EP1011631A1

EP1011631A1 - Antacid composition

Info

Publication number: EP1011631A1
Application number: EP97938349A
Authority: EP
Inventors: Ashok Premchand Luhadiya; Vikram Goel
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1997-08-15
Filing date: 1997-08-15
Publication date: 2000-06-28
Also published as: AU4070397A; CA2301292A1; JP2000503035A; WO1999008656A1

Abstract

A composition is disclosed, comprising an antacid active having from about 0.29 gram/cc to about 1.5 gram/cc of bulk density and a carrier.

Description

ANTACID COMPOSITION

FIELD

The present invention relates to an antacid composition. More specifically the invention relates to an antacid composition comprising an active ingredient and a carrier.

BACKGROUND

Antacid compositions are widely used for treating upper gastrointestinal tract distress (e.g., stomachache, dyspepsia, indigestion, etc.). A variety of forms of antacid compositions are currently available, for example, solid forms such as tablets and granules, or liquid forms including gel types. Tablets which are readily chewed and/or swallowed are a typical antacid product form.

Many consumers, particularly those who have difficulty swallowing a tablet, (e.g., the aged or children) prefer tablets which can be readily ingested by chewing. Therefore, an important consideration for consumer acceptance of such solid-type antacid compositions is good mouthfeel, especially non-grittiness in the mouth. "Mouthfeel" is the overall sensation of the product in the mouth and "non-grittiness" is an attribute of good mouthfeel that relates to the textural aspects of the granules and the feeling on the upper palate. Providing good mouthfeel has typically been problematic in the production of antacid tablets.

A variety of approaches have been developed to obtain chewable antacid tablets having good mouthfeel as well as improved dissolution and/or disintegration properties. These conventional approaches for overcoming undesirable mouthfeel range from using a choice of ingredients such as actives, excipients, or others having specific characteristics or levels, to a manufacturing process for a preparation of soft granules which contribute to desirable mouthfeel. For example, these approaches have included using a binding agent with a low level of granulating fluids, masking for desirable taste, using small size particles, but coated, e.g., with oil to decrease the feeling of hardness, and preparing granules by high shearing or kneading during agglomeration of*the granules.

Chewable antacid tablets comprising a particular small particle size range of calcium carbonate in combination with certain excipients such as sucrose and mannitol have previously been made. See H.A. Fountaine, U.S. Patent 4,446,135. However, the smaller particle size tends to impart a chalky, gritty taste to the tablet. Pharmaceutical tablets (e.g., vitamin, antacid, analgesic) comprising an excipient having a specified bulk density, and a specified level of calcium carbonate per tablet, have also been made. See B. T. Palermo, U.S. Patent 3,384,546. However, the choice of active ingredients and excipients is limited and the dosage level of active ingredients is also limited. Neither of these conventional approaches successfully provides tablets having good mouthfeel as well as a high concentration level of active ingredients. Higher concentration of actives in tablets, for example, can result in tablets which are larger and bulkier than those of conventional size, thereby difficult to ingest by chewing.

On the basis of the foregoing, there is a need for an antacid composition having pleasant mouthfeel, which is non-gritty in the mouth, and which can deliver a high dose of active ingredient per tablet. None of the existing art provides all of the benefits and advantages of the present invention.

SUMMARY

The present invention is directed to a composition comprising an antacid active having from about 0.29 gram/cc to about 1.5 gram/cc of bulk density, and a carrier. The present invention is further directed to a composition comprising: (a) granules comprising an active antacid having a bulk density of from about 0.29 gram/cc to about 1.5 gram/cc and a carrier; and (b) a tableting aid.

These and other features, aspects, and advantages of the present invention will become better understood from a reading of the following description, and appended claims.

DETAILED DESCRIPTION

While the specification concludes with claims particularly pointing out and distinctly claiming the invention, it is believed that the present invention will be better understood from the following description. All percentages and ratios used hereinafter are by weight of total composition, unless otherwise indicated.

All measurements referred to herein are made at 25°C unless otherwise specified. All percentages, ratios, and levels of ingredients referred to herein are based on the actual amount of the ingredient, and do not include solvents, fillers, or other materials with which the ingredient may be combined as a commercially available product, unless otherwise indicated.

