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Publication numberUS3639168 A
Publication typeGrant
Publication dateFeb 1, 1972
Filing dateApr 29, 1969
Priority dateApr 29, 1969
Also published asCA936098A1, DE2020620A1, DE2020620B2
Publication numberUS 3639168 A, US 3639168A, US-A-3639168, US3639168 A, US3639168A
InventorsAnthony Monti, John P Troy, Charles B Broeg
Original AssigneeSucrest Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Direct compression vehicles
US 3639168 A
Abstract
Direct compression vehicle useful for preparation of tablets by the direct compression technique is obtained by dispersing a diluent such as sugar, in a fully hydrated hydratable polymer, such as starch, drying the resulting dispersion, and reducing the dried product to particles of the desired size. The vehicle can be admixed with the active material and, if desired, a lubricant, and the resulting mixture compressed without prior granulation or slugging to form a tablet.
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Description  (OCR text may contain errors)

States Patent Monti et all,

DIECT COMPRESSION VEHICLES Anthony Monti, lrvington; John P. Troy, Hicksville, both of N.Y.; Charles B. Brueg,

Inventors:

Short Hills, NJ.

Assignee: SuCrest Corporation, NY, NY.

Filed: Apr. 29, 1969 Appl. No.: 820,283

[1.5. Ci ..127/29, 8/79, 99/26, 99/134 R, 99/141 A, 127/63, 264/122, 424/154, 424/156, 424/157, 424/158, 424/230, 424/280, 424/358, 424/361, 424/362, 424/363 Int. Cl. ..Cl3f 3/00 Field oi Search ..127/29, 30, 63; 99/134 R References Cited OTHER PUBLICATIONS Little d M tshe ,f a l WW5. $999"? Feb. 1, 1972 tion, 44- 53, The Northern Publishing Co., Ltd. Liverpool, 1963.

Primary Examiner-Morris O. Wolk Assistant Examiner-Sidney Morantz Att0rneyl(enyon & Kenyon Reilly Carr & Chapin [5 7] ABSTRACT 10 Claims, No Drawings DIRECT COMPRESSION VEHICLES 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.

There are two general methods for forming tablets, i.e., compression of a dry particulate material and trituration, or molding of a moist material, of which the first technique is by far the most frequently employed. 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.

First, most active materials possess poor compression pro perties, and thus are unsuitable for this technique. In addition, many actives are required in such small amounts per unit dosage form that direct compression of the active alone is im practical, if not impossible. As a result, 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. In addition, 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.

To date, however, no material has been found which satisfies all of these criteria. For example, of the most popular of such compression vehicles, spray-dried lactose possesses poor stability and discolors on storing, dicalcium phosphate provides tablets having poor strength, and microcrystalline cellulose is expensive.

It is an object of the present invention to provide a new direct compression vehicle.

It is a further object of this invention to provide a multicomponent compression vehicle which may be combined with an active and, if desired, a lubricant, and the resulting dry mixture subjected to direct compression.

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. Thus, 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. In addition, 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. In the event the diluent is a sugar, it 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. Illustrative examples of 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. 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.

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. In a preferred technique, 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. In this technique, 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.

In such a process 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. Thus, the temperature of the dehydrated material should not exceed about 350 F. and the operating conditions of the drums should be adjusted accordingly. At the line of transfer to the reel, which is rotating with a peripheral speed greater than that; of the drum, 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. Since 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.

If only one takeoff reel is used, it will, of course, be necessary to provide a scraper or other means on the opposite drum to prevent passage of the hot dehydrated film therearound and force it over onto the other drum.

Although in the foregoing description of the method mention has been made ofa two-drum dryer with either a single or two takeoff reels, it will be appreciated that a single drum dryer with a single takeoff reel can be used with equal effectiveness.

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. On the other hand, U.S. Pat. No. 2,963,373 to Monti et al. dis closes an icing percursor comprising agar or carrageen and starch and/or sugar which is prepared according to the foregoing technique, and it has been found that the resulting product is an excellent direct compression vehicle in accordance with this invention. Other previously known products which may be employed as directly compressible vehicles are the modified polysaccharide gums of Monti et al. disclosed in U.S. Pat. No. 3,042,668.

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.

By the term active material is meant 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.

The following examples are illustrative. Unless otherwise specified, all parts and percentages are by weight.

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.

In a second run equal parts of the flake and sucrose were mixed and pulverized, and then magnesium stearate was blended in to provide 49 parts each of flake and sucrose and 2 parts magnesium stearate. Tablets compressed at 3,000 p.s.i. and ejected at 60 p.s.i. had a hardness of 20.75 and evidenced no capping, and those compressed at 9,000 p.s.i. and ejected at 95 p.s.i. had a hardness of 37.5 kg. and evidenced no capping.

