SK76595A3 - Antacid composition and method of production - Google Patents

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

The present invention relates to an antacid composition

Technical field

The present invention relates to manufacture. The present invention relates to methods of treatment

Neutralization is the change of a solution from an acidic or alkaline region to a neutral region, achieved by adding an adequate amount of either an alkaline or acidic substance. Antacids or acid neutralizing agents are active substances which are capable of neutralizing fluids. Among the many circumstances that affect neutralization include the acidity of the solution form and various properties, such as the rate of the drug substance. The slow rate of neutralization by the problems to be considered in the development of the compositions, especially which is limited in need of relief from administration of the antacid, minutes or longer after administration of the antacid. Water-soluble drug substances, i.e. substances having a solubility of less than about 10 mg / ml, tend to be excreted from the gastro-intestinal tract before they are able to react with excess gastric acid.

body groups can adversely, dose dissolution is a significant antacid active substance, patients stomach, at least 20 those containing water-soluble. For example, the pain associated with over-acidification often has to wait

U.S. Pat. 4,533 antacid tablets that contain a creamy surface containing et al./ mentions chewing in the mouth to a smooth provides maximum antacid tablets have an original size while the particles are thoroughly

543 / Morris disintegrates a tasteless emulsion that contacts particles of antiacid. in each case antacid particles having particles of less than 100 millimicrons coated with a mixture of a fatty substance or an oil, a flavoring surfactant. Morris et al. however, it does not disclose antacid particles which essentially consist of an aluminum-based neutralizing agent or does not propose to increase the rate of neutralization by its small antacid particles.

U.S. Pat. No. 3,873,778 (Diamond et al.) Discloses a method of making improved antacid particles. The size of the antacid particles falls within the range of 0.05 to 300 μπι. Antacid particles, however, are coated with oil.

U.S. Pat. No. 4,271,142 discloses a portable liquid antacid. Example 8 of this patent specifies an antacid particle size of up to 50 millimicrons. However, such parts are coated with oil.

French patent no. No. 2,512,344 discloses an antacid suspension produced by mixing magnesium hydroxide in powder form, fragmenting and dispersing the particles is from 5 to 10 microns.

% of ammonium and / or hydroxide with water and then mechanical mixtures up to medium size

It would be desirable to be able to produce a composition comprising stable dispersible antacid particles in a size range corresponding to a small number of micrometers that are not surely flocculants or agromerates due to interparticular attraction forces and do not require the presence of an oil coating or crosslinking base. In addition, it would be highly desirable to produce antacid compositions that exhibit an increased rate of neutralization.

SUMMARY OF THE INVENTION

The present inventors have discovered stable, dispersible antacid particles and a process for their preparation by wet grinding in the presence of a grinding medium, optionally in conjunction with a surface modifier, the particles can be formulated into antacid compositions that exhibit a markedly higher rate of neutralization.

The present invention provides an antacid composition comprising particles consisting essentially of an aluminum-based neutralizing agent, optionally having a surface modifier adsorbed on its surface, the agent having an average particle size of less than about 3 µπι.

Another embodiment of the present invention provides a method of making the above composition comprising the step of dispersing an aluminum-based neutralizing agent in a liquid dispersing medium and using a mechanical device in the presence of a grinding medium to reduce the particle size to less than about 3 µmη. If desired, the particle size may be reduced in the presence of a surface modifier or the particles may be contacted with the surface modifier after attrition.

Advantages of the invention include

1. a simple and conventional process for the production of antacid compositions having a particle size of less than about 3 μιη by wet grinding, optionally in conjunction with a surface modifier; and

(2) an unexpectedly increased rate of neutralization.

Description of the drawing in the drawing

A single figure illustrates the increased rate of neutralization of artificial gastric juice using the composition of the present invention as compared to the prior art.

Preferred embodiments are now described.

The present invention describes improved antacid compositions consisting of particles having a small average size. These compositions represent an improvement over the prior art in that their rate of neutralization is considerably higher than that of the prior art. The invention is described herein in connection with a preferred use in neutralizing gastric juice.

Particles suitable for practicing the present invention include an aluminum-based neutralizing agent. This agent is present in a separate crystalline phase. The crystalline phase differs from the non-crystalline or amorphous phase, which is often the result of a precipitated technique.

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The agent is sparingly soluble and dispersible in at least one liquid medium. The term "sparingly soluble" means that the agent has a solubility in the liquid dispersing medium of less than about 10 mg / ml and preferably less than about 1 mg / ml. The preferred liquid dispersant is water. The invention may be practiced with other liquid media in which the agent is of limited solubility and dispersibility. Such media include, for example, aqueous salt solutions, sunflower oil, and solvents such as ethanol, tert-butanol, hexane, and glycol. The pH of the aqueous dispersing medium can be adjusted by techniques known in the art.

