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United States Patent (19) 11 Patent Number: 5,709,886

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United States Patent (19) 11 Patent Number: 5,709,886 USO05709886A Unitedo States Patent (19) 11 Patent Number: 5,709,886 Bettman et al. 45 Date of Patent: Jan. 20, 1998 54) EFFERVESCENT MICROCAPSULES 3,860,733 1/1975 Morse et al. ............................ 426/302 3,872227 3/1975 Hoff et al. ... ... 514/198 75 Inventors: Marie Jean Bettman, Dayton; Phillip 4411,933 10/1983 Samejima et al. ... ... 427/213.3 J. Percel, Troy; Thomas C. Powell. 4,831,058 5/1989 Pankhania et al. ..................... 514/570 5,084.278 1/1992 Mehta ..................................... 424/44 Alexandria, all of Ohio 5,178,878 1/1993 Wehling et al. ........................ 424/466 0. 5,215,755 6/1993 Roche et al. ............................ 424/480 73 Assignee: Vandalia,Eurand America, Ohio Incorporated, 5,306,506 4/1994 Zema et al. ............................. 424/466 FOREIGN PATENT DOCUMENTS (21) Appl. No.: 802,147 0069097-A2 1/1983 European Pat. Off.. 22 Filed: Feb. 19, 1997 Related U.S. Application Data Primary Examiner-Robert H. Harrison Attorney; Agent, or Firm-John W. Routh 62) ision of Ser. No. 383,342, Feb. 3, 1995, Pat No. 5,639, 57 ABSTRACT (51) Int. Cl. ................... B01J 13/08 Taste masked effervescent microcapsules are provided each 52) U.S. Cl. ................ 424/495; 427/213.3; 428/402.24 microcapsule containing an effervescent admixture of 58) Field of Search ................................. 424/495, 489, sodium bicarbonate and citric acid microencapsulated with 424/490, 494, 466; 427/213.3; 428/402.24 ethylcellulose, the effervescent microcapsules being useful in formulating taste masked effervescent chewable tablets 56) References Cited also containing microencapsulated, unpleasant tasting drugs such as non-steroidal, anti-inflammatory, NSAID drugs. U.S. PATENT DOCUMENTS 1,356,544 10/1920 Miller ...................................... 424/45 1 Claim, No Drawings 5,709,886 1. 2 patients and provide an effective means for control of pain EFFERVESCENT MCROCAPSULES and inflammatory processes, particularly for the rheumatoid This application is a divisional application of application arthritis and osteoarthritis patients. However, these non Ser. No. 08/383,342, filed Feb. 3, 1995, now U.S. Pat. No. steroidal anti-inflammatory drugs have severe bitter taste and aftertaste, and have an adverse mouth feel when taken 5,639,475. orally. BRIEF DESCRIPTION OF THE INVENTION Therefore, in order to make wider use of them while The present invention is directed to taste-masked effer substantially eliminating the bitter taste, aftertaste and vescent microcapsules and chewable tablets made there adverse mouth feel and make these drugs more pleasant from. More particularly the present invention is directed to 10 upon taking them orally, there has long been desired a way individual taste masked microcapsules each containing an to insure delivery of these drugs in their desired concentra effervescent admixture of sodium bicarbonate and citric acid tions while avoiding their extremely bitter taste, lingering and taste masked chewable tablets containing the efferves aftertaste and adverse mouth feel effects referred to above cent microcapsules together with microcapsules containing connected with their ingestion orally thereby encouraging an NSAID or other unpleasant tasting pharmaceutical mate 15 patient compliance. rial. The effervescent microcapsules of the present invention SUMMARY OF THE INVENTION are manufactured by microencapsulating a granulation of sodium bicarbonate and citric acid in a heated coacervation According to this invention, taste-masked effervescent medium including cyclohexane, an encapsulating polymer microcapsules are provided each containing an effervescent 20 admixture of sodium bicarbonate and citric acid. The effer and a phase inducing polymer and subsequently cooling the vescent microcapsules in turn provide taste-masked effer coacervation medium. The microcapsule containing the vescent chewable tablets when combined with microcap unpleasant tasting component of the taste masked chewable sules containing an unpleasant tasting pharmaceutical tablets and the tablets themselves are manufactured by material. The taste-masked effervescent chewable tablets methods well known to the art. 25 represent an improved delivery system for the objectionable BACKGROUND OF THE INVENTION tasting NSAIDS. For example, the taste masked effervescent microcapsules maintain a controlled effervescent reaction in The process for the preparation of individual taste masked the mouth without a "burst" effect. Also the effervescent bitter tasting pharmaceuticals by microencapsulation of the microcapsules provide increased product stability and less pharmaceutical in a coacervation medium containing 30 