WO1999010000A1

WO1999010000A1 - Combined preparations for treating upper gastrointestinal tract distress

Info

Publication number: WO1999010000A1
Application number: PCT/IB1998/001205
Authority: WO
Inventors: Sekhar Mitra; Kishorkumar Jivanlal Desai
Original assignee: The Procter & Gamble Company
Priority date: 1997-08-25
Filing date: 1998-08-06
Publication date: 1999-03-04
Also published as: JP2001513570A; AU8354498A

Abstract

The invention concerns multilayer combined preparations for oral administration to be used for disorders of the upper gastrointestinal tract, such as heartburn, indigestion or H. pylori infections. The preferred form is a tablet which releases a bismuth compound in the stomach and a proton pump inhibiting compound into the intestine. This is achieved by making an enteric coated core containing the proton pump inhibitor with an outer layer containing the bismuth compound.

Description

COMB INED PREPARATIONS FOR TREATING UPPER GASTROINTESTINAL TRACT DISTRESS

BACKGROUND OF THE INVENTION

The present invention relates to ingestible pharmaceutical compositions comprising one or more proton pump inhibitors and one or more bismuth materials for treating upper gastrointestinal tract distress. Such distress includes those distress problems brought on by food, alcohol, over indulgence, or gastro esophageal reflux disease, among many others.

Pharmaceutical actives, such as bismuth and proton pump inhibitors, useful for treating upper gastrointestinal tract distress (such as heartburn, indigestion, stomachache, etc.) are widely used. They vary depending on the particuluar active ingredients, and increasingly differ in flavor, texture and even form. However, since bismuth acts in the stomach while enteric coated proton pump inhibitors are absorbed in the intestines, neither material alone can give total relief to sufferers of the upper gastrointestinal problems.

Thus, it is an object of the present invention to provide ingestible pharmaceutical compositions containing a proton pump inhibitor and bismuth useful for treating upper gastrointestinal tract distress (e.g., upset stomach, heartburn, indigestion, H. pylori infections) which provide faster relief and/or greater efficacy. Furthermore, an object is to provide methods for treating upper gastrointestinal distress by administering pharmaceutical compositions according to the present invention.

These and other objects of the present invention will become readily apparent from the detailed description which follows.

All percentages and ratios used herein are by weight, and all measurements are made at 20 to 45°C, unless otherwise specified.

SUMMARY OF THE INVENTION

The present invention is directed to ingestible pharmaceutical compositions comprising one or more proton pump inhibitors and one or more bismuth materials for treating upper gastrointestinal tract distress.

The present invention is also directed to methods for providing immediate relief due to the release of an bismuth in the stomach and longer term relief because of the presence of the proton pump inhibitor in the intestines. These methods comprise orally administering to a human patient in need of such treatment a safe and effective amount of the compositions described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising: (a) at least one proton pump inhibitor and (b) at least one bismuth material capable of being released in the stomach useful for treating upper gastrointestinal tract distress.

The proton pump inhibitor can be any of the materials which function to cause the pumps which provide acidic material to the stomach environment to cease functioning. These materials are advances in materials which reduce the input of acid (H2 blockers) in those individuals who suffer from gastrointestinal tract distress. Examples of such materials, include, but are not limited to omeprazole, lansaprazole, rabeprazole and prantoprazole and appropriate salts of these materials . Mixtures of the proton pump inhibitors may also be used. The proton pump inhibitors are used in the amount of from about 0.5% to about 90%, preferably from about 1% to about 40%o, most preferably from about 2% to about 6% of the dosage form composition.

In the compositions of this invention, the bismuth is preferably administered as a pharmaceutically-acceptable salt. Such bismuth salts include, for example, bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato bismuthate, bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof. Bismuth citrate, bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof are preferred bismuth salts for use in this invention. A variety of such compositions containing bismuth salts are commercially-available, including, for example, DeNol, containing tripotassium dicitrato bismuthate (sold by Gist-Brocades N.V.), Noralac, containing bismuth aluminate, alginic acid, and magnesium carbonate (manufactured by North American Pharmaceuticals), Roter bismuth, containing bismuth subnitrate ( sold by Roter Laboratories ), Fensobar Polvo, containing bismuth subcarbonate among other materials (manufactured by USV Pharmaceutical Corporation ), and Pepto-Bismol, containing bismuth subsalicylate (sold by The Procter & Gamble Company).

In addition, excipients may be included in the proton pump inhibitor portion, as well as in the bismuth portion. The term "excipients", as used herein, means one or more compatible solid or liquid filler diluents which are suitable for oral administration to a human. The term "compatible", as used herein, means that the components of the compositions of the present invention are capable of being commingled with the pharmaceutical active, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the compositions under ordinary use situations. Excipients must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human being treated.

