EP0491754A1 - Magnesium carbonate and oil tableting aid - Google Patents
Magnesium carbonate and oil tableting aidInfo
- Publication number
- EP0491754A1 EP0491754A1 EP90913312A EP90913312A EP0491754A1 EP 0491754 A1 EP0491754 A1 EP 0491754A1 EP 90913312 A EP90913312 A EP 90913312A EP 90913312 A EP90913312 A EP 90913312A EP 0491754 A1 EP0491754 A1 EP 0491754A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- oil
- particulate
- composition
- tableting aid
- tableting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
Definitions
- the present invention relates to the field of tableting aids and specifically tableting lubricants and disintegrants.
- tablets are not limited to pharmaceuticals and have been applied in areas as diverse as detergents, beverages and sweeteners. Tablets are successful devices for delivering intended ingredients because of their wide consumer acceptance, convenience, ease of use and economy.
- material which is to be tableted is deposited into a cavity, and one or more punch members are then advanced into the cavity and brought into intimate contact with the material to be pressed, whereupon compressive force is applied. The material is thus forced into conformity with the shape of the punches and the cavity. Hundreds, and even thousands, of tablets per minute can be produced in this fashion.
- Various tableting methods well known to those skilled in the art, are comprehensively discussed in Lieberman, Pharmaceutical Dosage Forms: Tablets Volume 1. Second Edition, Revised and Expanded Copyright 1989 by Marcel Dekker, Inc.
- granulation techniques may also be used as a pre-treatment.
- Most powders cannot be compressed directly into tablets because they lack the proper characteristics. These characteristics include a lack of *compressibility and a lack of necessary lubrication. See Lieberman, supra at page 148.
- materials to be delivered are often pretreated either alone or in combination with other fillers to form granules that readily lend themselves to tableting. This process is known as granulation.
- "granulation" is any process of size enlargement whereby small particles are- gathered together into larger, permanent aggregates to yield a free-flowing composition having a consistency similar to that of dry sand.
- tablet formulations typically include other additives such as diluents, flavors, colors disintegrating agents and lubricants, all of which may be added during granulation or thereafter.
- Lubricant refers to a material which can reduce the friction between the tablet, the die walls and the punch faces, which occurs during the compression and ejection of a tablet.
- Lubricants in general, prevent sticking of tablet material to the punch faces and die walls.
- the term “antiadherents” is sometimes used to refer to substances which in some formulations are needed to aid the lubricant and prevent films from forming on the punch faces.
- lubricant- is used generically and includes “antiadherents”. Tablet sticking during formation and/or ejection may pose serious production problems such as reduced efficiency, irregularly formed tablets, and non-uniform distribution of intended agents or intended ingredients to be delivered thereby. These problems are particularly severe with high speed tableting approaches and methods.
- Lubricants may be intrinsic or extrinsic.
- extrinsic lubricants can provide effective lubrication, their use requires complex application equipment and methods which add cost and reduce productivity. Therefore, extrinsic lubricants generally are considered to be undesirable. See Leal, et al. , U.S. Patent No.
- 3,042,531 which describes another form of extrinsic lubrication by disclosing the compression of a lubricant tablet just prior to the tableting of the desired composition.- After compaction of the lubricant tablet, a lubricated residue remains in the punch and cavity walls such that a subsequent tablet is lubricated. This obviously cuts tableting efficiency in half, raises cost and yields unwanted waste; namely the lubricant tablets.
- Intrinsic lubricants are incorporated in the material to be tableted. Magnesium, calcium and zinc stearates and stearic acid have long been regarded as the most efficient intrinsic lubricants in common use. Concentrations of 0.3% to 2.0% are usually effective. Unfortunately, metallic stearates and stearic acid are not water soluble. This fact can seriously hinder tablet disintegration. Additionally, when these materials are used in products which are reconstituted into a solution prior to use, they leave an objectionable "scum" on the surface of the resulting solution.
- a number of water soluble or water dispersible lubricants may be used. Unfortunately what these substances gain in water solubility, they sacrifice in lubrication efficiency.
- Other traditional intrinsic lubricants include hydrogenated and partially hydrogenated vegetable oils, animal fats, polyethyleneglycol, polyoxyethylene monostearate, talc, light mineral oils, sodium benzoate, sodium lauryl sulphate, and the like. See European Patent Application No. 0,275,834, the disclosure of which is incorporated by reference. See also Leal et al., U.S. Patent No. 3,042,531. Lubricants can be particularly important when compounding an effervescent tablet.
- effervescent tablets could not be produced on high speed equipment without a suitable lubricant.
- Effervescent granulations are inherently difficult to lubricate partly because of the nature of the raw materials used and partly because of the requirement for rapid disintegration of the tablet.
- Typical intrinsic lubricants sacrifice either lubrication efficiency or desirable disintegration properties.