need for humidity control during processing, for example, cyclohexane, an encapsulating polymer and a phase induc ing agent is well known in the art. A typical process is manufacture on a conventional tablet press. described in U.S. Pat. No. 3,860,733 to Lewis D. Morse et DETALED DESCRIPTION OF THE al which discloses microencapsulation of vitamin mixes by INVENTION polymer/polymer incompatibility coacervation. A disclosed 35 In the process of the invention, the preferred weak acid for coating polymer is ethylcellulose, a disclosed phase induc use in providing effervescence is citric acid although other ing polymer is polyethylene and a disclosed solvent for the weak acids may be used such as fumaric acid and tartaric polymers is cyclohexane. Because of its detailed description acid. The effervescence ingredients can be combined with of the coacervation process, U.S. Pat No. 3,860,733 is excipients other than maltodextrin such as mannitol, incorporated herein by reference in its entirely. Another sodium-citrate, dextrin and the like. The proportions of description of the preparation of ethylcellulose microcap sodium bicarbonate to citric acid to excipient are about sules by the liquid-liquid phase separation of ethylcellulose 55:40:5 in the granule product from the granulation process in cyclohexane is given in U.S. Pat. No. 4411,933, which which can be any of the granulation processes known to the patent disclosure is also incorporated herein by reference in art. See for example, U.S. Pat. No. 5,084.278 although the its entirety. 45 fluid bed granulation process is preferred. The ethylcellulose Effervescent granulations and tablets made therefrom are concentration in the cyclohexane can vary so as to provide also known to the art. For example, U.S. Pat. No. 3,872,227 a suitable film coating on the granules but usually is such as to Dieter Hoffetal discloses granulations of sodium citrate, to provide 2.01% to about 5.01% by weight at the encap citric acid, saccharin and coloring, granulated in alcohol and sulated granule. dried, the granulations being a pre-mix further admixed with 50 Suitable water-insoluble NSAID drug materials which other materials including amplicillin and sodium bicarbonate can be used in accordance with this invention include, but and then tableted to form effervescent tablets. are not necessarily limited to, the following: naproxen, Non-steroidal anti-inflammatory drugs (NSAID) having ibuprofen, sulindac, diclofenac, fenclofenac, alclofenac, analgesic and anti-inflammatory properties have been ibufenac, isoxepac, furofenac, tiopinac, zidometacin, widely administered orally in the treatment of mild to severe 55 acemetacin, fentiazac, clidanac, oxipinac, Zomepirac sodium pain, particularly for rheumatoid arthritis and osteoarthritis and pharmaceutically acceptable water-insoluble salts patients. Tolerance or addiction to these drugs is not gener thereof. Other unpleasant tasting pharmaceuticals include ally a problem with their continuous use in the treatment of acetaminophen and aspirin and caffeine. pain or in the treatment of acute or chronic inflammatory The encapsulation process used to encapsulate the states. However, these drugs generally have a higher poten unpleasant tasting drug materials can be any taste masking tial for adverse side effects at the upper concentrations encapsulation process known to the art, and the encapsulat (limits) of their effective dose ranges. Therefore, it is impor ing polymer can be any pharmaceutically acceptable poly tant that such non-steroidal anti-inflammatory drugs be mer such as ethycellulose, gelatin, cellulose acetate phtha accurately measured and administered orally. late and mixtures thereof. The phase inducing substance can These non-steroidal anti-inflammatory drugs, e.g., ibu 65 be sodium sulfate, sodium hexametaphosphate, polyethyl profen and naproxen, have been widely prescribed by phy ene or an organosilicon polymer. Note U.S. Pat. No. 4411, sicians. These drugs are in general tolerated well by most 933. 5,709,886 3 4 The proportion of microencapsulated effervescent gran was removed when the cyclohexane mixture temperature ules in the final taste masked tablets of the invention is reached 80°C. The mixture was allowed to cool slowly to generally about 8% to about 10% by weight encapsulated 30°C. with continued agitation. At 30° C. the contents of the breaker were washed twice with fresh cyclohexane and effervescent granules based on the weight of the taste decanted into a Buchner filter, then and tray dried overnight. masked tablet. The amount can be varied depending on the The effervescent microcapsules were sieved through 12 particular NSAID drug used in the tablet and on the degree mesh, U.S. Standard sieve, bottled and labeled. of mouth cleansing effect desired from the effervescent In the above microencapsulation
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