Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-12-28
2001-08-28
Webman, Edward J (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S426000
Reexamination Certificate
active
06280772
ABSTRACT:
BACKGROUND OF THE INVENTION
Because of the irregularly timed therapeutic effects of drugs as administered via tablets, powders, or injections, controlled time-release has always been a desirable goal. Many methods for accomplishing this have been proposed (Blume; Kydonieus; Rosoff; Roseman et al.). Disadvantages of most of these methods include: (1) Introduction of extraneous non-degradable material; (2) Heterogeneity of drug/material composite. (3) Incompatibility with living tissues. These disadvantages apply to aspirin and related drugs. Although the use of time-tested biodegradable matrices such as polyglycolide (Gilding et al.), the first synthetic absorbable suture material (Schmitt et al.), would appear to be well-suited for such uses, polyglycolide has not been used because “ . . . its low solubility in common solvents has made the formulation of composites difficult and its use in drug delivery problematic.” (Linhardt; Yoles et al.). However, polylactide and poly(lactide-co-glycolide) which are soluble under certain circumstances have been used to some extent (Fong, Asch et al., Hutchinson et al., Ikada et al., Murakami, Ramstack et al.).
Reported examples of the controlled release relating to aspirin follow. Evaluation of sustained release of acetylsalicylic acid complexed with an ion-exchange resin was made by comparing urinary excretion rates with that of acetylsalicylic acid alone. It was concluded that more critical and quantitative evaluation of resinate drug medication for more effective in vitro tests was needed (Chapman et al., 1959).
Slow dissolution may be provided by coating the aspirin tablet, or crystals from which it is formed, with poly(salicylic anhydride) [H-(OC
6
H
4
CO)
n
OH where n is 2-6]. Coating can be effected by heating the tablets or crystals for 20 min. at 120° C. or by treating them with a solution of the polymer in a solvent, preferably by dipping the tablets in a 1% solution of polymer in benzene followed by drying and successive dippings, 5 in all. Relative solubility of differently prepared tablets in 0.1 N HCl stirred at 200 rpm at 37° C. was determined (Tanner et al., 1968).
Aspirin or pancreatin may be encapsulated by dispersing them in solutions of polycarbonates, poly(vinyl chloride), cornstarch, polystyrene, cellulose acetate phthalate, poly(acrylic acid), or shellac, in organic solvents, dispersing the dispersions formed in aqueous solutions of inorganic salts, e.g. ammonium sulfate, disodium hydrogen phosphate, sodium chloride, or calcium chloride, and removing the organic solvent. Thus, a dispersion of 1 g. of pancreatin in a solution of 2 g. of aspirin in 20 g. of acetone was added to 60 g. of ammonium sulfate in 100 g. of water at 15° C. and heated 2 h at 30° C. to give capsules of 1.5-2 mm. diameter containing 30% enzyme, and soluble in intestinal juice (Kitajima et aL, 1970).
Encapsulation of acetylsalicylic acid in Na CM (carboxymethyl)-cellulose, a maleic anhydride-styrene copolymer, or a methacrylic acid-methyl methacrylate copolymer was accomplished by spraying a dilute solution of the CO
2
H-containing polymer and the oil, etc. into a dilute aqueous aluminum sulfate solution. For example, an emulsion of 5:14 oil and 1% Na—CM-cellulose was sprayed into a 0.1 M aluminum sulfate solution to prepare capsules having an average diameter of 1.2 mm. (Schoen et al., 1970).
Tablets, capsules, and gels were prepared containing granules of acetylsalicylic acid, ethoxyethyl cellulose, and dimethylpolysiloxane, which resulted in sustained release of sspirin. Thus, 1000 g. of powdered acetylsalicylic acid of 0.177 mm. diameter was added to 70 g. of Ethocel 20 (ethoxyethyl cellulose, ethoxy content 12%) in 300 mL in 1:1 toluene-dichloromethane. dimethylpolysiloxane (30 g.) in 90 mL of toluene was added and the solvent evaporated; the formed paste was extruded to give particles of 1 mm. diameter, which were hardened and dried. The granules obtained were filled into gelatin capsules. Tablets were prepared containing the above granules 0.715, starch 0.040, glycerol palmitate stearate 0.030, talcum 0.005, and microcrystalline cellulose 0.010 g. (Casadio et al., 1972).
