Patent Description:
Histamine H2 -receptor antagonists, for example cimetidine, ranitidine, nizetidine, roxatine and famotidine, reduce acid secretion by acting directly on the acid-secreting parietal cell located within the gastric gland of the stomach wall.

Although histamine H2 -receptor antagonists are remarkably effective in the treatment of many gastric disorders, in particular peptic and gastric ulcers, there exist certain patient groups which do not respond to treatment. In addition, the time lapse between dosing and onset of action limits the potential benefit of histamine H2 -receptor antagonists in the treatment of acute, self-limiting gastric disorders.

Histamine H2 -receptor antagonists are of potential benefit in the self-medication of acute, self-limiting gastric disorders such as hyperacidity. However, their slow onset of action is unlikely to meet the consumer requirement for rapid relief of symptoms.

Co-administration of histamine H2 -receptor antagonists and other pharmaceutically active materials, including antacids, has been investigated. The rationale for co-administration with antacid is that the antacid brings about rapid relief from the symptoms of excess stomach acidity by neutralization whereas the histamine H2 -receptor antagonist acts independently by inhibiting secretion of acid from the parietal cell.

Antacids used today are made from a variety of inorganic salts such as calcium carbonate, sodium bicarbonate, magnesium salts and aluminum salts. Magnesium hydroxide and aluminum hydroxide are the most potent magnesium and aluminum salts and are often used in combination. In addition, aluminum oxide, magnesium oxide, magnesium carbonate, aluminum phosphate, magaldrate, magnesium trisilicate, and aluminum sucrose sulfate (sucralfate) are also employed.

However, co-administration of famotidine is often very difficult because famotidine is extremely sensitive to humidity and can immediately start to degrade in such conditions.

<CIT> relates to a stable pharmaceutical composition comprising famotidine coated with cellulose acetate or the combination cellulose acetate and hydroxypropyl cellulose, calcium carbonate and magnesium hydroxide.

<CIT> relates to a pharmaceutical composition comprising cimetidine granules coated with a partially hydrogenated vegetable oil.

The invention relates to the development of new improved soft chewable dosage form comprising a first active pharmaceutical ingredient encapsulated in a lipid material/matrix wherein the lipid material comprises a primary lipid and a second lipid, wherein the second lipid is medium-chain triglycerides (MCT), wherein the lipid encapsulated active pharmaceutical ingredient is embedded in a soft chewable dosage form and wherein the soft chewable dosage form comprises at least a second active pharmaceutical ingredient. One example comprises famotidine encapsulated in a lipid material as defined by the claims and embedded in a soft chewable dosage form comprising at least one antacid.

The invention enables for the first time the delivery of a famotidine/antacid combination in a soft chewable dosage form. The format ensures the stability of famotidine and offers a better sensory experience in terms of soothing and coating the painful esophageal tissues, giving consumers a faster acting remedy.

Soft chew forms inherently have a high-water content. A high level of water can contribute to degradation (hydrolysis of famotidine) if raw famotidine is blended into the matrix. In the case of the present invention, the lipid insert/material prevents ingress of water into the famotidine particles and prevents further interaction and hydrolysis.

Finally, the invention relates to the soft chewable dosage form for use in a method as defined above and below in the application for the treatment of a subject suffering from a disease or disorder in the gastro intestinal tract, such as heart burn.

<FIG> shows force measurements on samples with different amounts of MCTs.

In the context of the present application and invention the following definitions apply:
The term "soft chewable" is intended to mean a dosage form which retains its integrity and texture upon chewing, does not break into discrete, solid pieces or particulates upon chewing and is intended to be swallowed. The soft chew is palatable, edible, and is similar in texture to confectionery taffy or nougat.

The term "%w/w" is intended to mean the percentage of an ingredient(s)/ the total percentage by weight of the composition (<NUM> %).

A "dosage", "dosage form", "dose unit" or "dose" as used herein means the amount of a pharmaceutical ingredient comprising therapeutically active agent(s) administered at a time. "Dosage", "dosage form", "dose unit" or "dose" includes administration of one or more units of pharmaceutical ingredient administered at the same time.

