Process for manufacturing bite-dispersion tablets

Details Process for manufacturing bite-dispersion tablets Process for manufacturing bite-dispersion tablets

2000-06-08

2002-11-05

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Food or edible as carrier for pharmaceutical

C424S464000, C424S465000, C514S772300, C514S778000, C514S779000, C514S781000, C514S783000, C514S784000, C514S785000, C514S786000

Reexamination Certificate

active

06475510

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to method of manufacture of bite-dispersion (fast dispersible) tablets containing taste masked medicaments for oral administration without water.
BACKGROUND OF THE INVENTION
Tablets of medicaments developed for the treatment of a variety of diseases are the most preferred dosage forms based on the ease of administration and patient compliance. However, most of medicaments are bitter tasting, and persons orally taking these medications experience some discomfort or pain. In order to avoid this bitter taste, medicaments are therefore swallowed. However, infants and the elderly both experience some difficulty in swallowing. Thus, we are confronted with two problems—suppression of bitter taste and the rapid disintegration of tablets in the oral cavity in order to avoid the difficulty of swallowing.
The following methods have been used for taste masking of pharmaceuticals, viz., addition of sweetener or flavors, microencapsulation and coating of medicaments with materials, generally polymers, soluble in stomach. U.S. Pat. No. 5,260,072 discloses a method of making chewable tablets of taste-masked medicaments, whereby the taste masking is achieved by rotogranulating the active material with a binder and carrier material and coating the rotogranulations with a taste masking polymer blend of cellulose acetate, or cellulose acetate butyrate and polyvinyl pyrrolidone. Alternative approaches of the prior art (U.S. Pat. No. 5,084,278) include microencapsulating the tablet core containing bitter actives with polymers such as ethyl cellulose, methamethacrylate copolymers. Medicament absorbates with complex silicates such as magnesium aluminum silicate, magnesium trisilicate or cation exchange resin have also been proposed U.S. Pat. No. 3,085,942, 3,140,978, 4,711,774 and 5,219,563 and WO 96/39126).
WO 96/23494 discloses a taste masking method by wet granulating the active medicament, a silicate adsorbate, and a weak base such as calcium carbonate, which acts as a dissociation agent and compressing the granulation into tablets. U.S. Pat No. 5,275,823 teaches a method of preparing chewable tablets containing unpleasant tasting medicaments such as cimetidine by coating cimetidine with Eudragit E 100 and incorporating certain hygroscopic water-insoluble substances such as Al/Mg antacids as external excipients. The major drawback of these above noted methods is that the tablets still need to be swallowed and complete release of the active medicament may take up to 2 hours depending on the polymer system used therein.
Japanese Patent No. 55-8966 and 62-265234 disclose addition of lecithin (phosphatidylcholine) and cephalin singly, or in combination with lecithin. Japanese Patent No. 55-108254 proposes the use of an absorbent material. U.S. Pat. No. 5,407,921 discloses a method for suppressing the bitter taste by adding an acidic phospholipid or an acidic lyso-phospholipid. Bitter substances are commonly hydrophobic and it is believed that hydrophobic interactions with the receptor sites lead to their binding. Y. Katsuragi and coworkers [Pharm. Research Vol. 12, 658-662, 1995; Nature, 365:213-214, 1993; Brain Research, 713, 240-245, 1996; Biochimica et Biophysica Acta, 1289, 322-328, 1996] disclose the use of lipoproteins, PA-LG or PA-LA composed of phosphatidic acid (PA) and &bgr;-lactogloblin (LG) and PA and (&agr;-lactalbumin, respectively. These lipoproteins being hydrophobic, reversibly suppress the responses of the target sites for bitter substances. U.S. Pat. No. 5,407,921 discloses addition of acidic phospholipid or lysophospholipid for suppressing the bitter taste. These methods have been found, by themselves, to be insufficient to give the desired suppression of the bitter taste of certain pharmaceuticals.
Technologies for producing tablets which rapidly disintegrate in the oral cavity have also been described in the literature. These include immediate disintegrating tablets (WOWTAB®) of Yamanouchi Pharmaceuticals Company of Japan fast-dissolving tablets (WO 95/33446) of Proctor & Gamble Company; Lyoc® from Laboratoire Farmalyoc; fast dissolving taste masked OraSolv tablets from Cima Labs Inc.; FlashTab tablets of Prographarm; fast dissolving lyophilized dosage forms in blisters (Zydis®) from RP Scherrer; and the rapidly dissolving tablets of Fuisz Technologies all of which involve laborious manufacturing processes. Further, these tablets need to be packed in special packages.
The WOWTAB technology, noted above (Japanese Patents Nos. 6-010112, 6-086652, 6-0616) comprises coating a pharmaceutically active ingredient and mannitol/lactose with maltose, initially crystalline changing to an amorphous state, and then granulating. These granules are compressed into porous tablets at very low compression forces. When subjected to high humidity, maltose absorbs moisture to recrystallize, therefore the residual moisture in the formulation is removed prior to packaging. The tablets of hardness of 3-5 kP thus obtained, were found to require special packaging to avoid attrition during storage/transport.
The technology described in Proctor & Gambles WO 95/33446 patent application comprises forming a nonrupturable drug matrix by first dissolving/dispersing in water a taste masking agent such as xanthan gum, methylmethacrylate copolymer etc. and a pharmaceutically active agent and then driving off the moisture and blending with an orally acceptable carrier (effervescent) such as sodium bicarbonate and compressing into tablets. Moisture and heat sensitive actives cannot be processed, and the process is a time consuming and expensive one.
The flash dispersal technology of Cima relies on compressing into soft friable tablets blends of an effervescent couple and commercially available microencapsulated medicaments. The process is thus a complicated and expensive one which also requires stringent environmental controls (<20° C./10% relative humidity and tablet hardness ~1-2.5 kP) and also specialized packaging.
The Lyoc technology involves freeze drying a suspension of a medicament and excipients into pre-formed blisters. This technology is obviously not suitable for most active ingredients. Furthermore, the technology requires specialized equipment and is expensive.
FlashTab is a flash dispersal system which involves coating a drug with a Eudragit polymer (methylmethacrylate copolymer) to provide rapid release of the drug in the stomach, and formulating this microencapsulated drug with an effervescent couple to produce a flash dispersal tablet. The microencapsulation system currently uses an undesirable solvent based manufacturing process, and the cost of goods is high.
U.S. Pat. No. 5,407,921 describes a method of suppressing the bitter taste of materials to be placed in the oral cavity, such as foods, drinks and medicaments.
The process described in WO 94/08576 (Glaxo Group Limited) consists of first encapsulating ranitidine or a suitable salt form in polymer matrix such as ethylcellulose or using molten waxy material such as Carnauba wax, glyceryl tristearate or tripalmitate (high molecular weight straight chain saturated or unsaturated fatty acids, esters and alcohols) to obtain substantially tasteless ranitidine granules with a drug content of about 20% w/w, granulating said granules with xylitol, flavor, etc. and compressing into chewable tablets or dispersing in molten triglyceride suppository base and theobroma oil and preparing tablet shaped moulds. In either case, the process is laborious and expensive.
A need exists for a cost effective, rapid operation process for producing tablets containing medicaments, which provide for ease of oral administration (fast disintegration in the mouth without water) and taste-masking of any bitter ingredients.
SUMMARY OF THE INVENTION
The present invention is to a fast dispersing tablet, also referred to as a bite-dispersable tablet, containing an active ingredient. The pharmaceutically acceptable fast-dispersing tablet formulation of the present invention has a structure comprising compacted gran

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