US3490742A - Compressed tablets - Google Patents

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US3490742A
US3490742A US3490742DA US3490742A US 3490742 A US3490742 A US 3490742A US 3490742D A US3490742D A US 3490742DA US 3490742 A US3490742 A US 3490742A
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amylose
tablets
tablet
example
percent
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George K Nichols
Rolland W P Short
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Tate and Lyle Ingredients Americas LLC
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Tate and Lyle Ingredients Americas LLC
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; THEIR TREATMENT, NOT COVERED BY OTHER CLASSES
    • A23PSHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P10/00Shaping or working of foodstuffs characterised by the products
    • A23P10/20Agglomerating; Granulating; Tabletting
    • A23P10/28Tabletting; Making food bars by compression of a dry powdered mixture
    • CCHEMISTRY; METALLURGY
    • C08ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08LCOMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L3/00Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08L3/12Amylose; Amylopectin; Degradation products thereof
    • CCHEMISTRY; METALLURGY
    • C11ANIMAL AND VEGETABLE OILS, FATS, FATTY SUBSTANCES AND WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
    • C11DDETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
    • C11D17/00Detergent materials characterised by their shape or physical properties
    • C11D17/0047Detergents in the form of bars or tablets
    • C11D17/0065Solid detergents containing builders
    • C11D17/0073Tablets
    • C11D17/0086Laundry tablets

Description

United States Patent 3,490,742 COMPRESSED TABLETS George K. Nichols and Rolland W. P. Short, Decatur,

Ill., assignors to A. E. Staley Manufacturing Company, Decatur, Ill., a corporation of Delaware No Drawing. Filed Jan. 14, 1966, Ser. No. 535,258 Int. Cl. Clld 7/56, 7/18 US. Cl. 252-99 3 Claims ABSTRACT OF THE DISCLOSURE Compressed tablet formed of a mixture of an active ingredient and a binder-disintegrant ingredient imparting direct compressibility to said mixture, i.e. non-granular amylose.

Disclosure of the invention This invention relates to a binder-disintegrant for compressed tablets. More particularly, it relates to the manufacture of compressed tablets which has an acceptably short disintegration time in aqueous media by virtue of their content of the said binder-disintegrant.

Of the multitude of forms in which pharmaceu ical products may be dispensed, the compressed tablet form is, by far, that most frequently employed today. The compressed tablet provides definite practical advantages over liquid and powder preparations. For this reason, practically every medicament capable of being embodied in such tablet has been marketed in this form. Convenience to patient, physician and pharmacist, ease of administration and, most important, accuracy of dosage are among the advantages that have led to the constantly increasing use of medicament-containing compressed tablets. Furthermore, the development of machinery for the high speed, large volume production of uniform tablets has a so been responsible for their steadily growing importance in the pharmaceutical trade.

In fields other than the pharmaceutical, the compressed tablet also plays an important role as a dispensing unit of a w de variety of materials. Perhaps most familiar are the tabletted laundry products, such as detergents and bleaches. that are sold today in competition to powdered or liquid products. Nevertheless, such diverse materials as perfumed bath water softeners, confections, artificial sweetners, plant foods, wed killers and dyes are widely marketed as compressed tablet formulations.

Obviously, the characteristics of compressed tablets embodying various materials will differ depending on the purpose and mode of use of the several tablets. However, these characteristics fall generally into three areas of consideration.

First is the ability of the tablet to disintegrate in the fluid medium into which it is properly introduced and the rate of such disintegration. In many cases rapid disintegration is to be desired. For example, a laundry detergent tablet should disintegrate immediately on being added to the water in a washing machine. Similarly, a tablet embodying an ingestible analgesic, such as aspirin, should rapidly break down in the digestive juice of the stomach so as to make the active ingredient promptly available to the organism. On the other hand, a tablet designed for use as a throat lozenge may properly be slowly disintegratable in the salivary fluid in order that the medicament may be released over a relatively prolonged period. The present invention is particularly concerned with tablets of relatively rapid disintegration capability.

The second and third characteristics to be considered, friability and hardness, are closely related in that a tablet that is suflicicntly hard will ordinarily not exhibit excessive friability. An excessively friable tablet is sub- LbLuAmL-L Ice ject to size reduction by virtue of dusting and crumbling. As a consequence, at least some diminution in dosage in a pharmaceutical tab et results. As an additional consequence, obliteration of tablet markings may occur. In any event, dusting and crumbling make for an unattractive and unsatisfactory product of limited consumer appeal.

Insufliciently hard tablets, in addition to exhibiting the effects of excessive friability, are prone to breakage and chipping, particularly in transport where they may be subjected to repeated mechanical shock.

Accordingly, for most purposes, and particularly for pharmaceutical application, a hard, non-friable tablet possessing acceptable disintegration characteristics is the goal of the tablet manufacturer. Other properties are, of course, important such as color stability and nonhygroscopicity, but the desideratum remains the production of a tablet of the type described.

Certain materials such as paradichlorobenzene, hexamethylenetetramine and certain medicaments are readily compressed into a firm, coherent mass in a tablet machine. However, most tablets prepared by direct dry compression are formed from a mixture of at least an active ingredient and a binding agent and generally also contain additional ingredients such as filler, colorants, lubricants, disintegrants and the like.

The terms binder or bonding agent and filler or bulking agent are self-explanatory. A disintegrating agent is one whose presence in the tablet is effective when the tablet is placed in the proper fluid environment to destroy the cohesiveness that gives structural stability to the tablet prior to its use.

It should be pointed out that a given material desirably may perform more than one of the single functions of binding, filling and promoting desired disintegration. For that reason, the term binder-disintegrant is herein employed to describe the component, other than the active ingredient, that is employed to provide the improved compressed tablets of the present invention.

