GB2195890A - Improving palatability of pharmaceutical chewable tablets - Google Patents

Abstract

The present invention provides lipid-containing solid pharmaceutical compositions comprising: (a) from about 10% to about 50% of a lipid material; (b) from about 10% to about 50% of a dispersant (e.g. a hydrophilic saccharide); and (c) a safe and effective amount of a pharmaceutically active material. wherein the lipid component of said composition comprises at least about 70% of SOS triglycerides, and from about 4% to about 20% of combined SUU/UUU/SLS triglycerides, wherein S is stearic (St) or palmitic (P) and U is oleic (O) or linoleic (L), and wherein the St:P weight ratio is about 0.8% or less. The compositions as described are antacid chewable tablets wherein the lipid formulation is to improve palatability, and effective dispersion in the mouth and stomach.

Description

SPECIFICATION Palatable solid pharmaceutical compositions BACKGROUND OF THE INVENTION This invention relates to palatable solid pharmaceutical compositions useful in humans and other animals. In particular, it relates to such compositions comprising a pharmaceutical active in a lipid-containing matrix. Preferred compositions further relate to highly palatable tablets, which are chewable or liquify in the mouth, useful for the treatment of gastrointestinal disorders.

Pharmaceutical compositions may be produced in a variety of dosage forms, depending upon the desired route of administration of the active material. Oral dosage forms, for example, include such solid compositions as tablets, capsules, granules and bulk powders, and such liquid compositions as solutions, emulsions, and suspensions. The particular dosage form utilized may, of course, depend upon such factors as the solubility and chemical reactivity of the pharmaceutical active. Further, the dosage form may be selected so as to optimize delivery of the pharmaceutical active and/or consumer acceptability of the composition.

Tablet compositions offer many advantages, including ease of product handling, chemical and physical stability, portability (in particular, allowing ready availability to the consumer when needed), aesthetic acceptability, and dosage precision, (i.e., ensuring consistent and accurate doses of the pharmaceutical active). However, liquid formulations may offer advantages in the treatment of certain disorders, such as disorders of the upper gastrointestinal tract, wherein delivery of an active material dissolved or dispersed in a liquid ensures rapid and complete delivery to the afflicted area. In an effort to obtain the therapeutic advantages associated with liquid formulations as well as the broad advantages associated with solids, many chewable tablet formulations have been developed and described in the pharmaceutical literature. See, for example, L.Lachman, et al., The Theory and Practice of Industrial Pharmacy (2nd Ed., 1976).

Many such compositions are antacids, for the treatment of gastric hyperacidity and related disorders. Many antacid compositions in liquid form are quite effective due to the ready availability of the antacid active material (which is typically water-insoluble) suspended in a liquid vehicle.

There are also many solid antacid formulations, typically chewable tablets, which are designed to deliver small particles of antacid active to the stomach after chewing of the tablet.

Chewable tablets, such as antacid tablets, often contain high levels of mannitol or similar binders as well as methylcellulose, glycine, or other binding agents. Other chewable tablets are described in the literature containing fatty materials. See, for example, U.S. Patent 4,230,693, Izzo, et al., issued October 28, 1980, U.S. Patent 4,327,076, Puglia, et al., issued April 27, 1982, U.S. Patent 4,327,077, Puglia, et al., issued April 27, 1982, U.S. Patent 4,533,543, Morris, et al., issued August 6, 1985, and U.S. Patent 4,581,381, Morris, et al., issued April 8, 1986.

Many such solid antacid formulations fail to offer equivalent efficacy to liquid antacid compositions, for a variety of reasons. For example, the tablets may be incompletely chewed due to poor palatability of the composition. This problem is particularly acute with antacids, since the active materials in these products often have a metallic flavor and an astringent, chalky mouth feel. Such compositions may also have a gummy texture, and are subject to "taste fatigue", i.e., the composition is perceived to be less palatable after ingestion of multiple doses. Further, the binders and other materials used in such chewable tablets may prevent rapid and effective delivery of active mqterials to the stomach.

It has been found that tablet formulations containing selected lipid materials are highly palatable and effective compositions for the delivery of pharmaceutical active materials. In particular, compositions of this invention provide better taste, mouth feel, and storage stability then compositions known in the art. Such compositions containing high levels of stearic/palmitic and oleic triglycerides (as further defined herein) afford, for example, improved palatability, lower taste fatigue, and efficacy more equivalent to liquid antacid formulations, than compositions known in the art.