- magnesium stearate used in conventional amounts is an effective lubricant, it may actually retard disintegration. This is not a generally insurmountable problem in effervescent formulations because of the disintegrating action of the effervescents. It may, however, slow disintegration sufficiently to reduce the commercial appeal of a tablet so formulated. Furthermore, where larger quantities of lubricant are required by the difficulty of tableting certain ingredients, the long disintegration time caused by the lubricant may become significant.
- Disintegration in the non-effervescent context generally ' refers to the break up of a tablet after administration.
- lubricants and disintegrants generally functionally oppose each other. See Lieberman, supra at pg. 108.
- conventional disintegrants possess binding and or adhesive properties which inhibit the lubrication efficiency of a lubricant.
- Flavors may be adde ⁇ . in an attempt to mask objectionable tastes, or merely to make the taking the medicine more pleasurable.
- Doran et al. U.S. Patent No. 4,352,821 is directed to a flavored compressible tableting agent formed from fructose and a carrier therefore.
- the carrier is preferably an edible substantially water insoluble inorganic salt and may include tri-calcium phosphate, di-calcium phosphate anhydrous, magnesium carbonate and mixtures thereof.
- the continuous process for the production of a comestible tablet comprises continuously contacting different ingredients together at high shear while atomizing a solvent of at least one ingredient into the mix.
- the atomized solvent may include water soluble sweetening agents, water soluble artificial sweetening agents, dipeptide base sweeteners and mixtures thereof.
- One aspect of the present invention provides ' a dry particulate tableting aid comprising a particulate magnesium carbonate having adsorbed thereon at least one oil, the oil being added to the magnesium carbonate in an amount effective to produce a free-flowing, dry, particulate tablet aid.
- the oil is safe for mammalian consumption.
- the ratio of oil to magnesium carbonate by weight is at least about 0.15:1, more desirably between about 0.15:1 and about 0.6:1, and most preferably between about 0.25:1 and about 0.45:1.
- This aspect of the invention incorporates the discovery that magnesium carbonate can adsorb a relatively large amount of oil and still remain a dry, free-flowing particulate material having lubrication and -?-
- the aid is a free-flowing, particulate material, it can be incorporated into particulate tableting compositions, and uniformly distributed throughout the composition by dry blending using conventional equipment and techniques. Further, the preferred aids according to the invention are readily dispersable in water and neither produce an undesirable "scum" nor materially retard tablet disintegration while providing an effective degree of lubrication.
- the dry tableting aid in its preferred forms is exceptionally effective in tableting processes. Thus, minor amounts of the preferred tableting aids according to this aspect of the invention, when incorporated in a tableting composition, will provide effective intrinsic lubrication.
- the minor amount of tableting aid will also facilitate the controlled disintegration of tablet formulated therewith. Furthermore, according to this aspect of the present invention, a relatively large amount of the tableting aid may be incorporated into a tablet to further facilitate the disintegration of the tablet, without adverse effects to either lubrication efficiency, or the normal problems attendant the use of higher weight percents of a lubricant.
- Preferred tableting aids according to this aspect of the invention are sodium and sugar free. Moreover, because the components of the preferred tableting aids of the present invention are readily available in bulk, they can be produced effectively at low cost effective.
- the oil may be a flavored oil.
- the tableting aid thus serves as a flavorant as well, and eliminates the need for a separate flavorant.
- the oil serves both as a part of the lubricant/disintegrant and as a carrier for oil-soluble flavor components.
- a further aspect of the invention provides a composition of matter comprising a particulate tableting aid as aforesaid, including magnesium carbonate and a flavored or non-flavored oil, and an effective amount of at least one intended ingredient.
- the intended ingredient may be a pharmaceutically active ingredient, and may be present in a pharmaceutically effective amount.
- the composition may further include one or more additional adjuvants selected from the group consisting of flavors, diluents, colors, binders, fillers, additional disintegration agents and lubrication and effervescent agents. Compositions incorporating an effervescent agent are particularly preferred.
- Still further aspects of the present invention provide a process of producing a tablet comprising the step of forming a tablet by the application of compressive force to a tableting composition as aforesaid, and tablets made by such process
- FIG. 1 is a graphical representation of the effect of lubrication concentration on disintegration time of directly compressible calcium carbonate.
- FIG. 2 is a graphical representation of the effect of lubricant concentration on hardness of directly compressible calcium carbonate.
- FIG. 3 is a graphical representation of the effect of lubricant concentration on the friability of directly compressible calcium carbonate.
- FIG. 4 is a graphical representation of the effect of lubricant blending time . on the hardness of directly compressible calcium carbonate.
- FIG. 5 is a diagramatic representation of the effect of lubricant blending time on disintegration time of directly compressible calcium carbonate.
- FIG. 6 is a graphical representation of the effect of the tableting aid or TA of the present invention, in combination with magnesium stearate on the disintegration time of directly compressible calcium carbonate.
- FIG. 7 is a diagramatic representation of the effect of lubricant blending time on the disintegration time of AVICEL tablets.
- FIG. 8 is a graphical representation of the effect of the tableting aid, also referred to as TA, on the disintegration time of AVICEL tablets containing 1.0 percent magnesium stearate.