In general, three methods are known for the preparation of the mixture to be fed to the tablet making machine. The most simple procedure involves intimately and uniformly blending the several dry pulverulent components, that is, the active ingredient, binder, filler, disintegrant, lubricants, colorants, etc. If the pulverulent admixture thus obtained displays the requisite flowability for adequate feeding, as a dry powder to the tablet machine, this would obviously be the method of choice. However, as is well known, certain pulverulent materials do not exhibit adequate flowability, and the consequent poor feeding to the tablet-making machine can cause variation in weight of the tablets. Poor feeding can also affect the hardness of the tablet inasmuch as the possibly resultant incomplete filling of the molding cavi y lessens the pressure to which the cavity charge is subjected. Nevertheless, if the flowability of the pulverulent feed mixture is acceptable, this is the obviously desirable method in the preparation of the feed mixture material because of its simplicity and the minimum expenditure of labor in its practice.

In each of the other methods, the goal is the preparation of the feed materials in the form of free-flowing granules. Both a wet and dry technique of granulation are practiced; the latter is commonly referred to as slugging or double compression. The present invention, whi e particularly directed to the manufacture of tablets by the direct dry compression method, nevertheless is concerned also with the manufacture of tablets from granules produced by dry granulation.

As is readily apparent, the extra step of forming granmanufacture. Furthermore, extreme care in formulation must be exercised with a view to the availability of a therapeutic agent administered orally as a tablet so made. That is, the tablet may have an acceptable rate of disintegration in, for example, the gastric fluids, but tablet disintegration may not necessarily immediately expose the particles of the therapeutic agent to the solubilizing fluid. In other words, tablet disintegration may in effect, reconstitute the granules, which, in turn, must themselves disintegrate to expose the surface of the therapeutic agent particles to solvent action.

The double-compression or slugging technique does not present all of the difficulties inherent in wet granulation. Nevertheless, it does impose on the manufacturer the necessity of employing at least two additional manufacturing steps. After the pulverulent admixture of active ingredient, filler, binder and the like is prepared, large tablets or slugs are formed therefrom by dry compression molding. These slugs are then ground to granules of desired size. These granules may be used directly as the feed to the tablet-making machine or they may be further blended with other ingredients, such as lubricants, before being formed into tablets.

It is obvious that, if possible, granulation is advantageously avoided. Heretofore, however, the alternative of preparing compressed tablets by direct compression has met with limited acceptance, principally because of the unavailability of suitable and inexpensive materials capable of binding the tablet constituents into tablets of acceptable physical properties. For example, at present the most widely used material for binding tablets by the direct compression method, spray-dried lactose, is unacceptable in many uses because of its marked tendency to turn brown on aging. It is evident that there is a need for an improved material for the dry binding of compressed tablets, a material allowing for the manufacture of tablets of excellent disintegratahility, resistant to breakage and crumbling and generally suitable for use.

Accordingly, it is an object of the present invention to provide an improved binder for the manufacture of compressed tablets. It is another object of the invention to provide such an improved binder having characteristics that permit it to function as a disintegrant. It is an additional object of the invention to provide compressible, binding compositions having free flowing characteristics. It is yet a further object of the invention to provide a compressed tablet, containing a binder-disintegrant, that is hard, non-friable and readily disintegratable in an aqueous medium. It is still another object of the invention to provide a ibinder-disintegrant for slugs for use in a dry granulation process, which slugs can be reduced to granules adapted to being compressed into tablets without additional treatment. The means of attaining these and related objects will be evident from the following description and examples.

In its broadest aspect, the present invention relates to the use of non-granular amylose as an especially effective binder-disintegrant for use in the direct compression method of tablet manufacture. Non-granular, superficially dry amylose having a moisture content of at least 5 percent by weight, can be directly compressed into tablets which resist breaking and crumbling and which disintegrate rapidly in aqueous media. It combines, in one material, the desired properties of a binding agent and of a disintegrant. Accordingly, in many instances the preparation of the feed material for the tablet-making machine involves blending of only two materials, the active or functional ingredient and the amylose. However, as will be frequently desirable, the inclusion of other materials such as colorants and lubricants is readily accommodated.

Amylose is non-discoloring on aging and is, of course, generally regarded as safe for human consumption since it is a fraction of starch.

Because of its superior binding power, amylose can be used to prepare slugs for use in the double compression process for preparing granular tabletting feed material.

Tablets prepared from such granulated feed material are found to possess essentially the same characteristics of hardness, non-friability and good disintegratability as those possessed by tablets made by direct compression using amylose as a binder. However it will normally be found that, as a practical matter, the dry granulation method need not be resorted to.

The binder-disintegrant of the present invention may be used with a wide variety of active or functional ingredients. Furthermore, the amount employed can be varied over wide limits depending on a number of factors such as the nature of the active ingredient and of other desired additives. The determination of the amount will be evident to those skilled in the art or will be readily determinable by simple, empirical tests from the information herein. One factor is the ease with which the active ingredient may be made into a tablet. For example if the active ingredient does not, of itself, bond together well under compression the proportion of amylose will be relatively large, and it will serve as both binder and disintegrant. At the other extreme, the active ingredient may itself be an adequate binder, and the amylose serves principally as a disintegrant and as a secondary binder. When the amount of active ingredient is quite small, so that a tablet of acceptably large size could not be prepared from this ingredient alone, the amylose can be present in the tablet as the major constituent and serve also as an inert filler.

As will be understood, amylose is defined as that constituent of starch which is a linear polymer of glucose. The other constituent of starch, which is found associated with amylose in varying proportions depending on the starch source, is designated amylopectin and is a polymer of glucose, the units of which are linked in a highly branched structure.

These two fractions of starch have substantially different properties. Of most importance in the present instance is the difference in solubility characteristics. Amylose is substantially insoluble in cold water whereas amylopectin may be dissolved therein to give relatively concentrated solutions.

Amylose derived from any variety of starch may be employed in the practice of the present invention. As a practical matter, of course, the starch source must contain a substantial proportion of amylose. Accordingly, the starch source material may be starch from corn, rice, wheat, potato, tapioca, sage, sorghum and the like, including the high-amylose varieties. Because of its availability and relative cheapness, amylose derived from corn is particularly preferred.

