WO1992004889A1

WO1992004889A1 - Effective solid non-lozenge anti-acid/anti-gas medicament

Info

Publication number: WO1992004889A1
Application number: PCT/US1991/006857
Authority: WO
Inventors: Robert Alan Agnoli; Michelle Geraldine Ellegood; Ronald Matthew Smalley; Robert C. Cuca
Original assignee: Beecham Incorporated
Priority date: 1990-09-21
Filing date: 1991-09-20
Publication date: 1992-04-02
Also published as: EP0553194A1; EP0553194A4; IE913309A1; ZA917557B; JPH06504038A

Abstract

This invention relates to solid pharmaceutical medicaments, particularly non-lozenges, and the method for making such non-lozenge, wherein the non-lozenge contains an antacid and an anti-flatulent ingredient enrobed in a sucrose/corn syrup base.

Description

EFFECTIVE SOLID NON-LOZENGE

ANTI-ACID/ANTI-GAS MEDICAMENT

BACKGROUND

This invention relates to solid pharmaceutical medicaments, particularly lozenges, and the method for making such lozenge, wherein the lozenge contains an antacid and an anti-flatulent ingredient enrobed in a sucrose/corn syrup base.

Flatulence is a form of dyspepsia which is caused by an

accumulation of gas in the stomach or intestines. It may be from air which has been carried into the stomach along with food or liquid. Or, the gas may be formed by digestive activity in the stomach or the intestine, or by fermentation or putrification of ingested foods.

Simethicone, a defoaming agent, is now commonly administered orally to manage excess gas. This silicon-containing compound has the property of promptly reducing gas, thus reducing the patient's

distended and bloated feeling. Generally, from 20 to 40 mg of

simethicone is administered per unit dose as a means for reducing such stomach and/or intestinal gas.

The generation of gas is frequently accompanied with gastric hyperacidity. Thus, it is not uncommon for a patient to consume an antacid at the same time she seeks relief from excess gas.

Simethicone itself is not viewed as having any material or useful effect on gastric hyperacidity. Reduction of gas does not indirectly appear to reduce such gastric hyperacidity. Conventional treatment often involves consuming both an antacid and simethicone wherein the antacid is one of any number of the usual alkali metal salts, including aluminum salts which have been developed and approved for treating gastric hyperacidity.

Since hyperacidity and gas are so frequently encountered in episodes of gastric stress, combining simethicone and an antacid in a single formulation would have the advantage of assuring that they are administered in a proper relative ratio and are jointly consumed, thus maximizing the effect of both. However, it has long been known that most antacids inactivate simethicone by adsorption (study of Morton Rezak, J. Pharm. Sci. 55:538-539, May, 1966). Some of the antacids that have marked deleterious effects on the defoaming activity of simethicone are aluminum hydroxide, magnesium carbonate, bismuth subcarbonate, magnesium carbonate-aluminum hydroxide co- precipitates, and others. The antacids that have the least effect on simethicone's capability of reducing gas are sodium bicarbonate and sodium citrate. Antacids with a medium effect are said to be calcium carbonate, magnesium tricylicate and magnesium hydroxide.

A number of attempts have been made to overcome the

deleterious effects of antacids intimately mixed with simethicone in solid dosage forms. Primarily these attempts are focused on

manufacturing formulations wherein these two ingredients are physically separated. Two primary approaches have evolved, one, wherein either the simethicone or antacid has been trapped within a protected material or secondly, and the commercially available product, has been to create a two-layer product where one layer contains simethicone and the other the antacid.

Most of the off-the-shelf antacid/simethicone tablets currently available have been reported to have not only the simethicone partially deactivated but, in most cases, completely deactivated. Thus, most of these antacids were reported to not have passed the USP XXII defoaming test for simethicone. Only a few of these products, on some occasions, were reported to barely pass the test.

Though two-layer tablets are the most common tablet form, in some it has been reported that approximately 90% of the simethicone migrated into the antacid layer of the tablet. It has been speculated that this simethicone migration occurred after the tablet was

manufactured allegedly due to the strong attractive force on the simethicone by the antacid. A complete understanding of this

phenomenon is currently not available however.

Other reported attempts to produce commercially viable

simethicone/antacid formulations include entrapping the simethicone in sorbitol or alternatively a mixture of glycerol and corn syrup solids. However, notwithstanding these reports in the patent literature, no commercial product appears to be available currently embodying these two forms of entrapment.