All publications, patent applications, and issued patents mentioned herein are hereby incorporated in their entirety by reference. Citation of any reference is not an admission regarding any determination as to its availability as prior art to the claimed invention.

As used herein, "comprising" means that other steps and other components which do not affect the end result can be added. This term encompasses the terms "consisting of and "consisting essentially of."

The present invention relates to a composition comprising an antacid active and a carrier. The antacid active of the present invention has a characteristic bulk density in the range from about 0.29 gram/cc to about 1.5 gram/cc. Herein, "bulk density" refers to the overall density of a plurality of particles and the amount of void space between the particles, indicating the fluffiness of the bulk of particles. The bulk density can be measured by methods which have been conventionally used for determination of physical properties of particles (e.g., described Pharmaceutical Dosage forms; Tablets, vol. 2, pages 289-290, 1990, issued by Marcel Dekker, Inc.) The composition of the present invention including an antacid active of the bulk density specified herein provides excellent mouthfeel and a high concentration of antacid actives.

A. Active ingredient

Herein, "antacid active" refers to the material intended to be delivered to (e.g. ingested by) the user for therapeutic treatment. Antacid actives which can be used in the present invention include those selected from the group consisting of a metal carbonate compound, a metal hydroxide compound, a metal oxide compound, a bismuth subsalicylate, and mixtures thereof.

Nonlimiting examples of the antacid actives include, for example, aluminum carbonate, calcium carbonate, magnesium carbonate, aluminum hydroxy-carbonate, dihydroxy aluminum sodium carbonate, aluminum hydroxide, magnesium hydroxide, aluminum phosphate, calcium phosphate, aluminum magnesium glycinate, magnesium glycinate, dihydroxy aluminum amino acetate, dihydroxy aluminum aminoacetic acid, aluminum magnesium hydrated sulfate, magnesium aluminate, magnesium oxide, magnesium alumino silicate, magnesium trisilicate, sucralfates, and mixtures thereof.

Preferred antacid actives are selected from the group consisting of calcium carbonate, dihydroxy aluminum sodium carbonate, aluminum hydroxide, magnesium hydroxide, and mixtures thereof; more preferably calcium carbonate. In a preferred embodiment, the antacid active is used at a level of from about 24% to about 70%, more preferably from about 40% to about 60%, by weight of the mixture of the antacid active and the carrier.

B. Carrier Carriers used for the composition of the present invention are selected depending upon their compatibility with the antacid active, and the desired characteristic of the product. Exemplary carriers useful in combination with the antacid actives herein include those selected from the group consisting of sugar, sugar alcohols, and mixtures thereof. Nonlimiting examples of sugars useful herein include lactose, glucose, maltodextrins, and sucrose. Sugar alcohols useful herein include sorbitol, xylitol, mannitol and maltitol. A preferred carrier of the present invention is selected from the group consisting of sucrose, mannitol, and mixtures thereof. A highly preferred carrier is sucrose. The carrier is present at an effective level, preferably at a level of from about 27% to about 73%, more preferably from about 40% to about 60% by weight of the mixture of the antacid active and the carrier.

In addition, it is recognized that some carriers of the present invention may also have properties as a binding agent. These carriers may be useful for providing improved binding of the composition, especially those which are in the form of tablets.

C. Additional Ingredients

The compositions of the present invention may further comprise additional ingredients selected from the group consisting of a granulating fluid, a binding agent, a coloring agent, a flavor, a tableting aid, and mixtures thereof. Trtese additional ingredients are discussed in more detail, below. Preferably, the additional ingredients mentioned may be present in from about 0.1% to about 30%, by weight of compositions. It is believed that excess amounts of additional ingredients present during preparation of granules may not be distributed uniformly.

Preferably, for tableting embodiments, the additional ingredients are in a solid form to facilitate operating flowability and product stability.

The additional ingredients must be of sufficiently high purity and of sufficiently low toxicity to render them suitable for ingestion. Additional ingredients other than described below that are useful for the tablet forms of the compositions of the present invention further include, for example, diluents such as glucose, mannitol and direct compressible sugar; flavoring agents; sweetening agents; stabilizing agents such as agar, pectin, gums and starches; antioxidants such as ascorbic acid and BHA; cooling agents such as TK-10, WS-3 and WS- 23; preservatives such as potassium sorbate and sodium benzoate, and the like, referred to Upson et. al in U.S. Patent 5,244,670; as well as other non-toxic compatible substances used in pharmaceutical formulation.