A slow-release acetylsalicylic acid preparation, maintaining a steady level of 5-6 mg. % of acetylsalicylic acid in the plasma of rabbits throughout 24 hr. after oral administration. Administration at 100 mg./kg. was recommended for further clinical trial. Composition of the specific preparation was not given (Naplatanova et al., 1972).
Particle size and total exchange capacity were examined for 22 cation and anion exchangers used as binders for drugs with sustained-release action. The sustained-release effect was examined with standard preparations containing acetylsalicylic acid by the half-hange method. Release of aspirin was very slow and incomplete even after 6 h. Ion exchangers for preparing sustained-release preparations should be used discriminately (Stivic et al., 1974).
In vitro, EtOH increased the solubility of sustained release tablets of acetylsalicylic acid made with Eudragit retard-1, Methocel 65, or carbopol 934 but inhibited that of preparations made with Precirol (Froemming, 1975).
Intact and subdivided controlled-release tablets of acetylsalicylic acid showed no significant difference in cumulative release in vitro (Bechgaard et al., 1977).
Timed-release aspirin tablets were prepared by coating aspirin particles with cellulose acetate phthalate and a plasticizer in an organic solvent and pressing together layers of this coated aspirin and uncoated aspirin. E. g., 65 kg. of acetylsalicylic acid were treated with 2 gal. of a coating solution containing cellulose acetate phthalate 6, dichloromethane 17, diethyl phthalate 1.2, and acetone 15 kg, the coated aspirin granules dried, and ground to 20 mesh. Tablets containing 6 mg. of the above coated aspirin and 4 mg. of uncoated aspirin mixed with starch were pressed in a conventional 2-layer press. The uncoated layer dissolved readily in simulated gastric juice while the coated layer dissolved little in the simulated gastric juice but completely in simulated intestinal juice (Guy et al., 1977).
Aspirin was treated with dextrins to form aspirin-dextrin inclusion compounds with no side effects. Thus, tablets were prepared containing the powdered inclusions compound 2000, crystalline cellulose 500, and Mg stearate 30 g. The inclusion compounds were sustained-release compared to aspirin alone as reflected by blood aspirin concentrations in rabbits (Fujimoto, 1978).
Sustained-release pharmaceuticals were manufactured by adsorption of drugs onto bead-shaped active charcoal. Thus, 30 g. aspirin was dissolved in EtOH, the solution mixed with 100 g. bead-shaped charcoal to give the adsorbed aspirin (Sakauchi et al., 1979). Sustained-release aspirin tablets were also evaluated by using polyethylene as insoluble matrix and ethyl cellulose binder in different proportions (Khan, 1980).
Microspheres with a core material (drug) encapsulated with a polymer coating were prepared by dissolving the polymer in a solvent in which the drug is insoluble and polymer precipitated by phase separation to encapsulate the core. Temperature of the system was −40 to −100° C. A solution of 1.0 g poly(DL-lactic acid) in 50 mL toluene was cooled to 65° C. and micronized Mellaril pamoate (0.5 g) was dispersed in the solution. Isopropyl alcohol (150 mL) was added dropwise to the solution and the microcapsules settled. The product was washed twice with heptane and dried to give spherical microcapsules with 25-50 m diameter (Fong, 1980).
Plasma salicylate concentrations during multiple-doses of an uncoated and a sustained-release aspirin preparation were compared. Sustained-release aspirin preparations produced plasma salicylate concentrations comparable to those obtained with uncoated aspirin tablets administered more frequently (Karahalios et al., 1981).
Antiinflammatory tablets with retarded action are prepared containing the active ingredient, a regulator for-release of active ingredient, and an erosion promoter in relati
Baylor University
Head Johnson & Kachigian
Webman Edward J
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