It would be desirable to have a commercially acceptable stable product which solves the problem of combining an antacid and

simethicone in a single unilayer tablet in a way that did not inactivate the simethicone. This invention provides such a non-lozenge solid medicament formulation which has been found to be very stable with regard to simethicone defoaming activity over long periods of time. SUMMARY OF THE INVENTION

One aspect of this invention is a solid non-lozenge antacid/antigas medicament comprising sucrose/corn syrup candy-based

particulates containing simethicone in an amount between 5 - 25% weight/weight and a food-grade emuisifier in an amount sufficient to solubilize the simethicone in the candy base wherein the particulates are dispersed in a powder-based antacid-containing preparation and wherein the particulate comprise between 5 - 25% weight/weight of the finished medicament.

In a second aspect, this invention relates to a method for making a solid non-lozenge anti-gas/anti-acid medicament, which process comprises utilizing a food-grade emuisifier to solubilize between about 5 - 25% weight/weight of simethicone in a sucrose/corn syrup candy base; dispersing said particles of sucrose/corn syrup candy-base in a powder-based antacid-containing preparation wherein the product contains between 5 - 25% by weight/weight of the candy-base.

DETAILED DESCRIPTION OF THE INVENTION

In the broadest embodiment, the medicament of this invention will be some non-lozenge form of an orally acceptable formulation such as a tablet, capsule, caplet, or pill. The medicament will comprise candy-base particles containing dispersed simethicone and a second solid formulation which comprises the antacid and excipients useful for making a tablet or pill antacid medicament. Particles, particulates, of candy-based simethicone material will be such size so as not to induce capping or delamination, the phenomenon of tablet or pill breakage occurring during manufacturing of the tablets due to the lack of physical stability in the tablet itself caused by the dispersed particulates.

The candy-base used in this invention is prepared from sucrose and/or corn syrup or corn syrup solids. Corn syrup and corn syrup solids are interchangeable terms in this invention. Water content is the only difference, in fact, in the use of these terms, as corn syrup solids are merely the anhydrous or low water content version of corn syrup. The phrase "sucrose/corn syrup solids" includes those

formulations where 100% sucrose is used; those formulations where some ratio of sucrose and corn syrup are used; or those formulations where only corn syrup or corn syrup solids are used. A preferred formulation is a 50-50 sucrose/corn syrup mixture. Sucrose and corn syrup are well known commodities available in food grade quality from many commercial sources. A review of their chemical make up, physical characteristics, biological activity, commercial sources and the like can be found in the book titled The Handbook of Sugars, 2nd, Avi Publishing Co., Inc., Westport,

Connecticut, USA.

Simethicone is described in the Official Monograph of the United States Pharmacopeia, XXII as a mixture of fully methylated linear siloxane polymers containing repeating units of the formula [- (CH₃)₂SiO-]_n stabilized with trimethylsiloxy end blocking units of the formula [(CH₃)₃SiO-] and silicon dioxide. It contains not less than 90.5% and not more than 99.0% of polydimethylsiloxane ([-(CH₃)₂SiO- ]_n) and not less than 4.0% and not more than 7% of silicon dioxide.

Dimethylpolysiloxane is sometimes referred to as polysiloxane or organopolysiloxane. Another way to express this simethicone

formulation is by the general formula:

where R represents a lower alkyl group not exceeding five carbon atoms or an organic radical such as phenyl and n can be from 0 to 2000. Most advantageously, the siloxanes will be methylpolysiloxanes of at least 200 cs viscosity at 20°C, preferably with a viscosity of between 250 and 1000 cs at 25°C. Preferably the methylsiloxanes will contain from 1.9 to 2.1 methyl radicals per silicone atom.

Any simethicone which meets the present or future USP

monograph standards can be used in this invention. It may be prepared by means known in the art. Several fine chemical houses make simethicone for commercial sale, material specifically produced for use in treating flatulence as per the USP monograph. For example, Dow

Chemical Company or Dupont are sources of simethicone meeting USP standards.

The amount of simethicone used in the candy base can vary between 5 and 25% on a weight-weight basis. It is preferred to use between about 12 - 16% simethicone and most preferred to use about 15.5% simethicone. Emulsifiers, surfactants, are used in this invention to create a candy-base/simethicone emulsion. Simethicone, it has been found, oil out of the candy-base. This is apparently because the sugars as well the water which may be present are sufficiently hydrophilic so as to repel the hydrophobic simethicone at usual processing temperatures f or preparing candy. This oiling out phenomena results in simethicone not being well mixed with the sugars and hence not becoming well

entrapped or enrobed in the candy-base. Or the simethicone that is entrapped in the heating and mixing step is in the form of globular deposits of such size that when the base is comminuted, ground, in the next of the preparation steps, these globular deposits are sheared open and the simethicone is released onto the particulates' surface. This released simethicone must be washed away so the particulates can be used in the subsequent processing step(s). All this results in difficulty in creating a well mixed simethicone candy-base material with

reproducible simethicone loading.