The amylose commercially available contains some amylopectin as an impurity, together with minor amounts of fatty acids, proteins, cellulose, and ash. Accordingly, for the purpose of the present invention, amylose is taken to mean a carbohydrate material containing not less than about 50 percent by weight of amylose based on the weight of total dry carbohydrate substance.

As above stated, the preferred non-granular amylose for use in the practice of the present invention is that obtained by the fractionation of corn starch. While any suitable method may be used to isolate the amylose, a particularly convenient method is described in U.S. Patent 3,067,067, to Etheridge et al. In brief, the process of this patent is carried out by forming a fluid solution of corn starch and water at a temperature above about 250 F. This fiuid aqueous solution is then cooled to a temperature between F. and the atmospheric boiling point. The solution, which contains more than about 2.5 percent by weight of starch dry substance, is then maintained at this temperature for a period of time sufficient to stabilize the solution. During this period an amylose-rich, particulate solid fraction separates from the solution. This fraction is recovered, washed and dried. Drying is preferably carried out by the spray drying of an aqueous dispersion of this fraction, the dispersion being obtained by reslurrying the washed, wet

recovered solids. The dried product, which is a preferred form of amylose for use in the practice of the present invention, is a free-flowing white powder.

While spray drying is the preferred method of isolating the amylose material, other methods are available. For example, the washed solids, still wet with water, may be reslurried in a solvent, such as methanol, which is miscible with water and non-solvent for the product. On filtering or centrifuging the water is largely removed with the methanol. The residual methanol may then be removed by gentle tray drying, particularly at reduced pressure. Any drying method that does not alter the free-flowing characteristics of the amylose material and which does not result in a significant increase in the cold water solubility of the material may be employed.

The amylose obtained by separation from starch is referred to as non-granular amylose for the reason that the starch from which it is derived is totally solubilized in order to free the amylose; in the solubilization, the starch granule structure is destroyed and, naturally, does not persist in the particulate amylose product.

For the purposes of the present invention, the term non-granular amylose includes a non-granular starch having an acceptably large content of amylose. For example, a starch containing at least 50 percent of amylose on a dry carbohydrate basis may be dispersed in water and the resulting dispersion heated at a temperature and for a time sufficient to dissolve the starch and thereby to break down the starch granules. The gel obtained on cooling of this solution may be redispersed in water and the resulting dispersion can be spray-dried to give a non-granular, high-amylose starch product acceptable for use as a binder-disintegrant for compressed tablets in accordance with this invention.

In particular reference to the factor of disintegration of amylose-containing tablets in aqueous media, it should be noted that the amylose should generally contain not more than about 20 percent of cold-water-soluble material as determined in a manner to be hereinafter described. If the content of cold-water-soluble material is significantly higher than this value, the aqueous medium may be imbibed by the outer surface of the tablet to cause superficial swelling or gumming. This layer acts as a barrier that inhibits penetration of the aqueous fluid more deeply into the tablet body. Consequently, disintegration may be markedly delayed or even prevented indefinitely. The amount of cold-water-soluble material contained in the amylose is readily determined by the following procedure: One gram of the starch product, ground to pass a 40 mesh sieve, is shaken two hours with 50 grams of distilled water at 25 C. in a 100 ml. Kohlrausch flask with a Burrell wrist-action shaker. Water is then added to the flask to the 100 ml. mark, the contents are mixed thoroughly, transferred to a 250 ml. round bottom centrifuge tube and centrifuged for 15 minutes at 2000 rpm. A 25 ml. aliquot of the clear centrifugate is transferred to a tared aluminum pan and evaporated to dryness on a steam bath. The dish is then dried to a constant weight in an oven at 110 C. The weight of dried material in the pan multiplied by 400 and divided by the dry substance weight of the original sample is the cold-water solubility of the starch product.

For the amylose of this invention to serve effectively as a binder, it must contain more than about 5 percent moisture and, preferably, it should contain at least about 9 percent moisture. When less than 5 percent of moisture is present in the amylose portion of the tablet formulation, the tablet lacks resistance to breaking and crumbling. Nevertheless, when the moisture content of the amylose in the tablet formulation is less than that required for satisfactory binding, the amylose still functions effectively as a disintegrant. The moisture content of the amylose may permissibly be as high as 18 percent, although generally a maximum value of about 15 percent is preferred. Some reduction in tablet hardness results if the moisture content of the amylose exceeds this value.

As has been hereinbefore indicated, a tablet formulation may contain only the non-granular amylose binderdisintegrant and the active or functional ingredient. It may also, if desired, contain additional materials such as bulking agents, lubricants, colorants, flavoring agents and the like. A particular and somewhat surprising aspect of the present invention is that such formulations may advantageously contain as an auxiliary hardening agent, a small amount, relative to the amount of the non-granular amylose, of amylopectin. The advantage to be had thereby is unexpected in view of the fact that it is generally desirable that the amylose binder-disintegrant contains as high a percentage of amylose as possible. In other words, the content of the amylopectin contaminant associated with the amylose should be as small as possible. Furthermore, amylopectin itself, because of its relatively high cold-water solubility, is an extremely poor disintegrant, although it has generally acceptable binding properties. Nevertheless, amylopectin, as a separate ingredient, may be added to a granular amylose-containing formulation in an amount equal to about 25 percent by weight of the amylose. As a result, the hardness of tablets produced from the formulation is markedly enhanced without significant sacrifice in the disintegratability of the tablet.

The particle size of the non-granular amylose binderdisintegrant to be employed in the preparation of a given tablet-formulation is a matter of choice readily apparent to those skilled in the art. In general, no difference in the quality of product will be noted between a tablet made from, for example, a formulation containing non-granular amylose finer than 325 mesh (US. Standard Sieve Series, A.S.T.M. Specification) and one in which an amylose of average particle size of to 325 mesh is employed. However, as a practical matter, material finer than 325 mesh is undesirable because of its marked tendency to dusting during the tabletting operation. In general, material having an average particle size in the range of 60 to 325 mesh is preferred.

