SOLID ORAL DOSAGE FORMS CONTAINING ALGINIC ACID AND FAMOTIDINE Field of the Invention This invention relates to solid oral dosage forms of a pharmaceutical composition for treating gastric disorders. The instant dosage forms contain famotidine and alginic acid separated by an alginic acid- impermeable barrier. This invention also relates to methods of making these solid oral dosage forms, as well as therapeutic and prophylactic methods using same.

Background of the Invention H2 antagonists are commonly prescribed to treat and prevent ulcers in the walls of the stomach, duodenum and esophagus. H2 antagonists are also used to treat non- ulcerative conditions. Damage to the mucus lining surrounding these tissues permits stomach acids to erode the underlying tissue. Commonly known H, antagonists for the treatment of ulcers include cimetidine, ranitidine, nizatidine, roxatidine, and famotidine.

Combinations of alginates with certain H2 antagonists have been disclosed generally. U. S. Patent No. 5,007,790 discloses a solid state drug containing cimetidine and sodium alginate. GB 2,222,772 discloses the H2 antagonist ranitidine and alginic acid. GB 2,207,865 discloses a composition comprising the H antagonist famotidine and alginate, wherein the composition is used to treat wounds rather than inhibit gastric acid. EP 290,229-B discloses the H, antagonist

cimetidine and alginate. See, also, U. S. Patent No.

4,996,222.

More specifically, a number of combinations of H2 antagonists and antacids have been disclosed for providing symptomatic relief of certain stomach disorders. See, e. g., FR 2,648,710; GB 2,219,940; EP 294,933 A; EP 286,781 A; SU 1,362,477 A, U. S. Patent No.

EP 233,853; WO 92/09286; and Martindale's Extra Pharmacopoeia, p. 1432. WO 95/01795 and WO 95/01780 both disclose the use of famotidine/alginate combinations to treat stomach disorders, wherein the famotidine and alginic acid are in direct contact.

Summary of the Invention This invention provides a solid oral dosage form for treating a gastric disorder comprising effective doses of (a) famotidine or pharmaceutically acceptable salt thereof, and (b) alginic acid, wherein the oral dosage form has at least one portion containing the famotidine or pharmaceutically acceptable salt thereof, at least one portion containing alginic acid, and a pharmaceutically acceptable barrier separating the famotidine-containing and alginic acid-containing portions, the barrier being impermeable to alginic acid.

This invention, in one embodiment, also provides a solid oral dosage form for treating a gastric disorder comprising (a) an effective dose of famotidine or pharmaceutically acceptable salt thereof in the form of granules having a nonenteric coating impermeable to alginic acid, (b) an effective dose of alginic acid free of said nonenteric coating, and (c) a pharmaceutically acceptable excipient.

This invention further provides a method for manufacturing the instant solid oral dosage form, comprising the steps of (a) pressing one of two granulations to form a first layer having one exposed surface, the first granulation comprising a pharmaceutically acceptable excipient and an effective dose of famotidine or pharmaceutically acceptable salt thereof, and the second granulation comprising a

pharmaceutically acceptable excipient and an effective dose of alginic acid, (b) coating the exposed surface with a pharmaceutically acceptable material which forms a barrier impermeable to alginic acid, (c) contacting the coated surface with the remaining granulation, and (d) pressing the granulation and coated layer to form a multi-layered solid oral dosage form, wherein the alginic acid and the famotidine or pharmaceutically acceptable salt thereof are separated by the barrier.

This invention further provides another method for manufacturing the instant solid oral dosage form comprising the steps of (a) combining (i) an effective dose of famotidine or pharmaceutically acceptable salt thereof in the form of granules having a nonenteric coating impermeable to alginic acid, (ii) an effective dose of alginic acid free of said nonenteric coating, and (iii) a pharmaceutically acceptable excipient, so as to form a mixture thereof, and (b) pressing the resulting mixture to form a solid oral dosage form, wherein the alginic acid and the famotidine or pharmaceutically acceptable salt thereof are separated by the nonenteric coating.