SUMMARY OF THE INVENTION The present invention provides lipid-containing solid pharmaceutical compositions comprising: (a) from about 10% to about 50% of a lipid base material; (b) from about 10% to about 50% of a dispersant; and (c) a safe and effective amount of a pharmaceutical active material; wherein the lipid component of said composition comprises at least about 704/0 of SOS trigiycerides, and from about 4% to about 20% of combined SUU/UUU/SLS triglycerides, wherein S is stearic (St) or palmitic (P) and U is oleic (0) or linoleic (L), and wherein the St:P weight ratio is about 0.8% or less. Preferably the lipid component of the present compositions contains about 8% or less of SLS triglycerides, about 9.5% or less of SSO triglycerides, about 2.5% or less of SSS triglycerides, and about 4% or less of other glycerides.Preferably, the lipid-containing compositions of the present invention contain from about 0.1 % to about 3.0% of an emulsifier.

Among the preferred lipid-containing compositions of this invention are chewable tablets useful for the treatment of upper gastrointestinal disorders., such as an antacid composition containing from about 10% to 65% of an acid neutralizing material. The present invention also provides coated unit dosage compositions which comprise the lipid-containing solid compositions of this invention coated with a solid coating material.

DESCRIPTION OF THE INVENTION The compositions of the present invention contain a pharmaceutical active material in a vehicle containing a lipid base material and a dispersant material. In addition, the compositions of the present invention may contain optional pharmaceutically-acceptable components which may modify their physical characteristics and/or therapeutic effects. All components of the present compositions must, of course, be pharmaceutically-acceptable. As used herein, a "pharmaceuticallyacceptable" component is one which is suitable for use with humans and/or other animals without undue adverse side effects (such as toxicity, irritation and allergic response) commensurate with a reasonable benefit/risk ratio.

Specifically, the compositions of the present invention comprise: (a) from about 10% to about 50% of a lipid base material; (b) from about 10% to about 50% of a dispersant material; and (c) a safe and effective amount of a pharmaceutical active material; wherein the lipid component of said composition comprises at least about 70% of SOS triglycerides and from about 4% to about 20% of combined SUU/UUU/SLS triglycerides, wherein S is stearic (St) or palmitic (P) and U is oleic (0) or linoleic (L), and the St:P weight ratio is about 0.8 or less. As used herein, all percentages are by weight of total composition, except with respect to percentages of glycerides present in the lipid component of the present compositions. Such percentages of glycerides, as used herein, are by weight of total lipid component in the particular composition.

Further, as used herein, the term "safe and effective amount" refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific "safe and effective amount" will, obviously, vary with such factors as the particular condition that is being treated, the severity of the condition, the duration of the treatment, the physical condition of the patient, the nature of concurrent therapy (if any), and the specific formulation and optional components employed.

Preferably, the lipid base material is present in the present compositions at a level of from about 20% to about 40%, more preferably from about 25% to about 40%. Also preferably, the dispersant material is present at a level of from about 20% to about 40%, more preferably from about 20% to about 35%. Specific components, and optional materials useful in these chewable tablet-compositions are further described below.

These compositions may be provided in unit-dosage form, as compressed or molded tablets.

Compressed tablets are produced by compression of tablet components, in a solid or semi-solid state mixture. Molded tablets are produced by forming a liquid product mass, i.e., by melting the fatty carrier materials and admixing the other components, followed by pouring into tablet-form molds, and cooling to a solid state. Although these compositions may be swallowed whole or in part without chewing, the present compositions are preferably comprised so as to facilitate chewing and/or melting in the mouth. The present compositions thereby facilitate dispersion of the pharmaceutical active material in saliva and (after swallowing, ultimately) in the gastric fluids of the stomach.

The molded uncoated compositions of this invention, while in a liquid mixture (melted) at approximately 40"C, preferably have a viscosity of less than about 12,000 centipoises (cps), as measured by a Brookfield Viscometer (Model RVT/2 Helipath, spindle C, at 10 rpm). More preferably, the present compositions have a viscosity of less than about 7000 cps. Such a viscosity may be obtained by selection of particle size of the pharmaceutical actives material and dispersant material, and by incorporation of selected optional components, as described below.

Preferably, the mean particle size of such particulate materials is from about 4 microns to about 10 microns, more preferably from about 6 microns to about 10 microns. Also preferably, less than about 10% of the particulates have a particle size greater than about 30 microns. (As used herein, "particle size" of a particulate refers to the diameter of a sphere having a volume equal to that of said particulate.) Compositions having such preferred viscosities are described in copending U.S. Patent Application Serial No. (P & Case 3572), fled October 6, 1986.

Also preferably, the compositions of this invention contain less than about 1% of materials that are liquid at ambient conditions in addition to any liquid components of the lipid material. More preferably, these compositions contain less than about 0.5% of such additional liquid materials.