The term "gastric disease or disorder" is primarily intended to mean an increased production of the acid secretion which leads to heartburn and bothersome gas symptoms in a subject, also named indigestion. Indigestion, also known as dyspepsia, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier than expected when eating. Dyspepsia is a common problem and is frequently caused by gastroesophageal reflux disease (GERD) or gastritis.

In one embodiment the invention relates to a soft chewable dosage form comprising a first active pharmaceutical ingredient encapsulated in a lipid material/matrix wherein the lipid material comprises a primary lipid and a second lipid, wherein the second lipid is medium-chain triglycerides (MCT), wherein the lipid encapsulated active pharmaceutical ingredient is embedded in a soft chewable dosage form and wherein the soft chewable dosage form comprises at least a second active pharmaceutical ingredient. In one example the encapsulated active pharmaceutical ingredient comprises at least one histamine H2- receptor antagonist, such as cimetidine, ranitidine, nizatidine, roxatidine and famotidine, their pharmaceutically acceptable salts, isomers and salts of isomers.

In another embodiment the H2 receptor antagonist is famotidine and the second active pharmaceutical ingredient is at least one antacid.

The particle size of the lipid encapsulated famotidine is from about <NUM> microns to about <NUM> microns, such as from about <NUM> microns to about <NUM> microns.

The famotidine is embedded and present in the dosage form within a lipid matrix as a solid bead. The bead may be applied on the surface or inserted (as an insert) into the soft chew dosage form. In order to prepare this bead, famotidine is suspended or dispersed in a lipid base and deposited as a bead. It may be deposited and solidified as a bead which is later applied to the soft chew; or applied in a liquid form and deposited on the soft chew which is solidified in-situ. This solidification may be facilitated by an additional cooling step at room temperature, or a temperature cooler that room temperature (<NUM>). The famotidine is present in the lipid bead as a dispersed solid or in a solid solution.

The diameter of the lipid bead of the present invention is from about <NUM> millimeters to about <NUM>, or from about <NUM> millimeters to about <NUM> millimeters. The weight of the lipid bead can range from about <NUM> to about <NUM>, or from about <NUM> to about <NUM>.

In another embodiment, the famotidine is present as a plurality of particulates, wherein such particulates are coated with at least one lipid material or polymer. As used herein, a plurality of particulates is defined of at least two particulate units comprising famotidine.

The at least one antacid is selected from the group consisting of calcium carbonate, sodium bicarbonate, magnesium hydroxide, aluminum oxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, aluminum phosphate, magaldrate and magnesium trisilicate.

The lipid material that encapsulates/coats the active pharmaceutical ingredient is selected from the group consisting of Cetostearyl alcohol, Glyceryl dibehenate, glyceryl palmitostearate, mono/diglycerides or hydrogenated vegetable oil or vegetable oil. Other examples of lipid materials include, but are not limited to, fatty acid esters such as sucrose fatty acid esters, mono, di, and triglycerides, glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-<NUM>, lauroyl macrogol-<NUM> glycerides, and stearoyl macrogol-<NUM> glycerides; phospholipids such as phospholipids include phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, and phosphotidic acid; waxes such as carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; and fats such as hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil; and free fatty acids and their salts. These lipids are also suitable for use as the primary lipid within the lipid bead or material.

A second lipid is added to the primary lipid in order to soften or modify the texture of the lipid bead or material. The second lipid acts as a plasticizer. The second lipid for use as a plasticizer is medium chain triglycerides (MCTs). The second lipid (plasticizer) may be present within the lipid bead or material at an amount from about <NUM> percent to about <NUM> percent, or from about <NUM> percent to about <NUM> percent by weight of the lipid bead or material.

In certain embodiments an emulsifier may be added to the primary lipid in order to soften or modify the texture of the lipid bead or material. Emulsifiers include but are not limited to polyethylene sorbitan monooleate (polysorbate <NUM> and <NUM>), glycerides, glyceryl esters, glyceryl monolineoleate, and monolineoleate. The emulsifier may be present within the lipid bead or material at an amount from about <NUM> percent to about <NUM> percent, or from about <NUM> percent to about <NUM> percent by weight of the lipid bead or material.

If famotidine is the active pharmaceutical ingredient it may be in the form of granulate, bead or compressed tablet.