Some examples of substances which can serve as excipients are sugars such as lactose, glucose and sucrose; starches such as corn-starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcelluloses, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar; and alginic acid; as well as other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, sweetening agents (including nonnutritive sweeteners such as aspartame and saccharin), tableting agents, stabilizers, antioxidants, cooling agents, and preservatives, can also be present. Other compatible pharmaceutical additives and actives which are not pharmaceutical actives useful for treating upper gastrointestinal tract distress (e.g., NSAI drugs; pain killers; muscle relaxants) may be included in the compositions of the present invention. Another agent found useful in the present compositions is an antiflatulant such as simethicone. Also, it is to be noted that in addition, other materials having cooling properties may optionally be included within the excipients, such as menthol, menthol-like compounds such as N-ethyl-p- menthane-3-carboxamide ("WS-3", supplied by Sterling Drugs), as well as 3 - 1 - methoxy propane 1, 2 - diol. Additionally, any of the common antacids may be included in the present compositions. These include, for example, aluminum carbonate, aluminum hydroxide, aluminum phosphate, aluminum hydroxy-carbonate, dihydroxy aluminum sodium carbonate, aluminum magnesium glycinate, dihydroxy aluminum amino acetate, dihydroxy aluminum aminoacetic acid, calcium carbonate, calcium phosphate, aluminum magnesium hydrated sulfates, magnesium aluminate, magnesium alumino silicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, sucralfate, and mixtures thereof.

The choice of excipients to be used in conjunction with the pharmaceutical actives of the present compositions is basically determined by the tablet dose form for the compositions. Excipients suitable for the preparation of tablet dosage forms for oral administration are well-known in the art. Their selection will depend on secondary considerations like taste, cost, shelf stability, which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art. The only requirement is that the pharmaceutical active is available in safe and effective amounts.

The bismuth is provided with the proton pump inhibitor (PPI) in a manner which will allow the bismuth to be released into the stomach and the PPI to be released in the intestines.

The PPI component of the present tablets may have mixed with the PPI active alkaline agents such as those described in US Patent 4,853,230, August 1, 1989 to Longren et al, incorporated herein by reference in its entirety. The PPI may also have a first coating of a water dispersible layer and a second layer of an enteric coating as described in the '230 patent.

The product forms of the present invention are many and varied. They are common in that the PPI has an enteric coat allowing it to pass through the acidic environment of the stomach and into the intestines where the PPI is absorbed. The following is a listing of some of such forms, although many others are ones which could equally be used.

The PPI may be in particulate form, wherein the PPI has an enteric coat on each particle, preferably with a barrier coat on the enteric coat, and the bismuth is also in particulate form and put into capsules or a sachet.

Still another execution is a multilayer tablet (two or more layers) wherein the PPI and the bismuth can be in one or more layers. One such execution is one wherein the PPI forms a core of a tablet, the core having a first enteric coating, a second non- enteric coating, and a final coating of an bismuth.

Still another execution is where the PPI is in particulate form and has an enteric coating. The particles are dispersed in a suitable matrix and the total matrix is made one layer of a trilayer product with a non-enteric coating forming a layer attached to the PPI layer and a third layer of an bismuth attached to the non-enteric layer.

Another execution is a multi-particulate form wherein both the PPI and the bismuth are present in such form.

Another patent describing suitable coatings on the PPI is US Patent 4,786,505, November 22, 1988 incorporated by reference herein in its entirety. This patent discloses a variety of enteric coatings such as cellulose acetate phthalate, polyvinyl acetate phthalate, and acrylic acid polymers among many others.

It is to be appreciated that many different executions can be made and that the present invention is not restricted to those described above.

The present invention also relates to methods for treating upper gastrointestinal tract distress in humans. These methods comprise orally administering to a human in need of such treatment a safe and effective amount of a proton pump inhibitor and an bismuth useful for treating upper gastrointestinal tract distress.

The following example further describes and demonstrates an embodiment within the scope of the present invention. This example is given solely for the purpose of illustration and are not to be construed as a limitation of the present invention as many variations thereof are possible without departing from the spirit and scope.

Example I

Ingredients Composite Wt

Bismuth sυbsalicvlate (BSS) layer

BSS Cake 262.5

Calcium carbonate 67.5

Mannitol 67.5 color 0.70

Povidone 13.50

Magnesium Stearate 5.40

Microcrystalline Cellulose 213.4

Sodium starch glycolate 40.3 polysorbate 80 3.4

Colloidal silicon dioxide 0.7

Separating/barrier layer

Microcrystalline Cellulose 200.00

Omeprazole layer

Omeprazole enteric coated 10 mg of omeprazole Microcrystalline cellulose 175.00

Preparation:

BSS Layer: Mix Calcium carbonate with 1/2 dye, avicel, and 1/3 sodium starch glycolate. Then blend & dry with BSS cake and polysorbate 80 with chopper on to produce fine powder. Then blend with mannitol, remaining dyes, povidone and 1/3 sodium starch glycolate with chopper on. Granulate with water, blend, dry to 3% moisture. Blend with remaining sodium starch glycolate and cool. Prepare final blend with colloidal silicon dioxide and then finally with magnesium stearate. Pass through 12 mesh screen. Compress into layer. Separating/barrier layer: Use as receive. And compress into center layer

Omeprazole layer: Blend enteric coated omeprazole and avicel together. And compress into final layer.