- the particulate tableting aid includes magnesium carbonate and an oil.
- the magnesium carbonate may be commonly available in bulk particulate form from a number of manufacturers. Where the tableting aid_is to be employed in a comestible or pharmaceutical tablet, food or pharmaceutical grade magnesium carbonate should, be employed.
- the specific parameters of comestible magnesium carbonate may be obtained by reference to the United States Pharmacopoeia, the pertinent portions of which are hereby incorporated by reference. So-called “heavy" magnesium carbonate is particularly preferred. However, light grade magnesium carbonate may also be used.
- the particulate magnesium carbonate may have a particle size such that at least 90 percent of the particulate will pass through a 325 mesh screen.
- heavy magnesium carbonate is used having a particle size such that between about 97 to about 99 percent of the particulate will pass through a 325 mesh screen.
- heavy magnesium carbonate has a loose bulk density of between about 10 and about 14 lbs./cu.ft.
- Light magnesium carbonate which is also useful in the practice of the present invention will generally have a size such that about 99 percent of the particulate will pass through a 325 mesh screen.
- the loose bulk density of light magnesium carbonate is generally between about 5 and 8 lbs./cu.ft.
- the terms by particulate, particle, etc. it is understood that any particle, grain, granule or powder is contemplated.
- oil refers to a liquid having lubricating properties.
- the oil is an organic liquid.
- the most common organic oils include mineral oils, which consist essentially of paraffins and/or hydrocarbons, and vegetable and animal oils, which consist essentially of triglycerides.
- mineral oils which consist essentially of paraffins and/or hydrocarbons
- vegetable and animal oils which consist essentially of triglycerides.
- any oil may be utilized in a tableting aid according to the present invention. Where the tableting aid is to be used in making a pharmaceutical or comestible tablet, the oil is desirably safe for mammalian consumption.
- the oil may be either flavored or non- flavored. Although many oils have some weak, incidental flavor or aroma, the term "flavored" and “non-flavored” are used with reference to oil in the ordinary sense of those terms.
- a "flavored oil” is one which has a strong, readily perceptible taste or aroma and which is capable of imparting such taste and/or aroma to other ingredients when a minor proportion of the oil is mixed with such other ingredients.
- the preferred non-flavored oils for use in tableting aids according to this embodiment of the invention include mineral oils of the type known in the trade as white mineral oil, soy bean oil and other vegetable oils.
- the flavored oils which may be utilized according to the present invention generally include volatile flavor and/or aroma ingredients in an oily base or carrier.
- the oily base or carrier may be derived from the same or different source as the flavor and/or aroma ingredients.
- citrus oils such as lemon oil, orange oil and the like generally include natural volatile ingredients of the citrus fruit together with an oily carrier likewise derived from the citrus fruit.
- Other flavored oils which may be utilized according to the present invention include mixtures of natural or artificial flavoring and aroma imparting ingredients in a mineral or vegetable oil base.
- the term "fold" may be employed to describe the strength of the flavorants or aromas in a flavored oil, and particularly in naturally derived flavored oil.
- description of a flavored oil as "N-fold” should be understood as meaning that the oil contains N times as much of the most significant flavor or aroma ingredients per unit volume compared to the naturally occurring flavored oil.
- higher fold oils "are more concentrated and hence are more flavorful and aromatic.
- the flavored oils are selected from the group consisting of citrus extracts, fruit extracts (non-citrus) , and plant extracts, and mixtures thereof.
- the preferred mineral oils, for use in the present invention have a viscosity of between about 10 and about 100 and more preferably about 30 to about 75 centist ⁇ kes of 40° C.
- the preferred mineral oils for use in the present invention have a specific gravity typically between about 0.84 and about 0.88. In a particular preferred embodiment of the present invention, a specific gravity of about 0.87.
- Typical triglyceride-based * oils have specific gravity of between about 0.90 and 0.92.
- the ratio of oil to magnesium carbonate should be as high as possible consistent with maintenance of a dry, free-flowing powdery consistency in the tableting aid.
- the ratio of oil to magnesium carbonate on a volume to weight basis desirably is at least about 0.2 to about 0.6, preferably about 0.3 to about 0.5 and most preferably about 0.4.
- the ratio of oil to magnesium carbonate by weight may be at least about 0.15, more desirably about 0.15 to about 0.6, more preferably about 0.25 to about 0.45, and most preferably about 0.36.
- any oil soluble material may be carried by the oil and delivered as part of the tableting aid of the present invention.
- the magnesium carbonate may be mixed with the oil using substantially any suitable mixer. Closed mixing vessels are preferred to avoid inadvertent loss of magnesium carbonate during the mixing process.
- the mixing procedure can be performed in closed mixers of the type commonly employed for vacuum granulation processes in the pharmaceutical industry, although no vacuum is normally applied during the mixing procedure.
- Certain vacuum granulating mixers have an enclosed mixing vessel with a propeller rotatably mounted at the bottom of the vessel for stirring the contents, and a further, small propeller commonly referred to as a "chop" mounted on a small shaft adjacent the periphery of the vessel.