Essential Components As described above, the present chewable tablet compositions contain three essential components: a lipid base material, a dispersant material, and a pharmaceutical active material. These compositions may contain optional components, such as emulsifiers, tempering aids, flavorants and colorants.

Lipid Material/Component: The compositions of the present invention contain one or more materials, herein "lipid base materials", which together with all other mono-, di- and tri-glycerides (if any) in the compositions form the "lipid components" of the chewable tablet compositions. Compositions having lipid components similar to those useful herein are described in U.S. Patent 4,594,259, Baker, et al., issued June 10, 1986 (incorporated by reference herein).

The lipid component of the present composition contains certain key triglycerides: saturatedoleic-saturated ("SOS"), saturated-unsaturated-unsaturated ("SUU"), unsaturated-unsaturated-unsaturated ("UUU"), saturated-linoleic-saturated ("SLS"), saturated-saturated-oleic ("SSO"), and saturated-saturated-saturated ("SSS") triglycerides, i.e., referring to the chemical structure of the fatty acid moiety of each glyceride in the key triglyceride. As used herein, "S" refers to the stearic ("St") or palmitic ("P") fatty acid residues of the glyceride molecule and ("U") refers to the oleic ("0") or linoleic ("L") fatty acid residues of the glyceride molecule.

The percentages of these triglycerides (by weight) in the lipid component can be determined by Argentation Thin Layer Chromatography (herein "Argentation"). This method, in essence, allows separation of individual triglycerides from a mixture according to the degree of unsaturation (i.e., the number of unsaturated fatty acid glycerides in the triglyceride) and the relative position of the fatty acid glyceride on the entire triglyceride molecule. However, chain length of the saturated fatty acids cannot be determined by this method. For example, Argentation can be used to distinguish SOS, SSO and SOO triglycerides, but cannot be used to distinguish POP, POSt, and StOSt triglycerides. One Argentation method that may be used to determine the triglyceride composition of the fat component of the present invention is described in U.S.

Patent 4,594,259, incorporated above.

The SOS triglycerides and combined SUU/UUU/SLS triglycerides are by far the most important. The SOS triglycerides, (i.e., the StOSt POSt and POP triglycerides) determine the mouth melt properties of the fat composition. The combined SUU/UUU/SLS triglycerides, more appropriately referred to as the "liquid" triglycerides, determine the firmness of the fat composition, and to some degree its final melting temperature. As used herein, the percentage of "combined SUU/UUU/SLS triglycerides" refers to the total percentage of SUU, UUU and SLS triglycerides present, by weight, in the lipid component.

The SOS triglycerides are present at a level of at least about 70% by weight of the lipid component. Preferably, these SOS triglycerides are present at at least about 80% by weight, more preferably at at least 85% by weight. The combined SUU/UUU/SLS triglycerides are present at from about 4 to about 20% by weight of the fat component, preferably at from about 8 to about 15%. Preferably, the SUU triglycerides comprise at least about 50% by weight, and preferably at least about 80% by weight, of the combined SUU/UUU/SLS triglycerides.

Another important aspect of the lipid component of the present compositions is the St:P weight ratio. This ratio indirectly measures the proporton of POP, POSt and StOSt triglycerides present in the lipid component. This St:P ratio is about 0.8 or less, preferably about 0.5 or less, more preferably about 0.2 or less. The weight percentages of the stearic (St), and palmitic (P), as well as the oleic (0) and linoleic (L), fatty acid residues of the various triglycerides are measured by determining the Fatty Acid Composition. In particular, the level of StOSt triglycerides present in the lipid component is preferably minimized for improved mouth melt properties.

These StOSt triglycerides are preferably present at about 20% or less by weight of the SOS triglycerides, more preferably at about 15% or less by weight, and more preferably at about 10% or less by weight.

Preferably the levels of the SLS, SSO and SSS triglycerides are minimized. The maximum level of SLS triglycerides is preferably about 8% or less by weight of the lipid component. The maximum level of SSO triglycerides is preferably about 9.5% or less by weight of the lipid component. The maximum preferred level of SSO triglycerides varies depending upon the St:P ratio of the lipid component, and the amount of butterfat (or fats having butterfat-like triglycerides) in the lipid component. (Such materials might be added, aside from the lipid base material, as a flavorant in the present compositions.) For example, as the St:P ratio reaches the maximum of about 0.8, the maximum level of SSO triglycerides is preferably about 6% or less by weight.

Also, as the amount of butterfat reaches the maximum of about 20% by weight of the lipid component, the maximum level of SSO triglycerides is preferably about 5% or less by weight.