The bulk density of the binder-disintegrant, which affects the tablet-making process, can readily be determined for a given formulation by the skilled formulator, aided by simple experiment. Since the proper bulk density of the total formulation is the practical aim, consideration will necessarily be given to factors other than the bulk density of the binder-disintegrant. The nature of the active or functional ingredient and of any other additives and the quantitative makeup of the formulation must be taken into account. Furthermore, adjustment of the size of the cavity of the tabletting machine affords the formulator a degree of flexibility as to bulk density. Finally, dry granulation may be resorted to in the case of a formulation of ordinarily undesirably low bulk density.

It is, of course, understood that a filler or a binder-disintegrant for use in a tablet that is to be ingested should be non-toxic. Furthermore, they should be inert in the sense that they do not react with the active ingredient in a manner that may interfere with the ready availability of such ingredient to the organism. Additionally, these materials should be such that the intimate, uniform mixture constituting the feed material to the tabletting machine is mechanically stable. That is, the composition of a given volume of feed materials should remain constant under the conditions of vibration which obtain during machine operation. If the mixture tends to classify to a significant extent there will result a change in composition between tablets made at the beginning of an operation when the feed hopper of the tablet-making machine is full, and those made near the end of the operation when the hopper is almost empty. Weight variation, changes in physical characteristics, and change in drug content may be encountered in the tablets produced.

In the examples that follow the active or functional ingredients are given only to illustrate typical tablet formulations. Since it is essentially inert, the non-granular amylose of the present invention is also suitable for use with a wide variety of functional ingredients. The examples, therefore are given by way of non-limiting illustration only. In these examples, unless otherwise noted, the nongranular amylose utilized is spray dried amylose derived from corn starch according to the method of U.S. Patent 3,067,067. Unless otherwise specified, all parts are by weight and each formulation contains 100 parts.

Example 1 This example is intended to illustrate the effectiveness of non-granular amylose as a binder-disintegrant in tablets containing ascorbic acid as the functional ingredient.

A superficially dry tablet formulation was prepared by thoroughly blending 5 parts of ascorbic acid and 95 parts of non-granular amylose material having an amylose content of 90.9 percent on a dry substance basis. The amylose had a moisture content of 12.2 percent. Accordingly, the moisture content of the formulation was 11.6 percent by weight based on the total weight of the formulation. The formulation was passed through an SO-mesh screen and was tabletted on a Colton No. 204 four-punch press manufactured by the Colton Division of Cherry-Burrell Corporation, Detroit, Mich. A set of /8" diameter standard cup punches and dies was employed and the press was operated at 35 r.p.m. to produce 140 tablets per minute. The press is capable of developing a maximum pressure of 7400 psi. The tablets produced were of good general appearance and were uniform as to size and weight and were within the specification described in the Pharmacopeia of the United States of America, 16th edition, page 942.

Fifteen of the tablets thus produced were selected at random and their resistance to breaking, as a measure of hardness, was determined on a Strong-Cobb tablet hardness tester, Power Model B, manufactured by Strong- Cobb Arner, Inc. of Cleveland, Ohio. This tester consists essentially of an anvil, a pressure operated plunger and a pressure gauge. A tablet is placed on the anvil and the plunger is brounght into contact with the tablet. The plunger is then forced against the tablet with increasing pressure until the tablet breaks. The pressure gauge is read at the time of break. The pressure required to break the tablet is determined by multiplying the gauge reading by a factor of 0.78. The value, in kilograms per square centimeter, is a measure of the hardness of the tablet. A minimum hardness of 5 kilograms is considered satisfactory. -Each of the tablets tested had a hardness greater than this value. The average hardness value for the 15 tablets is set out in Table I.

Twenty tablets were randomly selected from the tablets produced and their aggregate weight was determined to the nearest 0.1 milligram. The tendency to crumble, or friability (expressed as percent weight loss), was determined according to the Roche test which is described in the Journal of the American Pharmaceutical Association, scientific edition, vol. 45 (1956) pages 114 to 116 inclusive. A percent weight loss in excess of 1 percent is considered unsatisfactory. As shown in Table I, the percentage weight loss of the 20 tablets tested was significantly less than this minimum value.

The time required for the tablets to disintegrate in water was determined according to the procedure for uncoated tablets described in Pharmacopeia of the United States of America, 16th edition, pages 934 to 936 inclusive. Six tablets were selected at random for use in this test procedure. The time required for each tablet to disintegrate was observed, and the first and last are set out in Table I. A disintegration time of not more than minutes is considered satisfactory. As shown in Table I, the tablets of this example disintegrated in a far smaller period of time.

As stated in the test outlined in the Pharmacopeia, disintegration is considered to have occurred when any residue remaining on the screen support of the test apparatus is a soft mass having no palpably firm core. In the present instance no soft mass remained on the screen; disintegration was sufiiciently complete that essentially all of the disintegrated material had passed through the screen support.

TABLE I Time of disintegration in Percent weight minutes for Ex. Av. hardness, loss in iriabil- N o. kgJern. 1 ity test First tablet Last tablet The results are set in Table I together with the results obtained in certain succeeding examples. As shown therein, the tablets described possess excellent resistance to crumbling and breaking and are capable of rapid disintegration in an aqueous medium.

Example 2 Tablets were prepared according to the method of Example 1 from a formulation differing from that of the said example only in that its moisture content was only 8.8 percent of the formulation weight. The hardness of fifteen randomly selected tablets was determined; an average value of 8.3 kilograms per square centimeter was observed. This example indicates that the tablet hardness, although acceptably high, was substantially decreased as a result of reduction of moisture content of the formulation.

Example 3 Example 4 This example is intended to illustrated the compatibility of amylose with a typical additive employable in tablet preparation to increase the tablet hardness without significantly increasing disintegration time. The additive employed was an acid-modified, pregelatinized starch from dent corn of ordinary amylose content prepared by the extrusion procedure described in US Patent 3,137,592 by Thomas F. Protzman and John A. Wagoner, issued June 16, 1964.

