Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-09-19
2003-06-10
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
Reexamination Certificate
active
06576250
ABSTRACT:
FIELD OF THE INVENTION
The present application relates to pharmaceutical compositions and methods of delivering active ingredients through the rectum or vagina, and in particular to compositions and methods using effervescent agents as penetration enhancers to promote rectal or vaginal delivery of an active ingredient.
BACKGROUND OF THE INVENTION
Although generally not well accepted, various proposals have been advanced for rectal and vaginal administration of drugs. Because some veins in the rectum and vagina lead directly to the general circulation, when drugs are administered through the rectum or vagina, they have the advantage of bypassing the gastrointestinal and heptic metabolism process (i.e., reducing the first-pass effect). This can lead to faster onset of action and/or improved bioavailability of a drug. In addition, delivery of a drug through the rectum and vagina can be useful for patients unable or unwilling to take drugs orally or intravenously.
To improve the bioavailability of poorly absorbed drugs across the rectal and vaginal mucosa, penetration enhancers have been employed. Penetration enhancers are typically low molecular weight compounds, which enhance drug absorption across the mucosal membrane. There are generally five major classes of penetration enhancers: (1) bile salts and their derivatives (e.g., taurcholate, deoxcholate, and glycocholate); (2) chelators (e.g., citric acid, enamines, EDTA); (3) fatty acids and their derivatives (e.g., arachidonic acid, oleic acid, sodium caprylate, monoolein); (4) surfactants (e.g, SDS, polyoxyethylene-20-cetylether); and nonsurfactants (e.g., 1-alkylazacycloalkanone unsaturated ureas). Penetration enhancers are thought to increase drug permeability by affecting the membrane transport pathways and/or reducing the barrier effect of the mucosal lining.
Although generally effective, many of the penetration enhancers referred to in the current literature damage the absorbing tissues, often causing extensive tissue damage. Moreover, some penetration enhancers are also known to be toxic, such as bile salts, and therefore their use has been very limited. Accordingly, due to their side effects, penetration enhancers are often not a practical solution to the problem of poor bioavailability in the administration of active ingredients through rectum, vagina and elsewhere.
Therefore, there is a need for safe and effective penetration enhancers for the delivery of active ingredients across the rectal and vaginal mucosa.
SUMMARY OF THE INVENTION
The pharmaceutical compositions of the present invention comprise rectal or vaginal dosage forms containing an active ingredient in combination with an effervescent penetration enhancer for improving absorption of the active ingredient across the rectal and vaginal mucosa membranes, respectively. The effervescent agent can be used alone or in combination with a pH adjusting substance that alters the pH of the localized environment of the site of dissolution and absorption in the rectum or vagina to further improve dissolution and absorption.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The pharmaceutical compositions of the present invention comprise rectally and vaginally administrable active ingredients in combination with an effervescent agent for influencing absorption of a drug in the rectum or vagina, respectively. Effervescence leads to an increase in the rate and/or the extent of absorption of the drugs, and in particular, drugs that are known or suspected of having poor bioavailability. It is believed that such increase can result from reducing the thickness and/or the viscosity of the mucus layer; alteration of the tight junctions between cells, thus promoting absorption through the paracellular route; inducing a change in the cell membrane structure, thus promoting transcellular absorption; and increasing the hydrophobic environment within the cellular membrane.
The pharmaceutical compositions include an active ingredient, which is administerable through the rectum or vagina, depending on the selected route of administration, and an amount of effervescent agent effective to aid in penetration of the drug in the rectum or vagina, respectively. The amount of effervescent employed must not merely permit rapid dispersion of the medicament, but must aid in penetration of the drug across the rectal or vaginal mucosa. In this regard, the pharmaceutical compositions of the present invention may be distinguished from other effervescent compositions on the basis of the amount of effervescent material that they contain.
The term “effervescent penetration enhancer” includes compounds which evolve gas. The preferred effervescent penetration enhancers evolve gas by means of a chemical reaction which takes place upon exposure of the effervescent penetration enhancer to small amounts of water and other fluids in the rectum or vagina, respectively. Such water-activated materials must be kept in a generally anhydrous state and with little or no absorbed moisture or in a stable hydrated form, since exposure to water will prematurely disintegrate the composition. The acid and base sources may be any which are safe for human or mammalian use. Suitable sources include acid and hydrite antacids such as, for example, citric, tartaric, amalic, fumeric, adipic, and succinics. Suitable base sources include carbonate sources, such as dry solid carbonate and bicarbonate salt, such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like. The effervescent penetration enhancers of the present invention are not, however, limited to those that are based upon a reaction that forms carbon dioxide. Reactants which evolve oxygen or other gases and which are safe for human or mammalian use are also considered within the scope of the present invention.
The pharmaceutical compositions of the present invention should preferably contain at least about twice as much base as active ingredient (on a weight basis) together with the proportionate amount of an appropriate acid for generating the effervescent reaction. More preferably, the pharmaceutical compositions should contain at least about three times as much base as active ingredient (on a weight basis) together with the proportionate amount of an appropriate acid. It is particularly preferred that sufficient effervescent material be provided such that the evolved gas is more than 5 cm
3
, upon exposure of the composition to an aqueous environment in the rectum or vagina, respectively. These high concentrations of effervescent agents are needed to generate effervescence in sufficient amounts to promote permeability and absorption of the active ingredient across the rectal and vaginal mucosa. However, the amount of effervescent agent must be optimized for each specific active ingredient and for delivery in the rectum or vagina, respectively.
The pharmaceutical compositions may also include one or more pH adjusting substances. For active ingredients that are weakly acidic or weakly basic, the pH of the aqueous environment can influence the relative concentrations of the ionized and the unionized forms of the active ingredient present in solution, according to the Henderson-Hasselbach equation. The pH of solutions in which an effervescent couple with equimolar amounts of base and acid has dissolved is slightly acidic due to the evolution of CO
2
. Thus, the pH of the localized environment of the rectum or vagina (i.e., the contents of the rectum or vagina in immediate contact with the composition, including any active ingredient dissolved from the composition) may be altered to achieve desired relative proportions of ionized and unionized active ingredients by incorporating in the compositions certain pH adjusting substances.
Suitable pH adjusting substances include any pH adjusting substance that is safe for mammalian use. More preferably, the pH adjusting substances include any weak acid or weak base. These include, but are not limited to, any of the acids or bases previously mentioned
Eichman Jonathan D.
Hontz John
Khankari Rajendra K.
Pather S. Indiran
Robinson Joseph R.
Cima Labs Inc.
Lerner David Littenberg Krumholz & Mentlik LLP
Spear James M.
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