This invention still further provides a method of treating a subject afflicted with a gastric disorder which comprises administering to the subject the instant solid oral dosage form.

Finally, this invention provides a method of preventing a gastric disorder in a subject which comprises administering to the subject the instant solid oral dosage form prior to a gastric disorder- causing event.

Brief Description of the Figures Figure 1 shows a perspective view of a bi-layered pharmaceutical tablet in accordance with the instant invention.

Figure 2 shows a sectional view of a bi-layered pharmaceutical tablet in accordance with the instant invention.

Figure 3 shows a sectional view of an inner core/outer coating-type swallowable pharmaceutical tablet in accordance with the instant invention.

Figure 4 shows a sectional view of an inner core/outer coating-type chewable pharmaceutical tablet in accordance with the instant invention.

Detailed Description of the Invention Both famotidine and alginic acid are therapeutic agents useful for treating gastric disorders.

Surprisingly, it was discovered that alginic acid, unlike certain other therapeutic acids, actually degrades famotidine. This degradation prevents the production and use of combination therapeutics wherein famotidine and alginic acid are in direct contact. The instant invention overcomes this problem by providing solid oral dosage forms for treating gastric disorders, which contain famotidine and alginic acid separated by an alginic acid-impermeable barrier.

More specifically, this invention provides a solid oral dosage form for treating a gastric disorder comprising effective doses of (a) famotidine or pharmaceutically acceptable salt thereof, and (b) alginic acid, wherein the oral dosage form has at least one portion containing the famotidine or pharmaceutically acceptable salt thereof, at least one portion containing alginic acid, and a pharmaceutically acceptable barrier separating the famotidine-containing and alginic acid-containing portions, the barrier being impermeable to alginic acid.

In one embodiment, the instant dosage form contains one famotidine-containing portion and one alginic acid-containing portion. In another embodiment, the instant dosage form contains a plurality of famotidine-containing portions and/or a plurality of alginic acid-containing portions.

As used herein, the term"gastric disorder" includes, without limitation, heartburn, sour stomach,

acid indigestion, upset stomach caused by any of the preceding three disorders, and gastric esophageal reflux disease ("GERD").

The instant dosage form can be any solid form including, for example, chewable tablets, swallowable tablets, and hard and soft gel capsules. Swallowable tablets include, for example, fast dissolving and non- fast dissolving tablets. The instant dosage form also includes, for example, layered forms (e. g., layered, swallowable tablets) and non-layered forms (e. g., chewable tablets). In the preferred embodiment, the instant dosage form is a chewable tablet.

As used herein, the term"famotidine"includes all possible hydrates, stereoisomers and polymorphs thereof.

Famotidine is commercially available (e. g., Yamanouchi Pharmaceuticals, Japan), as is alginic acid (e. g., Kelco Nutrasweet (San Diego, CA), and the Encyclopedia of Pharmaceutical Excipients, 1st Ed.).

As used herein, the term"pharmaceutically acceptable salts"refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, aluminum, ferric, manganic salts and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, tertiary and quaternary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, amino acids generally and

lysine, arginine and histidine specifically, caféine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purines, piperazine, piperidine, polyamine resins and the like.

As used herein, the term"effective dose"shall mean a therapeutically effective dose if the instant dosage form is used therapeutically, or a prophylactically effective dose if the instant dosage form is used prophylactically. Methods of determining effective doses of famotidine and alginic acid are known in the art. For example, these effective doses can readily be determined mathematically from the results of animal studies. In one embodiment of the instant invention, the effective dose of famotidine per dosage form is from about 5 mg to about 100 mg, and preferably, is 10 mg, 20 mg or 40 mg. In another embodiment, the effective dose of alginic acid per dosage form is from about 100 mg to about 1000 mg. In a further embodiment, the effective dose of alginic acid is from about 100 mg to about 500 mg. Preferably, the effective dose of alginic acid is 250 mg.

In the instant dosage form, the barrier "separates"the famotidine-containing and alginic acid- containing portions if it prevents the alginic acid from increasing the degradation rate of famotidine or its salt by more than 10% compared to the degradation rate of a non-alginic acid-containing, but otherwise identically formulated solid dosage form, as measured at ambient temperature and humidity over at least 18 months, and preferably 36 months.