A superficially dry formulation was prepared by thoroughly blending 10 parts of the pregelatinized starch and parts of non-granular amylose material of 92.9 percent purity. The moisture content of the formulation was 11.8 percent by Weight based on the weight of the formulation. Following the method of Example 1, tablets were prepared from this formulation and evaluated. The general excellence of the tablets, particularly their increased hardness as compared with the tablets of Example 3, is indicated by the values set out in Table I above.

Example 5 This example illustrates further the compatibility of amylose with a commonly used additive employed as a lubricant in tablet manufacturing. The additive used was magnesium stearate.

A superficially dry formulation containing 0.5 part of magnesium stearate intimately mixed with 99.5 parts of amylose material was prepared. The amylose material contained 89.5 percent of amylose, dry weight basis, and

9 the formulation had a moisture content of 11.6 percent by weight based on the total weight of formulation. Tablets were prepared and tested according to Example 1. These tablets were of excellent appearance and adequately met the specifications as to hardness, friability and disintegration time in an aqueous medium set out in Example 1.

Example 6 This example is intended to illustrate the use of nongranular amylose as a binder in tablets in which the functional ingredient is non-pharmaceutical. A laundry bleach tablet was prepared from the following formulation.

Parts Sodium hexametaphosphate Sodium perborate 16 Sodium sulfate ll Non-granular amylose 63 The tablet was of excellent appearance and distintegrated in water in a time consonant with its intended use.

Example 7 This example illustrates the versatility of non-granular amylose as a disintegrant-binder in respect of a variety of functional ingredients. Tablets of generally excellent characteristics were prepared from the following formulations.

Example 8 This example illustrates the feasibility of recompacting tablets containing non-granular amylose as a disintegrantbinder and hence the feasibility of using this binder in a dry granulation operation or in the salvaging of reject tablets in production.

Ascorbic acid tablets of Example 1 were ground in a Wiley mill, passed through an 80 mesh screen, and retabletted. A comparison of the original tablets and those resulting from recompaction may be made by noting the values listed for Examples 1 and 8 in Table I above, sample 8 being the value obtained with the recompacted material.

Example 9 This example is intended to illustrate the mechanical stability of formulations for the preparation of pharmaceutical tablets in which non-granular amylose materials is employed as the binder-disintegrant. Aspirin 200 mesh powder was thoroughly blended with non-granular amylose in a twin shell blender, Patterson-Kelley Model LB2630. The amylose constituted about percent by weight of the formulation. A similar feed material was prepared in which the aspirin was in the form of 40 mesh crystals. In similar fashion two lots of feed material were made containing about 40 percent of ascorbic acid, the balance being amylose. In one lot the ascorbic acid was in the form of 200 mesh powder, while in the other 40- 80 mesh crystals were used. Two kilograms sample lots of each were used in the preparation of tablets. Sample 10 tablets were collected at intervals. These were weighed and analyzed for drug content. The results, set out in Table II, indicate the uniformity of these measured values. It is to be noted that the several feed materials represent wide ranges in both particle size and the ratio of amylose to drug constituent.

TABLE 11 Sampling Tablet, Dru g, time, wt. weight Drug minutes grams percent Ascorbic acid owder 0-1 2295:. 006 40. 4 Do. 16-17 232;i=.00-i 40. 2 Do 24-25 2333;. 005 40. 3 D0. 32-33 2331006 40.6 Ascorbic acid, crystaL- 0-1 254:1; 00s 42. 3 Do. 8-9 2531.004 41.7 16-17 253i. 006 41. 6 24-25 2513;. 008 4'2. 5 0-1 232:. 004 78. 9 16-17 2403:. 004 77. 8 32-33 239i. 003 78. 0 40-11 2383:0015 79. 5 0-1 2463:. 007 78. 1 12-13 2525:. 006 78. 0 28-29 2481. 007 78. 1 36-37 2421.010 78. 1

Example 10 This example is intended to illustrate the availability to the organism of drugs ingested in the form of direct compression tablets employing amylose as a binder-disintegrant. Tablets containing 20 percent of aspirin and percent of non-granular amylose and tablets containing 55 percent of sodium p-aminosalicylate, 5 percent of talc and 40 percent of non-granular amylose were employed.

Eight apparently healthy adult males were chosen as subjects. Prior to breakfast each subject voided completely and drank 240 ml. of water. One hour later the subjects voided again and were each given a known dosage of aspirin with an aditional 240 ml. of water. Half of the group received this dosage in the form of commercially available control tablets; the rest received it in the form of the tablets above described. One hour after dosing they were allowed to eat, and their food intake was not thereafter controlled. Urine samples were collected at 0, 1, 2, 4, 8 and 24 hours; the sample taken immediately before dosing was the first of this series. Aspirin content was determined on the basis of total salicylate content using Trinders reagent. The mean and range of cumulative urinary excretion were plotted for each time period. Total drug excretion and rate of drug excretion were essentially the same for the two groups.

The experiment was repeated with the sodium p-aminosalicylate tablets. In this case the group which had taken the control aspirin tablets now received the above described amylose-containing tablets. The control tablets were given to those who had taken the amylose-containing aspirin tablets. The sodium p-aminosalicylate in the urine was determined by the method of Way et al. (J. Pharmacal. and Exptl. Therap. 93, 368; 1948). Again, the total drug excretion and rate of drug excretion were the same for the two groups.

Example 11 This example is illustrative of the use of a non-granular starch of high amylose content as a binder-disintegrant in compressed tablets.

Starch having an amylose content of 55 percent by weight on a dry solids basis was mixed with water to give a slurry having a solids content of 18 percent. The starch was solubilized by heating the slurry to a temperature of about 315 F. by the action of steam in an apparatus of the type described in US. Patent 2,805,966. The solution obtained was discharged to a tank which was open to the atmosphere and was allowed to cool to ambient temperature. A firm gel was obtained. This was cut into coarse pieces which were added to water with vigorous agitation. Agitation was continued until a fiuid, free-flowing dispersion of the gel resulted. This dispersion was dehydrated by spray drying to give the recovered non-granular starch in the form of a free-flowing, finely divided powder having a moisture content of 12 percent.

