Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-11-21
2004-06-15
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S464000, C424S465000, C424S468000, C424S474000, C424S490000, C424S493000, C424S451000, C424S452000, C424S475000, C424S494000, C424S495000, C424S496000, C424S491000, C424S497000, C424S498000
Reexamination Certificate
active
06749867
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to stabilized formulations of acid-labile drugs that provide a delayed and rapid release of the drug into the gastrointestinal tract. More particularly, the invention relates to an omeprazole formulation comprising a thick coating not containing a conventional enteric release polymer.
BACKGROUND OF THE INVENTION
Omeprazole is the first of a new class of drugs that inhibits gastric secretion by altering the activity of H
+
/K
+
ATPase, the final common step of acid secretion in gastric parietal cells. Omeprazole is indicated as therapy for short-term treatment of active duodenal ulcers and is also used in the treatment of severe erosive esophagitis or poorly responsive symptomatic gastroesophageal reflux disease (GERD).
The plasma half-life of omeprazole is about 60 minutes; however, the duration of action of a single-dose may exceed 24 hours. The recommended dose of omeprazole is 20 mg daily for 4-8 weeks that may be repeated, if necessary.
Pilbrant and Cederberg (1985) reported on the physical and chemical properties of omeprazole. The drug has low water solubility and is chemically unstable in an acidic environment. Omeprazole degrades very rapidly in acidic aqueous solutions, and the rate of degradation proceeds with a half-life of less than 10 minutes, at pH values below 4. Although it is very slightly soluble in water, the drug is very soluble in alkaline solution as the negatively charged ion. At pH 6.5, the half-life of degradation was reported to be about 18 hours, and at pH 11, the half-life extends to several hundred days. Preformulation studies indicated that moisture, solvents, and acidic substances had a deleterious effect on the stability of omeprazole.
The resting pH of the stomach is generally less than 2 and a meal may increase the pH to between 3 and 5. The major physiological stimulus for acid secretion in the stomach is the ingestion of food, especially if the meal has a high protein content. It is the protein component of the meal that possesses the greatest buffering capacity. Foods, such as milk, can raise the gastric pH to values as high as 6. Gastric emptying times can show considerable variation between subjects according to the test methods used, and can generally vary between 0.5-2.0 hours.
To protect omeprazole from the hostile environment of the stomach, Pilbrant and Cederberg, and others, have applied an enteric coat to solid substrates, such as granules, containing omeprazole prior to conducting bioavailability studies in humans. A fully bioavailable dosage form for omeprazole must release the active drug rapidly in the proximal part of the gastrointestinal tract.
In U.S. Pat. No. 4,786,505, Lovgren et al disclose a pharmaceutical preparation containing omeprazole and salts together with other alkaline compounds. A core containing omeprazole is surrounded by an enteric release coating. A subcoating, that is water soluble or rapidly disintegrating in water, separates the core from the enteric coat that protects the preparation from the hostile environment of the stomach. Enteric coatings are also disclosed in U.S. Pat. No. 5,385,739. The subcoat or separating layer in the '505 patent and in U.S. Pat. No. 4,853,230, also serves to separate the omeprazole from the acidic pH environment of the enteric polymers, i.e., enteric polymers are generally applied as a solution to a core containing a drug. Such enteric polymers are generally acidic, and therefore are capable of degrading omeprazole in the core during application of the coating to the core. Conventional enteric polymers may include shellac, Eudragit™ L100 and S100, Eudragit™ L30D 55 and Eudragit FS30D, cellulose acetate phthalate, PVAP, HPMCAS and HPMCP, or similar materials that are insoluble in acidic environments or water and pass into solution at pH values above pH 5.0, the pH of the upper GI tract downstream from the stomach. Each of these references discloses that a separating layer must be used between the enteric coat and the core and that an enteric coat must be used in order to provide a suitable release profile. However, given the tendency of enteric release polymers to degrade omeprazole, a subcoating is required. The requirement for a subcoating unnecessarily complicates manufacture of a stabilized dosage form. The subcoating in these formulations does not delay release of the omeprazole from the core to any significant extent.
None of the known omeprazole formulations have employed non-enteric coatings, i.e., coatings that do not rely upon pH changes that occur in the GI tract, to effect a delayed and subsequently rapid release of omeprazole. Use of only a non-acidic non-enteric coating to effect the delayed and rapid release of omeprazole would be beneficial as it would simplify the method for manufacturing a stabilized dosage form.
SUMMARY OF THE INVENTION
The present invention seeks to overcome at least some of the above-mentioned disadvantages inherent in known omeprazole-containing formulations. Stable and bioavailable omeprazole solid dosage forms are disclosed herein. Accordingly, one aspect of the invention provides a stabilized formulation containing omeprazole, or a salt thereof, wherein the formulation does not require a separating layer or an enteric release coating. The present formulation provides a physically and chemically stable delivery system for omeprazole and its salts, maintains drug stability during storage, stabilizes omeprazole in the acidic portions of the GI tract of a patient, and provides a rapid release of omeprazole in the upper GI tract. The formulation of the invention does not require or include an enteric coating or a separating layer to protect the omeprazole in the core of the tablet.
The present omeprazole formulation can exist as any multiparticulate form such as granules, spheroids, microspheres, seeds, pellets, beads, microcapsules, agglomerates, mini-tablets or tablets that are manufactured employing conventional techniques and pharmaceutical excipients. The formulation optionally contains an alkalizing agent present in the core of the dosage form and/or in the non-enteric coating surrounding the core.
Instead of an enteric coating, the formulation of the invention includes a non-enteric time-release (TR) coating applied directly over the omeprazole-containing core. This coating can be applied using conventional or perforated coating pans, fluidized bed equipment or by compression coating. The composition of this coating is designed such that the core of the dosage form will rapidly (immediately or catastrophically) disintegrate into an aqueous environment of use when non-acidic media or digestive juice in the environment come into contact with the core. The TR coating generally possesses erosion and/or diffusion properties that are essentially independent of the pH of the external aqueous medium and of the enzymes and bile salts present in the GI tract.
One embodiment of the invention provides a solid dosage form for providing a delayed and subsequently rapid release of omeprazole into an environment of use, wherein the dosage form comprises:
a core comprising omeprazole and at least one pharmaceutical excipient, wherein the core rapidly releases the omeprazole after the core is contacted with an aqueous fluid in an environment of use; and
a non-enteric water soluble time-release coating surrounding and in contact with the core, wherein the coating delays the contact of the core with the aqueous fluid in the environment of use for a sufficient period of time to delay the release of the omeprazole from the core, and the coating subsequently loses its physical integrity after the delay period thereby permitting the core to rapidly release the omeprazole into the environment of use.
Specific embodiments of the invention include those wherein: 1) the dosage form includes plural coated cores which are granules, beads, pellets, spheroids, microspheres, or seeds that are compressed into a tablet or filled into a capsule; 2) the core contains one or more osmotic agents that p
McGinity James W.
Robinson Joseph R.
Innovar L.L.C.
Matos Rick
Page Thurman K.
Sheikh Humera N.
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