The barrier of the instant dosage forms can be any pharmaceutically acceptable material capable of separating the two portions of the dosage forms. In one embodiment, the barrier is a pharmaceutically acceptable film-forming polymer.

Pharmaceutically acceptable polymers that can be used to form the barrier include, for example, cellulose derivatives, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyethylene glycols, copolymers of styrene and acrylate, copolymers of acrylic acid and methacrylic acid, copolymers of methacrylic acid and ethylacrylate, copolymers of methyl methacrylate and methacrylate, copolymers of acrylic acid and tertiary amino alkyl methacrylate, copolymers of ethacrylate and tertiary amino alkyl methacrylate, copolymers of ethylacrylate methyl methacrylate and quaternary amino alkyl methacrylate, and combinations of two or more thereof.

Barrier-forming cellulose derivatives include, for example, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate and combinations thereof. The acrylic acid and methacrylic acid copolymers listed above also include copolymers of sodium and potassium salts thereof.

An example of a barrier-forming ester copolymer of methacrylic and tertiary amino alkyl methacrylate is dimethylaminoethyl methacrylate-methacrylate. An

example of a barrier-forming copolymer of ethylacrylate methyl methacrylate and quaternary amino alkyl methacrylate is (ethylacrylate-methyl methylacrylate) triethylaminoethyl methacrylate chloride.

This invention also provides a solid oral dosage form for treating a gastric disorder comprising (a) an effective dose of famotidine or pharmaceutically acceptable salt thereof in the form of granules having a nonenteric coating impermeable to alginic acid, (b) an effective dose of alginic acid free of said nonenteric coating, and (c) a pharmaceutically acceptable excipient.

Pharmaceutically acceptable excipients used in the instant dosage forms include, but are not limited to, fillers, binders, sweeteners, artificial sweeteners, lubricants, glidants, disintegrants, colors, adsorbents, acidifying agents and flavoring agents.

The choice of excipient will depend on the solid oral dosage form desired (e. g., tablets or capsules), and whether the dosage form is to be chewed or swallowed whole.

The following is a non-limiting list of excipients that could be used in a chewable solid oral dosage form: (a) sweeteners such as mannitol, dextrose, fructose, sorbitol, sucrose and lactose; (b) binders such as microcrystalline cellulose, alginic acid, carboxymethyl cellulose and hydroxypropyl cellulose; (c) artificial sweeteners such as aspartame, sucralose and saccharin; (d) lubricants such as magnesium stearate, talc, stearic acid, calcium stearate, zinc stearate, stearic acid, hydrogenated vegetable oil,

leucine, glycerides, and sodium stearyl fumarate; (e) acidifying agents such as citric acid and malic acid; (f) flavoring agents such as artificial and natural flavors; and (g) fillers such as dibasic calcium phosphate dihydrate and monobasic calcium phosphate monohydrate. Additional excipients are listed in the Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association.

Coated famotidine granules can be formed by granulating the famotidine with suitable granulation excipients in a granulation process, such as a conventional wet granulation or rotogranulation. The granules produced by these processes are preferably spherical in shape with a particle size from about 150 microns to about 500 microns for swallowable solid dosage forms, and a particle range of from about 150 microns to about 300 microns for chewable forms, in order to avoid a gritty texture.

After the granulation, the granules can be coated using a conventional coating process such as roto- coating, Wurster coating or fluid bed particle coating.

Preferably, the coating material is a pharmaceutically acceptable film-forming polymer that is physiologically inert, prevents the alginic acid from penetrating or coating the coated granule, and provides a coating that is easily broken down in the stomach (i. e., forms a nonenteric coating). In this embodiment, the alginic acid is free of the nonenteric coating, i. e., it is uncoated, so that it rapidly disperses in the stomach to provide an anti-foaming effect. Suitable nonenteric, pharmaceutically acceptable film-forming polymers are exemplified in the Examples below.