Tablets were prepared by compression of a thoroughly blended mixture of 30 parts of ascorbic acid and 70 parts of the above-described starch. These tablets, evaluated according to the procedures described in Example 1, displayed an average hardness of 8.4 kg./sq. cm., a weight loss of 0.11% and a disintegration time of 2.5 to 3.0 minutes.

Example 12 This example is intended to illustrate the use of nongranular amylose material in preparing a tablet for accurate measurement of an active ingredient other than a pharmaceutical. Following the method of Example 1, tablets were prepared from a formulation containing 95 parts of the non-granular amylose material of that example and parts of the root-growth stimulant, l-naphthaleneacetic acid. Tablets of generally excellent characteristics were obtained. Since the weight of an individual tablet is approximately 0.25 gram, it contains about 0.0125 gram of active material. Accordingly, a very dilute solution containing 12.5 ppm. of active material is obtained when the tablet is allowed to disintegrate, with agitation, in one liter of water.

Example 13 This example illustrates the use of the non-granular amylose in the preparation of a unit-of-use tablet containing a flavoring agent as the active ingredient. Following the procedure of Example 1, tablets were prepared from a thoroughly blended formulation containing 30 parts of non-granular amylose material and 70 parts of a commercially available, dehydrated, powdered garlic. Excellent tablets were obtained which disintegrated rapidly in water to release the particles of garlic. The tablets were so sized that each was equivalent, in flavoring power, to about one-half of a garlic clove of average size.

Example 14 This example provides a further illustration of the preparation of a unit-of-use tablet by the method of the present invention. According to the procedure of Example 1, tablets were prepared containing 50 parts of nongranular amylose material and 50 parts of a direct dye, sold under the trademark Pontamine Blue AX Concentrate. These tablets disintegrated readily in water to give a solution of the dye suitable for use in the dyeing of cotton fabric.

Since many embodiments of this invention may be made and since many changes may be made in the described embodiments, the foregoing is to be interpreted as illustrative only. The invention is, therefore, defined in the following claims.

We claim:

1. A dry compressed tablet requiring a disintegrant and binder having resistance to breaking and crumbling and being disintegrative in aqueous media comprising (a) an active ingredient and (b) a non-granular amylose material selected from the group consisting of non-granular amylose separated by fractionation of starch and nongranular amylose prepared by dissolving granular high amylose starch in water, causing the solution to gel and redispersing and drying said gel, said non-granular amylose material containing at least 50% of amylose on a dry carbohydrate basis and having a content of solid matter soluble in cold water not exceeding 20% by weight, a moisture content of from about 5 to 18% total Weight basis, and an average particle size of from to 325 mesh, and said amylose material adapted to two-fold function as the essential compressed tablet disintegrant and binder in the direct compression method of tablet manufacture.

2. A dry compressed tablet requiring a disintegrant and binder having resistance to breaking and crumbling and being disintegrative in aqueous media comprising (a) an active ingredient and (b) corn amylose material containing at least 50% by weight of amylose and not more than about 20 percent by weight of cold-water soluble material, the balance of the carbohydrate in said amylose material consisting essentially of amylopectin, and having a moisture content of about 5 to about 18 percent and an average particle size of from 60 to 325 mesh, obtained by fractionation from totally solubilized corn starch, wherein the starch granular structure has been destroyed and does not persist, adapted to two-fold function as the essential compressed tablet disintegrant and binder in the direct compression method of tablet manufacture.

3. A compressed tablet according to claim 2 formed by direct dry compression of the ingredients thereof.

References Cited UNITED STATES PATENTS 3,067,067 12/1962 Etheridge et al 127-71 3,101,299 8/1963 Ferrand 167-82 3,117,014 1/1964 Klug 260233.3 XR 3,128,209 4/1964 Gerrnino et a1 127-71 3,175,948 3/1965 Kolf et al 167-82 XR 3,181,998 5/1965 Kanig 167-82 3,293,132 12/1966 Stoyle et a1 167-82 3,332,848 7/1967 Magid 167-82 3,034,911 5/1962 McKee et al. 106-210 3,222,220 12/1965 Wurzberg et al 127-32 3,265,509 8/1966 Wurzberg et al 99-134 3,396,226 8/1968 Cavalli et al 424-280 OTHER REFERENCES Chem. Abstracts 54: P9220h (1960).

Milo Sovich: Drug and Cosmetic Industry 92(5); 557-558, 656, 662-665, 667-669, May 1963, Direct Compression of Tablets.

Kwan et al.: J. Pharm. Sci. 55(3); 340-343, March 1966, Evaluation of Amylose as a Dry Binder for Direct Compression.

Chem. Abstracts 50: 7398h (1956).

Whistler et al., Industrial Gums, Polysaccharides and Their Derivatives, pp. 675-684 (1959), Academic Press, New York, NY.

