNS), it is first administered into the systemic bloodstream. Once the drug has been distributed throughout the bloodstream, it has to penetrate a complex system of tight endothelial junctions in the capillaries supplying the CNS comprising the so-called blood-brain barrier (BBB). The blood capillaries of the BBB are relatively impermeable to large molecules, particularly the charged, polar or ionizable ones. Thus, the BBB serves the function of keeping the environment of central nervous system constant and preventing potentially harmful molecules from passing from the bloodstream through the BBB into the CNS. Holver, many useful drugs are unable to efficiently penetrate the blood-brain barrier and reach therapeutic concentrations in the CNS. Yet others create therapeutic levels in the CNS only when their concentration in the bloodstream is increased to dangerously high levels, which leads to increased incidence of severe adverse effects, such as liver damage or kidney failure. There are also drugs that penetrate the BBB relatively Ill but cause severe systemic side effects on other organs when administered in the general bloodstream even at low concentrations.
Many drugs have a net charge, or have a polar structure, or are ionizable, or have a large molecular size. As a result, any of these drugs are unable to efficiently penetrate biological membranes (largely composed of hydrophobic lipids) including those comprising the superficial protective layer termed epidermis, or mucous membranes such as nasal mucosa. Holver, even uncharged and non-polar drugs may be significantly impeded in their transport across the BBB if, for example, the drug tends to form a large molecular complex with itself or with other molecules in the bloodstream such as albumin protein. In order to facilitate the delivery of drugs with poor penetration potential, several approaches of physical or chemical enhancement have been proposed.
For the purpose of this invention, “electrotransport” is defined as any form of electrically assisted delivery of a substance through a mammalian tissue, such as nasal mucosa, at least partially induced or enhanced by the application of an electrical potential. Thus, the term “electrotransport” as used herein includes without limitation previously defined terms such as iontophoresis, electrotransport, iontokinesis, electroporation and electroosmosis, and the combination of, which comprises the transport of a substance (either charged or neutral) at least partially induced or enhanced by the application of an electric potential, as in U.S. Pat. Nos. 5,298,017, 5,736,580, 5,749,847. In any given electrotransport process, hoIver, more than one of these processes may be occurring simultaneously to a certain extent. In the present disclosure, the term “electrotransport” is used in its broadest possible interpretation so that it includes the electrically induced or enhanced transport of a biomolecular agent, which may be charged or uncharged, or a mixture thereof, regardless of the specific mechanism(s) of transport. A drug can therefore travel into and across the nasal mucosa, and/or across cell membranes into the olfactory nerve terminals, and/or through the cribriform lamina (located at the roof of the nose in the olfactory region) and across soft tissues along the olfactory pathway, and/or into the cerebrospinal fluid (CSF). For example, the term electrotransport as used herein includes without limitation electroporation folloId by iontophoresis and/or electroosmosis, or iontophoreses and/or electroosmosis folloId by electroporation.
The term “phonophoresis” as used here is defined without limitation as any form of transport of a substance through mammalian tissue induced or enhanced by the application of ultrasound. The biomolecular agent can thereby travel into or across the treated tissue, and/or across the cell membrane into the cell, and/or across the nuclear membrane into the nucleus. For examples of ultrasound enhancement of drug delivery see U.S. Pat. Nos. 4,948,587 and 4,767,402 the disclosures of which are incorporated herein by reference in their entirety.
As described in U.S. Pat. No. 5,023,085 the disclosures of which are incorporated herein by reference in their entirety, iontophoresis can be combined with the use of a chemical or biological agent enhancing transdermal flux to achieve an increased efficiency of drug delivery across the skin for both topical and systemic drug delivery. As described in U.S. Pat. No. 5,624,898 the disclosures of which are incorporated herein by reference in their entirety, some lipophilic substances can augment the passive absorption of a limited group of neurologic agents from nasal cavity into olfactory nerve terminals with subsequent neuronal transport to the brain. In addition, PCT Patent Application PCT/EP96/05086 of Nov. 21, 1996 (WO 97/18855, published May, 29 1997) the disclosures of which are incorporated herein by reference in their entirety, discloses a drug delivery system that employs iothophoresis or phonophoresis in order to enhance drug transport, whereas a drug can be delivered from the nasal cavity directly into the CNS, without entering the general blood circulation, through the olfactory pathway, or through the sclera or cornea of the eyeball and via the ocular neural pathway. This approach is neither topical nor systemic, but rather involves delivery of a drug from the nasal cavity or an ocular surface area to a remote site in the CNS. Thus, the disclosed system provides a high efficiency enhancement of drug delivery to the CNS and allows controlling the rate of drug administration. HoIver, in some circumstances, this approach results in a new problem of causing local damage to the tissues directly underlying the active ele
Cohen Jerry
Intrabrain International NV
Page Thurman K.
Perkins, Smith & Cohen, ll
Ware Todd D.
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