1. Granulating fluid The composition of the present invention may include granulating fluid.

Herein, "granulating fluid" means a fluid which is suitable for making granules, wherein the granulating fluid is applied onto a mixture of the antacid active and the carrier, then removed during a drying step to form granules. It is believed that excessive levels of granulating fluids tend to cause hardness of the granules, thereby resulting in an undesirably gritty feeling.

Examples of suitable granulating fluids useful herein include water, a mixture of water and ethyl alcohol, and isopropyl alcohol; more preferably water. The granulating fluid may be present in an amount depending upon the wetting capacity of the mixture of the active ingredient and the carrier, preferably from about 1 % to about 10% by weight of the granules.

2. Binding agent

The composition of the present invention may also include a binding agent. Inclusion of a binding agent is particularly useful when a carrier, such as mannitol, may have a limited ability to bind the components used for the composition. It is believed that insufficiencies in binding ability tend to cause compositions in tablet form, and especially those having a disc type shape\ to break off into two pieces along the diameter during the manufacturing process. This splitting of the tablet is commonly referred to as "capping." The levels and types of binding agent are selected depending upon the character of the carriers, compatibility with other components, and desired characteristic of the final product.

Examples of useful binding agents include sugar, sugar alcohols, starches such as starch paste and pregelatinized starch, polyvinylpyrrolidone, cellulose derivatives, gelatin, gums, and mixtures thereof. Preferred binding agents include sucrose, glucose, and mixtures thereof.

In certain embodiments, the binding agent and the carrier may be made of the same material (e.g., a sugar carrier, and a granulating fluid comprising water and sugar as the binding agent). Alternatively, the binding agent and the carrier may be altogether different. Preferably, the binding agent can be added to the granulating fluid, then mixed with the granules so as to become uniformly distributed in the granules.

The binding agents may be present in an effective amount, preferably from about 0.1 % to about 10% by weight, more preferably from about 0.2% to about 5%, more preferably still from about 0.5% to about 3%. 3. Coloring agent

The composition of the present invention may further include a coloring agent. Preferably, the coloring agent is added with the granulating fluid to facilitate uniform distribution and mixing. The coloring agent is present at an effective level, preferably from about 10ppm to about 500ppm, more preferably from about 20ppm to about 250ppm by weight.

4. Tableting aids

Herein, "tableting aids" refers to an ingredient that is added to the granules in small quantities to provide flowability to the granules, to reduce friction, and/or to ease removal of the tablets from the tableting machine. The tableting aids useful herein include, for example, magnesium stearate, stearic acid, aerosol, talc, and mixtures thereof. The tableting aid of the composition of the present invention, especially those in the form of a tablet, is preferably present in an amount sufficient to prevent the tablet from breaking into two pieces, preferably from about 2% to about 8%, by weight of the tablet. D. Granulation

Preferably, the composition of the present invention can be provided as granules comprising an antacid active and a carrier. The antacid actives include granules having a bulk density of from about 0.29 gram/cc to about 1.5 gram/cc. Such granules comprising the antacid actives having the bulk density specified provide excellent benefits such as softness in the mouth. Herein, "softness" refers to a mouthfeel property that tends to correlate to the resistance of a material to deformation by an indentor of specific size and shape under a known load; the lower the resistance, the "softer" the material. Herein, "good mouthfeel" is characterized by softness and a non-chalky, non-gritty texture. Without being bound by theory, it is believed that a property of granules, which are soft, play an important role in good mouthfeel of the compositions, including those in the form of a tablet made by the granules mentioned above. The compositions produced by granules which have a softness property have a pleasant, non-gritty mouthfeel. It is also believed that the granules, which are soft, may provide tablets having a good dissolution and/or disintegration property when contacted with water or saliva.