In addition to famotidine and antacid(s) the soft chewable dosage form may also comprise simethicone as an active pharmaceutical ingredient. Simethicone may be present in the soft chew base comprising antacid, or in the lipid bead or pellet comprising famotidine.

The soft chewable tablet may further comprise one or more ingredient(s) selected from the list consisting of fats, proteins, colorings, flavors, sweeteners, thickeners, emulsifiers, antioxidants, preservatives, lubricants, glidants, gelling agents and disintegrants.

Example of flavors are peppermint, spearmint, eucalyptus, licorice, vanilla, caramel, mixed berries, mixed fruits, black current, blue berry, cherry and lemon.

If needed one or more of the active pharmaceutical ingredients are taste masked. Taste masking technologies are well known for a person skilled in the art.

Examples of excipients include fats, proteins, fillers, glidants, lubricants, sweeteners, flavors, coloring agents, fillers, binding/gelling agents and mixtures thereof.

Suitable lubricants include long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.

Suitable glidants include colloidal silicon dioxide.

Examples of sweeteners include, synthetic or natural sugars; artificial sweeteners such as saccharin, sodium saccharin, sucralose, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, cyclamate, dihydrochalcone, alitame, miraculin and monellin; sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, and xylitol; sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called laevulose), and lactose (also called milk sugar); isomalt, stevia, and mixtures thereof.

Examples of coloring agents include lakes and dyes approved as a food additive.

Examples of fillers that may be used include corn syrup, sucrose, starches, fats, proteins and gelatin. Additional materials that may be used in the soft chew base include corn syrup solids, sucrose, starches, fats, proteins and/or gelatin.

In one embodiment the dosage form is coated. The dosage form may be coated with a sugar or sugar alcohol-based coating or a film coating. Examples of materials for sugar or sugar alcohol-based coatings include but are not limited to sucrose, dextrose or xylitol. Examples of polymers for use in a film coating include but are not limited to hypromellose and polyvinyl alcohol and polyvinyl alcohol:polyethylene glycol co-polymers and mixtures thereof.

The amount of famotidine may be from about <NUM> to about <NUM> and the amount of the antacid(s) from about <NUM> to about <NUM>. The amount of famotidine within the lipid bead portion may be from about <NUM> percent to about <NUM> percent, or from about <NUM> percent to about <NUM> percent by weight of the lipid bead portion.

The histamine H2-receptor antagonist such as famotidine may be present in an amount of from about <NUM> to about <NUM>, such as <NUM> to <NUM> or <NUM> to <NUM> or <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>.

The antacid may be present in an amount of from about <NUM> to about <NUM>. If two different antacids are utilized, they may be in the same amount or different amounts depending on the specific combinations. Examples are a dosage form having calcium carbonate in an amount from about <NUM> to about <NUM>, such as <NUM>, <NUM>, <NUM>, <NUM> or <NUM> and magnesium hydroxide in an amount from about <NUM> to about <NUM>, such as about <NUM>- about <NUM>, such as <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM>. If aluminum oxide or aluminum hydroxide is used it may be used in an amount from about <NUM> to about <NUM>, such as <NUM>, <NUM>, <NUM> or <NUM>.

In another aspect the invention relates to a soft chewable tablet, wherein the encapsulated active pharmaceutical ingredient is loperamide and the other active pharmaceutical ingredient is at least one simethicone.

It is also desirable for the lipid bead containing famotidine and the surrounding soft chew base containing antacid to have a similar texture upon chewing. The texture can be determined through analysis of force over time. In this aspect of the invention, the force-over-time total area difference is less than <NUM>/sec between the lipid bead and the soft chew base.

In another aspect of the invention the famotidine does not degrade over time. In this aspect the amount of total famotidine impurities in the dosage form is less than <NUM>% when stored at <NUM> and <NUM>% relative humidity for <NUM> months, and less than <NUM>% for any single impurity when stored at <NUM> and <NUM>% relative humidity for <NUM> months.

The following examples are intended to illustrate, but not to limit, the invention in any manner, shape, or form, either explicitly or implicitly.

The famotidine hot melt solution and integrated soft chew were prepared as follows:.