The antacid composition comprises particles consisting essentially of an aluminum-based neutralizing agent. By essentially consisting of particles it is meant that the particles are substantially free of, for example, oil coatings known in the art. Preferred aluminum-based neutralizing agents that can be used in the practice of the present invention include aluminum hydroxide, aluminum bicarbonate, magnesium aluminate glycinate, and dihydroxyaluminium aminoacetate. A preferred aluminum-based neutralizing agent is aluminum hydroxide.

In preferred embodiments, the antacid composition further comprises particles of a magnesium-based compound. Preferred 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 the invention comprises a separate phase of an aluminum-based neutralizing agent as described above, optionally having a surface modifier adsorbed on its surface. Suitable surface modifiers are believed to include those that adhere to the surface of the particles but do not chemically attach to them.

Suitable surface modifiers may advantageously be selected from known organic and inorganic pharmaceutical excipients which serve to dilute or increase in volume for easier preparation and administration of the drug (vehicle, excipient). Such vehicles include various polymers, low molecular weight oligomers, natural products, and surfactants. Preferred surfactants include nonionic and anionic surfactants. Representative examples of vehicles include simethicone, gelatin, casein, lecithin (phosphatides), gum arabic, cholesterol, tragacanth, stearic acid, benzalkonic chloride, calcium stearate, glyceryl monostearate cetostearyl alcohol, cetomacrogol, emulsifying waxes, polyoxyethylesterol, sorbitan ester, sorbitan ester derivatives, polyoxyethylenated castor oil, fatty acids polyoxyetylsorbitanom, e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium hlintý, triethanolamine, polyvinyl alcohol and polyvinylpyrrolidone detailed in (PVP). Most of these Handbook of Vehicles publications are Pharmaceutical

Excipients, printed together by an American

Pharmaceutical in the field.

Association and the Pharmaceutical Society of Great Britain, The

Pharmaceutical Press (1986), which is incorporated herein by reference. 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 the sequential addition of ethylene oxide and propylene oxide to ethylenediamine, dextran, lecithin, sodium sulfosulfate, diosulfate OT, the sulfosulfate OT, the diosulfate salt. available from American Cyanamide, Duponol P, which is sodium lauryl sulfate, available from DuPont, Triton X-200, which is an alkyl aryl polyestersulfonate, available from Rohm and Haas, Tween 80, which is a polyoxyethylene sorbitan fatty acid ester, available from 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 as such. Furthermore, the individually adsorbed surface modifier molecules are substantially free of intramolecular crosslinking.

As used herein, the term particle size refers to a number average particle size as determined by a conventional particle size measurement technique well known to those skilled in the art, such as flow sedimentation fractionation, photon correlation spectroscopy, or disk centrifugation. By an effective average particle size of less than 3 μπι, it is meant that at least 90% of the particles have a weight average particle size of less than about 3 μπι when measured by the above-mentioned technical method.

The compositions of the invention may be produced by a process comprising the steps of dispersing an aluminum-based neutralizing agent in a liquid dispersing medium and using a mechanical device, in the presence of a grinding medium, to reduce the particle size to less than about 3 µπι. An aluminum base average particle size less than 1 μπι. If magnesium-based particles are present, it is preferred that they have a particle size of less than about 3 μπι, and more preferably less than about 1 μπι.

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Optionally, the particles may be reduced in size in the presence of a surface modifier or the particles may be contacted with the surface modifier after attrition.

A particular method of making the compositions of the present invention is set forth below.

The selected aluminum-based neutralizing agent is obtained commercially and / or is prepared by a technique known in the art, in conventional coarse-grained form. It is preferred, but not necessary, that the particle size of the coarse selected aluminum-based neutralizing agent be less than about 100 µmη, as determined by network analysis. If the coarse grain size of the aluminum-based neutralizing agent is greater than about 100 μιη, then it is preferred that the particle size of the aluminum-based neutralizing agent is reduced to a size of less than 100 μιη, using a conventional milling method such as air jet milling or fragmentation milling, prior to using the milling method of the invention.

The coarse-grained aluminum-based neutralizing agent can then be added to the liquid medium in which it is substantially soluble to form a premix. The concentration of the aluminum-based neutralizing agent in the liquid medium may vary from about 0.1 to 60% by weight, preferably from 5 to 30% by weight. It is preferred, but not necessary, that a surface modifier is present in the premix. The concentration of the surface modifier may vary from 0.1 to about 90% by weight, preferably from 1 to 75% by weight, more preferably from 20 to 60% by weight, based on the total weight of the combination of the aluminum-based neutralizing agent and the surface modifier. The apparent viscosity of the premix suspension is preferably less than about 1000 mPa.s.

