ANTACID COMPOSITION AND METHOD OF PRODUCTION

Abstract: An antacid composition comprising particles consisting essentially of an aluminum-based neutralizing agent having an average particle size of less than about 3 microns and a method for preparing the composition. These compositions exhibit significantly enhanced rate of neutralization over compositions containing larger particles and are useful in treating mammals for pain associated with stomach acid.

Description: ANTACID COMPOSITION AND METHOD OF PRODUCTION FIELD OF INVENTION This invention relates to antacid compositions, and to a method for the preparation thereof. This invention also relates to the use of these compositions in methods of treating mammals. BACKfiROπrlD OF THE INVENTION Neutralization is the change of a solution from acid or alkaline to neutral through the addition of an adequate amount of either an alkaline or acidic substance. Antacids belong to the class of drugs that are able to neutralize bodily fluids. Many factors can affect neutralization including the acidity of the solution, the dosage form and various properties, e.g., dissolution rate of the drug. Slow rate of neutralization is a significant problem encountered in the development of antacid compositions, particularly those containing an active ingredient that is poorly soluble in water. For example, patients seeking relief for pain associated with stomach acid by taking an antacid often must wait for at least twenty minutes or longer after administration of the antacid. Poorly-water soluble drugs, i.e., those having a solubility less than about 10 mg/ml, tend to be eliminated from the gastrointestinal tract before being able to react with excess stomach acid. U.S. Patent 4,533,543 (Morris et al) discloses a chewable antacid tablet which disintegrates in the mouth becoming a smooth creamy pleasant-tasting emulsion which affords maximum surface contact of the particles of the antacid. Each antacid tablet contains solid antacid particles having a primary particle size of less than 100 millimicrons, which particles are thoroughly coated with a mixture of a fatty material or oil, a surfactant and a flavorant. Morris et al, however, do not disclose antacid particles consisting essentially of an aluminum-based neutralization agent or suggest an enhanced rate of neutralization of their small antacid particles. U.S. Patent 3,843,778 (Diamond et al) describe a process for preparing improved antacid particles. The size of the antacid particles fall within the range of 0.05 - 300 microns. However, the antacid particles are coated with an oil. U.S. Patent No. 4,271,142 describes a portable liquid antacid. Example 8 therein specifies an antacid particle size of 50 millimicrons. However, such particles are coated with an oil. French Patent 2,512,344 discloses an antacid suspension prepared by mixing aluminum hydroxide and/or magnesium hydroxide in powder form with water and then mechanically fragmenting and dispersing the mixture until the mean particle size is 5-10 microns. It would be desirable to be able to prepare compositions containing stable dispersible antacid particles in the low micron-size range which do not appreciably flocculate or agglomerate due to interparticle attractive forces and do not require the presence of an oil coating or a crosslinked matrix. Moreover, production of antacid compositions displaying enhanced rates of neutralization would be highly desirable. SUMMARY QF THE INVENTION We have discovered stable, dispersible antacid particles and a method for preparing such particles by wet milling in the presence of grinding media optionally in conjunction with a surface modifier. The particles can be formulated into antacid compositions exhibiting remarkably high rates of neutralization. This invention provides an antacid composition comprising particles consisting essentially of an aluminum- based neutralizing agent having optionally a surface modifier adsorbed on the surface thereof, said agent having an average particle size of less than about 3 microns. Another embodiment of this invention provides a method of preparing the above-described composition comprising the steps of dispersing an aluminum-based neutralization agent in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size to less than about 3 microns. Optionally, the particles can be reduced in size in the presence of a surface modifier or the particles can be contacted with a surface modifier after attrition. Advantages of this invention include 1) the simple and convenient method for preparing antacid compositions having particles less than about 3 microns in size by wet milling optionally in conjunction with a surface modifier and 2) the unexpectedly enhanced rate of neutralization. BRIEF DESCRIPTION OF THE DRAWTNC; The sole Figure illustrates the increase in the rate of neutralization of simulated gastric fluid for the composition of this invention compared to the prior art. DESCRIPTION OF PREFERRED EMBODIMENTS The present invention describes improved antacid compositions comprised of particles having a small average particle size. These compositions are an improvement over the prior art in that their rate of neutralization is greatly enhanced over that of the prior art. The invention is described herein in connection with its preferred utility of neutralizing gastric fluid. The particles useful in the practice of this invention comprise an aluminum-based neutralizing agent. This agent exists in a discrete, crystalline phase. The crystalline phase differs from a non-crystalline or amorphous phase which often results from precipitation techniques. The agent is poorly soluble