Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-12-21
2002-12-03
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S043000, C424S464000, C424S489000, C424S044000
Reexamination Certificate
active
06488961
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to an effervescent composition and a method of preparing same. More specifically, it relates to an effervescent granule having a controllable rate of effervescence, the granule being made by a hot-melt extrusion process.
BACKGROUND OF THE INVENTION AND DESCRIPTION OF THE PRIOR ART
Effervescent granules have found a variety of uses over the years. These include dental compositions containing enzymes, contact lens cleaners, washing powder compositions, beverage sweetening tablets, chewable dentifrices, denture cleaners, surgical instrument sterilizers, effervescent candies, as well as many pharmaceutical formulations such as for analgesics, antibiotics, ergotamines, digoxin, methadone and L-dopa.
Film-coated effervescent granules are known in the art. Polymers such as cellulose acetate phthalate or hydroxypropyl methylcellulose have been used. Such coatings have been introduced in order to increase tablet stability as well as to control dissolution rate and to target particular regions of the gastrointestinal tract.
Hot-melt extrusion as a method of preparing pharmaceutical formulations has previously been disclosed; however, effervescent formulations prepared by hot-melt extrusion are not known.
Hot-melt extrusion processes in the art have generally required extremely elevated temperatures (>150° C.), which temperatures could degrade extruded materials. It has not been appreciated that effervescent compositions, which are inherently heat labile, can be hot-melt extruded without significant degradation or decompaction.
Lindberg (Acta). Pharm. Suec. (1988), 25, 239-246) teaches a continuous wet granulation method for preparing effervescent granules. The process includes the steps: (1) mixing powdered citric acid and NaHCO
3
in the hopper of a Baker Perkins cooker extruder and granulating the mixture with ethanol.
U.S. Pat. No. 4,153,678 and British Patent Application Laid-Open No. 2083997 disclose effervescent tablets for addition to animal drinking water, respectively containing levamisole and vitamins or minerals as active components. U.S. Pat. No. 3,667,929 discloses that, an effervescent powdery composition coated by pulverizing active components such as piperazine acid salt, copper sulfate or sodium nitrate, an acid substance and carbonate together with a hydrophobic or a slowly dissolving material, is useful as an agent for addition to animal drinking water or a material for horticultural use.
Effervescence can be defined as the evolution of bubbles of gas in a liquid. As set forth in chapter 6 of Pharmaceutical Dosage Forms: Tablets Volume I, Second Edition. A. Lieberman. ed. 1989, Marcel Dekker, Inc. (the entirety of which is hereby incorporated by reference), effervescent mixtures have been known and used medicinally for many years. As discussed in this text, and as commonly employed, an effervescent tablet is dissolved in water to provide a carbonated or sparkling liquid drink. In such a drink the effervescence helps to mask the taste of medicaments. However, the use of effervescent tablets to prepare a beverage including medicaments, is not convenient. It requires preparatory steps before administration of the drug and also requires the presence of a suitable mixing container.
Effervescent tablets have also been used in the dental area. Westlake, U.S. Pat. No. 1,262,888, Howell, U.S. Pat. No. 3,962,417 and Aberg U.S. Pat. No. 4,753,792 disclose effervescent dentifrice tablets adapted to foam in the mouth of a patient so as to provide a tooth cleansing action.
An effervescent dosage form which incorporates microparticles which are susceptible to rupture upon chewing or which are adapted to provide substantially immediate release of the pharmaceutical ingredients contained in the microparticles is disclosed in U.S. Pat. No. 5,178,878 to Wehling et al. The microparticles comprise a drug encapsulated in a protective material. The microparticles are then mixed with an effervescent agent and then the mixture compressed into tablets.
Kond et al., in U.S. Pat. No. 5,223,246, disclose a water soluble effervescent composition prepared by hot-melting (1) an active component and (2) an acid and a carbonate for effervescent, with (3) a water soluble adjuvant whose melting point is not lower than 40° C., for addition to drinking water. The effervescent composition was prepared by mixing the active agent, the acid, the carbonate and the water soluble adjuvant and then heating the entire mixture to melt the adjuvant and subsequently cooling the mixture to room temperature while stirring to form effervescent particles.
Thus, there is no teaching or suggestion in the art of preparing effervescent granules by hot-melt extrusion. Despite prior efforts towards developments of suitable effervescent granules, there have been unmet needs heretofore for improved effervescent granules having controllable rates of effervescence and for methods for their preparation.
SUMMARY OF THE INVENTION
The present invention provides an effervescent granule having a controllable rate of effervescence prepared by hot-melt extruding (i) an acidic agent, (ii) an alkaline agent, and (iii) a hot-melt extrudable binder which melting or softening point temperature is less than about 150° C. and which is capable of forming a eutectic mixture with the acidic agent. The acidic and alkaline agents should be able to effervesce when placed in an aqueous solution. A formulation according to this aspect of the invention can provide a rate of release of an active ingredient that ranges from immediate to a delayed or controlled release over a prolonged period of many hours.
One aspect of the present invention provides a solid pharmaceutical dosage form adapted for direct oral administration, i.e., for direct insertion into the mouth of a patient. A dosage form according to this aspect of the present invention includes a mixture incorporating a water and/or saliva activated effervescent granule having a controllable rate of effervescence and a therapeutic compound.
According to another aspect of the present invention, it has been found that combination of the effervescent granules with the other ingredients can provide effective taste masking of particularly poor tasting compounds. This aspect of the invention thus provides a dosage form which offers both immediate or extended release and effective taste masking.
The effervescent granules taught herein can be used in pharmaceutical, veterinary, horticultural, household, food, culinary, pesticidal, agricultural, cosmetic, herbicidal, industrial, cleansing, confectionery and flavoring applications.
Formulations incorporating the effervescent granules according to one aspect of the present invention can further include one or more additional adjuvants and/or active ingredients which can be chosen from those known in the art including flavors, diluents, colors, binders, filler, surfactant, disintegrant, stabilizer, compaction vehicles, and non-effervescent disintegrants. The effervescent granules themselves do not generally include therapeutic compounds or other active ingredients.
The present invention also provides a method of preparing an effervescent granule having a controllable rate of effervescence where the method comprises mixing and hot melt extruding a hot-melt extrudable binder and an acidic agent to form a eutectic mixture which eutectic mixture is then mixed and hot-melt extruded with an alkaline agent to form the effervescent granule. The hot-melt extrusion process herein advantageously allows for extremely short exposure times of compounds to elevated temperatures as well as a higher throughput than batchwise hot-melt methods.
In particular embodiments, effervescent granules including a pharmacologically active agent are provided. In some aspects, by way of example, and while not intending to constitute an exclusive list, these pharmacologically active agents may comprise, in at least some embodiments, the following pharmacologically active agents: phenanthrene derivatives (e.g. morphine sulfate), synthetic and no
McGinity James W.
Robinson Joseph R
Dees Jose′ G.
Ethypharm, Inc.
Haghighatian Mina
Lathrop & Gage L.C.
Mayfield Denise L.
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