Food grade emulsifiers greatly reduce the oiling out phenomena and make it possible to prepare well mixed simethicone containing candy-bases. Emulsifiers also make it possible to reduce substantially the temperature at which the candy-base is processed into the

crystalline form, the candy-base.

Food grade emulsifiers useful in this invention include anionic, cationic and non-ionic surfactants which are or are found to be

acceptable for use in pharmaceutical preparations or for use in foods. It is expected that the full spectrum of emulsifiers will be useful in this invention, provided a particular emuisifier is compatible with the candy-base sugars and simethicone. Lists of such emulsifiers can be found in the Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, as well as other sources. These emulsifiers are commercially available or can be made by published procedures.

Preferred emulsifiers are the glycerol esters, including all forms of the mono, di or triglycerides derivatives of this trihydroxy propane compound. Triglycerol monooleate is particularly preferred. It is available commercially under the name Mazol PGO 31 K.

These emulsifiers can be used in any amount which effectively emulsifies the simethicone. Normally, it is expected this will be an amount of about 0.5 to 5.0% by weight/weight of the candy-base. It is preferred to use about 2% of the emuisifier for about a 15%

concentration of simethicone, or an amount which is a proportional ratio thereof where the amount of simethicone is increased or

decreased.

Other excipients may be added to the candy-base. Colorants can be added to the simethicone confection, preferably at the liquid premix stage. For example, the color blue can be imparted to the simethicone candy base using FD&C blue No. 1. Preservatives, flavoring agents and the like may also be used in the candy portion of these medicaments.

Simethicone candy base particulate size can influence, or induce, tablet capping. It is thought that particulate size and particulate number exist in an inverse ratio. That is, as the number of particulates decreases, the size of the particulate matter can be increased and visa versa. No particular ratio has been precisely determined. But, insofar as tableting is concerned, capping is avoided by limiting particulate size to between No. 16 and 50 U.S. mesh size when incorporated into the antacid formulation in amounts between 5 - 25% by weight/weight. Capping concerns can be further addressed by adding excipients to the antacid formulation which will increase particulate binding. For example, microcrystalline cellulose can be added to the finished granulation to act as an auxiliary binder.

The antacid component, or acid neutralizing substance, which are useful in this medicament can be any of the various antacids now approved or which might be approved for use in neutralizing gastric hyperacidity. These are salts of certain alkali metals or such other metals as aluminum, bismuth, or co-precipitates thereof. Illustrative of antacids are sodium bicarbonate, sodium citrate, calcium carbonate, calcium phosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, and magnesium tricylicate. Also included within this invention are aluminum hydroxide, bismuth subcarbonate, magnesium carbonate-aluminum hydroxide co-precipitates and the like. Also, salt such as calcium caseinate, calcium phosphate, magnesium phosphate, aluminum phosphate, dihydroxy aluminum amino acetate, and potassium phosphate could be used in the practice of this invention. Calcium carbonate is the most preferred antacid. It, and other basic compounds of use herein are available from many different commercial sources, or can be prepared by published procedures. Preferably the antacid will b present in an amount between about 250 and 1000 mg per unit dose. Sufficient candy base particulate will be incorporated into the final product so as to deliver an effective amount of simethicone. A useful amount may vary anywhere between 5 and 40 mg per tablet. As routine matter, simethicone is normally present in either 20 and 25 mg amounts per tablet in antacid/anti-gas formulations. Preferably the simethicone particulate containing material will be present in an amount between amount 5 to 10% (w/w) of the finished medicament formulation which contains the antacid formulation also. The

simethicone concentration can be manipulated to result in a

formulation having the desired amount of simethicone by varying the simethicone concentration in the candy base.

The simethicone candy base can be prepared by any number of means known in the art. A particularly useful means for its

preparation is to combine the sugar/corn syrup solids and surfactants, along with any additional excipients such as dyes, and make a thorough mix of this combination of materials. Normally the sugars are mixed and heated, then surfactant and any water is added. However, it may be possible to make an initial mixture containing all of these components after which heat is applied while stirring to form an intimate mixture. After the sugar/surfactant mix has been processed for a discrete period of time, simethicone is added with additional heating and stirring. Optionally, additional sugars such as corn syrup solids may be added following the addition of the simethicone. Dyes may be added at any time. Preferably, however, the dye is added last with some additional mixing and heating to affect the uniform mixing of all the components. Optionally, this heated formulation can then be run through an emulsion-forming device to assist in making a

sugar/simethicone emulsion.