- the small shaft is provided with means for rotating it and also for sliding the shaft so as to move the chop up and down within the vessel, towards and away from the propeller.
- This form of mixer also has a spraying nozzle and a spray ingredient tank connected to that nozzle so that liquid ingredients can be introduced into the interior of the vessel while stirring proceeds.
- about 50 to about 90 percent and desirably about 60 to about 80 percent of the magnesium carbonate used in making the tableting aid is loaded into the vessel first, and the oil is added by discharging it from the spraying tank into the vessel while the propeller and chopper are operated to stir the vessel contents. After all of the oil has been added, the propeller and chopper are stopped, and the remainder of the magnesium carbonate is added and stirring is resumed using the propeller and chopper. It is not essential that the oil be introduced into the vessel as a spray.
- a further aspect of the present invention provides a composition of matter which is formed by blending the particulate tableting aid * previously described with at least one intended ingredient.
- the term "intended ingredient(s)" should be understood as referring to an ingredient or ingredients which is capable of performing a function when a tablet containing the ingredient is used.
- the intended ingredients used in the present composition may include essentially any ingredients that can be provided as a tablet.
- the intended ingredients may include specific flavors, nutrients and the like. It may also include soaps, detergents, surfactants, foaming agents, anti foaming agents, absorption agents, dyes and the like.
- pharmaceutical or pharmaceutically active ingredients the inventors do not wish to be bound to a definition which excludes delivery of medication to animals. Furthermore, for the purposes of this invention, the.
- pharmaceutically active ingredient is understood to include vitamins and minerals as well as other ingredients commonly regarded as nutritional supplements and combinations thereof.
- Other pharmaceutically active ingredients may include antacids, analgesics, anti-inflammatories, antibiotics, vitamins, minerals, laxatives, anorexics, antiasthmatics, antidiarrhetics, antiflatuents. antimigraine agents, antispasmodics, sedatives, antihyperactives, tranquilizers, antihistomines, decongestants, beta-blockers, antialcoholism agents, cough suppressants, fluoride supplements, antiseptics and combinations thereof.
- the amounts of the intended ingredient or ingredients in the composition is selected according to conventional criteria associated with the individual ingredients.
- An effective amount of each intended ingredient is specifically contemplated.
- the term "effective amount", as used with reference to an intended ingredient, should be understood as referring to an amount of the intended ingredient sufficient that a tablet containing a . reasonable amount of the composition will contain enough of the intended ingredient to perform the normal function of that ingredient.
- a pharmaceutically effective amount is contemplated.
- a pharmaceutically effective amount is the amount or quantity of a drug, mineral or substance which is sufficient to elicit the required or desired therapeutic response.
- composition may also include one or more additional adjuvants which can be chosen from those known in the art including flavors, diluents, colors, binders, fillers, lubricants, disintegrants and effervescent agents.
- additional adjuvants which can be chosen from those known in the art including flavors, diluents, colors, binders, fillers, lubricants, disintegrants and effervescent agents.
- the composition includes an effervescent agent.
- binders which may prove useful according to the present invention are acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sucrose, polyvinylpyrrolidone, microcrystalline cellulose, sorbitol, and the like. Binders may be used in an amount of about 5 to about 25 weight percent of the total composition.
- Coloring agents may include titanium dioxide, dyes suitable for food such as those known as F.D.& C. dyes, etc.
- Flavors incorporated in the composition apart from the tableting aid may be chosen from synthetic flavor oils and flavoring aromatics and/or oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof. These may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil. Also useful as flavors are vanilla, citrus oil including lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. The amount of flavoring may depend on a number of factors, including the strength of the taste desired.
- the particulate tableting aid of the present invention includes a flavored oil
- less additional flavorant need be incorporated in the composition apart from the aid.
- the flavorant in the tableting aid constitutes essentially all, or at least the major portion of, the flavorant in the entire composition.
- incorporation of the flavorant in the tableting aid evades the need to add other flavorants. This is particularly advantageous as it is often difficult to dispense a conventional flavorant uniformly throughout a tableting composition.
- Effervescent agents may include any combination of ingredients which will yield a gas when the tablet is employed.
- the most common effervescent agents such as alkali bicarbonates or carbonates and food acids such as citric acid yield carbon dioxide upon contact with water.
- the magnesium carbonate in the lubricant when combined with a suitable reactive acid may enhance the effervescent qualities of the effervescent composition produced thereby.
- Effervescent materials typically are present in amounts of up to 95 weight percent but preferably are present in an amount of from about 60 to 90 percent by weight of the final composition.
- the resulting material is a dry, free-flowing particulate material.
- dry means material having no distinct, flowable liquid phase, thus, it is believed that there may be a microscopic coating of liquid oil overlying all surfaces of the magnesium carbonate particles. Any such microscopic liquid phase does not behave as liquid in that it is tightly adsorbed on the surfaces and does not exhibit any perceptible flow under ordinary conditions.
- free-flowing refers to a particulate material which is substantially free of large lumps or aggregates and which can be poured.
