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
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
• • 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
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

• This invention relates to direct compression vehicles. More particularly, this invention relates to a particulate composition which can be admixed with an active and optionally, a lubricant, and the resulting mixture directly compressed into a tablet without the necessity of granulation or slugging of the mixture.
• The-compression technique may be further subdivided into three major categories, viz direct compression, wet granulation and dry granulation.
• the direct compression technique is the most desirable, in that it employs the fewest steps and, in the case of the production of tablets containing sensitive or unstable actives, such as certain pharmaceuticals, minimizes the exposure to water or other conditions tending to adversely affect stability of the active. Unfortunately, however, it has been found that the direct compression technique is of limited applicability.
• the active must be admixed with a direct compression vehicle, i.e., an inert composition which is compatible with the active and has good compressibility.
• the direct compression vehicle should have good flowability, good stability under normal ambient conditions, no adverse effect on tablet disintegration time, the ability to produce good table surfaces, and low cost.
• the direct compression vehicles of the present invention comprise minute particles of a dispersion of certain watersoluble or dispersible inert diluents in a matrix ofa hydratable high polymer.
• the diluent can be any normally solid material, i.e., any material which is solid under conditions of normal atmospheric pressures and temperatures, provided it is inert, edible and permissable in the table formed from the direct compression vehicle.
• it can be water-soluble or insoluble in water. If insoluble, however, it must be capable of reduction to a size which is useful in the direct compression vehicle of this invention, i.e., a size below about 200 mesh, and preferably below about microns.
• Preferred diluents include normally saccharine materials, i.e., a mono or disaccharide such as glucose, mannose, galac tose, fructose, arabinose, xylose, sucrose, maltose and lactose; as well as certain polyols of the formula HOCHACI-IOHMCH OH wherein .x is 1-4, such as glycerol, erythritol, arabitol, xylitol, adonitol, mannitol, dulcitol and sorbitol.
• certain salts may be employed, including sodium chloride, sodium citrate, calcium carbonate, calcium sulfate and tricalcium phosphate.
• the diluent may be one or a mixture of two or more of the aforesaid substances.
• the diluent may be of synthetic or natural origin, and may be supplied to the mixing step in the form ofa solution or syrup, such as molasses, affination syrup, invert syrup and the like.
• the hydrated polymer includes hydrophilic polysaccharides, hydrocolloids or proteinaceous materials which, although not soluble in water, are hydrated upon admixture with water, and when substantially fully hydrated form a clear aqueous sol of swollen polymer and water.
• hydrophilic polysaccharides hydrocolloids or proteinaceous materials which, although not soluble in water, are hydrated upon admixture with water, and when substantially fully hydrated form a clear aqueous sol of swollen polymer and water.
• these high polymers include starch, agar, locust bean gum, carrageen, dextrin, cereal flour and the like.
• the polymer, diluent and water are admixed in any convenient manner and in proportions such that there is obtained a substantially clear fluid mixture comprising an aqueous solution or dispersion of diluent dispersed throughout the swollen hydrated polymer.
• a substantially clear fluid mixture comprising an aqueous solution or dispersion of diluent dispersed throughout the swollen hydrated polymer.
• the precise conditions and proportions will vary widely, depending upon the polymer employed, and the amount of and additive employed.
• the amount of water necessary to hydrate the hydrophilic polymer is either known or is readily determined by the simple experiment of adding water in known amount to a known amount of dry polymer until a clear sol is obtained. in general, at least about 8 parts of water are required per part of starch or dextrin, at least about 25 parts of water are required per part of locust bean gum, and at least about 33 of water are required per part of agar and carrageen.
• the foregoing amounts of water provide tablets of optimum strength, but lesser amounts of water, for example as low as 50 percent or more of the above values, can be employed and still obtain a useful tablet.
• the diluent When the diluent is insoluble in water, no additional water is required. When, however, the diluent is water-soluble, enough additional water must be employed to dissolve the additive. For example, if sucrose is added to a clear, fully hydrated starch the resulting mixture becomes more fluid because the sucrose has a greater affinity for water than starch, and thus removes some of the water of hydration. If, however, in addition to the 8 parts water per part starch neces sary for fully hydration, there is added at least 0.5 part water per part sucrose to ensure solution of the sucrose, the starch remains hydrated. Although greater quantities of water can be employed if desired, they are unnecessary and, in fact, are dis advantageous in increasing the heat load for drying and may preclude the use of certain drying techniques, such as drum drying, which require a relatively viscous. liquid.