and dispersible in at least one liquid medium. By "poorly soluble" it is meant that the agent has a solubility in the liquid dispersion medium of less than about 10 mg/ml, and preferably of less than about 1 mg/ml. A preferred liquid dispersion medium is water. The invention can be practiced with other liquid media in which the agent is poorly soluble and dispersible including, for example, aqueous salt solutions, safflower oil and solvents such as ethanol, t-butanol, hexane and glycol. The pH of the aqueous dispersion media can be adjusted by techniques known in the art. The antacid composition comprises particles consisting essentially of an "aluminum-based neutralization agent". By "consisting essentially of" it is meant that the particles are essentially free of, e.g., oil coatings which are known in the art. Preferable aluminum-based neutralization agents which may be used in the practice of this invention include: aluminum hydroxide, aluminum hydroxycarbonate, aluminum magnesium glycinate and dihydroxy aluminum aminoacetate. A preferred aluminum- based neutralization agent is aluminum hydroxide. In preferred embodiments, the antacid composition further comprises particles of a magnesium- based compound. Preferable magnesium compounds include magnesium aluminate, magnesium hydroxide, magnesium carbonate, magnesium oxide and magnesium trisilicate. A preferred magnesium based compound is magnesium hydroxide. The composition of this invention contains a discrete phase of an aluminum-based neutralizing agent as described above optionally having a surface modifier adsorbed on the surface thereof. Useful surface modifiers are believed to include those which physically adhere to the surface of the particles but do not chemically bond to them. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Representative examples of excipients include simethicone, gelatin, casein, lecithin (phosphatides) , gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol and polyvinylpyrrolidone (PVP) . Most of these excipients are described in detail in the Handbook of Pharmarpii ir.al Excipients. published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, The Pharmaceutical Press, 1986, the disclosure of which is hereby incorporated by reference in its entirety. The surface modifiers are commercially available and/or can be prepared by techniques known in the art. Preferred surface modifiers include Pluronic F68 and F108, which are block copolymers of ethylene oxide, Tetronic 908, which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, lecithin, Aerosol OT, which is a dioctyl ester of sodium sulfosuccinic acid, available from American Cyanamid, Duponol P, which is a sodium lauryl sulfate, available from DuPont, Triton X-200, which is an alkyl aryl polyester sulfonate, available from Rohm and Haas, Tween 80, which is a polyoxyethylene sorbitan fatty acid ester, available from ICI Specialty Chemicals, and Carbowax 3350 and 934, which are polyethylene glycols available from Union Carbide. A particularly preferred surface modifier is simethicone. Preferred surface modifiers do not chemically react with the agent or itself. Furthermore, the individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinkages. As used herein, particle size refers to a number average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. By "an effective average particle size of less than 3 microns" it is meant that at least 90% of the particles have a weight average particle size of less than about 3 microns when measured by the above-noted techniques. The composition of this invention can be prepared in a method comprising the steps of dispersing an aluminum- based neutralizing agent in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of less than about 3 microns. In preferred embodiments, the aluminum-based neutralizing agent has an average particle size of less than 1 micron. When magnesium-based particles are present, it is preferred that they have a particle size of less than about 3 microns, and more preferably of less than about 1 micron. Optionally, the particles can be reduced in size in the presence of a surface modifier, or can be contacted with a surface modifier after attrition. A specific procedure for preparing the compositions of this invention is set forth below. The aluminum-based neutralizing agent selected is obtained commercially and/or prepared by techniques known in the art in a conventional coarse form. It is preferred, but not essential, that the particle size of the coarse aluminum-based neutralizing agent selected be less than about 100 microns as determined by sieve analysis. If the coarse particle size of the aluminum-based neutralizing agent is greater than about 100 microns, then it is preferred that the particles of the aluminum-based neutralizing agent substance be reduced in size to less than 100 microns using a conventional milling method such as airjet or fragmentation milling prior to using the milling method of this invention. The coarse aluminum-based neutralizing agent selected can then be added to a liquid medium in which it is essentially insoluble to form a premix. The concentration of the aluminum-based neutralizing agent in the liquid medium can vary from about 0.1 - 60%, and preferably is from 5 -30% (w/w) . It is preferred, but not essential, that the surface modifier be present in the premix. The concentration of the surface modifier can vary from about 0.1 to about 90%, and preferably is 1 - 75%, more preferably 20 - 60%, by weight based on the total combined weight of the aluminum-based neutralizing agent and surface modifier. The apparent viscosity of the premix suspension