- free-flowing particulate materials exhibit an angle of repose less than about 50 degrees, so that when the particulate material is placed in a pile the surface of the pile will lie at an angle of less than about 50 degrees to the horizontal.
- the tableting aids of the present invention may be advantageously used as a tableting lubricant and/or as a tableting disintegration agent. That is to say, the tableting aid of the present invention may serve either as lubricant or as disintegration agent, or as both simultaneously.
- the number of factors controlling the release rate of the intended ingredient is reduced by using the tableting aid according to the invention instead of conventional lubricants and disintegrants, it is easier to control and "tailor" the release rate thereof.
- the magnesium carbonate and oil aid discussed above may be present in the composition in relatively small amounts, typically about 1.5 percent by weight or less, and preferably about 1 percent by weight or less, particularly when used solely as an intrinsic lubricant. Most preferably, the tablet aid constitutes about 0.5 to about 0.8 percent by weight of the tableting composition.
- the tableting aid of the present invention may be present in significantly higher amounts, up to about 20 weight percent based on the weight of the total composition. However, in a preferred embodiment according to the present invention, between about 0.5 to about 10 percent by weight of the total composition may comprise the tableting aid of the present invention. In a more preferred embodiment, the tableting aid of the present invention may be present in an amount of between about 1.0 and about 5.0 percent by weight.
- the tableting aid is a dry free- flowing particulate material, it can be blended with other particulate constituents by ordinary dry blending techniques, as by tumbling in a twin-shell blender.
- the dry free-flowing particulate tableting aid can be readily distributed with good uniformity throughout the tableting composition.
- the tableting composition may be subjected to granulated processes wherein the tableting composition is admixed with a minor proportion of liquids and the liquid is subsequently removed, leaving behind agglomerated granules.
- the so granulated composition can be subjected to conventional screening techniques to provide the desired particle size distribution according to conventional criteria.
- the tableting composition, with or without such an intermediate granulation step may then be formed into tablet by compression using conventional tableting equipment.
- the tableting equipment is arranged to fill a tubular die with the tableting composition and to advance a pair of closely fitting punches into the die to thereby compress the composition and form the tablet, where upon the finished tablet is ejected from the punch and die assembly.
- Tableting aids according to the present invention provide excellent intrinsic lubrication.
- the tableting operation ordinarily proceeds without problems caused by friction between the tableting composition and the punches and/dies, and without difficulties posed by adhesion of the tableting composition to the punches and/or dies.
- the tableting lubricant does not appreciably impede formation of a strong, coherent tablet upon compaction in the punch and die assembly. This is marked contrast to the action of many other common lubricants, such as stearates.
- Tableting compositions incorporating stearate intrinsic lubricants commonly exhibit sensitivity to "over mixing". Thus, such compositions have an optimum degree of mixing. If this optimum degree of mixing is exceeded during formulation of the composition, so as to intimately distribute the stearate throughout the composition, the resulting tablets generally are soft and weak.
- the tableting aid according to the present invention when used as a tableting lubricant, ordinarily does not materially retard disintegration of the finished tablet.
- the tableting aid of the present invention actually facilitates disintegration even when used in amounts more common to lubricants.
- a tablet incorporating lubricants according to the preferred embodiments of the present invention in the amounts required to provide effective lubricating action, ordinarily will disintegrate in substantially the same time or less time than a tablet which does not incorporate an intrinsic lubricant.
- the stearate lubricants when present in amounts effective to provide substantial intrinsic lubrication commonly retard disintegration of the finished tablet, particularly if the tableting composition has been mixed to more than the optimum degree.
- the present tableting ' aid when utilized in the amount required for effective lubrication and or disintegration, is readily dispersible in water when the tablet is dissolved in water.
- the aid disperses without a visible trace and without formation of an objectionable film or "scum". This is of particular importance in the case of effervescent tablets intended to be dissolved in water. The reasons for this good dispersion performance are not fully understood.
- the oil incorporated in the aid ordinarily is insoluble in water.
- the present tableting aids provide effective lubricating actions at extremely low concentrations in the tableting composition, there is ordinarily not enough oil present to result in a visible film or scum.
- the present invention is not limited by any theory of operation, it is believed that the oil when adsorbed on the magnesium carbonate, is held in the form of a microscopic film rather than in the form of globules or droplets. This effect may also aid in dispersion of the oil upon disintegration of the tablet.
- the tableting aid of the present invention is intended to be used as either a disintegrant alone, or as both a lubricant and a disintegrant, it should be present in an amount sufficient to provide for effective disintegration of a tablet into which it is incorporated. Thus, if it is desired that the tablet completely disintegrate in less than ten minutes, an amount of disintegrant effective to provide for a disintegration time of less than ten minutes is contemplated.
- the lubricating aspects of the tableting aid of the present invention do not present any added disintegration problems.
- the amount of the tableting aid of the present invention which is effective to provide desirable disintegration properties is invariably an amount sufficient to provide effective intrinsic lubrication. It is understood, of course, that the tableting aid of the present invention may be combined with other conventional lubricants or disintegrants as desired. These may include, as lubricants, those compositions previously discussed herein.