For the SSS triglycerides, the maximum level is preferably about 2.5% or less by weight, more preferably about 2% or less by weight.

Other glycerides can be present at about 4% or less by weight of the lipid component. As used herein, the term "other triglycerides" refers to SOS, SUU, UUU, SLS, SSO and SSS triglycerides wherein S is neither palmitic (P) nor stearic (St) or wherein U is neither oleic (0) nor linoleic (L). Also included in this term are the saturated-saturated-linoleic (SSL) and the unsaturated-saturated-unsaturated (USU) triglycerides, as well as the mono- and diglycerides.

The lipid base material preferably consists entirely of a fat having a low St:P ratio (about 0.2 or less). This low St:P ratio fat can be made by first preparing a fat high in SOS, and especially POP, triglycerides. To increase the level of liquid triglycerides, this POP fat can be blended with a fat high in SUU/UUU/SLS, and especially POO, triglycerides. The amount of the POP and SUU/UUU/SLS fat blended together can be varied so as to achieve the desired triglyceride composition for the lipid component. Preferably, the POP fat comprises from about 80 to 100% by weight of the lipid base material, while the SUU/UUU/SLS fat comprises from 0 to about 20%.

A preferred source of POP fat is derived from palm oil by a triple stage solvent fractionation process disclosed in U.S. Patent 4,588,604, Baker, et al., issued May 13, 1986 (incorporated by reference wherein). As used herein, "palm oil" refers to unfractionated whole palm oil or partially fractionated palm oil. As used herein, "solvent fractionation" refers to the steps of providing a fat dissolved or melted in a suitable solvent (hereinafter defined), crystallizing fat crystals from the solvent and then separating the fat crystals (stearine fraction) from the solvent phase which contains the olein (liquid) fraction. In the first stage of this process, most of the liquid SUU/UUU/SLS triglycerides are removed.In particular, palm oil is initially melted in a suitable solvent, One or more olein fractions are then removed from the melted palm oil by solvent fractionation to provide a stearine fraction. This stearine fraction contains less than about 10% (preferably less than about 5%) by weight SUU/UUU/SLS (POO) triglycerides. The olein fraction(s) obtained during this first stage contain predominantly the SUU/UUU/SLS triglycerides and are useful as hereafter described.

The second fractionation stage of this process primarily involves removal of the SSO triglycerides. In particular, the stearine fraction from the first state is melted in a suitable solvent and then one or more olein fractions are removed by solvent fractionation to provide another stearine fraction. This stearine fraction from the second stage contains less than about 8% (preferably less than about 5%) by weight SSO triglycerides.

The third fractionation stage primarily involves removal of the SSS triglycerides. In particular, the stearine fraction from the second stage is melted in a sitable solvent and then a stearine fraction is again removed. This stearine fraction from the third stage contains most of the SSS triglycerides originally present in the palm oil. The olein fraction obtained in this third stage provides the POP fat which has less than about 2.5% by weight SSS triglycerides.

Suitable solvents for use in this triple stage fractionation process include hexane, hexane/C,-C3 alcohol mixtures (e.g., hexane/isopropyl alcohol), and especially acetone. The particular temperatures used for crystallization and separation of the stearine fractions from the olein fractions and the weight ratios of solvent to fat used for the solvent fractionations performed in the various stages of this process can vary, especially depending on the solvent used. Also, it is frequently desirable to perform several solvent fractionations in one or more of the three fractionation stages in order to effect better separation and removal of the SSU/UUU/SLS, SSO and SSS triglycerides, without significant loss of the key SOS triglycerides.

The POP fat, useful as a preferred lipid material in the present invention, can also be derived synthetically. In particular, 1,3-dipalmitin can be esterified with oleic anhydride using an esterification catalyst to obtain relatively pure, POP fats. For example, such methods are set forth in Example 2 of U.S. Reissue Patent 28,737, Yetter, reissued March 16, 1976 (describing esterification of 1,3-dipalmitin with oleic anhydride to obtain a POP fat containing 90-95% oleic acid at the 2-position); Example 2 of U.S. Patent 3,410,881, Martin et al., issued November 12, 1968 (describing esterification of 1,3-dipalmitin with oleic anhydride using perchloric acid as the catalyst, to obtain a POP fat containing 92% oleic acid at the 2-position); and Example 4 of U.S.

Patent 3,989,728, Martin, issued November 2, 1976 (describing esterification of 1,3-dipalmitin with oleic anhydride using ferric chloride as the catalyst, to obtain a POP fat containing 90-95% oleic acid at the 2-position). All of the foregoing patents on esterification of 1,3-dipalmitin by oleic anhydride are incorporated herein by reference.