In addition, such granules comprising the antacid actives having the bulk density specified herein also can provide higher loose bulk density to tapped bulk density, thereby providing improved processability. Herein, "higher loose bulk density to tapped bulk density" means "loose bulk density (LBD)" divided by "tapped bulk density (TBD)." Herein, "TBD" means the density of the granules obtained after 100 times tapping the measuring cylinder or tapping until no further reduction in volume is noted. Herein, "LBD" means the density of the granules in the same measuring cylinder, prior to tapping. TBD is indicative of the amount of void space between the granules when compared with LBD. The LBD to TBD ratio is a measurement for indicating flowability of granules when compressed into tablets. Higher LBD to TBD values provide improved flowability for compression, thereby facilitating processability for making tablets. Consequently, higher LBD to TBD overcomes the need for pre-compression of granules for making tablets and overcomes caking problems during bulk handling of granules.

Preferably, for preparation of granules which are soft, the antacid actives can be selected based on the carrier, for example, sugar, sugar alcohols, or their combination. More preferably, the antacid active and its bulk density can be selected on the basis of the properties of the carrier. Preferably, when the antacid actives have a bulk density of from about 0.29 gram/cc to about 0.7 gram/cc, the suitable carrier may be sugar. For the antacid actives having a bulk density of from about 0.7 gram/cc to about 1.5 gram/cc, the use of sugar alcohols in conventional granulating methods may be required.

In a preferred embodiment, the granules are compressed into tablet.

E. Method for making tablets

The compositions of the present invention can be produced by any method useful for forming antacid compositions known in the art. These conventional methods include granulating methods: either wet or dry granulating method, preferably wet granulating. Depending on the properties of the ingredients (e.g., active ingredients, carriers, flavors, coloring agents, and the like) to be formulated into granules, one method may provide a more favorable end product over the other method. The wet granulation method is widely used and usually produces the most satisfactory results in tablets. See E.J. de Jong; "The preparation of microgranulates, an improved tableting technique," Pharmaceutical Weekblad, 104(23), pages 469-474, 1969 and E.J. de Jong, U.S. Patent 3,266,992. The tablet forms of the compositions of the present invention also can be made by any method which is conventionally used for tableting. Preferably, the tableting method includes preparation of granules by the wet granulating method as described above. Direct compression may also be chosen for the present composition, as long as producing non-gritty tablets does not cause capping. See, for example, Blaaze, T. Palermo, et al., U.S. Patent 3,384,546.

EXAMPLES

The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

The components shown below can be prepared by any conventional method known in the art. Suitable methods and formulations are as follows: Examples I - V

For Examples I through V, low bulk density calcium carbonate having from ]0.29 to 0.7 gram/cc of bulk density is prepared (KOTCAL H, 0.29-0.35 of BD from Kotak Chemicals Ltd.; CALFORT 3, 0.7 of BD from SA. Reverte'). The calcium carbonate and the sugar are mixed in a planetary mixer bowl (Rama Pharma, India). Water containing a color is sprayed onto the mixture in the planetary mixer bowl during blending. The mixture is blended about 5 minutes at 60rpm. After the mixing is completed, the planetary mixer bowl is closed. The planetary mixer bowl is then heated to a temperature of at least about 80°C for about 20 minutes to agglomerate the mixture. The resulting agglomerates are dried at about 60°C in a tray drier. The dried agglomerates are passed through #14 sieves. The resulting granules provide a soft mouth feel with minimal to no grittiness.

The granules are mixed with mannitol and blended for about 4 minutes. Flavor is then added and blended for about 4 more minutes. Magnesium stearate and Talc (in 1:1 ratio) are added, and the ingredients are mixed for another 2 minutes. The mixture is fed into a tableting machine to be compressed into tablets.

__| II Ml IV V

Calcium carbonate*

KOTCAL H 23.36 36.39 - - -

CALFORT 3 - - 61.32 49.80 45.70

Sugar 50.08 50.60 24.18 22.64 41.35

Mannitol 20.00 4.00 2.18 18.01 4.35

Tableting aids^** 2.86 2.81 3.14 3.26 2.93

Flavor 0.19 0.19 0.19 0.19 0.19

Color 0.01 0.01 0.01 0.01 0.01

Water balance to 100

Calcium carbonate;

KOTCAL H; 0.29-0.35 gram/cc of Bulk Density from Kotak Chemicals Ltd.