- Disintegrants include starches as corn starch, potato starch and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, gums such as agar, guar, locust bean, karaya, pectin and tragacanth. Also included are the so-called superdisintegrants including modified carboxymethyl cellulose, cross-linked polyvinylpyrrolidine and soy polysaccharides.
- the total amount of the combination of tableting aid and lubricant or disintegrant used should not exceed the ranges provided hereby.
- a low sodium effervescent analgesic composition was prepared which included the dry, free- flowing, particulate tableting lubricant prepared in Example II above.
- Base #0 * 8029-LSI consists of a granulation of: magnesium carbonate, potassium bicarbonate, calcium carbonate, sodium bicarbonate, citric acid which is not self lubricating.
- **Base #07149-NSI is a granulation consisting of: magnesium carbonate, potassium bicarbonate, calcium carbonate, citric acid to form an effervescent system which is not self lubricating.
- compositions of EXAMPLE VI were formed into tablets by compression using conventional high speed rotary tableting equipment. Specifically, the tableting equipment is arranged to fill a tubular die with the tableting compositions of EXAMPLE VI. A pair of closely fitting punches are advanced into the die to thereby compress the compositions and form tablets thereby. The tablet is ejected from the punch and die assembly.
- the composition of TI tableted well and lubricated well When deposited into a glass of water at room temperature, foam was generated. After one minute, the tablet floated to the surface and after two minutes, the tablet had completely dissolved. The taste was very good. There was no precipitate.
- composition of T2 tableted well and lubricated well When deposited into a glass of water at room temperature, foam results. The tablet remained at the bottom of the glass and completely dissolved within about 90 seconds. The taste was excellent. In fact, the taste was better than the tablets formed from the composition, TI.
- EXAMPLE VIII A vitamin composition was prepared which included the dry, free-flowing, particulate tableting lubricant of the present invention. m ⁇ /tab 2000 tabs( ) *Base #06209-1 3084.4 6169.0 Ascorbic Acid 575.0 1150.0
- Base #06209-1 is a granulation consisting of:
- Vitamin E 50% CWS 880.0 1760.0 Aspartame 30.0 60.0
- the Aspartame was screened through a 10 mesh screen and, along with the lubricant, were mixed with the original mixture for 5 min. without vacuum and at a prop rate of 20 rpm.
- the mixture was then discharged from the processor into a large bag.
- the Beta-Carotene and Orange flavor were added to the bag and all of the ingredients were thoroughly mixed.
- EXAMPLE X The following is a comparative example of the relative ability to lubricate of a magnesium composition prepared in the manner according to the present invention. Specifically, the following tableting aids, not in accordance with the invention, were prepared: Magnesium oxide (heavy)/mineral oil (MGOMO-2) ; Magnesium oxide (light)/mineral oil (MGOMO-1) ; Magnesium oxide (light)/orange oil (MGOOL-1) .
- Tablet Weight 3140.0 mg The tablets produced had irregular edges and were generally poorly formed indicating insufficient lubrication ability.
- FIG. 1 the effect of lubricant concentration on the disintegration time of directly compressible calcium carbonate was determined and is graphically represented. Tablets having a weight of 1.40 grams were produced by blending various concentrations of magnesium stearate, the tableting aid of the present invention or LUBRITAB brand tableting lubricant for 5 minutes with directly compressible calcium carbonate. LUBRITAB is hydrogenated vegetable oil available in solid form from Edward Mendell Co., Inc. Six tablets including each of the three lubricants/aids were tested and the averages taken and disintegration was measured in 0.1 N HCL at .37 degrees C. As FIG.
- Example XI the effect of lubricant concentration on the hardness of directly compressible calcium carbonate was determined and is graphically represented.
- 20 tablets of each of the three additives described in Example XI were used to determine the average for each data point and tablets were prepared as in Example XI.
- Tablets containing LUBRITAB demonstrated superior hardness as the percent of lubricant in the tablets increased from 0.5 to 1.5 weight percent.
- the tablets containing the tableting aid of the present invention also showed acceptable hardness.
- Magnesium stearate possessed the lowest overall hardness and showed a maximum hardness at a concentration of 1 percent. As concentration increased beyond 1 percent hardness of tablets produced thereby decreased.
- EXAMPLE XIII EXAMPLE XIII
- Friability is a measure of a tablet's ability to withstand the physical trauma encountered in handling, such as during counting, packaging, or shipping. Friability is measured by placing 10 tablets into a friabilator after having first determined the weight of the tablets. The tablets are then rotated in the friabilator for 100 rotations and the final tablet weight is determined. The tablet's hardness and structural integrity are related to the amount of weight loss with a lower weight loss equating to a harder tablet. Friability equals the difference between the initial weight of the tablet and the final weight, divided by the initial weight with the remainder multiplied by 100. Thus the higher the weight loss, the higher the percentage friability. Tablets were prepared as in Example XII.