is preferably less than about 1000 centipoise. The premix can be used directly by subjecting it to mechanical means to reduce the average particle size in the dispersion to less than 3 microns. It is preferred that the premix be used directly when a ball mill is used for attrition. Alternatively, the aluminum-based neutralizing agent and, optionally, the surface modifier, can be dispersed in the liquid medium using suitable agitation, e.g., a roller mill or a Cowles type mixer, until a homogeneous dispersion is observed in which there are no large agglomerates visible to the naked eye. It is preferred that the premix be subjected to such a premilling dispersion step when a recirculating media mill is used for attrition. The mechanical means applied to reduce the particle size of the aluminum-based neutralizing agent conveniently can take the form of a dispersion mill. Suitable dispersion mills include a ball mill, an attritor mill, a vibratory mill and media mills such as a sand mill and a bead mill. A media mill is preferred due to the relatively shorter milling time required to provide the intended result, i.e., the desired reduction in particle size. For media milling, the apparent viscosity of the premix preferably is from about 100 to 1000 centipoise. For ball milling, the apparent viscosity of the premix preferably is from about 1 up to about 100 centipoise. Such ranges tend to afford an optimal balance between efficient particle fragmentation and media erosion. The grinding media for the particle size reduction step can be selected from rigid media preferably spherical or particulate in form having an average size less than about 3 mm and more preferably, less than about 1 mm. Such media desirably can provide the particles of the invention with shorter processing times and impart less wear to the milling equipment. The selection of material for the grinding media is not believed to be critical. It has been found that zirconium oxide, such as 95% ZrO stabilized with magnesia, provide particles having levels of contamination which are believed to be acceptable for the preparation of pharmaceutical compositions. However, other media, such as zirconium silicate, glass, stainless steel, titania, alumina and 95% ZrO stabilized with yttrium, are expected to be useful. Preferred media have a density greater than about 3 g/cm 3 . The attrition time can vary widely and depends primarily upon the particular mechanical means and processing conditions selected. For ball mills, processing times of up to five days or longer may be required. On the other hand, processing times of less than 1 day (residence times of one minute up to several hours) have provided the desired results using a high shear media mill. The particles must be reduced in size at a temperature which does not significantly degrade the aluminum-based neutralizing agent. Processing temperatures of less than about 30 - 40°C are ordinarily preferred. If desired, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures which are safe and effective for the milling process. For example, ambient processing pressures are typical of ball mills, attritor mills and vibratory mills. Processing pressures up to about 20 psi (1.4 kg/cm 2 ) are typical of media milling. The surface modifier, if it was not present in the premix, can be added to the dispersion after attrition in an amount as described for the premix above. Thereafter, the dispersion can be mixed, e.g., by shaking vigorously. Optionally, the dispersion can be subjected to a sonication step, e.g., using an ultrasonic power supply. For example, the dispersion can be subjected to ultrasonic energy having a frequency of 20-80 kHz for a time of about 1 to 120 seconds. The antacid composition of the invention preferably comprises from 5 to 80 percent by weight particles. The relative amount of aluminum-based neutralizing agent and surface modifier can vary widely and the optimal amount of the surface modifier can depend, for example, upon the particular surface modifier selected or the critical micelle concentration of the surface modifier, if it forms micelles. The surface modifier preferably is present in an amount of about 0.1-10 mg per square meter surface area of the aluminum-based neutralizing agent. The surface modifier can be present in an amount of 0.1-90%, preferably 20-60% by weight based on the total weight of the dry particle. A simple screening process has been developed whereby compatible surface modifiers and aluminum- based neutralization agents can be selected which provide stable dispersions of the desired particles. First, coarse particles of the aluminum-based neutralizing agent are dispersed in a liquid in which the drug is essentially insoluble, e.g., water at 5% (w/w) and milled for 60 minutes in a DYNO-MILL under the standard milling conditions which are set forth in Example 1 which follows. The milled material is then divided into aliquots and surface modifiers are added at concentrations of 2, 10 and 50% by weight based on the total combined weight of the aluminum-based neutralizing agent and surface modifier. The dispersions are then sonicated (1 minute, 20 kHz) to disperse agglomerates and subjected to particle size analysis by examination under an optical microscope (1000 x magnification) . If a stable dispersion is observed, then the process for preparing the aluminum-based neutralizing agent surface modifier combination can be optimized in accordance with the teachings above. By stable it is meant that the dispersion exhibits no flocculation or particle agglomeration visible to the naked eye at least 15 minutes, and preferably, at least two days or longer