Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-03-05
2001-01-30
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S456000, C514S457000
Reexamination Certificate
active
06180666
ABSTRACT:
INTRODUCTION
Technical Field
This invention is directed to the field of pharmacology and particularly to the formulation of oral pharmaceutical compositions for increased bioavailability and reduced inter- and intra-individual variability.
Background
Pharmacokinetics is the study of the fate of pharmaceuticals from the time they are ingested until they are eliminated from the body. The sequence of events for an oral composition includes absorption through the various mucosal surfaces, distribution via the blood stream to various tissues, biotransformation in the liver and other tissues, action at the target site, and elimination of drug or metabolites in urine or bile.
Bioavailability of a drug (pharmaceutical composition) following oral dosing is a critical pharmacokinetic determinant which can be approximated by the following formula:
F
oral
=F
ABS
×F
G
×F
H
where F
oral
is the oral bioavailability fraction, which is the fraction of the oral dose that reaches the circulation in an active, unchanged form. F
oral
is less than 100% of the active ingredient in the oral dose for four reasons: (1) drug is not absorbed out of the gut lumen into the cells of the intestine and is eliminated in the feces; (2) drug is absorbed into the cells of the intestine but back-transported into the gut lumen; (3) drug is biotransformed by the cells of the intestine (to an inactive metabolite); or (4) drug is eliminated by the cells of the liver, either by biotransformation and/or by transport into the bile. Thus, oral bioavailability is the product of the fraction of the oral dose that is absorbed (F
ABS
), the fraction of the absorbed dose that successfully reaches the blood side of the gastrointestinal tract (F
G
), and the fraction of the drug in the GI blood supply that reaches the heart side of the liver (F
H
). The extent of gut wall absorption, back transport and metabolism, and liver elimination are all subject to wide inter- and intra-individual variability.
Previous investigations arising in the laboratory of one of the present inventors resulted in new understandings of factors involved with bioavailability and in the invention described in U.S. Pat. No. 5,567,592. The '592 patent describes general methods for increasing bioavailability of oral pharmaceutical compositions and methods for identifying compounds that increase bioavailability. However, although that invention made it possible to investigate a number of classes of compounds not previously thought to be useful in enhancing bioavailability, the actual process of identifying specific classes of compounds that are superior bioenhancers, among those bioenhancers which work to some degree, still remains a process of investigation and discovery. For example, the use of essential oils to enhance bioavailability of an orally administered pharmaceutical composition is disclosed in U.S. Pat. No. 5,665,386.
SUMMARY OF THE INVENTION
An object of this invention is to identify compositions with superior ability to increase drug bioavailability, particularly by increasing net drug absorption and/or decreasing drug biotransformation in the gut wall by inhibiting cytochrome P450 drug metabolism.
Another object of the invention is to provide compositions that strongly inhibit enzymes of the cytochrome P450 3A class (CYP3A) in the gut in preference to in other locations, such as the liver, which was previously thought to be the primary site of drug metabolism.
One specific object of the present invention is to reduce inter-individual variability of the systemic concentrations of the active pharmaceutical compound, as well as intra-individual variability of the systemic concentrations of the pharmaceutical compound being administered.
The invention is carried out by co-administering a gallic acid ester with an oral pharmaceutical compound (drug) or compounds to increase drug bioavailability. Particularly preferred esters are octyl gallate, propyl gallate, lauryl gallate, and methyl gallate. The compositions and methods of the invention can be used to increase drug efficacy in humans and in other mammals. Although veterinary use is specifically contemplated, the primary use will be in human treatment. Administration schemes include, but are not limited to, use of oral and topical formulations in humans and use of similar formulations for livestock.
DESCRIPTION OF SPECIFIC EMBODIMENTS
Gallic Acid Esters Increase Drug Bioavailability
The present invention arises from continued research into the factors affecting drug bioavailability that were described in earlier applications arising from the laboratory of one of the present inventors. “Drug bioavailability” is defined here as the total amount of drug systemically available over time. The present invention provides a method for increasing drug bioavailability by inhibiting drug biotransformation in the gut using one or more of the compounds described herein. The compound(s) responsible for increased drug bioavailability is a gallic acid ester. The present inventors have discovered that gallic acid esters, in general, are capable of inhibiting the enzyme(s) responsible for drug biotransformation in the gut.
In general, the present invention provides a method for increasing the bioavailability of an orally administered pharmaceutical compound (particularly one which is hydrophobic) by orally co-administering the pharmaceutical compound to a mammal in need of treatment with an amount of a gallic acid ester sufficient to provide integrated systemic concentrations over time of the pharmaceutical compound greater than the integrated systemic concentrations over time of the pharmaceutical compound in the absence of the gallic acid ester. At least one gallic acid ester is utilized in the method of the invention to increase bioavailability. However, two or more gallic acid esters may be used simultaneously in the practice of the invention, leading to further increased bioavailability of the pharmaceutical compound, depending on the particulars of the compound. Changes in the integrated systemic concentrations over time are indicated by “area under the curve” (AUC) measurements, an accepted pharmacological technique described in detail below.
Gallic acid esters
Gallic acid esters useful in the present invention have the general formula shown below:
The R group may be an alkyl, alkenyl, alkynyl, aryl, benzyl, phenyl, alicyclic, or heterocyclic group, all of which groups may be substituted or unsubstituted. R is preferably a C
1
-C
22
alkyl group, a C
2
-C
22
alkenyl group or a C
2
-C
22
alkynyl group, all of which groups may be substituted or unsubstituted and may be straight chain or branched chain. R is more preferably a C
1
-C
12
alkyl group, particularly a methyl, propyl, octyl or dodecyl (lauryl) group, or a C
2
-C
19
alkenyl group, particularly a cis-9-hexadecenyl (palmitoleyl), cis-9-octadecenyl (oleyl), cis,cis-9,12-octadecadienyl (linoleyl), trans,trans-9,12-octadecadienyl (linolelaidyl), cis,cis,cis-9,12,15-octadecatrienyl (linolenyl), trans,transtrans-9,12,15-octadecatrienyl (linolenelaidyl), cis,cis,cis-6,9,12-octadecatrienyl (gamma-linolenyl), trans-9-octadecenyl (elaidyl) or trans-9-hexadecenyl (palmitelaidyl) group.
Many of the gallic acid esters used in the practice of the present invention are commercially available compounds or may be readily synthesized by methods that are well known in the art, for example, by refluxing gallic acid and the appropriate alcohol (R-OH) in the presence of acid using standard conditions as described in Vogel, A.,
Vogel's Textbook of Organic Chemistry,
4
th
Edition, revised by Furniss, B. S. et al., Longman Inc., N.Y. (1978).
In a recently published example, lauryl gallate was prepared in greater than 90% yield by refluxing gallic acid and lauryl alcohol in dioxane in the presence of p-toluenesulfonic acid and zeolite (Chen, L. and Wu, K., New process of synthesis of lauryl gallate,
Huaxue Shiji
19:382 (1997).
The gallic acid ester is preferably presented for coadministration in a ratio of gallic acid ester to drug in
Benet Leslie Z.
Wacher Vincent J.
AnMax, Inc.
Cooley & Godward LLP
Spivack Phyllis G.
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