- Tablets containing LUBRITAB exhibit a decrease in the percent friability as the concentration of lubricant increases. Thus at higher concentrations, LUBRITAB may produce tablets of superior hardness.
- magnesium stearate At a concentration of 0.5 percent, tablets containing magnesium stearate have a percent friability approximately equal to tablets prepared with the tableting aid of the present invention. However, as the concentration of magnesium stearate increases, the percent friability of the tablets produced dramatically increase. Tablets including the tableting aid of the present invention, also referred to as TA, show a more consistent substantially constant percent friability as the concentration of lubricant increases.
- the tableting aid of the present invention provides acceptable friability throughout the entire range of concentrations tested.
- Example XII the hardness of tablets containing LUBRITAB was highest over the complete range of blend times from 5 to 15 minutes.
- Blend time is understood to mean the amount of time that a lubricant is blended with an intended ingredient and/or other ingredients prior to tableting.
- the tablets containing the tableting aid of the present invention possessed a more linear progression over blend time but at a lower degree of hardness throughout the entire blend time range tested.
- Magnesium stearate exhibited the lowest level of hardness overall and the hardness of tablets dropped dramatically as blend time exceeded 10 minutes.
- disintegration time of the tablet produced is 3 times that of the tablet using the tableting aid of the present invention.
- blend time is extended to 15 minutes disintegration time of a tablet produced with LUBRITAB is between about 20 and 25 minutes. All the tablets including magnesium stearate disintegrated in excess of 60 minutes.
- ⁇ Magnesium carbonate tableting aid formed in accordance with Example II.
- the average disintegration time of 3 tablets of formulation TI blended for 5 minutes was 7.0 minutes.
- the average disintegration time of 3 tablets of formulation TI blended for 20 minutes was 35.5 minutes.
- the average disintegration time of 3 tablets of formulation T2 blended for 5 minutes was 4.5 minutes.
- the average disintegration time of 3 tablets of formulation T2 blended for 20 minutes was 5.1 minutes.
- magnesium stearate is very sensitive to blend time and disintegration time increases with blend time.
- the tableting aid of the present invention retains a substantially constant disintegration time throughout the entire range of tested blend times.
- AVICEL is a popular tableting binder which when used, generally requires the use of disintegrant and a lubricant.
- the need to include both additives is eliminated.
- the reduction in the number of ingredients can allow for a reduction in the. weight and size of a tablet. This may be particularly important when preparing tablets for those who are uncomfortable about ingesting large tablets.
- the effect of TA, the tableting aid of the present invention, on the disintegration of AVICEL tablets containing 1.0 percent magnesium stearate was measured and is graphically represented.
- Tablets of AVICEL were prepared by blending 500 mg of AVICEL with 5 mg of each of magnesium stearate and TA. Mixing was at a low speed for 20 minutes. Tablets disintegrated in an average of 5.8 minutes. When compared to the average disintegration time of AVICEL tablets containing only magnesium stearate as prepared and tested in Example XVII, tablets containing both additives disintegrated on an average of six times faster.
- the tableting aid of the present invention provides acceptable and often superior hardness, superior lubrication properties and vastly superior disintegration properties without being sensitive to concentration, blend time, and the like.
- the tableting aid of the present invention provides an extremely versatile and useful product which maximizes the advantageous properties which are desirable while minimizing foreseeable disadvantages.
- a powder composition may be compressed, typically within a small tube or bore commonly referred as a filling chamber or cavity, to form a slug.
- the slug may be inserted in a capsule shell, as by ejecting the slug from the filling chamber or cavity into the capsule shell.
- tablette and “tableting” as used in this disclosure should be understood as including such a slug and formation of such a slug.
- INDUSTRIAL APPLICABILITY The present invention is applicable to the preparation of tablets of pharmaceutical compositions.
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Abstract
Un matériau facilitant la fabrication des comprimés comprend de la magnésie carbonatée à teneur en huile adsorbée, et assure des caractéristiques de lubrification et de désintégration utiles.A material for facilitating the manufacture of the tablets includes carbonated magnesia with an adsorbed oil content, and provides useful lubrication and disintegration characteristics.