Preferred coatings include, for example, cellulose acetate, cellulose triacetate and cellulose acetate butyrate with polyvinyl pyrrolidone, methylaminoethyl- methacrylate and neutral methacrylic acid esters (Eudragit E-100), copolymers of 2-vinylpyridine and styrene and hydroxypropylcellulose. Preferred grades of polymers include, for example, cellulose acetate 320-S, 398-10,437-75S; cellulose acetate butyrate 171, 381 and 500 (both of cellulose acetate and cellulose acetate butyrate are available from FMC and fully described in Cellulose Esters: Polymers for Drug Delivery published in 1986); Povidone K29/32 and K90 (which is fully described in the USP); Klucel EF, LF and JF (HPC having an average molecular weight of from about 60,000 to about 125,000); Methocel E5 and E15; Natrosol 250L; and Ethocel N10. In the preferred embodiment, the nonenteric coating comprises cellulose acetate and hydroxypropyl cellulose.

The amount of coating applied as a weight percentage of the coated granule may vary with the coating process, coating granulation and granules used.

The appropriate amount of coating can be determined by determining the degradation of famotidine, or pharmaceutically acceptable salt thereof, with various coating thicknesses according to the degradation tests set forth in The United States Pharmacopeia XXII. As a general rule, the amount of coating will vary from about 8% to about 20% of the weight of the coated granule. In one embodiment, granules of famotidine formed by a wet rotogranulation process are roto-coated with from about 8% to about 18% by weight of a polymer blend of cellulose acetate and hydroxypropyl cellulose.

The preferred granulation process for famotidine is to granulate it with a granulation excipient selected from the group consisting of sugars (such as lactose, confectioners sugar or mannitol), microcrystalline cellulose, and cellulose. The weight percentages of the components of this granulation process are as follows: famotidine, 2%-3.5%; granulation excipient, 76. 5%-90%; and coating, 8%-20%.

This invention further provides a method for manufacturing the instant layered solid oral dosage form, comprising the steps of (a) pressing one of two granulations to form a first layer having one exposed surface, the first granulation comprising a pharmaceutically acceptable excipient and an effective dose of famotidine or pharmaceutically acceptable salt thereof, and the second granulation comprising a pharmaceutically acceptable excipient and an effective dose of alginic acid, (b) coating the exposed surface with a pharmaceutically acceptable material which forms a barrier impermeable to alginic acid, (c) contacting the coated surface with the remaining granulation, and (d) pressing the granulation and coated layer to form a multi-layered solid oral dosage form, wherein the alginic acid and the famotidine or pharmaceutically acceptable salt thereof are separated by the barrier.

Suitable methods for manufacturing multi-layered solid dosage forms are known in the art. Two sources for these techniques are Remington's Pharmaceutical Sciences, 18th Edition published by Mack Publishing

Company and the three volume series Pharmaceutical Dosage Forms: Tablets, Volumes 1-3,2nd edition, edited by Herbert A. Lieberman, et al., published by Marcel Dekker.

Generally, the first layer formed in this process is a soft layer to allow the barrier to be put in place and provide an even appearance to the interface between the layers. The barrier may be applied as a granulation to be pressed onto a layer or spray coated on the surface of the first layer. The coatings suitable for spray coating granules of pharmaceuticals as hereinafter provided are also suitable for use as spray-on barrier layers. In the instant manufacturing method, the excipients and coating materials are the same as discussed above for the other embodiments of this invention.

This invention further provides a method for manufacturing the instant non-layered solid oral dosage form comprising the steps of (a) combining (i) an effective dose of famotidine or pharmaceutically acceptable salt thereof in the form of granules having a nonenteric coating impermeable to alginic acid, (ii) an effective dose of alginic acid free of said nonenteric coating, and (iii) a pharmaceutically acceptable excipient, so as to form a mixture thereof; and (b) pressing the resulting mixture to form a solid oral dosage form, wherein the alginic acid and the famotidine or pharmaceutically acceptable salt thereof are separated by the nonenteric coating.

This invention still further provides a method of treating a subject afflicted with a gastric disorder which comprises administering to the subject the instant solid oral dosage form.