To make candy, sugars are usually heated to 100°C or more to form a molten mass of sugars so the materials can be thoroughly mixed and additives incorporated into the mix. For example, mixtures of sugars and corn syrup materials are often heated to 110 - 120°C at which point additives such as simethicone are added with stirring to attempt a mix of these materials. These temperatures caused two undesirable phenomena with a sugar/corn syrup mix and simethicone. First, the simethicone oils out of the hot sugar mass and as a result if became difficult to mix well the sugars and simethicone. Secondly, the simethicone began to evaporate, boil off, at these temperatures, a phenomena somewhat enhanced by the fact the simethicone oils out of the hot sugar melt. The addition of a surfactant makes it possible to carry out the mixing step at between 45 - 50°C. This mix could then be dehydrated at elevated temperature and reduced pressure to give a candy-base which could be ground, screened and dispersed in a powder formulation containing the anti-acid. It is preferred to reduce the moisture content to 3% or less, most preferably 1% or less and to keep the moisture content at that level during the further processing and making the tablets and during subsequent shipping and storage. This simethicone containing candy-base is then milled and sieved in

preparation for being incorporated into the antacid containing

formulation.

Maintaining a discrete particle size range has been shown to provide a more stable formulation, i.e., a formulation in which the simethicone retains its activity at the highest level for the longest period of time. The particulate size preferably will fall into a range wherein about 10% of the material will be retained on a U.S. 20 screen and about 20% will pass through a U.S. 50 mesh screen.

The ultimate form of this medicament is a tablet, caplet, capsule, pill or similar dry, non-lozenge embodiment wherein the candy

particulates are dispersed. Tablets and the like are well known in the art. They can be using excipients like talc, starch, agents to assist with dissolution, agents to act as binders, lubricants, fillers and such In this instance, one preferred embodiment is the formulation sold under the mark Turns, an antacid.

Tablets, etc., are prepared by mixing the simethicone containing candy-base particulates with a selected antacid base composition formulation and processing the combination into the solid non-lozenge medicament of choice. This process is simply accomplished by

mechanically mixing powdered antacid formulation and candy-base until thoroughly mixed, then processing the mix through a tableting machine. Before the final mixing step, other excipients such as colorants or flavorings may be added, the resulting blend can be processed through tableting or pill making machinery, or can be filled in to hard gelatin capsules or formed into caplets, any of which may be subsequently coated with any coating or coatings.

To demonstrate the actual working of this invention, a number of examples are set forth hereafter. These examples are intended only to illustrate the invention. They are not to be taken as limiting of the invention, nor limiting of the claims appended hereto. Reference is made to the claims solely for determining what is reserved to the inventors hereunder.

EXAMPLES EXAMPLE 1

A standard antacid tablet formulation was prepared by a semi- wet granulation process and contained the ingredients recited in Table I.

EXAMPLE 2

A 12% simethicone containing candy-base formulation was prepared from the profile of materials in Table II.

*Triglycerolmonooleate

These materials were confected as follows: The sucrose and water were weighed into a stainless steel beaker and warmed to produce a clear solution. Corn syrup was added and stirring continued with a split disk stir. At 80°C, 4.5 gm of the triglycerol monooleate was added. At 110°C simethicone was added and the formulation heated further. At 120°C red dye No. 40 was added. The melt was further heated to 138°C and poured onto an aluminum pan. A portion of this was ground using an A-10 analytical mill. Material from this grind which passed through a No. 20 screen was used in manufacturing a tablet which contained an antacid and the simethicone containing candy base particulates. About 310 gm of the antacid formulation recited in Example 1 was combined with 39.83 gm of the foregoing simethicone particulate matter. The granulation from Example 1 was blended with simethicone-containing particulates by paper rolling. Tablets were prepared on a standard tableting machine using a punch.

Two tablets were tested for their defoaming capability by the official Monograph in USP XXII (p. 1248-1249). The two tablets effected defoaming in three and two seconds, respectively. The USP standard is 45 seconds. One day later, two additional tablets were tested by this method and showed defoaming times of nine and eight seconds.

Example 3

An antacid/simethicone tablet formulation where the

simethicone was not incorporated into the candy matrix was prepared and tested as a means for comparing the utility and efficacy of the simethicone/candy base particulate containing antacid-anti-gas formulation of this invention. Simethicone, 1.37 gm, was taken up in 10X sugar (10.01 gm) and dispersed in the antacid formulation of

Example 1. A mortar and pestle was used to mix together the dry calcium carbonate antacid formulation and the blended

simethicone/1 OX sugar mix. This blend was tableted and its anti-foam, or defoaming, activity was tested on the same day. This formulation defoamed in 19 minutes and 35 seconds using the USP XXII procedure referred to in Example 2.