• the ratio of water-soluble additive to hydratable polymer can vary widely, depending upon the particular materials employed and the characteristics desired in the product direct compression vehicle. In general, however, ratios offrom about 0.25 to about 250 parts of additive per part of polymer, preferably from about 2 to about 50 parts additive per part of polymer, are useful. Ratios of from about 20 to about 30 parts additive per part of polymer are most preferred.
• Drying of the resulting dispersion may be effected by a variety of techniques, such as spray drying, tray drying, drum drying and the like.
• the dispersion is dried by deposition on a heated surface to effect evaporation and convert the dispersion into a dry, hot, plastic film, remov' ing the film from the heated surface and attenuating the film while simultaneously cooling it, to convert the plastic film to a brittle or frangible condition. After the film has been thus cooled, it is fragmented and ground to a desired particle size and the ground product is employed.
• the mixture of hydratable polymer and diluent should, of course, have the property of being plastic when in a hot, dry state.
• a preferred way to practice the method of this invention is through the use of a heated drum dryer and a cooled rotary takeoff reel located a slight distance therefrom with a current of cooling air passing therefrom.
• the dispersion of the aqueous solution of a saccharine material and the high polymer is prepared and introduced into the nip between a pair of steam-heated oppositely rotating drums at a rate to effect rapid evaporation of the water, but without permitting the resultant dehydrated product, which contains not more than 4 percent moisture, and which forms a relatively thick plastic film on the surfaces of the drums, to reach a temperature at which destructive decomposition would begin.
• the temperature of the dehydrated material should not exceed about 350 F. and the operating conditions of the drums should be adjusted accordingly.
• the hot dehydrated film is removed by a doctor blade from its associated drum and transferred to the reel across a current of cooling air, having a 60-80 F. temperature, which effects an initial cooling'of the dehydrated material to near room temperature.
• This cooling effect is enhanced by the thinning or drawing down of the film as a consequence of having the reel operate at the greater peripheral speed.
• the reel is also cooled by 60-80 F. air
• the thin film is further cooled to a room temperature of about 70 F. to about 95 F. and the cooling air at the line of removal of the film from the reel aids both its removal therefrom and a final cooling to a brittle or frangible state.
• the frangible film then drops away from the reel as a brittle sheet or fragments onto a conveyor for transport to a storage bin or to a comminuting device for reduction to the desired particle size for direct tabletting.
• the dried product is broken up into particles having the desired dimensions and, if necessary, screened to achieve the proper size range and distribution.
• the resulting particulate product comprises minute particles of the water-soluble additive dispersed throughout the high-polymer matrix, and is substantially different in appearance and properties from mixtures of the same dry materials which are obtained by dry blending, or even wet granulation techniques.
• the reason for the difference is that none of the heretofore known techniques for preparing tabletting materials or blends employ sufficient water to both hydrate the polymer and dissolve the additive.
• the granular direct compression vehicle of this invention is admixed with the active which it is desired to incorporate into tablet form and, if necessary, a lubricant, and the mixture tabletted by known direct compression procedures.
• the proportions of vehicle, active and lubricant are not critical, and obviously depend upon the active and the unit dose desired in the tablet. In general, however, the direct compressionvehicle will comprise at least percent of the tabletting mixture, and thus the resulting tablet, although amounts within the range of from about 70 percent to about 95 percent are most common.
• active material any material intended for ingestion having a beneficial or desirable effect on the user.
• suitable active materials include therapeutic materials, such as anesthetics, antibiotics, antitussives, vitamins, aspirin, antacids, and the like; foodstuffs such as cocoa, dried oats, fruit flakes and the like; edible dyes and other food additives; and so on.
• the vehicle is a free-flowing granular material and imparts improved flow characteristics to the active material and other components of the blend, thereby assuring ease of tabletting.
• the blend of direct compression vehicle, active material and other additives is mixed and directly compressed to form a tablet employing conventional techniques and apparatus.