Approximately <NUM> batches were prepared according to the base ratio formula in Table <NUM>. Materials in the meltable edible matrix were melted in a stainless-steel vessel at approximately <NUM>. Famotidine was dispersed in the molten material and was continuously mixed to maintain uniform distribution. A pipette was used to transport measured amount of molten mixture to form beads which then solidified upon cooling. Variations in separate materials within the Base formula are shown in Table <NUM>.

The beads from Example <NUM> (Formulas <NUM> -<NUM>) were exposed to different conditions in amber glass jars to determine the stability of Famotidine. The famotidine and famotidine impurity assay was analyzed versus a stock standard famotidine solution prepared at <NUM>µg/mL, using an HPLC with the following parameters:.

Sample preparation included the following steps:
For samples containing glyceryldibehenate (Compritol): <NUM> chloroform was added and swirled until dissolved. Diluted to volume, with chloroform and mixed well.

For samples containing cetostearyl alcohol (Crodacol): <NUM> methanol was added and mixed using mechanical shaker until dissolved. Diluted to volume, with methanol and mixed well.

Table <NUM> summarizes the stability study results.

The formulas in SAMPLES <NUM> and <NUM> were selected for Open Dish Stability evaluation. The samples were placed into an open dish and placed into the respective stability environment.

Table <NUM> summarizes the stability results of Famotidine in the beads during an Open Dish Study at <NUM>/<NUM>% RH (relative humidity) for <NUM> months. Minimum degradation of Famotidine was observed after <NUM> months.

In order to soften the beads so that the texture is similar to the soft chew, different levels of MCT were added to Crodacol and Compritol as shown in Table <NUM>, with associated force measurements.

Force Measurements were analyzed to compare the beads in Table <NUM> to the commercial Rolaids® Soft Chew, to more closely match the organoleptic texture between a soft chew ingredient and the bead. Hardness was measured using a Texture Profile Analyzer with the following test parameters:.

Results: Blends containing <NUM>% MCT oil had the lowest hardness values (not included in graph). For stability studies, <NUM>% MCT oil was selected to minimize leaching of the oil from the bead into the soft chew matrix.

<FIG> shows the force measurements on samples with different amounts of MCTs.

The Rolaids® softchew was used for a base stability study when combined with the famotidine beads. The stability results are shown in Table <NUM>.

The bead ingredients for use in combination with the Softchew are shown in Table <NUM>.

Sample Prep for Stability Study: <NUM> gm Rolaids® Softchew was cut into <NUM> pieces. Approximately total of <NUM> of beads with Famotidine were weighed out for each test condition. One or two beads were inserted into each cut chew piece, and was performed twice for each condition.

Sample Storage: Samples were placed in an amber jar and placed on stability at Initial and 40C/<NUM>%RH for <NUM> weeks, <NUM> weeks, <NUM> months and <NUM> months timepoints.

The following ingredients are displayed on the package for the commercial Rolaids® Softchew.

In Each Chew: Calcium Carbonate USP (<NUM>), Magnesium Hydroxide USP (<NUM>).

Corn Starch, Corn Syrup, Corn Syrup Solids, Glycerin, Hydrogenated Coconut Oil, Lecithin, Natural and Artificial Flavors, Red <NUM> Lake, Sucrose, Water.

Each chew contains: calcium <NUM>, magnesium <NUM>. Store between <NUM> degrees to <NUM> degrees F (<NUM> degrees to <NUM> degrees C) in a dry place.

For hot melt coating, Glyceryl palmitostearate (commercially available as Precirol ATO from the Gattefosse corporation) is heated to a temperature of about <NUM> and sprayed on Famotidine granulation from Part A, in the Huttlin Diskjet unit. The particles were coated with <NUM>% weight gain.

The following dosage form was prepared using the famotidine coated particles in Part A.

Claim 1:
A soft chewable dosage form comprising a first active pharmaceutical ingredient encapsulated in a lipid material/matrix, wherein the lipid material comprises a primary lipid and a second lipid, wherein the second lipid is medium-chain triglycerides (MCT), wherein the lipid encapsulated active pharmaceutical ingredient is embedded in the soft chewable dosage form, and wherein the soft chewable dosage form comprises at least a second active pharmaceutical ingredient.