Finally, this invention provides a method of preventing a gastric disorder in a subject which comprises administering to the subject the instant solid oral dosage form prior to a gastric disorder- causing event.

As used herein, a"gastric disorder-causing event" can be any event anticipated to cause a stomach disorder in a subject. In one embodiment, the event is the intake of food or beverage likely to cause a stomach disorder. In another embodiment, the event is sleep during which acid reflux is anticipated due to recent food intake or other cause. The instant dosage form can be administered at any suitable time prior to the gastric disorder-causing event. In one embodiment, the administering occurs within one hour of the event.

This invention will be better understood by reference to the Examples that follow, but those skilled in the art will readily appreciate that they are only illustrative of the invention as described more fully in the claims which follow thereafter. In addition, various publications are cited throughout this application. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

Example 1 Famotidine/Acid Powder Blend Degradation Test Procedure This experiment was designed to demonstrate that some acids degrade famotidine to a far less extent than does alginic acid. Famotidine powder was blended with citric acid, alginic acid, and 1-aspartic acid powders.

The following table shows the blends and their proportions.

Material Quantity (g) Blend I Famotidine 4 g citric acid 100 g Blend II Famotidine 4 g 1-aspartic acid 100 g Blend III Famotidine 4 g alginic acid 100 g Control Famotidine 4 g The above blends were accelerated at 40°C and 75% relative humidity. HPLC analysis was performed on the above after one week.

Results The following is a table of degradates for the control and each blend.

Sample A6 (%) A1 (%) famotidine (control) 0.019 0.033 famotidine/citric acid 0.000 100.0 famotidine/1-aspartic acid 0.018 0.100 famotidine/alginic acid 0.026 39.0

From the above data, it is seen that there is no significant difference in the A6 degradate. However, in the case of the A1 degradate, there is a radical difference in the extent to which the famotidine degrades in the presence of the above acids. Also, it appears that the famotidine does not significantly degrade in the presence of 1-aspartic acid. These data show that not all acids degrade famotidine to the same extent.

Example 2 Coated Famotidine Degradation Test Procedure Powder blends were mixed in a twin shell blender for 15 minutes. The ratio used was 1: 25 which corresponds to the ratio which would exist in a 10 mg famotidine/250 mg alginic acid product. Famotidine was coated with a cellulose acetate/hydroxypropyl cellulose blend at a 10% coat level. Samples were treated for two months in an open dish at 40°C/75% relative humidity.

Results The data below show some degradation even when the famotidine is coated (although substantially less than for the uncoated). The degradation observed with the coated famotidine/alginic acid mixtures is attributed to the very harsh conditions employed. It is anticipated that in a combination product containing coated famotidine with alginic acid in a somewhat protective package, the degradation of famotidine would be minimal.

Experiment Degradate (Al) Level (2 months) Uncoated Famotidine/Alginic Acid 100% Coated Famotidine/Alginic Acid 22.9% Uncoated Famotidine (Control) 0.04% Example 3 Sample Chewable Tablet Form The following formulation provides weight percentages of the various components of a chewable multilayered tablet.

Alginic Acid Layer Granulated Alginic Acid 4% to 25% Excipients Filler 0% to 45% Binders 0% to 10% Sweetener 8% to 50% Artificial Sweetener 2% to 5% Lubricant 0.25% to 5.0% Flavoring Agent 0.01% to 0.03% Famotidine Layer Coated Granules of Famotidine 1% to 20% Excipients Filler 0% to 70% Binder 0% to 10% Sweetener 10% to 80% Artificial Sweetener 0.5% to 3% Lubricant 0.25% to 5% Flavoring Agent 0.01% to 0.03% Barrier 10% to 20%

Example 4 Famotidine/Alginic Acid Chewable Bilayer Tablet Step 1: Coated Famotidine Granules The following ingredients are used in the granulation: lactose (impalpable NF 81%), famotidine powder (USP 13%), and hydroxypropylmethylcellulose (Methocel E-5, NF 6%).