The liquid SUU/UUU/SLS triglyceride portion of the low St:P ratio fat can be obtained from various sources, including SUU/UUU/SLS triglycerides produced synthetically. Such liquid triglycerides are typically derived from naturally occurring oils. Suitable oils high in such liquid triglycerides include cottonseed oil, soybean oil, sunflower oil, corn oil, peanut oil, safflower oil, and the like. These liquid triglycerides are preferably derived from the olein fraction(s) obtained in the first stage of the previously described triple stage fractionation process of palm oil. These olein fractions can be used as is, or are preferably fractionated to obtain a higher percentage of the more desirable POO triglycerides. In addition to providing liquid triglycerides, these olein fractions also contain desirable antioxidant tocopherols and trienols.

Dispersant Material: The compositions of this invention also contain a hydrophilic material, herein "dispersant material", which serves to aid dispersion of the pharmaceutical active and other materials of the composition in the mouth and/or stomach. Many dispersants among those useful herein are known in the pharmaceutical arts. Dispersant materials among those useful herein include sugars (such as sucrose, mannitol, sorbitol, dextrose, maltose, and lactose), starches and starch derivatives (such as corn starch and maltodextrin), microcrystalline cellulose, and mixtures thereof.

Among the preferred dispersant materials useful herein are sucrose, sorbitol, mannitol, and mixtures thereof.

Pharmaceutical Active Material: The present compositions also contains a "pharmaceutical active material", i.e., a material which is intended to have a physiologic effect on the human or lower animal to whom the composition is administered. Pharmaceutical active materials particularly useful in the chewable tablet formulations of this invention include those actives which become bioavailable and/or have their site of action in the mouth or stomach. The rapid dispersion of such active materials in the saliva, as afforded by the present chewable tablets, is particularly advantageous. Among such active materials are the analgesics, such as aspirin and acetaminophen, and materials useful in the treatment of gastrointestinal disorders.

Among the pharmaceutical active materials particularly useful in the compositions of this invention are the bismuth salts and the metallic antacid salts. Such bismuth salts include, for example, bismuth aluminate, bismuth citrate, bismuth nitrate, bismuth subcarbonate, bismuth subgalate, bismuth subsalicylate, and mixtures thereof. A particularly preferred bismuth salt is bismuth subsalicylate.Metallic antacid salts useful herein include, for example, aluminum carbonate, aluminum hydroxide, aluminum phosphate, aluminum hydroxycarbonate, 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, and mixtures thereof.

Aluminum magnesium hydroxide sulfate (also known as magaldrate) is a preferred metallic antacid salt useful herein.

Optional Components The compositions of this invention may also contain pharmaceutically-acceptable optional components which modify the physical and/or therapeutic effects of the composition. Such optional components may include, for example, emulsifiers, binders, lubricants, glidants, colorants, flavors and sweeteners. Such components are generally described in Marshall, "Solid Oral Dosage Forms", Modern Pharmaceutics, Volume 7, (Banker and Rhodes, editors), 359-427 (1979), incorporated by reference herein, and W. Gunsel, et al., "Tablets", The Theory and Practice of Industrial Pharmacy (L. Lachman, et al., editors, 2 ed.), 321-358 (1976), incorporated by reference herein.

The compositions of the present invention preferably contain from about 0.1 % to about 3.0%, preferably from about 0.8% to about 1.5%, of one or more emulsifiers, i.e., a material (or mixture of materials) which aids in dispersing a liquid in an otherwise immiscible liquid. Many such emulsifiers are known in the pharmaceutical arts. See, for example, M. Riegler, "Emulsions", The Theory and Practice of Industrial Pharmacy (L. Lachman, et al., ed. 1976), incorporated by reference herein.

Among the emulsifiers useful herein are the alkyl aryl sulfonates, alkyl sulfates, sulfonated amides and amines, sulfated and sulfonated esters and ethers, alkyl sulfonates, polyethoxylated esters, mono and diglycerides (which also constitute part of the lipid component, described above), diacetyl tartaric esters of monoglycerides, polyglycerol esters, sorbitan esters and ethoxylates, lactylated esters, propylene glycol esters, sucrose esters, and mixtures thereof.

Emulsifiers among those useful herein are described in McCutcheon's Emulsifiers and Detergents, North American Edition (1983), incorporated by reference herein.

Emulsifiers may be characterized by their hydrophilic/lipophilic behavior. This behavior can be numerically expressed for a given emulsifier by its hydrophilic-lipophilic balance (HLB). The HLB value of an emulsifier can be determined experimentally or computed (particularly for polyoxyethylene ethers) from its structural formula. In general, emulsifiers with high HLB values are more hydrophilic, and tend to favor formation of oil-in-water emulsions, as opposed to emulsifiers with lower HLB values.

