Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-10-20
2003-11-18
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S400000, C424S439000, C424S485000, C424S489000, C514S778000, C514S779000, C514S782000, C514S944000
Reexamination Certificate
active
06649191
ABSTRACT:
The present invention is concerned with compositions for oral administration which have the ability to mask the taste of an active ingredient contained therein as well as methods for the preparation of such compositions and their use in the administration of a wide variety of active ingredients. The invention is also concerned with the same compositions which control the rate of release of active ingredient contained therein.
Oral dosage forms provide a convenient vehicle through which one or more pharmaceutically active ingredients may be administered to a patient requiring therapy. A wide variety of dosage forms exist and the choice of any particular form depends upon individual requirements. Dosage forms may be prepared by granulating one or more active ingredients with a carrier or excipient to give a mixture that is suitable for further processing. Tablets are typically prepared by compressing the granulated mixture in a die, granules are prepared by extruding and optionally spheronising the mixture and capsules are prepared by filling a capsule shell with pre-prepared tablets or granules. Typical excipients include synthetic materials such as polyvinylpyrrlidone and co polymers of methacrylic acids is as well as natural polymers such as cellulose, starch and alginic acid.
Dosage forms produced in this way comprise particles of active ingredient and excipient which are packed together rather like balls in a box, so that when the form erodes discrete particles of active ingredient are exposed and then lost to the surrounding environment through dissolution. The rate at which the individual particles diffuse into the surrounding environments depends, in part, upon their size. Smaller particles having a larger surface area to volume ratio dissolve more rapidly than larger particles. Erosion of the dosage forms occurs upon ingestion causing the active material to be released to the surrounding environment. Unless such dosage forms are coated it may be possible to taste the active ingredient. Such dosage forms are unable to delay release of the active material.
A patient who is able to taste an active ingredient upon ingestion of the dosage form may be reluctant or even refuse to comply with the therapeutic regime imposed. The problem is particularly acute with both the elderly and very young who have trouble swallowing tablets. Taste masking is a recognised problem and has been discussed in an article entitled “Taste-masking of Oral Formulations” by Galanchi & Ghanta in Pharmaceutical Manufacturing Limited, 1996, Sterling Publications Ltd.
The therapeutic management of patients with phenylketonuria, for example, requires the administration at regular periods throughout the day of an amino acid protein substitute that excludes phenylalanine in order to maintain the plasma phenylalanine levels within an acceptable range. The protein substitutes are usually administered prior to mealtimes in the form of a drink, which is highly flavoured to mask the bad taste of the amino acids. Dissolution of the active material starts upon administration. Although this regime allows the phenylalanine levels to be adequately maintained within specified levels during the day, the impracticality of administering the protein substitute during the hours in which the patient is asleep means that it is not possible to maintain the olasma phenylalanine concentration at a constant level over a 24-hour period. This presents major problem with regards the therapeutic management of such patients.
It is well known to provide dosage forms with sugar coatings to mask the flavour of an unpleasant tasting active ingredient. However, the problem with this is that unless the dosage form is swallowed immediately the sugar coat rapidly dissolves and exposes the active material to the buccal environment, which leaves an unpleasant taste. These dosage forms are also unable to delay the release of an active material contained therein.
The problem of providing dosage forms with the ability to mask taste has been addressed in WO 93/01805. This disclosed rapidly disintegrating multiparticulate tablets prepared by granulating ethylcellulose or polymethacrylic acid coated crystals or granules of active material with excipients and flavouring and compressing the resulting mixture to form a tablet. This preparation requires a large number of processing steps, making these tablets both complicated and expensive to prepare.
Tablets coated with layers of alginic acid and calcium gluconate were found to mask the taste of the tableted active material for a limited period of time due to the formation of a gel upon ingestion of the dosage form (Kaneko et al, Chem. Pharm. Bull. 45(6), 1063-1068 (1997)). An outer coat of calcium gluconate gave a masking time of 1 minute, whereas an outer coat of alginate gave a masking time of between 0.5 and 3 minutes; the masking time was found to be dependent upon the relevant thickness of the alginate and gluconate coats. These tablets are suitable for administration if the residence time in the mouth is relatively short, but may cause problems if the patient is unable to swallow tablets, requires a dispersible dosage form or has a tendency to regurgitate any food ingested.
Alginic acid is a naturally derived polysaccharide formed from polymers of D-mannuronic acid and L-guluronic acid. Its use as a pharmaceutical excipient is well known (EP 0 213 083 and GT Colegrave, Proc. Intern. Symp. Control Rel. Bioact. Mat; 19 (1992) 271-272). Other naturally occurring polysaccharides include starch, cellulose, pectins and chitosans. None of these naturally occurring polysaccharides except starch are broken down by the human digestive enzymes in the small intestine although all are susceptible to microbiological attack by the microorganisms or flora inhabiting the large intestine of the digestive tract.
Alginic acid contains at least three different types of polymer segments: poly(&bgr;-D-mannopyransosyluronic acid) segments, poly(&agr;-L-gulopyranosyluronic acid) segments and segments with alternating sugar units. The ratios of the constituent monomers and the nature of the chain segments vary with the source and determine the specific properties of the polysaccharide. A useful property of alginates is their ability to form gels by reactions with cations, especially divalent cations such as calcium ions. The type of gel formed depends on the source of alginic acid. Alginates with a higher percentage of polyguluronate segments from more rigid, brittle gels whereas alginates with a higher percentage of polyguluronate segments or more elastic, deformable gels. The rate of gel formation as well as the quality and texture of the resultant gel can be controlled by the solubility and availability of the cation source.
The ability of alginic acid to form gels has been used in the preparation of a variety of dosage forms (Ostberg et al, International Journal of Pharmaceutics, 112 (1994) 241-248 and Ostberg et al, Acta Pharm. Nord. 4(4), 201-208 (1992)). Formulations containing theophylline, a relatively soluble drug, have been prepared by extruding a suspension of theophylline, in alginic acid solution into a theophylline-saturated solution of calcium chloride. The granules formed were found to be unsuitable for use as a controlled release formulations due to the high rate of release of active material in acidic media.
A further problem with formulations prepared according to the method of Ostberg is that upon formulation of the alginic acid drug suspension and extrusion of that suspension into calcium chloride solution, some of the particulate matter dissolves in the alginic acid solution and recrystallises at the surface of the microspheres upon drying. This means that using the methods of Ostberg it is neither possible to produce microspheres comprising particles or crystals of predefined size due to the soluablilisation thereof, nor is it possible to obtain microspheres having the active material homogeneously distributed throughout due to recrystallisation at the surface. Inhomogenieties in the structure of
Karkalas John
Tester Richard Frank
Drinker Biddle & Reath LLP
Glycologic Limited
Spear James M.
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