Process The above ingredients are blended and granulated in a Glatt rotogranulator. While the blended powders are rotating during fluidization, water is sprayed into the granulator so as to make spherically shaped particles. This process continues until the particles are about 60 to 80 mesh (180-250 microns) in size. The particles are dried to about 40°C and the moisture content of the particles is less than 1.0%.

The following ingredients are used in the coating process: famotidine rotogranulated particles 1000 g, cellulose acetate 398-10,95.3 g and Klucel EF (hydroxypropylcellulose), 40.6 g, which is a 70: 30 ratio of cellulose acetate to Klucel EF. The cellulose acetate and the Klucel are mixed in acetone and methanol in an 80: 20 ratio. The famotidine rotogranulated particles are placed into a Glatt Wurster Column or Glatt Rotor apparatus and the coating solution is sprayed on to achieve an 11% coating level.

The potency of the famotidine-coated particle is 11.57%.

Step 2: Bilayer Tablet Blend Layer 1 Coated Famotidine Particles 87 mg (corresponding to 10 mg Famotidine) Mannitol FL 2080 300 mg Sorbitol 30 mg Butterscotch Powder 11 mg Alpine Creme Powder 3 mg Sodium Saccharin 2 mg Magnesium Stearate 7 mg Red Ferric Oxide #347 0.25 mg Total 440.25 mg Layer 2 Alginic Acid 500 mg Sodium Bicarbonate 270 mg Mannitol FL 2080 400 mg Sorbitol 40 mg Butterscotch Powder 12 mg Alpine Crème Powder 3 mg Sodium Saccharin 2 mg Magnesium Stearate 7 mg Yellow #10 Lake 2 mg Total (Layer 2) 1236 mg Total Tablet Weight 1676.25 mg The amount of sodium bicarbonate can range from 100 to 300 mg. Other antacids such as calcium carbonate may also be used, e. g. 100-175 mg of calcium carbonate in layer 2 in addition to the sodium bicarbonate.

Example 5 Famotidine/Alginic Acid Swallowable Bilayer Tablet Step 1: Coated Famotidine Granules The ingredients and process for the coated famotidine granules are the same as for the chewable tablet shown in Example 4.

Step 2: Bilayer Tablet Blend The following is a list of ingredients for a swallowable table containing coated famotidine particles in one layer and alginic acid in the other layer.

Layer 1 Coated Famotidine Particles 87.0 mg Mannitol FL 2080 163.0 mg Microcrystalline Cellulose (e. g., Avicel) 25.0 mg Croscarmellose Na (e. g., Ac-di-Sol) 12.0 mg Magnesium Stearate 3.0 mg Red Ferric Oxide #347 0.11 mg Total 290.11 mg Layer 2 Alginic Acid 250 mg Microcrystalline Cellulose (e. g. Avicel) 25 mg Croscarmellose Na (e. g., Ac-di-Sol) 12 mg Magnesium Stearate 3 mg Yellow #10 Lake 0.5 mg Total 290.5 mg Total Tablet Weight (layer 1 + layer 2) 580.61 mg

Each layer is separately blended and compressed on a Stokes-Versa bilayer tablet press. Hardness should be between 8.0-10.0 kp and friability should be less than 1.0% on an Erweka Friabulator (25 drops/minutes for 4 minutes). Swallowable tablets may be subsequently film- coated and/or gel-dipped to improve swallowability.

Example 6 Weight Percentage Ranges Of Chewable Tablet Form The following formulation provides weight percentage ranges of the various components of a chewable tablet.

Granulated Alginic Acid 4% to 35% Coated Granules of Famotidine 2% to 8% Excipients Filler 0% to 55% Binders 0% to 20% Sweetener 0% to 75% Artificial Sweetener 0% to 10% Lubricant 0.25% to 6.0% Flavoring Agent 0.25% to 2.0% Example 7 Nonenteric Film-Forming Polymers Polymer System Coat Level Polymer Ratio Cellulose Acetate/PVP 8-18% 90/10 to 60/40 Cellulose Acetate Butyrate/PVP 8-18% 90/10 to 60/40 Cellulose Acetate/HPC 8-18% 90/10 to 50/50 Cellulose Acetate Butyrate/HPC 8-18% 90/10 to 50/50 Cellulose Acetate/