Example 4

Two formulations were prepared, one with the surfactant triglycerol monooleate and one without, to compare the effect of this component on the observed defoaming activity of the finished

antacid/anti-gas product. First an "intermediate" formulation was prepared containing the materials in Table III.

The candy base contained the materials recited in Table IV.

A candy-base without simethicone was prepared following the mixing procedures set out in Example 3. The "intermediate" (base plus simethicone) was prepared by mixing the simethicone with just the candy-base. This provided an intermediate material where the simethicone was adhered to a candy base; this provided a method for introducing the simethicone into a hot candy mix by some means other than simply pouring the simethicone into the hot candy mix. In this instance, the intermediate material was kneaded into the hot candy- base. This material was then cooled, pulverized, screened through No.s 12 and 20 screens, mixed with powdered antacid formulation from Example 1 and tableted. A parallel formulation was prepared except the Mazol PGO 31 K was not included. In preparing this second

formulation without the Mazol surfactant, simethicone was not evenly distributed in the candy. It tended to roll off during the kneading process. The resulting simethicone containing candy-base was again pulverized, screened, mixed with the antacid formulation and tableted.

Antacid/simethicone formulations with the surfactant defoamed in two seconds (material which passed through a No.12 screen) or seven seconds (material which passed through a No. 20 screen). Tablets without the surfactant defoamed in five seconds (through No. 12 screen) and 15 seconds (through No. 20 screen). This was time zero data. Example 5

An antacid/simethicone formulation as per this invention was formulated using the antacid component recited in Example 1 and a simethicone candy-base similar to that recited in Example 2. The resulting product contained the ingredient profile of Table V.

Microcrystallme cellulose, NF, was added to avoid or reduce potential capping problems which might arise during tableting.

Final product was prepared by charging a ribbon mixer with the following ingredients: the master blend, red lake blend, cherry flavor, adipic acid, microcrystallme cellulose, blue simethicone candy base, and the remaining portion of the antacid blend. These materials were mixed for approximately 15 minutes and then compressed to a prior target weight of approximately 1489 mg. This gave a tablet which was approximately 0.18-0.20 inches thick with a hardness of 11-20 sc.

The defoaming activity of this formulation was then tested at time zero, one month and five months in comparison with nine other marketed antacid/anti-flatulent formulations. These results are set out in the Table VIA-VID.

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Claims

What is claimed is:

1. A solid non-lozenge antacid/anti-gas medicament

comprising sucrose/corn syrup candy-based particulates containing simethicone in an amount between 5 - 25% weight/weight and a food- grade emuisifier in an amount sufficient to solubilize the simethicone in the candy base wherein the particulates are dispersed in a powder- based antacid-containing preparation and wherein the particulate comprise between 5 - 25% weight/weight of the finished medicament.

2. The composition of claim 1 wherein simethicone is present in the candy base in an amount between about 12 - 16%.

3. The composition of claim 2 wherein simethicone is present in an amount of about 15.5%.

4. The composition of claim 3 wherein the surfactant is triglycerol monooleate.

5. The composition of claim 4 wherein the sugar base contains

50% corn syrup and 50% sucrose.

6. The formulation of claim 5 which contains between 500 and 1 ,000 mg of antacid neutralizing agent.

7. The composition of claim 6 wherein said acid neutralizing agent is calcium carbonate.

8. The composition of claim 7 which is a tablet.

9. The composition of claim 8 in which the simethicone containing candy-base contains a dye.

10. The composition of claim 9 wherein the tablet contains a flavoring agent.

11 . A method for making a solid non-lozenge anti-gas/anti-acid medicament, which process comprises utilizing a food-grade

emuisifier to solubilize between about 5 - 25% weight/weight of simethicone in a sucrose/corn syrup candy base; dispersing said particles of sucrose/corn syrup candy-base in a powder-based antacid- containing preparation wherein the product contains between 5 - 25% by weight/weight of the candy-base.

12. The method of claim 11 wherein the heated candy-base with simethicone is passed through an emulsion forming device.

13. The method of claim 12 wherein between about 10 and 20% of simethicone is used.

14. The method of claim 13 wherein the surfactant is a

triglycerol monoester.

15. The method of claim 14 wherein the surfactant is triglycerol monooleate.

16. The method of claim 15 wherein the surfactant is mixed with some or all of the. sugar base and then simethicone is added to that mixture.

17. The method of claim 11 which is carried out at between about 45 - 50°C.

18. A simethicone containing candy base produced by the method of any one of claims 11-16.