Another differing approach to the combination of omeprazole enteric coated forms with a bismuth involves the use of enteric coated particles with an additional "barrier" coating layer applied on top of the enteric coat. This particulate form could then be combined with a bismuth containing granulation/powder and compressed into a single layer tablet unlike the multi-layer tablet descried above. In this case, physical separation of the enteric coat and bismuth is obtained by applying a barrier layer directly to the pellets themselves unlike the barrier layer in the above example.

An example formulation would be the combination of the bismuth formulation in the above example blended with enteric coated particles of omeprazole with an additional barrier coating such as a low molecular weight hydroxypropyl methylcellulose (HPMC). The HPMC could be applied via spray coating as a 5-10% weight gain of the starting enteric coated particles.

Any of the other proton pump inhibitors, bismuth salts or optional components listed earlier can be used in place of the materials listed above, as well as other levels, and a similar result would be achieved.

Claims

What is claimed is:

1. A pharmaceutical composition comprising a proton pump inhibitor and a bismuth compound formulated to allow the bismuth to be released in the stomach and the proton pump inhibitor to be released in the intestines.

2. A composition according to Claim 1 wherein the composition is in the form of a multilayered tablet wherein the proton pump inhibitor is in enteric coated particulate form and such particles are dispersed within one layer with a non- enteric layer, preferably, separating the bismuth layer.

3. A composition according to Claim 2 wherein the bismuth compound active is selected from the group consisting of bismuth aluminate, bismuth subcarbonate, bismuth subcitrate, bismuth citrate, tripotassium dicitrato busmithate, bismuth subgalate, bismuth subnitrate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof. Bismuth citrate, bismuth subcitrate, tripotassium dicitrato bismuthate, bismuth tartrate, bismuth subsalicylate, and mixtures thereof.

4. A composition according to Claim 3 wherein the proton pump inhibitor is selected from the group consisting of omeprazole, prantoprazole, lansoprazole, pharmaceutically acceptable salts of these agents, and mixtures thereof.

5. A multilayered pharmaceutical tablet composition comprising:

(a) a first layer containing an enteric coated proton pump inhibitor;

(b) a second layer serving as a separating layer comprising a non-enteric material; and

(c) a third layer containing a bismuth material.

6. Pharmaceutical tablet compositions according to Claim 5 wherein the bismuth compound active is selected from the group consisting of, but are not limited to, omeprazole, lansaprazole, rabeprazole and prantoprazole and appropriate salts of these materials . and mixtures thereof.

7. Pharmaceutical tablet compositions according to Claim 6 wherein the proton pump inhibitor is selected from the group consisting of omeprazole, prantoprazole, lansoprazole and mixtures thereof.

8. A composition according to Claim 1 wherein the proton pump inhibitor is in the form of an enteric coated tablet with a coating of an bismuth.

9. A compositions according to Claim 1 wherein the proton pump inhibitor and the bismuth are present in a single layered tablet wherein an enteric coating is present on the proton pump inhibitor which also has a second non-enteric coating.

10. A composition according to Claim 1 wherein the proton pump inhibitor is in particulate form which have an enteric coating and are put into capsules with the bismuth present as a plug or loosely mixed with the proton pump inhibitor particles in the capsules.

11. A composition according to Claim 1 which also contains an antacid material.

12 A method for treating upper gastrointestinal tract distress in humans, said method comprises orally administering to a human patient in need of such treatment a safe and effective amount of a composition according to Claim 1.

13. A method for treating upper gastrointestinal tract distress in humans, said method comprises orally administering to a human patient in need of such treatment a safe and effective amount of a composition according to Claim 2.

14. A method for treating upper gastrointestinal tract distress in humans, said method comprises orally administering to a human patient in need of such treatment a safe and effective amount of a composition according to Claim 7.

15. A method for treating upper gastrointestinal tract distress in humans, said method comprises orally administering to a human patient in need of such treatment a safe and effective amount of a composition according to Claim 8.

16. A method for treating upper gastrointestinal tract distress in humans, said method comprises orally administering to a human patient in need of such treatment a safe and effective amount of a composition according to Claim 11.

17. A method for treating upper gastrointestinal tract distress in humans, said method comprises orally administering to a human patient in need of such treatment a safe and effective amount of a composition according to Claim 9.