• EXAMPLE 1 A mixture of 182 pounds of sucrose, 35 pounds of tapioca flour, 300 pounds of starch and 400 gallons of water was heated to 180 F., and 714 pounds ofa 70 percent invert syrup was added. The resulting mixture was 'drum dried to a moisture content of about 2.13 percent, and then broken up into flakes of about one half an inch. The resulting particulate flake material was admixed with calcium stearate in a ratio of 99 parts to 1 part and after pulverization to yield a product having a particle size of below about 200 mesh percent through 200 mesh), compressed to form l3/32-inch, 0.5-gram tablets at 1,000 and 3,000. The resulting tablets had Stokes hardnesses of 3.25 and 4.1 kilograms, respectively, and evidenced no capping.
• EXAMPLE 2 Employing procedures similar to those described in example l, a flake product containing about 46 parts invert sugar, 25 parts starch, 28 parts sucrose and 1 percent water was produced and admixed with Cab-O-Sil brand silica gel to provide a mixture containing 98 parts flake and 2 parts silica gel. The resulting mixture, after pulverizing, was tabletted at 3,000 and 9,000 p.s.i. The tablets produced at 3,000 p.s.i. were ejected at a pressure of 100 p.s.i., evidenced only slight capping and had a hardness of 19.5. At 9,000 p.s.i. and ejection pressure of 350 p.s.i. no capping was observed and tablet hardness was in excess of 45 kg.
• EXAMPLE 3 Employing procedures similar to those described in example l, a mixture of 350 pounds of starch and 284 pounds sucrose in 450 gallons of water and 571 pounds of 70 percent invert sugar was drum dried to about 2 percent moisture and crushed to form flakes having a size of about one-half an inch. The resulting product, after further pulverizing to below about 200 mesh, was compressed at 3,000 and 9,000 p.s.i. and 35 p.s.i. ejection pressure to form l3/32-inch tablets weighing 0.5 grams. Tablet hardness was 38.5 and greater than 45, respectively, and no capping was observed.
• the flake product was admixed with sucrose and calcium stearate to provide a mixture containing 60 parts flake, 39
• EXAMPLE 4 Employing procedures similar to those described in example l, a flake product containing 22.5 percent invert sugar, 42.4 percent sucrose, 32.1 percent starch and 3 percent moisture was blended to form a mixture of 66.6 parts flake, 32.35 parts sucrose and 1.0 parts calcium stearate. Tablets pressed at 1,000, 3,000 and 9,000 p.s.i. had hardnesses of 6.5, 14.5 and 23.0, respectively.
• EXAMPLE 5 Employing procedures similar to those described in example 1, a mixture of 1 part locust bean gum, 25 parts sugar and 100 parts water was heated to F. and drum dried to less than 1 percent moisture and reduced to /z-inch flakes. The resulting product, after pulverization to a product of less than about 200 mesh, was compressed at 4,500 p.s.i. to form a tablet having a hardness of greater than 42 kg.
• EXAMPLE 6 Employing procedures similar to those described in example l, a mixture of 4 parts of agar, 70 parts sucrose and 200 parts water was boiled and then drum dried and flaked. After pulverizing, the product was compressed at 4,500 p.s.i. to form a tablet having a hardness of greater than 42 kg.
• EXAMPLE 7 Employing procedures similar to those described in example 1, a mixture of 4 parts carrageen, 70 parts sucrose and 200 parts water was drum dried and flaked. The flake product, after pulverizing, was compressed at 4,500 psi. to form a tablet having a hardness of greater than 42 kg.
• said diluent is selected from the group consisting of a monosaccharide, a disaccharide, a polyol of the formula HOCH. (CHOH) ,.CH OH wherein x is 1 to 4, sodium chloride, sodium citrate, calcium carbonate, calcium sulfate or tricalcium phosphate.
• a method according to claim 1 wherein said hydratable polymer is selected from the group consisting of starch, agar, locust bean gum, carrageen, dextrin or cereal flour.
• a method according to claim 1 wherein the ratio of diluent to polymer is from about 0.25 to about 250 parts by weight diluent per part of polymer.
• a dry, granular direct compression vehicle comprising an inert, edible diluent dispersed throughout a matrix of starch prepared by mixing said diluent and starch with water in proportions sufficient to provide a substantially fluid mixture of an aqueous solution or dispersion of diluent dispersed throughout swollen, hydrated starch, and thereafter drying said mixture and forming particles therefrom.
• said diluent is selected from the group consisting of a monosaccharide, a disaccharide, a polyol of the formula HOCH (CHOH),CH OH wherein x is l to 4, sodium chloride, sodium citrate, calcium carbonate, calcium sulfate or tricalcium phosphate.
• a vehicle according to claim 8 wherein said diluent is selected from the group consisting of a monosaccharide or a disaccharide.
• a vehicle according to claim 8 wherein said diluent is selected from the group consisting of sucrose or invert sugar.

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Cited By (22)

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• 1969
  • 1969-04-29 US US820283A patent/US3639168A/en not_active Expired - Lifetime
• 1970
  • 1970-04-27 CA CA081244A patent/CA936098A/en not_active Expired
  • 1970-04-28 NL NL7006196A patent/NL7006196A/xx unknown
  • 1970-04-28 GB GB2039470A patent/GB1317025A/en not_active Expired
  • 1970-04-28 GB GB249373A patent/GB1317026A/en not_active Expired
  • 1970-04-28 DE DE2020620A patent/DE2020620B2/de active Pending
  • 1970-04-28 FR FR7015514A patent/FR2042384B1/fr not_active Expired
  • 1970-04-29 IT IT24038/70A patent/IT968012B/it active

Non-Patent Citations (1)

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