Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
2001-12-10
2004-04-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S439000, C424S484000, C424S485000
Reexamination Certificate
active
06719996
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field
The present invention relates to novel galenic compositions and, in particular, to compositions for oral administration of medicaments.
2. Description
Oral dosage forms are designed to enable sufficient availability of the active compound at its site of action. The bioavailability of a drug depends on several parameters, such as the physicochemical nature of the active compound, the dosage form, as well as physiological factors.
Many substances obtained from modern drug discovery are problematic because of insufficient bioavailability. Such molecules often exhibit very low aqueous solubility and limited solubility in oils. Thus, a problem arises if high drug loads must be obtained. This is often the case with compositions in soft or hard gelatin capsules, wherein not only is the solubility of the drug in the medium very low, but the filling volume of the capsules is limited.
To enhance bioavailability of orally administered drugs, Self-Emulsifying Drug Delivery Systems (SEDDS) may be used. SEDDS are mixtures of oils and surfactants, ideally isotropic (sometimes including cosolvents), which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastrointestinal tract. When such a composition is released into the lumen of the gut, it disperses to form a fine emulsion, so that the drug remains in solution in the gut, avoiding the dissolution step that frequently limits the rate of absorption of hydrophobic drugs from the crystalline state. The use of SEDDS usually leads to improved bioavailability and/or a more consistent temporal profile of absorption from the gut. A description of compositions of SEDDS can be found for instance in C. W. Pouton,
Advanced Drug Delivery Reviews,
25: 47-58 (1997).
While SEEDS increase bioavailability, solubility of the drugs in such systems may not be increased considerably . Additionally, SEDDS compositions are usually administered by means of capsules, whose volume cannot be arbitrarily increased without negatively affecting the patient's compliance. Accordingly, for elevated daily therapeutic amounts, a patient must swallow several capsules to provide his body with the necessary amount of drug.
The problem solved by the present invention is how to provide a galenic composition for oral administration of medicaments that show low bioavailability and poor solubility in polar and/or apolar media.
SUMMARY OF THE INVENTION
The subject invention provides a pharmaceutical composition for orally administering an active compound having a bioavailability of 20% or less. The composition comprises, based on the total weight of the composition, from about 0.01% to about 15% (w/w) of an active compound molecularly dissolved in the composition, from about 30% to about 80% (w/w) of an edible lipid matrix, and from about 1% to about 20% (w/w) of an edible emulsifier, the ratio between the dose weight of the active compound and its solubility in the composition being equal to or greater than 0.6 ml.
Preferably, the edible lipid matrix is present in a concentration of from about 50% to about 75% (w/w) of the total weight of the composition. Preferred concentrations emulsifier are from about 1% to about 10% (w/w) of the total weight of the composition and more preferably from about 2% to about 8% (w/w) of the total weight of the composition.
The lipid matrix is favorably selected from the group consisting of natural vegetable triglycerides, semi-synthetic vegetable triglycerides, and hydrogenated vegetable glycerides, for cocoa butter.
The emulsifier is favorably selected from the group consisting of lecithins and polyglycolized triglycerides, such as soya lecithin. Sweeteners and/or flavors may be added.
The ratio between the dose weight of the active compound and its solubility in the composition is favorably equal to or greater than 1.2 ml, more favorably between about 1.2 ml and about 10 ml, and most favorably between about 3 ml and about 7 ml.
Favored active compounds are selected from the group consisting of sulfonamides, dihydropiridines, isoquinoline derivatives, 4-phenylpyridin derivatives, and phenylamino-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl] derivatives. 4-Phenylpyridin derivatives are favored. Another favored group of active compounds are selected from the group consisting of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide; 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-1-yl)-4-o-tolyl-pyridin-3-yl]-isobutyramide; and 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.
Another aspect of the subject invention is a process for preparing a pharmaceutical composition. This process comprises (i) selecting an active compound showing a bioavailability of 20% or less, an edible lipid matrix, and an edible emulsifier; and (ii) mixing, based on the total weight of the composition, from about 0.01% to about 15% (w/w) of an active compound showing a bioavailability of 20% or less, from about 30% to 80% (w/w) of an edible lipid matrix, and from 1% to about 20% (w/w) of an edible emulsifier, so that the ratio between the dose weight of the active compound and its solubility in the composition is equal to or greater than 0.6 ml.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be discussed in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not limiting.
According to the present invention, the problem of providing a galenic composition for oral administration of medicaments which show low bioavailability and poor solubility in polar and/or apolar media is solved by providing a pharmaceutical composition for oral administration of an active compound showing a bioavailability of twenty percent (20%) or less, characterized in that it comprises, based on the total weight of the composition, from 0.01% to about 15% (w/w) of said active compound molecularly dissolved in the composition, from 30 to 80% (w/w) of an edible lipid matrix and from 1 to 20% (w/w) of an edible emulsifier, the ratio between the dose weight (mg) of the active compound and its solubility (mg/ml) in the composition being equal to or greater than 0.6 ml.
The definition of the bioavailability is given in the examples and the above value of 20% or less is determined on the basis of a simple oral formulation (e.g. a hard gelatin capsule) without additional exipients and wherein the active compound is in the crystalline form. The dissolution of solid pharmaceutical active compounds in polar and apolar media is dealt for instance in A. Martin,
Physical Pharmacy.
4th ed., Lea Febiger London, (1993), 221-237. The composition according to the present invention can be defined as Self-Emulsifying Lipid Matrix (SELM) since, as the SEEDS compositions, it emulsifies at 37° C. under condition of gentle agitation. The high percentage of fat (30-80%) enables to considerably increase the amount of drug molecularly dispersed in the dosage form. SELM formulations are applicable in the cases where the volume available for the molecular dispersion of the drug must be equal to or greater than 0.6 ml. The volume available for the molecular dispersion of the drug is defined as ratio between the dose weight of the active compound in the single dose (mg) and its solubility (mg/ml) in the composition.
Use of the subject compositions allows for a significant reduction in the number of unit doses that must be taken daily by patients, thus increasing the overall acceptance of a given medicament. It has been demonstrated, in particular in the case of children and elderly people, that the positive result of a therapy depends on patient compliance which can be negatively impacted by a complex program of administration.
The relative high amount of emulsifier in the present composition imbues a self-emulsifying character which considerably increases the bioavailability of the active compound in th
Kuentz Martin
Roethlisberger Dieter
Di Nola-Baron Liliana
Hoffmann-La Roche Inc.
Johnston George W.
Prior Kimberly J.
Rocha-Tramaloni Patricia S.
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