The premix may be used directly by subjecting to mechanical means measures to reduce the average particle size of the dispersion to less than 3 μιη. It is preferred that the premix be used directly when a ball mill is used for spreading. In another embodiment, the aluminum-based neutralizing agent and optionally the surface modifier can be dispersed in a liquid medium using a suitable mixing method, for example using a roller mill or a Cowles mixer, until a homogeneous dispersion is found in which large agglomerates are not visible to the naked eye. . It is preferred that the premix is subjected to a degree of pre-grinding of the dispersion when a recirculating media mill is used for spreading.

The mechanical device used to reduce the particle size of the aluminum-based neutralizing agent is usually in the form of a dispersing mill. Suitable dispersion mills include a ball mill, a pulverizer, a vibratory mill and an environment-containing mill such as a sand mill and a ball mill. The grinding environment is advantageous due to the relatively shorter grinding time required to achieve the intended result, i.e. the reduction in particle size. For medium grinding, the apparent viscosity of the premix is preferably from about 100 to about 1000 mPa.s. For ball milling, the apparent viscosity of the premix is preferably from about 1 to 100 mPa.s. Such a range tends to achieve an optimal balance between efficient particle fragmentation and environmental erosion.

The grinding media used for the particle size reduction step may be selected from solid media, preferably spherical or particulate, in a form having an average size of less than about 3 mm and more preferably less than about 1 mm. Such an environment may advantageously provide the particles of the invention at a reduced processing time and less grinding of the grinding equipment may occur. The choice of material for the grinding environment does not seem to be critical. It has been invented that zirconium dioxide, such as 95% zirconium dioxide stabilized with magnesium oxide, provides particles having a level of contamination that seems acceptable for the preparation of pharmaceutical compositions. However, it is believed that other environments such as zirconium silicate, glass, stainless steel, titanium dioxide, alumina and yttria stabilized 95% zirconia are also suitable. The preferred medium has a specific gravity of greater than about 3 g / cm ³ .

The spreading time can vary widely and depends in particular on the particular mechanical equipment and processing conditions selected. For roller mills, processing times of up to 5 days or longer may be required. In contrast, a treatment time of less than 1 day (residence time from about 1 minute to several hours) provides the desired results using high shear mills.

The particles must be reduced in size at a temperature that does not cause significant degradation of the aluminum-based neutralizing agent. Generally, operating temperatures below about 30 ° C to about 40 ° C are preferred. If desired, the production apparatus can be cooled by a conventional cooling apparatus. The process is conveniently carried out under ambient temperature conditions and at an operating pressure that is safe and effective for the grinding process. For example, the operating pressure corresponding to the environment is usual for ball mills, spreading mills and vibrating mills. Operating pressures of up to approximately 140 kPa are typical for environmental grinding.

The surface modifier, if not present in the premix, must be added to the dispersion after trituration in an amount as prescribed above for the premix. Then, the dispersion can be mixed, for example by vigorous shaking. If desired, the dispersion may be subjected to an ultrasonic treatment step, for example, when delivering ultrasonic energy. For example, the dispersion may be subjected to ultrasonic energy having a frequency of from 20 to 80 kHz for a period of from about 1 to 120 seconds.

The antancid composition of the invention preferably comprises from 5 to 80% by weight of the particles.

The relative amount of the aluminum-based neutralizing agent and the surface modifier can vary widely, and the optimum amount of the surface modifier can depend, for example, on the particular surface modifier selected or the critical micelle concentration of the surface modifier when in the form of micelles. The surface modifier is preferably present in an amount of from about 0.1 to 10 mg / m ² surface area of the aluminum-based neutralizing agent. The surface modifier may be present in an amount of from 0.1 to 90% by weight, preferably from 20 to 60% by weight, based on the total weight of the dry particles.

A simple series test method has been developed in which compatible surface modifiers and aluminum-based neutralizing agents can be selected that provide stable dispersions of the desired bases. First, the coarse-grained particles of the aluminum-based neutralizing agent are dispersed in a liquid in which the drug substance is substantially insoluble, such as water at a concentration of 5% by weight and milled for 60 minutes in a DYNO-MILL under normal grinding conditions as in the following Example 1. The milled material is then aliquoted and the surface modifier is added at a concentration of 2.10 and 50% by weight based on the total weight of the combination of the aluminum-based neutralizing agent and the surface modifier. The dispersion is then sonicated for 1 minute at a frequency of 20 kHz to disperse the agglomerates, and subjected to a particle size analysis which is determined by optical microscopy (at 1000X magnification). If a stable dispersion is observed, then the process for producing the combination of the aluminum-based neutralizing agent and the surface modifier can be optimized according to the above data. By stable is meant that the dispersion does not exhibit fluctuation or agglomeration of the particles visible to the naked eye for at least 15 minutes, and preferably for at least two days after manufacture.