The emulsifiers incorporated into the compositions of this invention preferably have an average HLB of at least about 8, preferably at least about 10. As used herein, the term "average HLB" refers to the weighted average of the HLB of all emulsifiers in the composition, i.e., HLB, =Wt%E1,+HLB2 + HLB2xWt%E2+ . . . HLBn x Wt%En total HLB= Wt%E,+Wt%E2+ . . . Wt%En wherein the composition contains "n" number of emulsifiers. In particular, the compositions of this invention also preferably contain one or more nonionic emulsifiers, each having an HLB of at least about 10, preferably at least about 11. Preferably such high LHB emulsifiers are present at a total level of from about 0.5% to about 2.0%, more preferably from about 0.6% to about 1.5%, more preferably from about 0.8% to about 1.0%.Mixtures of such high-HLB emulsifiers are preferred, particularly mixtures wherein at least one emulsifier has an HLB of at least about 12, preferably at least about 15.

High-HLB emulsifiers useful herein include polyoxyethylene (20) sorbitan monostearate (such as Tween 60, manufactured by ICI Americas, Inc.) sucrose mono esters, polyglycerol esters, and Pluronic F68, and mixtures thereof. Particularly preferred high HLB emulsifiers useful herein are described in copending U.S. Patent Application Serial No. (P & Case 3571), filed October 6, 1986, incorporated by reference herein.

The compositions of this invention may also contain one or more low-HLB emulsifiers (i.e., emulsifiers having HLB values less than about 10), particularly in order to improve rheology of the compositions in the mouth ("mouth feel"). Preferably, the present compositions contain from about 0.1% to about 1.0%, preferably from about 0.1% to about 5% of a low-HLB emulsifier.

The type and amount of emulsifiers useful in the present invention may be selected in order to obtain compositions with preferred melting viscosities, as described above. Such emulsifiers and other optional components useful in preferred compositions of this invention are described in U.S. Patent Application Serial No. (P & Case 3572), filed October 6, 1986, incorporated by reference herein.

As will be appreciated by those skilled in the art, the lipid base material of the present composition may be present in any of a number of crystal forms, or polymorphs. For compositions wherein POP fat is utilized as the lipid base material, it is preferred that the fat be present in the beta-prime-2 or beta-3 polymorph state. The crystal structure of the lipid base material useful herein may be affected by a variety of factors, as can be ascertained by one of skill in the art. Such factors include the presence of solids in the composition, the presence of emulsifiers, the processing conditions (particularly cooling temperatures and rates), and the particular lipid base material employed.

A preferred optional component in molded tablets of this invention (i.e., compositions that are formed upon solidification of a heated liquid composition after pouring into a suitable mold) is a "tempering aid". Such materials aid in the formation of a desired crystal structure for the lipid components of the present composition, such that the composition has a desired uniform, smooth, non-gritty texture and appearance. Tempering aids are preferably included at a level of from about 0.2% to about 2%.Among tempering aids useful herein are mixtures of mono- and diglycerides, such as Dur-Em 127 (manufactured by Durkee Foods, Division of SCM Corporation) and triglyceride mixtures, such as Cessa 60 (manufactured by Friwessa). (Such materials may also constitute part of the lipid component, described above.) Other preferred optional components useful herein include flavorants and sweeteners, at levels of from about 0.01% to about 1.0%. Colorants may be included at typical levels of from about 0.01% to about 0.5%.

As stated above, the present compositions may be coated, to provide a coated unit dosage form. The coated compositions of the invention comprise a lipid-containing composition of this invention, covered with from about 10% to about 50%, preferably from about 10% to about 30%, (by weight of final coated composition) of a solid, water-soluble coating material having a melting point greater than about 45"C. Such coated compositions preferably are in unit-dosage form, i.e., containing an amount of pharmaceutical active material suitable for administration to a human subject, in one dose, according to good medical practice. The coated compositions of this invention preferably contain from about 0.5 to about 2.5 grams, preferably from about 1.0 to about 2.0 grams, of the lipid-containing composition of this invention. Coating materials, and methods, among those useful herein are well known in the pharmaceutical arts. See, for example, W. Gunsel, et al., "Tablets", The Theory and Practice of Industrial Pharmacy (L.

Lachman, et al., editors, 2d ed.) 321-358 (1976), incorporated by reference herein. Preferred coatings and materials are described in U.S. Patent Application Serial No. (P & Case 3573), filed October 6, 1986, incorporated by reference herein.