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

parts sucrose and 1 part stearate, and the resulting mixture tabletted. At 3,000 psi. the ejection pressure was 50 p.s.i. and tablet hardness was 13.5. At 9,000 p.s.i. the ejection pressure was 45 p.s.i. and tablet hardness was 22. No capping was observed at either pressure.

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.

Each of the direct compression vehicles of the foregoing examples can be blended in accordance with the following recipes and compressed to form tablets or wafers.

CONFECTIONERY TABLETS OR WAFERS l. Leinon-flavorcd confectionery tablet:

100.0 pt. direct compression vehicle 10 pt. citric acid, dry 0.25 pt. encapsulated lemon flavor 0.10 pt. yellow color No.5

1.0 pt. magnesium stearate 2. Grape-flavored confectionery tablet:

500 pt. direct compression vehicle 50.0 pt. 6X powdered sugar 20 pt. tartaric acid 0.25 pt. grape flavor 0.05 pt. grape color pt. calcium stearate 3. Cherry-flavored confectionery tablet:

100.0 pt. direct compression vehicle 2.0 pt. fumaric acid 0.2 pt. cherry flavor 0.1 pt. red color pt. magnesium stearate B. PHARMACEUTICAL FORMULATIONS l. 50.0 pt. direct compression vehicle 37.5 pt. aluminum hydroxide l.0 pt. magnesium stearate 2. 100.0 pt. direct compression vehicle 25.0 pt. calcium carbonate 5.0 pt. magnesium carbonate I drop peppermint oil 2.0 pt. magnesium stearute 3. 100.0 pt. direct compression vehicle 25.0 pt. acetyl salicylic acid 150 pt. corn starch 2.0 pt. magnesium stearale 4. 90.0 pt. direct compression vehicle 10.0 pt. vitamin C in dry form 2.0 pt. magnesium stearate Other active ingredients of use in blends with the direct compression vehicle are: sodium bicarbonate, acetanilid, phenacetin, and magnesium trisilicate.

C. SPECIALTY PRODUCTS 1. lnvertase sugar tablet 964 pt, direct compression vehicle 3.6 pt. liquid triple strength invertase (K=0.9)

1.0 pt. magnesium stearate 2. Cocoa-sugar tablet 900 pt, direct compression vehicle 10.0 pl. high fat cocoa 0.2 pt. dcndritic salt 1.0 pt. magnesium stearate After blending, the mixture is tablette-rl to form a cocoa-sugar tablet.

3. Sugar-synthetic sweetener tablet 450.0 pt. direct compression vehicle 7.16 pt. calcium cyclamatc 0.8 pt. sodium saccharin 5.0 pt. calcium stearatc 4. Highly concentrated color tablet 90.0 pt. direct compression vehicle 10.0 pt. dried yellow FD&C No. 6 pt. sodium benzoate 5. Yeast Food Tablet 34.0 pt. calcium sulfate (2H 0) 23.0 pt. flour 9.0 pt. ammonium chloride 025 pt. potassium hromate 1775 pt. sodium dihydrogen phosphate l6.0 pt. salt 900.0 pt. direct compression vehicle 10.0 pt. magnesium stcarate What is claimed is:

1. In a method for producing a tablet by the direct compression of a mixture including an active material and a direct compression vehicle, the improvement of employing a dry granular direct compression vehicle comprising an inert, edible diluent dispersed throughout a matrix of a hydratable polymer prepared by mixing said diluent and said polymer with water in proportions sufficient to provide a substantially fluid mixture of an aqueous solution or dispersion of diluent dispersed throughout swollen, hydrated polymer, and thereafter drying said mixture, and forming particles therefrom.

2. A method according to claim 1 wherein said diluent is selected from the group consisting ofa 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.

3. 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.

4, 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.

5. The tablet produced by the process of claim 1.

6. 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.

7. A vehicle according to claim 6 wherein 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.

8. A vehicle according to claim 6 wherein said diluent is present in an amount of from about 0.25 to about 250 parts per part of starch.

9. A vehicle according to claim 8 wherein said diluent is selected from the group consisting of a monosaccharide or a disaccharide.

10. A vehicle according to claim 8 wherein said diluent is selected from the group consisting of sucrose or invert sugar.