after preparation. The resulting dispersion is stable and consists of the liquid dispersion medium and the above-described particles. The dispersion of aluminum-based neutralizing agent optionally with a surface modifier can be used in a liquid form, in the form of tablets, and other forms prepared by techniques well known in the art. Antacid compositions according to this invention include the particles described above and a pharmaceutically acceptable carrier therefor. Suitable pharmaceutically acceptable carriers are well known to those skilled in the art and include aqueous solutions, and other non-toxic physiologically acceptable carriers, adjuvants or vehicles for oral administration in solid or liquid form and the like. Suitable carriers and . excipients are described in the Handbook of Pharmaπpn1-ir;π1 Exripisnts. cited above. The antacid composition of this inventions can include natural and/or synthetic flavorants, such as cocoa, chocolate, mint chocolate, butter, milk, cream, vanilla, butter fat egg or egg white. The flavorant can be employed in amounts within the range of from about 0.05 to about 75% by weight of the composition. The antacid composition of the invention can also include pharmaceutically acceptable excipients, such as sweetening agents, including sugars, sugar alcohols, and synthetic sweeteners such as sorbitol, xylitol, saccharin salts, etc. as well as coloring agents and other flavoring agents. Additionally, the composition can include various inactive ingredients such as cellulose, hydroxypropyl cellulose, paraffins, such as butyl paraffin, and the like. The following example further illustrates the invention. EXAMPLE Approximately 300 ml of 1.1 mm diameter Zrθ 2 beads were placed into a 500 ml, polyethylene wide-mouth bottle together with approximately 6 oz (100 ml) of Mylanta® antacid suspension. The antacid suspension comprised particles of aluminum hydroxide and magnesium hydroxide, simethicone, hydroxypropyl cellulose, cellulose and butyl paraffin. The bottle was capped and rolled on a US Stoneware roller mill at 187 rpm for 1 week to reduce the particle size of the suspension. The initial particle size was measured using a Hiac Royko model 4100 particle sizer coupled to a model 3000 sample module and found to be between 10 and 20 microns. After milling, the particle size was again measured on the Hiac Royko and found to be less than 2 microns in diameter. The effect of diminished particle size was estimated using a modified FDA test to determine the rate and extent of neutralization of simulated stomach acid (i.e., 0.1 N HC1) by the unmilled and milled samples. Fifteen milliliters (15 ml) of 0.1 N HC1 was placed into a 100 ml beaker with approximately 35 ml of deionized water. A glass pH electrode was used to monitor the progress of the neutralization reaction after addition of equal amounts (1 ml) of either milled or unmilled aluminum-based suspensions to the test acid. In each case, the neutralization reaction reached the same neutral pH value indicating equal neutralization capacity. However, as indicated in the Figure, the milled formulation unexpectedly achieved this level within about 2 minutes while the unmilled formulation required in excess of 20 minutes to reach the final pH value. The invention has been described in detail with particular reference to preferred embodiments thereof, but it will be understood that variations and modifications can be effected within the spirit and scope of the invention.

Claims: What is claimed is: 1. An antacid composition comprising particles consisting essentially of an aluminum-based neutralization agent, said particles having an average particle size of less than about 3 microns. 2. The antacid composition as defined in claim 1, wherein said neutralizing agent has a surface modifier adsorbed on the surface therefore. 3. The antacid composition as defined in claim 1, wherein said neutralizing agent is aluminum hydroxide. 4. The antacid composition as defined in claim 1, further comprising particles of a magnesium-based compound. 5. The antacid composition as defined in claim 4, wherein said magnesium-based compound is magnesium hydroxide. 6. The antacid composition as defined in claim 2, wherein said surface modifier is simethicone. 7. The antacid composition as defined in claim 2, wherein said composition comprises five to eighty percent (5-80%) by weight of said particles. 8. An antacid composition comprising particles consisting essentially of magnesium hydroxide and aluminum hydroxide, said particles having an average particle size of less than about 3 microns. 9. An antacid composition as defined in claim 8, wherein said particle size is less than about one micron. 10. A method of preparing the antacid composition of claim 1, comprising the steps of: 1) dispersing an aluminum-based neutralizing agent in a liquid dispersion medium and 2) wet grinding in the presence of milling media to reduce the size of said agent to an average particle size of less than about 3 microns. 11. A method of treating a mammal comprising administering to the mammal an effective amount of the antacid composition of claim 1. 12. A method of treating a mammal comprising administering to the mammal an effective amount of the antacid composition of claim 6. 13. A method of treating a mammal comprising administering to the mammal an effective amount of the antacid composition of claim 8.

Inventors: LIVERSIDGE GARY G, MCINTIRE GREGORY L, LIVERSIDGE, GARY, G., MCINTIRE, GREGORY, L.
Applicants: STERLING WINTHROP INC, STERLING WINTHROP INC.
Application year: 1993
Main classification: A61K33
IPC codes: A61K9, A61K31, A61K33, A61P1