The resulting dispersion is stable and consists of a liquid dispersion medium and the particles described above. The dispersion of the aluminum-based neutralizing agent optionally with the surface modifier can be used in liquid form, in the form of tablets and in other forms made by techniques well known in the art.

The antacid compositions of the 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, i.e., drug enhancers, or vehicles for administration in solid or liquid form and the like. Suitable carriers and vehicles are described in Handbook of Pharmaceutical Excipients, cited above.

The antacid compositions of the present invention may comprise natural and / or synthetic flavors such as cocoa, chocolate, frosted chocolate, butter, milk, cream, vanilla and egg parts such as egg white. The flavoring may be used in an amount ranging from about 0.05 to about 75% by weight of the composition.

In addition, the compositions may include various inactive ingredients such as cellulose, hydroxypropylcellulose, paraffinic agents such as butyl paraffin and the like.

DETAILED DESCRIPTION OF THE INVENTION

The following example illustrates the invention in more detail

Example

Approximately 300 ml of 1.1 mm zirconia beads are placed in a 500 ml wide-necked polyethylene container, together with approximately 100 ml of Mylanta ^R antacid suspension. The antacid suspension consists of aluminum hydroxide and magnesium hydroxide particles, simethicone, hydroxypropylcellulose, cellulose and butyl paraffin. The container is capped and rotated in a US Stoneware Roller Mill at a rotation speed of 187 rpm for 1 week to reduce the particle size of the suspension. The initial particle size is measured using a Hiac Royko Model 4100 particle size device attached to the Model Sampler.

3000 and found to be between 10 and 20 μιη. After milling, the particle size is measured again on a Hiac Royko and found to be less than 2 μιη in diameter.

The particle size reducing effect is determined using a modified FDA assay to determine the rate and extent of neutralization of artificial gastric acid (i.e., 0.1-normal hydrochloric acid) on unground and ground samples. To this end, 15 ml of this 0.1 N hydrochloric acid is placed in a 100 ml beaker with approximately 35 ml of deionized water. A glass electrode for pH determination is used to monitor the neutralized reaction process after addition of an equivalent amount (1 ml) of either ground or unground aluminum based suspensions for acid testing. In any case, the neutralization reaction raises the pH to the same neutral level, indicating a neutralization capacity. However, as shown in the figure, the milled composition unexpectedly reaches this level within about 2 minutes, while the unground composition requires more than 20 minutes to reach the final pH.

The invention is described in detail with reference to preferred embodiments thereof, but it is to be understood that changes and other modifications may be made therein without departing from the scope and scope of the invention.

Claims (13)

PATENT CLAIMS An antacid composition, characterized in that it consists essentially of an aluminum-based neutralizing agent whose particles have an average particle size of less than about 3 μιη. Antacid composition according to claim 1, characterized in that the neutralizing agent has a surface modifier absorbed on its surface. The antacid composition of claim 1, wherein the neutralizing agent is aluminum hydroxide. The antacid composition according to claim 1, wherein the antacid composition comprises particles of a compound based on a magnesium compound. The antacid composition of claim 4, wherein the magnesium-based compound is magnesium hydroxide. The antacid composition of claim 2, wherein the surface modifier is simethicone. Antacid composition according to claim 2, characterized in that it contains 5 to 80% by weight of the particles. 8. An antacid composition comprising particles consisting essentially of magnesium hydroxide and aluminum hydroxide, the particles having an average particle size of less than about 3 μπι. The antacid composition of claim 8 comprising particles having a particle size of less than about 1 µιη. 10. A method for producing an antacid composition according to claim 1, comprising the steps of 1. dispersing the aluminum-based neutralizing agent in a liquid dispersing medium; and 2. wet grinding in the presence of a grinding medium to reduce the size of this reagent to an average particle size of less than about 3 μιη. 11. A method of treating a mammal, comprising administering to the mammal an effective amount of an antacid composition according to claim 1. 12. A method of treating a mammal, comprising administering to the mammal an effective amount of an antacid composition according to claim 6. 13. A method of treating a mammal, comprising administering to the mammal an effective amount of an antacid composition according to claim 8.