Plastic and nonmetallic article shaping or treating: processes – Encapsulating normally liquid material – Liquid encapsulation utilizing an emulsion or dispersion to...
Patent
1981-12-11
1984-04-10
Lovering, Richard D.
Plastic and nonmetallic article shaping or treating: processes
Encapsulating normally liquid material
Liquid encapsulation utilizing an emulsion or dispersion to...
424 34, 424 37, 424262, 4284022, 42840224, B01J 1302
Patent
active
044420510
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the encapsulation of Indomethacin.
It is known to encapsulate particulate material, including drugs, in a coacervate complex by the technique of aqueous complex coacervation in which micro-capsules having a core of the particulate material encased in a coating are formed by dispersing the particulate material in an aqueous solution of a pair of colloids of opposite electric charge and then causing a coacervate complex to phase out ("coacervate") of the aqueous solution to enrobe the particulate material. Usually, the colloids employed are gelatin and a polysaccharide, especially acacia (also known as "gum arabic") although other coacervate systems are known and used. The actual coacervation of the complex conveniently is caused by changing the pH of the aqueous solution although other means can be used. The aqueous complex coacervation technique has been used successfully with drugs to provide inter alia protection of the gastro-intestinal tract from irritants.
Indomethacin (i.e. 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole-3-acetic acid) is a drug having useful anti-inflammatory, analgesic and antipyretic activity. Unfortunately, it is an irritant to the gastro-intestinal tract and this side-effect has reduced its use. Since it is only sparingly soluble in water and insufficiently wetted to provide a homogeneous dispersion in aqueous solution, attempts to overcome its gastro-intestinal irritancy by encapsulation using aqueous complex coacervation have been unsuccessful. U.S. Pat. No. 3,557,279 describes the preparation of Indom ethacin micro-capsules having a gelatin/acacia coating using aqueous complex coacervation and in particular refers to dispersion of the Indomethacin in paraffin oil containing a surfactant. However, the resultant products are not satisfactory. Friable clumps are formed when no paraffin oil is used. When paraffin oil is used, the internal phase of the micro-capsules contains about 37% paraffin oil and micro-capsules of cosiderable size variation (at least 100 to 1500 microns) are formed. In both cases only thin walled micro-capsules are formed.
The Inventors have attempted to improve the wettability of Indomethacin by using ultrasonic vibrations, surface active agents and oils but without success in terms of obtaining a satisfactory encapsulated product. Although a homogeneous dispersion and coacervation was obtained using certain oils, particularly corn oil and arachis oil, the resultant encapsulated Indomethacin had poor flow properties. However, the Inventors have now found that a satisfactory encapsulated product having good flow properties can be obtained if the Indomethacin is mixed with a water-miscible liquid polyhydroxyalkane, such as liquid sorbitol or, especially, glycerol (i.e. 1, 2, 3-trihydroxypropane) to form a dispersion or paste before addition to an aqueous solution for gelatin/polysaccharide complex coacervation. They have found also that the resultant encapsulated product has reduced side-effects compared with currently available Indomethacin preparations.
According to the present invention therefore, there is provided a method of encapsulating Indomethacin comprising mixing Indomethacin with a water-miscible liquid polyhydroxyalkane to form a dispersion or paste, dispersing said dispersion or paste in an aqueous solution of a gelatin/polysaccharide complex coacervate system, causing coacervation of said system to encapsulate the Indomethacin with a coacervate complex, and hardening and dehydrating the resultant microcapsules.
Usually, the Indomethacin will pass through a 200 gauge US sieve size sieve. Preferably the Indomethacin has a 50% weight median diameter in the range 5 to 10 microns with less than 5% w/w of particles greater than 33 microns diameter. It is also preferred that the amount of the Indomethacin present is 15 to 20% by weight of the combined dry weight of the Indomethacin and the coacervate system.
The presently preferred polyhydroxyalkanes for use in the method of the invention are C.sub.3 -C.sub.6 straight ch
REFERENCES:
patent: 3495988 (1970-02-01), Balassa
patent: 3549555 (1970-12-01), Hiestand et al.
patent: 3557279 (1971-01-01), Morse
patent: 4010038 (1977-03-01), Iwasaki et al.
patent: 4082688 (1978-04-01), Egawa et al.
Carless John E.
Rowe James S.
Lovering Richard D.
Nicholas Proprietary Limited
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