S. K. ROSE, Primary Examiner US. Cl. X.R.

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US3622677A (en) * 1969-07-07 1971-11-23 Staley Mfg Co A E Compressed tablets containing compacted starch as binder-disintegrant ingredient
US3671633A (en) * 1971-05-10 1972-06-20 American Cyanamid Co Process for tabletting acetazolamide
US3679794A (en) * 1968-02-15 1972-07-25 Organon Nv Process for the manufacture of rapidly disintegrating solid dosage unit forms
US3725556A (en) * 1970-11-12 1973-04-03 D Hanssen Method of manufacturing rapidly disintegrating pharmaceutical tablets
US4055974A (en) * 1976-03-05 1977-11-01 International Spike, Inc. Disintegratable fertilizer tablet
US4097606A (en) * 1975-10-08 1978-06-27 Bristol-Myers Company APAP Tablet containing an alkali metal carboxymethylated starch and processes for manufacturing same
US4369308A (en) * 1981-07-24 1983-01-18 National Starch And Chemical Corporation Low swelling starches as tablet disintegrants
US4454108A (en) * 1981-09-04 1984-06-12 Chugai Seiyaku Kabushiki Kaisha Prolonged-action multiple-layer tablets
US4495177A (en) * 1983-01-17 1985-01-22 Shaklee Corporation Gel tableting agent
US4551177A (en) * 1984-04-23 1985-11-05 National Starch And Chemical Corporation Compressible starches as binders for tablets or capsules
US4601895A (en) * 1983-12-23 1986-07-22 Bayer Aktiengesellschaft Delayed-action acetylsalicylic acid formulations for oral administration
EP0499648A1 (en) * 1990-12-17 1992-08-26 National Starch and Chemical Investment Holding Corporation Enzymatically debranched starches as tablet excipients
WO1994001092A1 (en) * 1992-07-03 1994-01-20 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Composition for controlled release of an active substance and method for the preparation of such a composition
US5468286A (en) * 1989-10-25 1995-11-21 National Starch And Chemical Investment Holding Corporation Enzymatically debranched starches as tablet excipients
US5830884A (en) * 1995-01-18 1998-11-03 National Starch And Chemical Investment Holding Corporation Pharmaceutical products containing thermally-inhibited starches
US5879707A (en) * 1996-10-30 1999-03-09 Universite De Montreal Substituted amylose as a matrix for sustained drug release
US5914128A (en) * 1997-12-22 1999-06-22 Schering Corporation Orally administrable solid dosage form
US5916594A (en) * 1997-12-22 1999-06-29 Schering Corporation Process of making solid ribavirin dosage forms
US6051252A (en) * 1997-12-22 2000-04-18 Schering Corporation Orally administrable solid dosage form
US6083456A (en) * 1992-05-13 2000-07-04 Chemia, Inc. Air freshener
US6143324A (en) * 1998-02-03 2000-11-07 Cerestar Holdings B.V. Free-flowable directly compressible starch as binder, disintegrant and filler for compression tablets and hard gelatine capsules
EP1062945A1 (en) 1999-06-26 2000-12-27 Cerestar Holding B.V. Directly compressible starch as enhancer of properties of excipients when used as binder and disintegrant for compression tablets
US6251431B1 (en) * 1992-05-13 2001-06-26 Chemia Corporation Moth and insect repellant
EP1110550A2 (en) * 1999-12-22 2001-06-27 F. Hoffmann-La Roche Ag Composition comprising ascorbic acid and pectin
US6572887B2 (en) 2000-05-01 2003-06-03 National Starch And Chemical Investment Holding Corporation Polysaccharide material for direct compression
US20030117171A1 (en) * 2001-12-20 2003-06-26 Fujitsu Limited Input/output buffer circuit
US6607748B1 (en) 2000-06-29 2003-08-19 Vincent Lenaerts Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture
US20030215499A1 (en) * 2002-05-14 2003-11-20 Yong-Cheng Shi Use of completely linear short chain alpha-glucans as a pharmaceutical excipient
US20030215562A1 (en) * 2002-05-14 2003-11-20 Yong-Cheng Shi Slowly digestible starch product
US20030215561A1 (en) * 2002-05-14 2003-11-20 Yong-Cheng Shi Resistant starch prepared by isoamylase debranching of low amylose starch
US20030219520A1 (en) * 2002-05-14 2003-11-27 Yong-Cheng Shi Slowly digestible starch product
US20040023892A1 (en) * 2000-04-05 2004-02-05 Khazanov Veniamin A Pharmaceutical composition based on a non-steroid anti-inflammatory agent
US20040086566A1 (en) * 2002-11-04 2004-05-06 Alpharma, Inc. Waxy matrix dosage forms
US6846497B2 (en) 2003-01-30 2005-01-25 National Starch And Chemical Investment Holding Corporation Rapidly expanding starches with altered crystalline structure
US20050239679A1 (en) * 2002-10-18 2005-10-27 Solvay Interox Gmbh Method for producing dust-free alkaline earth peroxides
US20060008521A1 (en) * 2004-07-09 2006-01-12 Yeli Zhang Tablet excipient
US7008912B1 (en) 1997-03-11 2006-03-07 Henkel Kgaa Pressed piece which disintegrates in liquids
USRE39139E1 (en) 1997-03-13 2006-06-20 Henkel Kgaa Process for preparing household detergent or cleaner shapes
US20090011014A1 (en) * 2004-12-24 2009-01-08 Universite De Montreal Tablet Formulation for Sustained Drug-Release
US20090227536A1 (en) * 2001-09-03 2009-09-10 Chyi-Cheng Chen Compositions comprising pectin and ascorbic acid
WO2012003968A1 (en) 2010-07-06 2012-01-12 Grünenthal GmbH Novel gastro- retentive dosage forms comprising a gaba analog and an opioid

