Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-09-20
2002-07-02
Qazi, Sabiha (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S653000, C514S727000, C514S730000, C514S741000, C514S772000, C514S784000, C514S788000
Reexamination Certificate
active
06414033
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method for delivery of pharmaceutically effective amounts of drugs and therapeutic ions. More particularly, this invention relates to a method of formulating a dosage form that will move drugs, pro-drugs or therapeutic ions in either cationic or anionic form between voltaic cell compartments of the human body, such as from the mouth into the naso-pharyngeal area or into the lung. This invention utilizes the naturally occurring concentration gradients in the form of concentration cells, which are constituents of the anatomy. This invention also relates to a dosage formulation designed in consideration of naturally occurring pH gradients, Le., Teorell-Meyer gradients, and a method of treatment by delivering a pharmaceutically effective amount of ions or drugs using the formulation designed in consideration of Teorell-Meyer gradients.
BACKGROUND
A new method for delivery of ions and drugs in ionic form is disclosed, including dosage forms designed according to the method of this invention. This dosage form represents an active dosage form that uses charge as a driving principle and is a complete departure from passive dosage forms, The dosage form will be able to move either cations or anions by taking advantage of the naturally occuring concentration gradients that exist in concentration “cells” of the anatomy. One such concentration cell exists between from the mouth into the naso-pharyngeal area, trachea and possibly the lung. It is formed by the buccal cavity, the epiglottis and the naso-pharynx. By either raising or lowering the pH of the mouth to a suitable extent, by using a dosage form buffered at a correct pH, the ion or ionized drug or pro-drug will be moved electro-osmotically in accordance with Teorell-Meyer flux gradients.
The design of dosage forms according to this invention that are capable of moving ions, ionized drugs or carrier ions from one physiological compartment to another (defining a “cell”), in a pH dependent manner, derives mathematically from the Teorell-Meyer Theory. See, Teorell, T., Discussions Faraday Soc., 1956, 21(9), 305-369. The derivation according to this invention predicts that a dosage form buffered at the correct pH will be able to move either the desired positive or negative ions from compartment A to compartment B in an pH dependent osmo-electrophoretic manner, provided a flux gradient exists between two and possibly more compartments. Examples of such compartments are: mouth—nose; vagina—uterous—Fallopian tubes; outer and inner ear; and many others that are described in the work of Nordenstrom, B. E., Biologically Closed Electrical Systems: Clinical, Experimental and Theoretical Evidence of an Additional Circulatory System; Stockholm, Nordic Medical Publications, 1983, and Evans, E. E., Schentag J. J., Jusko W. J. eds, Applied Pharmacoldnetics: Principles of Therapeutic Drug Monitoring, 3rd ed, Vancouver, Wash., 1992, which are incorporated herein by reference.
Dosage forms designed according to the method of this invention are ideal for reaching one compartment from another and provide more direct application of drug to a target area than most conventional dosage forms, particularly those dosage forms that rely on systemic circulation. This allows the dosage form to actually contain a lower dosage of drug, since a higher percentage of drug is delivered to the target area. The drug can also be delivered directly to the target area as needed. Under some conditions where drug substances are transported through membranes, the drugs may become concentrated in the target tissues. In addition, fewer side effects should be expected from dosage forms according to this invention than from systemic dosage forms.
This dosage form will obviate conventional delivery systems such as nasal sprays. It is superior to such systems because it can be targeted to specific tissues in the body according to the prevailing Donnan Equilibrium of that tissue. These equilibria can be mapped. A Donnan Equilibrium is an area of fixed charge, held in place by the tertiary and quaternary struture of the constituent proteins in the target tissue. Thus a drug can be guided to a specific tisssue and leave another relatively or entirely untouched.
This method is applicable to almost any therapeutic agent that is capable of existing in ionized form, although those agents of lower molecular weight or size will be transported faster and are therefore preferred. Non-ionic agents require an ionizable carrier, which must meet the further requirements of providing for favorable release of the drug at the target site as well as being metabolizable or otherwise easily eliminated physiologically.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide for the design of pharmaceutical compositions which provide better, non-systemic delivery of drugs from a repository compartment of the human body to an adjacent compartment by utilization of the naturally occuring pH gradients between, the two compartments.
It is another object of the present invention to provide a pharmaceutical composition designed in consideration of the Teorell-Meyer gradient for the delivery of a drug from the mouth to the naso-pharyngeal area.
It is a further object of the invention to provide a method of non-systemic administration of an active drug or pro-drug to a patient.
Additional objects of the invention will become evident by study of the detailed description of preferred embodiments of the invention.
SUMMARY OF THE INVENTION
The above and other objects of the invention are provided by a method for formulating the composition of drug dosage forms which will deliver active drugs from a body compartment or organ in which it is placed, i.e., a repository compartment or organ, to a recipient compartment based on the Teorell-Meyer gradient of differing pHs between the two compartments. The method entails identifying both the repository and recipient compartments and determing the pH of each compartment, and is applicable to compartments that are adjacent or contiguous, or that are separated only by a thin membrane. In addition, the repository compartment is in the form of a cavity large enough to contain the desired doage form. Examples of such contiguous compartments include; the mouth and naso-pharynx, mouth-trachea-bronchioles and bronchi, and possibly lung, the surface of the eye, the sclera, the cornea, the anterior chamber, iris, posterior chamber, retina and possibly the optic nerve, the vagina-uterous-fallopian tubes and possibly the ovary, the middle and inner ear, epidural space-meninges-brain, to name a few. The method is also applicable to solid organs as well, such as the eye, liver and prostate. This invention is not limited in scope to the few compartment systems or organs listed here, but is meant to include any such compartment system as meets the basic requirements described herein. Such compartment systems may also be identified in Nordenstrom or Evans. Also, it is expected that a medical or pharmaceutical practitioner of ordinary skill in the art would appreciate the full range of applicability of the within invention.
Selection of contiguous repository/recipient compartment systems to which this invention would apply is dictated largely by pH differences between the two compartments, although other factors may be present as well. Generally, a difference of at least 0.1 pH units between the compartments is necessary, although the larger the pH difference the faster the active drug will be transported. A pH difference of 2.0 pH units is usually preferred, but a larger difference is possible according to the tolerance of the tissues. Thus, each dosage form has its own limits based on the practical pH difference between the compartments and each dosage form should be calculated according to the desired transport time that makes sense for the system. In the preferred embodiment of the mouth—nose system, the transport time should be within the twenty minutes needed to dissolve a typical lozenge. The pH difference, therfor
Browdy and Neimark
Choi Frank
Gelsus Research and Consulting, Inc.
Qazi Sabiha
LandOfFree
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