Methods The chewable tablet compositions of this invention may be made by either compression or molding techniques. Compression techniques generally involve admixture of materials in an essentially dry state, followed by compression in a desired tablet form, under pressure. Molding techniques generally involve admixture of components in an essentially liquid form, followed by pouring into a desired tablet mold and cooling to a solid, or semi-solid form.

The lipid base material used in molded compositions of the present invention is preferably in a stable crystal form, such that the composition is comprised of stable crystals less than about 5 microns, preferably from about 1 to about 2 microns, in size and the composition has a uniform, smooth, non-gritty appearance and rheology. Such parameters, and the factors which influence them, are analogous to parameters that are well known in the chocolate confectionary arts. As discussed above1 materials may be added to the present compositions which aid in obtaining a preferred, stable crystal structure, or "temper". Processing conditions for making molded compositions are also critical, and are preferably controlled to yield a preferred tempered composition.Such "tempering", for compositions utilizing POP fat as a lipid base material, typically involves cooling of the product in liquid form, to a temperature of approximately 22"C. This cooling induces formation of a variety of crystals of different melting points. The composition is then heated, with stirring, to approximately 29.5"C, melting the undesired lower-melting crystals.

(The fluid product at this point is thereby "seeded" with higher-melting crystals.) The fluid product is then poured into molds, vibrated to remove air bubbles, and slowly cooled to solidify the composition into a product having the desired crystal form.

The following non-limiting Examples illustrate the compositions, processes and uses of the present invention.

EXAMPLE I A coated antacid composition according to this invention was made comprising: Component % Bulk Composition % Final Tablet POP fatl 34.009 28.908 sucrose 31.640 26.894 magaldrate2 31.640 26.894 simethicone 0.991 0.842 Span 803 0.478 0.406 Tween 604 0.148 0.126 sucrose monoester5 0.487 0.414 sodium stearoyl lactylate6 0.009 0.008 Dur-Em 1277 0.498 0.423 peppermint oil 0.100 0.085 100.000 (Coating) Neosorb P100T8 8.700 lycasin 4.100 mannitol 2.200 100.000 1. lipid base material, comprising approximately 88% SUS triglyceride, with an St:P ratio of approximately 0.13 2. aluminum magnesium hydroxide sulfate, antacid active material 3. sorbitan molooleate emulsifier, HLB=4.3, manufactured by ICI Americas, Inc.

4. polyoxyethylene (20) sorbitan monooleate emulsifier, HLB=14.9, manufactured by ICI Americas, Inc.

5. emulsifier, HLB=15.0 6. emulsifier, HLB=9.0 7. tempering aid mixture of mono- and diglycerides, HLB=2.8, manufactured by Durkee Foods, Division of SCM Corporation.

8. fine sorbitol powder, manufactured by The Roquette Corporation A composition according to this invention was made by admixing the magaldrate and sugar, and heating to approximately 40"C. Separately, approximately 55% of the POP fat was melted at approximately 40"C, and approximately 10% of the Span 80 was added, and mixed. The POP-fat mixture was then added to the active/sugar mixture, maintaining the temperatures at approximately 40"C., and mixed for approximately 45 minutes. The mixture was passed through a 4-roll roller mill, at approximately 300 psi, to ensure adequate contact and mixture of the lipid base material and the powdered materials.The 4 mill rollers were at temperatures of approximately 27"C, 21"C, 21"C and 21"C, respectively.

Separately, the remaining portion of POP (approximately 45% of the original quantity) was admixed with the remaining portion of Span 80 (approximately 90% of the original quantity), the Dur-Em, and the sodium stearyl lactylate emulsifier, for approximately 10 minutes, at a temperature of approximately 50"C. The milled POP mixture was then added to this POP/emulsifier mixture, and mixed for approximately 15 minutes.

The sucrose monoester and Tween 60 were dissolved in ethanol, and then added to the composition. The peppermint oil and simethicone were then added, and the compositions mixed for approximately 45 minutes, maintaining the temperature at approximately 50"C. The composition was then cooled to approximately 22"C, and tempered by rapidly raising the temperature to approximately 29.5"C, forming seed crystals. The composition was then poured into tablet molds and allowed to solidify. The average tablet weight was approximately 2.2 g.

The tablets were then coated by placing them in a conventional coating pan apparatus. A portion of the lycasin was added, and the tablets evenly wetted. The mannitol was then added, and the tablets mixed for approximately 10 minutes, and then dried for approximately one hour.

The tablets were then coated with lycasin and Neosorb, following the same procedure, and dried for approximately 12 hours.