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40786589A | 1989-09-15 | 1989-09-15 | |
US407865 | 1989-09-15 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0491754A1 true EP0491754A1 (en) | 1992-07-01 |
EP0491754A4 EP0491754A4 (en) | 1992-08-12 |
Family
ID=23613857
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19900913312 Withdrawn EP0491754A4 (en) | 1989-09-15 | 1990-08-29 | Magnesium carbonate and oil tableting aid |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0491754A4 (en) |
JP (1) | JP3230814B2 (en) |
AU (1) | AU643703B2 (en) |
WO (1) | WO1991004018A1 (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK66493D0 (en) * | 1993-06-08 | 1993-06-08 | Ferring A S | PREPARATIONS FOR USE IN TREATMENT OF INFLAMMATORY GAS DISORDERS OR TO IMPROVE IMPROVED HEALTH |
US6028190A (en) | 1994-02-01 | 2000-02-22 | The Regents Of The University Of California | Probes labeled with energy transfer coupled dyes |
US6166024A (en) | 1995-03-30 | 2000-12-26 | Mayo Foundation For Medical Education And Research | Use of topical azathioprine and thioguanine to treat colorectal adenomas |
EP0893992B1 (en) * | 1996-04-16 | 2004-03-03 | Novartis Consumer Health S.A. | Fast disintegrating oral dosage form |
AT408416B (en) * | 1996-07-19 | 2001-11-26 | Norbert Fuchs | PHARMACEUTICAL OR DIETETIC COMPOSITIONS |
US7198653B2 (en) * | 2003-07-31 | 2007-04-03 | Delavau Llc | Calcium carbonate granulation |
US20080254119A1 (en) * | 2007-04-16 | 2008-10-16 | Wyeth | Imbedded liquid lubricants for tableting |
JP6334482B2 (en) * | 2015-08-28 | 2018-05-30 | 中野Bc株式会社 | Solid agent and production method thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE606519C (en) * | 1932-09-04 | 1934-12-04 | Heyl & Co | Process for the production of products containing viscous liquids in a granular form |
JPS5723691A (en) * | 1980-07-16 | 1982-02-06 | Masaaki Takahashi | Lubricant for processing |
US4409202A (en) * | 1980-04-07 | 1983-10-11 | Nabisco Brands, Inc. | Breath freshener composition and method |
FR2546064A1 (en) * | 1983-05-20 | 1984-11-23 | Fabre Sa Pierre | Magnesium-based effervescent pharmaceutical composition |
DE3500187A1 (en) * | 1984-01-06 | 1985-07-18 | Egyt Gyógyszervegyészeti Gyár, Budapest | STABLE PHARMACEUTICAL PREPARATIONS FOR TREATING KETONAEMIA AND METHOD FOR PRODUCING THE SAME |
EP0296118A2 (en) * | 1987-06-16 | 1988-12-21 | Warner-Lambert Company | Oil compositions of increased viscosity and method of preparing same |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4339428A (en) * | 1980-08-18 | 1982-07-13 | Bristol-Myers Company | Capsule product containing high dosage of aspirin in powder or granulated form and alkaline tablet or pellet comprising magnesium carbonate, calcium carbonate and a magnesium dry component |
US4609543A (en) * | 1983-11-14 | 1986-09-02 | Nabisco Brands, Inc. | Soft homogeneous antacid tablet |
US4818518A (en) * | 1984-11-16 | 1989-04-04 | Uop | Effervescent dentifrice |
US4605551A (en) * | 1984-11-30 | 1986-08-12 | William H. Rorer, Inc. | Dry oil coated antacid process |
GB9018839D0 (en) * | 1990-08-29 | 1990-10-10 | Newton John M | Slow release compositions |
-
1990
- 1990-08-29 WO PCT/US1990/004903 patent/WO1991004018A1/en not_active Application Discontinuation
- 1990-08-29 AU AU63511/90A patent/AU643703B2/en not_active Ceased
- 1990-08-29 EP EP19900913312 patent/EP0491754A4/en not_active Withdrawn
- 1990-08-29 JP JP51255090A patent/JP3230814B2/en not_active Expired - Fee Related
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE606519C (en) * | 1932-09-04 | 1934-12-04 | Heyl & Co | Process for the production of products containing viscous liquids in a granular form |
US4409202A (en) * | 1980-04-07 | 1983-10-11 | Nabisco Brands, Inc. | Breath freshener composition and method |
JPS5723691A (en) * | 1980-07-16 | 1982-02-06 | Masaaki Takahashi | Lubricant for processing |
FR2546064A1 (en) * | 1983-05-20 | 1984-11-23 | Fabre Sa Pierre | Magnesium-based effervescent pharmaceutical composition |
DE3500187A1 (en) * | 1984-01-06 | 1985-07-18 | Egyt Gyógyszervegyészeti Gyár, Budapest | STABLE PHARMACEUTICAL PREPARATIONS FOR TREATING KETONAEMIA AND METHOD FOR PRODUCING THE SAME |
EP0296118A2 (en) * | 1987-06-16 | 1988-12-21 | Warner-Lambert Company | Oil compositions of increased viscosity and method of preparing same |
Non-Patent Citations (3)
Title |
---|
BOYLAN J.C. ET AL 'Handbook of Pharmaceutical excipients' 1986 , AMERICAN PHARMACEUTICAL ASSOCIATION , WASHINGTON * |
PATENT ABSTRACTS OF JAPAN vol. 6, no. 94 2 June 1982 & JP-A-57 023 691 ( TAKAHASHI MASAAKI ) 6 February 1982 * |
See also references of WO9104018A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU643703B2 (en) | 1993-11-25 |
JPH05500059A (en) | 1993-01-14 |
AU6351190A (en) | 1991-04-18 |
JP3230814B2 (en) | 2001-11-19 |
EP0491754A4 (en) | 1992-08-12 |
WO1991004018A1 (en) | 1991-04-04 |
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