Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1995-10-17
2001-02-13
Harrison, Robert H. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S451000, C424S452000, C424S464000, C424S465000, C424S488000, C514S170000, C514S781000, C514S970000
Reexamination Certificate
active
06187339
ABSTRACT:
The present invention concerns solid pharmaceutical compositions comprising a water insoluble non-cross-linked polymeric excipient capable of binding water and less than 7% by weight of an oil or oily substance, and a process for the preparation of said solid composition.
Many solid pharmaceutical compositions are known in the art, see for instance the standard reference work of Gennaro et al., Remington's Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8, chapter 89: Pharmaceutical Preparations and Their Manufacture). Usually tablets or capsules are prepared from granules comprising the active ingredients and additives or excipients. These excipients include diluents, binders, glidants, lubricants, and the like. General methods of tablet preparation are the wet-granulation method, the dry-granulation method, and the direct compression method. Each of these methods has its disadvantages, especially when low dosage active ingredients are formulated. For instance, in the wet-granulation method the active ingredient is usually dissolved or dispersed in a liquid, which is frequently an organic solvent causing environmental problems. In the dry-granulation method it is extremely difficult to get acceptable content uniformity when low dosage active ingredients are used. Direct compression methods are not generally applicable, since only ingredients having all the physical requirements for the formation of a good tablet can be used, especially possessing good cohesive and flow properties. Only very few ingredients have these required properties.
Since it is of considerable advantage to increase the efficiency of tabletting operations and reduce costs by using the smallest amount of floor space and labour as possible, there is a need for a very simple method of preparing drug loaded carrier particles for use in tablets and capsules. Moreover, if low dosage active ingredients are compressed into tablets problems concerning the content uniformity can occur. Existing methods for preparing tablets with low dosage active ingredients suffer from complexity, environmental problems, or poor reproducibility. An improvement was disclosed by Vervaet et al. (Int. J. Pharmaceutics 108 (1994) 207-212), who prepared pellets from microcrystalline cellulose Avicel PH-101 and PEG-40 hydrogenated castor oil. These compositions contain 7-21% of hydrogenated castor oil and relatively small particle sized microcrystalline cellulose, and should be granulated, extruded and spheronised to obtain the pellets. Compositions comprising Avicel PH-101 were also disclosed in the intermediate PCT patent application WO 94/23700. Other methods requiring granulation are disclosed by I. Ullah et al. (Pharmaceutical Technology, September 1987, 48-54) and C-M. Chen et al. (Drug Development and Industrial Pharmacy, 16 (3), 1990, 379-394). According to these methods a moisture-activated dry granulation method was obtained by blending a drug with a dry binder, such as microcrystalline cellulose which is capable of absorbing remaining free moisture. Pharmaceutical compositions including water-swellable, but water-insoluble cross-linked polymers together with an oil, are disclosed in EP 598,337. Such compositions, however, have inadequate flow properties.
The present invention offers a solution for obtaining drug loaded carrier particles without the need of a granulation step by using a solid pharmaceutical composition comprising less than 7% by weight of an oil or oily substance, a low dosage active ingredient, and a water insoluble non-cross-linked polymeric excipient capable of binding water and having a mean particle size greater than 150 &mgr;m.
Water insoluble non-cross-linked polymeric excipients capable of binding water are diluents added to dosage units to increase the mixture and the resulting dosage units bulk. The preferred diluent in this invention is a carrier material with water uptake properties for incorporation of emulsions or oily liquids comprising a solution or dispersion of a low dose active agent. The preferred carrier materials are water insoluble cellulose or starch, like amorphous and microcrystalline cellulose or agglomerated starch, or mixtures thereof. The carrier material has a mean particle size greater than 150 &mgr;m (micrometer), and preferably at least 180 &mgr;m. The carrier material will typically make up from 20 to 99% by weight of the resulting pharmaceutical composition, which may contain apart from the carrier material capable of binding water any suitable pharmaceutically acceptable auxiliary. Auxiliaries include fillers, diluents, disintegrants, binders, colorants, lubricants, and the like. A preferred water insoluble non-cross-linked polymeric excipient capable of binding water is commercially available Avicel PH-200.
The active ingredient is processed in an oil or oily substance with preferably a melting point below 40° C. Preferably the pharmaceutical composition comprises a dosage of 0.005 to 5 percent by weight of the active ingredient.
The active ingredient can be any active ingredient, and preferably a steroid. Preferred steroidal agents are selected from progestagen, estrogen, and mixtures thereof. With more preference the progestagens are selected from desogestrel, 3-ketodesogestrel, Org 30659 (17&agr;-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one), levonorgestrel, and gestodene, whereas the estrogens are selected from ethinyl estradiol (EE), estradiol, and mestranol. Usually mixtures of progestagens and estrogens are used. Most preferred are tablets comprising desogestrel or ethinyl estradiol or mixtures thereof. Other suitable active ingredients are for example levothyronine, thyroxine, digitoxine and digoxine.
Oils for dissolving or suspending the progestagen and the estrogen can be of a natural, semi-synthetic or synthetic source. Fixed oils of vegetable origin consist mainly of (mixed) glycerides. Examples are arachis oil, castor oil, sesame oil, fractionized coconut oil (miglyols), ethyl oleate, maize oil, Gelucire (partial glycerides and polyglycide fatty acids), and the like. Other suitable liquids are liquid paraffin, dimethyl silicone fluid, triacetin, mono- and di-glycerides, and esters of polyethyleneglycol, propyleneglycol, polyglycerol, glycerol, or glyceryl. The content of oil or oily substances will typically make up less than 7% by weight of the mixture for tabletting or capsulation, and preferably less than 4%, and more preferably from about 0.1 to 4%. The active compound can also be processed to mixtures of the oily substance and water. Emulsions are an example of such mixtures. If the oil content is 0% (thus no oil is present in the composition), preferably an aqueous solution or dispersion of the active ingredient is used. Known techniques and compositions for preparing suitable mixtures with the active compounds, oils, oily substances and optionally water are applicable. Emulsifying agents can be of the group of viscosity increasing agents like sugars, polyethylene glycols, gelatines, hydroxypropylcellulose (HPC), amylopectin, starch, carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone, gums like Arabic and Guar gum, cellulose based and starch based materials, and the like. Also emulsifying agents with ionogenic properties (sodium laurylsulfate, sodium dioctylsulfosuccinate, cetrimonium bromide) and nonionogenic properties [monostearine (glycerol monostearate), monoleine, sorbitan esters (Spans), PEG-sorbitan ethers (Tweens, polysorbates), PEG-fatty acid esters (like the Polyoxyl 50 stearates), PEG-fat-alcohol ethers (Cetomacrogols) and the like] can be applied for stabilizing the emulsion.
The composition and concentrations of the components of the liquids (comprising the active compound) should be as such that agglomeration during mixing with the carrier-materials is avoided. For instance, agglomeration by addition of high concentrations of emulsifying agents of the group of viscosity increasing agents results in mixtures with unacceptable flow proper
de Haan Pieter
Poels-Janssen Henrika Gerardina Maria
Akzo Nobel N.V.
Blackstone William M.
Harrison Robert H.
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