Eudragit E100 8-18% All Ratios Cellulose Acetate Butyrate/ Eudragit E 100 8-18% All Ratios Ethyl Cellulose/PVP 8-18% 90/10 to 60/40 Ethyl Cellulose/HPC 8-18% 90/10 to 50/50 Ethyl Cellulose/Eudragit E 100 8-18% All Ratios HPC 10-20% NA HEC 10-20% NA Eudragit E 100 10-20% NA HPMC 10-20% NA HEC/HPMC 10-20% All Ratios HPC/HPMC 10-20% All Ratios HEC/HPC 10-20% All Ratios 2-Vinyl Pyrridine Styrene Co-Polymer 10-20% NA CA/2-vps 8-18% All Ratios CAB/2-vps 8-18% All Ratios Ethyl Cellulose/2-vps 8-18% All Ratios Cellulose Triacetate/PVP 8-18% 90/10 to 60/40 Cellulose Triacetate/HPC 8-18% 90/10 to 50/50 Cellulose Triacetate/ Eudragit E 100 8-18% All Ratios PVP-Polyvinylpyrrolidone HPC-Hydroxypropyl Cellulose HEC-Hydroxyethyl Cellulose HPMC-Hydroxypropylmethyl Cellulose CA-Cellulose Acetate CAB-Cellulose Acetate Butyrate 2-VPS-2-Vinyl Pyridine Styrene

Example 8 Physical Embodiments Of The Instant Dosage Forms Referring to Figures 1 and 2, indicated generally as 9 is a tablet constructed in accordance with one of the embodiments of the invention. Tablet 9 comprises a first portion or layer 10 containing alginic acid and a second portion or layer 11 containing a pharmaceutical suitable for the treatment of gastric disorders with each of the first and second layers 10, and 11 being separate and discrete from the other layer. Sandwiched between layers 10 and 11 is a barrier 12 which may be a film or diaphragm or membrane composed of plastic material. Barrier 12 maintains the alginic acid in first layer 10 out of contact with the pharmaceutical suitable for the treatment of gastric disorders in second layer 11 and prevents migration of the alginic acid from layer 10 to layer 11 as well as preventing migration of the famotidine from layer 11 to layer 10.

Referring to Figure 3, in this embodiment 19, the first portion containing the alginic acid is in the form of an inner core 20, and the second portion comprising the famotidine is in the form of an outer layer 21 encompassing inner core 20. Barrier 22 is disposed between inner core 20 and outer layer 21 and encompasses inner core 20. Outer layer 21 encompasses barrier 22. Barrier 22 may be in the form of a thin plastic film or sheet surrounding and enclosing inner core 20, or barrier 22 may be in the form of a thin plastic film applied as a coating on the outer surface 24 of inner core 20 before outer layer 21 is formed.

In the embodiments of Figures 2 and 3, the portions 10 and 20, containing the alginic acid, are

each a mixture of ingredients comprising alginic acid and a solid, inert filler or carrier or other alginic acid-adsorbing material.

Referring to Figure 4, in this embodiment 29, the first portion comprising the alginic acid is in the form of an inner core 30 which may consist entirely of alginic acid in its natural, viscous liquid condition.

The outer core comprising the famotidine 31 may be similar to the outer core 21 in the embodiment of Figure 3. The inner core of alginic acid is encompassed by and contained within a barrier 32 which may be in the form of a container for the liquid alginic acid, e. g., a soft, chewable gelatin capsule shell. As an alternative to providing the alginic acid within container 21 in its natural, viscous liquid condition, the alginic acid may be provided as part of a solid mixture, as is the case with both the alginic acid-containing layer 10 in the embodiment 9 of Figure 2 and the alginic acid-containing inner core 20 in the embodiment 10 of Figure 3.

In all of the above embodiments, the alginic acid is separate from the matrix formed by the famotidine in its respective portion (11,21 or 31), and the alginic acid remains separated from the matrix during an extended shelf life because the barrier (12,22,32) prevents the alginic acid from migrating into the famotidine.