Non-Patent Citations
Reference
1 *A. Little and K. A. Mitchell, Tablet Making, Second Edition, 44 53, The Northern Publishing Co., Ltd. Liverpool, 1963.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3873694 *Sep 27, 1973Mar 25, 1975Cpc International IncDirect compression tabletting composition and pharmaceutical tablets produced therefrom
US3900569 *Sep 15, 1972Aug 19, 1975Sucrest CorpDirect compression vehicle
US3958929 *Feb 8, 1974May 25, 1976Bayer AktiengesellschaftDyestuff preparations
US3961004 *Apr 11, 1974Jun 1, 1976Auburn Research FoundationMethod of tabletting using gluconolactone as the direct compression diluent
US3987204 *Apr 24, 1975Oct 19, 1976Sucrest CorporationTablets, tri-calcium phosphate, locust bean gum
US4007052 *Aug 1, 1975Feb 8, 1977Boehringer Mannheim G.M.B.H.Using a lubricant and a mold parting agent
US4036948 *Sep 3, 1975Jul 19, 1977Takeda Chemical Industries, Ltd.L-ascorbic acid tablets
US4115553 *Jun 24, 1974Sep 19, 1978Armour Pharmaceutical CompanyAntacid tablets
US4495177 *Jan 17, 1983Jan 22, 1985Shaklee CorporationGel tableting agent
US4650669 *Jul 30, 1985Mar 17, 1987Miles Laboratories, Inc.Storage stability
US4677130 *Oct 7, 1985Jun 30, 1987Great Lakes Chemical CorporationProcess of densification of N-halohydantoin compositions and products thereof
US4684534 *Feb 19, 1985Aug 4, 1987Dynagram Corporation Of AmericaCarbohydrate binder
US5066441 *Jun 6, 1988Nov 19, 1991Rhone-Poulenc Basic Chemicals Co.Process for compacting a calcium phosphate composition
US5254355 *May 29, 1992Oct 19, 1993Kraft General Foods, Inc.Process for beverage tablets and products therefrom
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US5807577 *Nov 22, 1995Sep 15, 1998Lab Pharmaceutical Research International Inc.Fast-melt tablet and method of making same
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US6083438 *Aug 5, 1998Jul 4, 2000Cerestar Holding B.V.Tabletting of erythritol
US7226620May 4, 2005Jun 5, 2007Rhodia Inc.and a binder comprising a polyvinylpyrollidone, carrageenan, or a guar gum; chewable oral dosage form
US7695528Feb 15, 2007Apr 13, 2010Delavau LlcCalcium carbonate granulation
US7807125Oct 25, 2006Oct 5, 2010Delavau LlcCalcium carbonate granulation
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US7883552Feb 15, 2007Feb 8, 2011Delavau LlcMixing calcium carbonate powder having a median particle diameter between about 0.1 and about 20 mu m in a high shear mixer; drying in a fluidized bed oven, thereby resulting in a calcium carbonate granulation having a tap density between about 0.9 g/cm3 and about 2.0 g/cm3
US8440236Oct 25, 2006May 14, 2013Delavau L.L.C.Useful in pharmaceutical and nutraceutical tableting and provide smaller tablet sizes
US8603544Jan 30, 2013Dec 10, 2013Delavau L.L.C.Calcium carbonate granulation
US8609140Jan 31, 2013Dec 17, 2013Delavau L.L.C.Calcium carbonate granulation
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US8663706Jan 30, 2013Mar 4, 2014Delavau L.L.C.Calcium carbonate granulation
US8668936Apr 20, 2012Mar 11, 2014Delavau L.L.C.Calcium carbonate granulation
US8697142Aug 9, 2012Apr 15, 2014Delavau L.L.C.Calcium carbonate granulation
US8709499Apr 20, 2012Apr 29, 2014Delavau L.L.C.Calcium carbonate granulation
US8728173Aug 10, 2012May 20, 2014Delavau L.L.C.Calcium carbonate granulation
US8728538Apr 20, 2012May 20, 2014Delavau L.L.C.Calcium carbonate granulation
US8741355Apr 20, 2012Jun 3, 2014Delavau L.L.C.Calcium carbonate granulation
US20110223211 *May 23, 2011Sep 15, 2011Laboratorios Lesvi, S.L.Pharmaceutical formulations containing irbesartan
EP0913148A1 *Aug 3, 1998May 6, 1999Cerestar Holding B.V.Tabletting of erythritol
Classifications
U.S. Classification127/29, 514/769, 424/686, 424/723, 424/722, 8/526, 514/777, 264/122, 426/650, 424/720, 424/690, 127/63, 424/606, 424/695, 424/687
International ClassificationA61K9/26, A61K9/20
Cooperative ClassificationA61K9/2059, A61K9/205, A61K9/2018
European ClassificationA61K9/20H6F4, A61K9/20H4B, A61K9/20H6F