Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-04-14
2001-12-18
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S464000, C424S474000, C424S475000, C424S451000, C514S023000
Reexamination Certificate
active
06331316
ABSTRACT:
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to an enteric-coated pharmaceutical composition in the form of a tablet which comprises an acid labile high drug load medicament, such as ddl, which is sensitive to a low pH environment of less than 3, and which includes an enteric coating such as Eudragit L-30-D 55 and a plasticizer, but which does not require a subcoat. The tablets have excellent resistance to disintegration at pH less than 3 but have excellent drug release properties at pH greater than 4.5. A novel method of making said pharmaceutical composition is also disclosed.
BACKGROUND OF THE INVENTION
Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant to stomach acid for required periods of time before they begin to disintegrate and permit slow release of the drug in the lower stomach or upper part of the small intestines. Examples of some enteric coatings are disclosed in U.S. Pat. No. 5,225,202 which is incorporated by reference fully herein. As set forth in U.S. Pat. No. 5,225,202, some examples of coating previously employed are beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac, as well as shellac and stearic acid (U.S. Pat. No. 2,809,918); polyvinyl acetate and ethyl cellulose (U.S. Pat. No. 3,835,221); and neutral copolymer of polymethacrylic acid esters (Eudragit L30D) (F. W. Goodhart et al., Pharm. Tech., pp. 64-71, April 1984); copolymers of methacrylic acid and methacrylic acid methylester (Eudragits), or a neutral copolymer of polymethacrylic acid esters containing metallic stearates (Mehta et al., U.S. Pat. Nos. 4,728,512 and 4,794,001).
Most enteric coating polymers begin to become soluble at pH 5.5 and above, with maximum solubility rates at pHs greater than 6.5.
Numerous enteric coated and/or extended release pharmaceutical compositions and the methods of making these compositions have been disclosed in the art. Prior art compositions, however, often comprise numerous extra ingredients in addition to the medicaments, such as fillers, buffering agents, binders and wetting agents, all of which add to the bulk of the composition and reduce the amount of active medicament which can be contained in the composition. The processes for preparing these aforementioned pharmaceutical compositions require multiple time consuming steps, including subcoating and outer coating steps. Furthermore, many of these pharmaceutical compositions are intended for delivery in the lower GI tract, i.e. in the colon, as opposed to the upper intestines, i.e. the duodenum of the small intestine.
U.S. Pat. No. 5,225,202 discloses enteric coated pharmaceutical compositions utilizing neutralized hydroxypropyl methylcellulose phthalate polymer (HPMCP) coating. The pharmaceutical compositions disclosed comprise an acid labile medicament core, a disintegrant, one or more buffering agents to provide added gastric protection in addition to the enteric coating, as well as the enteric coating and a plasticizer. The pharmaceutical composition may also include one or more lactose, sugar or starch fillers. According to the invention disclosed in this reference, when the core includes a drug which is incompatible with the enteric coating layer, an additional subcoat layer which acts as a physical barrier between the core and outer enteric coating layer is employed to prevent interaction of the acid labile drug and the acidic enteric coat. The HPMCP enteric coating starts its dissolution process at pH 5.0. The process of preparing this pharmaceutical composition requires numerous coating steps to apply the subcoat and then the enteric coat.
U.S. Pat. No. 5,026,560 discloses a pharmaceutical composition and method of making said pharmaceutical composition, wherein the pharmaceutical composition comprises a Nonpareil seed core produced by coating sucrose with corn starch, spraying the core with an aqueous binder in a solution of water or ethanol and with a spraying powder containing a drug and low substituted hydroxypropylcellulose, followed by the application of an enteric coating.
U.S. Pat. No. 4,524,060 recites a slow release pharmaceutical composition which provides a sustained release composition for treating hypertensive patients, and which comprises a mixture of micronized indoramin or a pharmaceutically acceptable salt thereof, a water-channeling agent, a wetting agent, a disintegrant, the mixture being in the form of a non-compressed pellet and having an enteric coat or sustained release coat permeable to gastrointestinal juices.
U.S. Pat. No. 5,536,507 is directed to a pharmaceutical composition having a delayed release coating or enteric coatings wherein the active agent in the composition is intended for release of a predominant amount of the drug at a point near the inlet to or within the large intestine and at a pH of approximately 6.4-7.0.
Pharmaceutical compositions which include a medicament which is unstable in an acidic environment such as the stomach and which is not adequately buffered, will require an enteric protective coating to prevent release of such medicament prior to reaching the intestines.
ddl, (also known as didanosine or 2′,3′-dideoxyinosine, and marketed by Bristol-Myers Squibb Co. under the brand name Videx®), is an acid labile drug which has the formula
and which has been shown to be effective in the treatment of patients with the HIV virus which causes AIDS. The composition and method of inhibiting HIV replication with 2′,3′-dideoxyinosine have been reported. See U.S. Pat. Nos. 4,861,759, 5,254,539 and 5,616,566, which are incorporated by reference herein. More recently, Videx® has become widely used as a component of the new therapeutic cocktails used to treat AIDS. It is also an acid labile medicament sensitive to a low pH environment and will degrade in the stomach.
Videx® is generally available in a variety of oral dosages, including Chewable/Dispersible Buffered Tablets in strengths of 25, 50, 100 or 150 mg of didanosine. Each tablet is buffered with calcium carbonate and magnesium hydroxide. Videx® tablets also contain aspartame, sorbitol, microcrystalline cellulose, Polyplasdone®, mandarin-orange flavor, and magnesium stearate. Videx® Buffered Powder for Oral Solution is supplied for oral administration in single-dose packets containing 100, 167 or 250 mg of didanosine. Packets of each product strength also contain a citrate phosphate buffer (composed of dibasic sodium phosphate, sodium citrate, and citric acid) and sucrose. A Videx® Pediatric Powder for Oral Solution is also available and which is supplied for oral administration in 4- or 8-ounce glass bottles containing 2 or 4 grams of didanosine respectively, and is to be mixed with commercial antacid before oral ingestion.
With particular emphasis on the tablets, whether ingested alone or as part of a combination (“cocktail”) therapy regimen, the current chewable/dispersible buffered tablets are not conducive from a patient ease of use standpoint. Whereas the other products which are a part of the AIDS therapeutic cocktail are capsules or tablets and easily swallowed, the Videx® (referred to herein as “ddl”) Chewable/Dispersible Buffered Tablets must be thoroughly chewed, manually crushed, or uniformly dispersed in water before administration. Because ddl degrades rapidly at acidic pH, ddl, in its chewable/dispersible form and its buffered powder for oral solution, contains buffering agents and is administered with antacids in the pediatric powder form. However, the presence of the large quantities of antacid components in the formulation can lead to significant GI imbalance as noted by severe diarrhea. Many patients also complain about chewing the large ddl tablets (dose=2 tablets of 2.1 g each), the taste of the ddl or the time required to disperse the tablets and the volume of fluid (4 oz) required for the dose. All these factors, coupled with t
Ullah Ismat
Wiley Gary J.
Bristol--Myers Squibb Company
Lopez Gabriel
Marenberg Barry J.
Page Thurman K.
Seidleck Brian K.
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