A coated antacid tablet, comprised as above, was administered to a human subject experiencing heartburn, and was effective in reducing the severity of symptoms.

EXAMPLE ll A coated antacid composition according to this invention is made comprising: Component % Bulk Composition % Final Tablet POP fat 28.0 23.80 sucrose 15.0 12.75 sorbitol 15.0 12.75 calcium carbonate 40.0 34.00 sucrose monoester 1.0 0.85 Tween 60 0.5 0.43 flavorant 0.5 0.42 100.00 (Coating sorbitol 3.00 corn syrup 1.00 sucrose 10.50 maltrin 0.50 100.00 A coated antacid composition, comprised as above, is made by a method analogous to that described in Example I. The tablets are formed into unit dosage tablets, containing approximately 2.2 grams of the lipid-containing composition.

EXAMPLE Ill A coated antacid composition according to this invention was made comprising: Component % Bulk Composition % Final Tablet POP fat 35.942 30.000 sucrose 26.119 21.800 magaldrate 35.703 29.800 Cessa 601 0.994 0.830 Myrij 522 0.503 0.420 Caprol PGE 8603 0.395 0.330 Polyaldo HGDS4 0.252 0.210 flavorant 0.092 0.077 100.000 (Coating) sorbitol solution5 10.700 lycasin 1.060 mannitol 4.023 Klucel EF6 0.750 100.000 1. triglyceride mixture, tempering aid, manufactured by Friwessa 2. polyoxyl (40) stearate, nonionic emulsifier, HLB=16.9, manufactured by ICI Americas, Inc.

3. decaglycerol mono-dioleate nonionic emulsifier, HLB= 11.0, manufactured by Capital City Pro ducts Co., division of Stokely-Van Camp, Inc.

4. hexaglycerol distearate nonionic emulsifier, HLB=7.0, manufactured by Glyco, Inc.

5. 70% solution 6. hydroxypropyl cellulose gum, manufactured by Hercules Chemical Company.

A coated composition, comprised as above, was made by a method analogous to that described in Example I.

EXAMPLE IV An uncoated composition according to this invention is made comprising: Component % by Weight POP fat 34.6 sucrose 32.0 magaldrate 32.0 sucrose monoester 0.5 lecithin 0.5 polysorbate 60 0.2 flavorant 0.2 EXAMPLE V An uncoated composition according to this invention is made comprising: Component % by Weight POP fat 35.00 mannitol 15.88 bismuth subsalicylate 25.95 calcium carbonate 20.00 Span 80 0.48 Tween 60 0.15 sucrose monoester 0.48 flavorant 1.60 sweetener 0.20 colorant 0.26 Unit dosage tablets, comprised as above, are made containing approximately 1.1 grams of composition per tablet. Two tablets are administered to a human subject experiencing nausea, lessening the severity of symptoms.

Claims (11)

1. A solid pharmaceutical composition comprising: (a) from about 10% to about 50% of a lipid material; (b) from about 10% to about 50% of a dispersant; and (c) a safe and effective amount of a pharmaceutical active material; wherein the lipid component of said composition comprises at least about 70% of SOS triglycerides, and from about 4% to about 20% of combined SUU/UUU/SLS triglycerides, wherein S is stearic (St) or palmitic (P) and U is oleic (0) or linoleic (1), and wherein the St:P weight ratio is about 0.8 or less.

2. A solid pharmaceutical composition, according to Claim 1, wherein the St:P ratio is less than about 0.2.

3. A solid pharmaceutical composition, according to Claim 2, wherein said lipid component contains about 8% or less of SLS triglycerides, about 9.5% or less of SSO triglycerides, about 2.5% or less of SSS triglycerides, and about 4% or less of other glycerides.

4. A solid pharmaceutical composition according to Claim 2, wherein said lipid base material is present at a level of from about 25% to about 40%.

5. A solid pharmaceutical composition according to Claim 4, wherein said dispersant material is present at a level of from about 20% to about 35%.

6. A solid pharmaceutical composition according to Claim 5, additionally comprising an emulsifier.

7. A solid pharmaceutical composition according to Claim 6, additionally comprising a tempering aid.

8. A solid pharmaceutical composition according to Claim 7, wherein said pharmaceutical active material is a material useful in the treatment of gastrointestinal disorders.

9. A solid pharmaceutical composition according to Claim 8, wherein said pharmaceutical active material is a metallic antacid salt.

10. A solid pharmaceutical composition according to Claim 8, wherein said pharmaceutical active material is a bismuth salt.

11. A coated solid pharmaceutical composition, in unit dosage form, comprising from about 50% to about 90% of a composition according to Claim 1, and from about 10% to about 50% of a coating material.