Bitterness-reduced oral pharmaceutical composition

Details Bitterness-reduced oral pharmaceutical composition Bitterness-reduced oral pharmaceutical composition

2002-03-14

2004-03-16

Prats, Francisco (Department: 1654)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S464000, C424S477000, C424S478000, C424S482000, C424S440000, C424S451000, C424S456000, C424S457000, C424S458000, C424S460000, C424S461000, C424S463000, C424S468000, C424S469000, C424S470000, C424S475000, C424S479000, C424S480000, C424S481000

Reexamination Certificate

active

06706284

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to an oral pharmaceutical composition in which bitterness of a drug having a bitter taste is reduced. Particularly, it relates to a bitterness-reduced oral pharmaceutical composition, which comprises one or more drugs having a bitter taste, one or more solid proteins and one or more pharmaceutically acceptable water-insoluble polymer bases, wherein the proteins are present in the polymer bases particularly as particles.
BACKGROUND OF THE INVENTION
Intrabuccally quick disintegrating tablets can be easily taken even by patients having a difficulty in swallowing. Since a drug having strong bitterness has a low bitterness-feeling concentration, so-called a threshold value, one feels bitterness when the drug is remained in a trace amount in the mouth. Accordingly, when a drug having strong bitterness is applied to intrabuccally quick disintegrating tablets, they cannot be taken easily because the period of time to feel bitterness in the mouth becomes apparently longer than the case of drugs having less bitterness. In addition, intrabuccally quick disintegrating tablets are regarded in most cases as a dosage form in which the taking ability of conventional tablets already on the market is improved. Thus, insurance of bioavailability after made into intrabuccally quick disintegrating tablets is an item naturally required to guarantee their quality. Virtually nothing is known about bitterness-reducing techniques for solving these problems by simultaneously achieving conflicting items, namely the control of excellent drug release in the mouth and the insurance of excellent drug release in the digestive tract, and further enabling application to intrabuccally quick disintegrating tablets.
It is well known that capsules are prepared by filling gelatin capsules with, e.g., a bitter drug and a filler as a preparation technique for masking bitterness of the bitter drug. However, since capsules are regarded as a dosage form which cannot be taken easily by patients having weak swallowing ability, particularly by old persons and babies, and when the current situation for the improvement of compliance is taken into consideration, selection of a bitterness controlling technique by capsules cannot always be said effective. Concern has been directed toward the development of a technique for controlling bitterness by a preparation designing of a drug itself or a preparation designing of a form containing the drug.
The current method frequently and generally used as a technique for controlling bitterness by a preparation designing is a method to coat granules or powders containing a bitter drug or a bitter drug itself making use of a pH-independent water-insoluble polymer base such as ethyl cellulose. In this method, it is intended to control release of a drug in the mouth to a minimum drug concentration human can feel its bitterness, namely threshold value or less, so that a drug having lower threshold value (a drug having stronger bitterness) requires larger coating amount to control releasing amount of the drug at a lower level. Thus, in the general coating method which uses a pH-independent water-insoluble polymer base, when taste of a bitter drug, particularly a bitter drug having low threshold value, in the mouth is controlled, namely when the drug release at an early stage is controlled, or when the controlling time is prolonged, it exerts influence also upon releasing amount of the drug when transferred into the digestive tract so that sufficient drug release cannot be obtained.
In addition, JP-A-2000-327561 (the term “JP-A” as used herein means an published Japanese patent application) discloses an invention regarding a granulating composition which is characterized in that a physiologically active component is dispersed in a gelatin gel. Particularly, its “Detailed Description of the Invention” describes that, when a physiologically active component having an unpleasant taste is dispersed as a powder form in an aqueous solution in which gelatin is dissolved and then the gelatin solution is gelled, e.g., by spraying and cooling the dispersion, powder form of the component is dispersed in the gelatin gel so that it renders possible production of a granulating composition in the form of granules in which the unpleasant taste (e.g., bitterness, sourness or astringency) of the component having unpleasant taste is effectively masked.
In general, an advantage of the use of gelatin as a coating base or matrix base in a pharmaceutical preparation is that the thus obtained preparation is quickly dissolved after its administration, but sufficient drug release control cannot be obtained in most cases due to the high solubility of gelatin. In fact, as is evident from the test data of Table 1 of the specification, drug release control by the technique is limited to 3 to 5 minutes, further drug release control in the mouth cannot be expected from the technical idea that gelatin is used and a granulating composition is produced by dispersing a bitter drug in its gel. Particularly, when application to a drug having considerably low threshold value and application to a dosage form such as intrabuccally quick disintegrating tablets in which a drug is retained in the mouth are taken into consideration, it is considered that a release control of 5 to 10 minutes is necessary so that there is room for further improvement.
Accordingly, the object of the present invention is to provide a bitterness-reduced oral pharmaceutical composition which has excellent drug release-controlling ability in the mouth even 5 to 10 minutes after its administration and excellent drug release ability in the digestive tract and can be applied to intrabuccally quick disintegrating tablets without using capsules.
DISCLOSURE OF THE INVENTION
In the case of coating which uses, e.g., a polymer base, a method in which coating is carried out by preparing a coating solution by dissolving all components is generally used, and control of the desired drug release is achieved by the coating amount and ratio of the components. For example, it is possible to delay or quicken the release by mixing a water-insoluble polymer base with a water-soluble polymer base and changing their ratio, or to delay or quicken the release by changing the coating amount. However, when drug release is controlled to control bitterness in the mouth, it exerts influence upon releasing amount of the drug when transferred into the digestive tract so that sufficient drug release cannot be obtained.
Under such circumstances, the present inventors have hit upon an idea on a use mode for effectively bringing out characteristics of protein as means for solving the problems. That is, when various examinations were conducted based on our test results that a protein under water-insoluble state effected, e.g., by thermal denaturation dissolves at markedly high speed in a digestive tract-imitated test, it was found a possibility that a protein which slowly dissolves or does not dissolve in a buccal-imitated test solution dissolves during a markedly short period of time by the action of enzymes when it is transferred into the digestive tract-imitated test solution. Illustratively, it was found that when a solid protein is allowed to be present in a polymer base membrane as one of bitterness controlling components, namely when the protein is coated by dispersing it in a water or organic solvent solution of a polymer base, control of drug release in a buccal-imitated test solution and quick drug release in a digestive tract-imitated test solution are simultaneously achieved.
In general, when drug is controlled in a buccal-imitated test solution, reactivity in a digestive tract-imitated test solution is also reduced accompanied thereby, but drug control in the buccal-imitated test solution became possible by allowing a protein to be present in a polymer base membrane and quick drug release in the digestive tract-imitated test solution was achieved.
Detailed mechanism of such a phenomenon is still unclear but considered as follows.
I. Contro

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