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US3679794A (en) * 1968-02-15 1972-07-25 Organon Nv Process for the manufacture of rapidly disintegrating solid dosage unit forms
US3622677A (en) * 1969-07-07 1971-11-23 Staley Mfg Co A E Compressed tablets containing compacted starch as binder-disintegrant ingredient
US3725556A (en) * 1970-11-12 1973-04-03 D Hanssen Method of manufacturing rapidly disintegrating pharmaceutical tablets
US3671633A (en) * 1971-05-10 1972-06-20 American Cyanamid Co Process for tabletting acetazolamide
US4097606A (en) * 1975-10-08 1978-06-27 Bristol-Myers Company APAP Tablet containing an alkali metal carboxymethylated starch and processes for manufacturing same
US4055974A (en) * 1976-03-05 1977-11-01 International Spike, Inc. Disintegratable fertilizer tablet
US4369308A (en) * 1981-07-24 1983-01-18 National Starch And Chemical Corporation Low swelling starches as tablet disintegrants
EP0070970A2 (en) * 1981-07-24 1983-02-09 National Starch and Chemical Corporation Low swelling starches as tablet disintegrants
EP0070970A3 (en) * 1981-07-24 1983-11-16 National Starch And Chemical Corporation Low swelling starches as tablet disintegrants
US4454108A (en) * 1981-09-04 1984-06-12 Chugai Seiyaku Kabushiki Kaisha Prolonged-action multiple-layer tablets
US4495177A (en) * 1983-01-17 1985-01-22 Shaklee Corporation Gel tableting agent
US4601895A (en) * 1983-12-23 1986-07-22 Bayer Aktiengesellschaft Delayed-action acetylsalicylic acid formulations for oral administration
US4551177A (en) * 1984-04-23 1985-11-05 National Starch And Chemical Corporation Compressible starches as binders for tablets or capsules
US5468286A (en) * 1989-10-25 1995-11-21 National Starch And Chemical Investment Holding Corporation Enzymatically debranched starches as tablet excipients
EP0499648A1 (en) * 1990-12-17 1992-08-26 National Starch and Chemical Investment Holding Corporation Enzymatically debranched starches as tablet excipients
US6254823B1 (en) 1992-05-13 2001-07-03 Norman Van Rees Air freshener
US6083456A (en) * 1992-05-13 2000-07-04 Chemia, Inc. Air freshener
US6251431B1 (en) * 1992-05-13 2001-06-26 Chemia Corporation Moth and insect repellant
US5585114A (en) * 1992-07-03 1996-12-17 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Composition for controlled release of an active substance and method for the preparation of such a composition
WO1994001092A1 (en) * 1992-07-03 1994-01-20 Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno Composition for controlled release of an active substance and method for the preparation of such a composition
US5830884A (en) * 1995-01-18 1998-11-03 National Starch And Chemical Investment Holding Corporation Pharmaceutical products containing thermally-inhibited starches
US5879707A (en) * 1996-10-30 1999-03-09 Universite De Montreal Substituted amylose as a matrix for sustained drug release
US7008912B1 (en) 1997-03-11 2006-03-07 Henkel Kgaa Pressed piece which disintegrates in liquids
USRE39139E1 (en) 1997-03-13 2006-06-20 Henkel Kgaa Process for preparing household detergent or cleaner shapes
US5916594A (en) * 1997-12-22 1999-06-29 Schering Corporation Process of making solid ribavirin dosage forms
US5914128A (en) * 1997-12-22 1999-06-22 Schering Corporation Orally administrable solid dosage form
US6051252A (en) * 1997-12-22 2000-04-18 Schering Corporation Orally administrable solid dosage form
US6143324A (en) * 1998-02-03 2000-11-07 Cerestar Holdings B.V. Free-flowable directly compressible starch as binder, disintegrant and filler for compression tablets and hard gelatine capsules
EP1062945A1 (en) 1999-06-26 2000-12-27 Cerestar Holding B.V. Directly compressible starch as enhancer of properties of excipients when used as binder and disintegrant for compression tablets
US6455069B1 (en) 1999-06-26 2002-09-24 Cerestar Holding B.V. Directly compressible starch as enhancer of properties of excipients when used as binder and disintegrant for compression tablets
EP1110550A2 (en) * 1999-12-22 2001-06-27 F. Hoffmann-La Roche Ag Composition comprising ascorbic acid and pectin
EP1110550A3 (en) * 1999-12-22 2001-09-19 F. Hoffmann-La Roche Ag Composition comprising ascorbic acid and pectin
US6974832B2 (en) 1999-12-22 2005-12-13 Dsm Nutritional Products Inc. L-ascorbic acid and pectin composition
US20010005514A1 (en) * 1999-12-22 2001-06-28 F. Hoffmann-La Roche Ag L-ascorbic acid and pectin composition
US20040023892A1 (en) * 2000-04-05 2004-02-05 Khazanov Veniamin A Pharmaceutical composition based on a non-steroid anti-inflammatory agent
US6572887B2 (en) 2000-05-01 2003-06-03 National Starch And Chemical Investment Holding Corporation Polysaccharide material for direct compression
US6607748B1 (en) 2000-06-29 2003-08-19 Vincent Lenaerts Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture
US20090227536A1 (en) * 2001-09-03 2009-09-10 Chyi-Cheng Chen Compositions comprising pectin and ascorbic acid
US8242096B2 (en) 2001-09-03 2012-08-14 Dsm Ip Assets B.V. Compositions comprising pectin and ascorbic acid
US20030117171A1 (en) * 2001-12-20 2003-06-26 Fujitsu Limited Input/output buffer circuit
US20030215562A1 (en) * 2002-05-14 2003-11-20 Yong-Cheng Shi Slowly digestible starch product
US20030215561A1 (en) * 2002-05-14 2003-11-20 Yong-Cheng Shi Resistant starch prepared by isoamylase debranching of low amylose starch
US6890571B2 (en) 2002-05-14 2005-05-10 National Starch And Chemical Investment Holding Corporation Slowly digestible starch product
US7081261B2 (en) 2002-05-14 2006-07-25 National Starch And Chemical Investment Holding Corporation Resistant starch prepared by isoamylase debranching of low amylose starch
US20030219520A1 (en) * 2002-05-14 2003-11-27 Yong-Cheng Shi Slowly digestible starch product
US20030215499A1 (en) * 2002-05-14 2003-11-20 Yong-Cheng Shi Use of completely linear short chain alpha-glucans as a pharmaceutical excipient
US6929817B2 (en) 2002-05-14 2005-08-16 National Starch & Chemical Investment Holding Corporation Slowly digestible starch product
US20050239679A1 (en) * 2002-10-18 2005-10-27 Solvay Interox Gmbh Method for producing dust-free alkaline earth peroxides
US7488439B2 (en) * 2002-10-18 2009-02-10 Solvay Chemicals Gmbh Method for producing dust-free alkaline earth peroxides
US20040086566A1 (en) * 2002-11-04 2004-05-06 Alpharma, Inc. Waxy matrix dosage forms
US6846497B2 (en) 2003-01-30 2005-01-25 National Starch And Chemical Investment Holding Corporation Rapidly expanding starches with altered crystalline structure
US20060008521A1 (en) * 2004-07-09 2006-01-12 Yeli Zhang Tablet excipient
US8871270B2 (en) 2004-07-09 2014-10-28 Corn Products Development, Inc Tablet excipient
US20090011014A1 (en) * 2004-12-24 2009-01-08 Universite De Montreal Tablet Formulation for Sustained Drug-Release
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