CALFORT 3; 0.7 gram/cc of Bulk Density from SA. Reverte' * Tableting aids; Magnesium stearate and Talc (in a 1 :1 ratio) Examples VI - IX

For Examples VI through IX, a high bulk density calcium carbonate having from 0.7 to 1.5 gram/cc of bulk density is prepared (BL-50, 1.01 of BD from SA. Reverte'; STURCAL-L, 0.80-0.96 of BD from Rhone-Poulenc). The high density calcium carbonate, mannitol, and sugar are mixed in a planetary mixer bowl (Rama Pharma, India). Water containing a color is sprayed onto the mixture in the planetary mixer bowl during blending. The mixture is blended about 12 minutes at 60rpm. The resulting agglomerates are sieved through #10 sieve and dried at about 60°C in a tray drier. The dried agglomerates are passed through #14 sieves. The resulting granules provide a soft mouth feel with minimal to no grittiness.

The granules are mixed with flavor and blended for about 4 minutes. Magnesium stearate and Talc (in 1 :1 ratio) are added, and the ingredients are mixed for another 2 minutes. The mixture is fed into a tableting machine to be compressed into tablets.

Example X

For Example X, the process is same as that for Examples VI - IX, except that no sugar is added during granulation. VI VII VIM IX X

Calcium carbonate^*

STURCAL-L 22.36 36.39 - - -

BL-50 - - 59.35 45.70 41.77

Sugar 10.08 20.24 4.18 22.49 -

Mannitol 56.00 34.36 26.61 22.49 41.77

Tableting aids^** 2.86 2.81 3.14 2.93 3.26

Flavor 0.19 0.19 0.19 0.19 0.19

Color 0.01 0.01 0.01 0.01 0.01

Water balance to 100

^* Calcium carbonate;

STURCAL-L, 0.80-0.96 gram/cc of Bulk Density from Rhone-Poulenc BL-50; 1.01 gram/cc of Bulk Density from SA. Reverte' High bulk density calcium carbonate having 0.7- 1.5 gram/cc ** Tableting aids; Magnesium stearate and Talc (in a 1 :1 ratio) The embodiments disclosed and represented by the previous examples have many advantages. For example, the chewable antacid composition comprising active ingredients having from about 0.29 gram/cc to about 1.5 gram/cc of bulk density provides a desirable mouthfeel and non-grittiness in the mouth, with a higher dose of an active per tablet than previously available. In addition, the granules comprising the active ingredient having such specific bulk density provide higher LBD to TBD, thereby facilitating production of the antacid composition.

Although the examples and embodiments described herein are illustrative of the invention, those skilled in the art will be able to recognize that variations or modifications in light thereof are fully within the scope of the invention.

Claims

What is claimed is:

1. A composition comprising an antacid active having a bulk density of from about 0.29 gram/cc to about 1.5 gram/cc, and a carrier.

2. The composition of Claim 1 , wherein the composition comprises from about 24% to about 70% of the antacid active and from about 27% to about 73% of the carrier by weight.

3. The composition of Claim 2, wherein the composition further comprises additional ingredients selected from the group consisting of a granulating fluid, a binding agent, a coloring agent, a flavor, a tableting aid, and mixtures thereof.

4. The composition of Claim 3, wherein

(a) the antacid active is selected from the group consisting of a metal hydroxide compound, a metal carbonate compound, a metal oxide compound, a bismuth subsalicylate, and mixtures thereof; and

(b) the carrier is selected from the group consisting of sugar, sugar alcohol, and mixtures thereof.

5. The composition of Claim 4, wherein the composition is in the form of a tablet.

6. A composition comprising:

(a) granules comprising an antacid active having a bulk density of from about 0.29 gram/cc to about 1.5 gram/cc and a carrier; and

(b) a tableting aid.

7. The composition of Claim 6, wherein the granules further comprise additional ingredients selected from the group consisting of a granulating fluid, a binding agent, a coloring agent, and mixtures thereof.

8. The composition of Claim 7, wherein the granules comprise from about 24% to about 70% of the antacid active and from about 27% to about 73% of the carrier by weight of the granules.

9. The composition of Claim 8, wherein

10. The composition of Claim 9, wherein the composition is in the form of a tablet.

11. A method for making an antacid composition, the method comprising:

(a) forming granules comprising from about 24% to about 70 % of an antacid active and from about 27% to about 73% of a carrier, wherein the active ingredient has bulk density of from about 0.29 gram/cc to about 1.5 gram/cc; and

(b) forming the granules into tablets.