JPH0749378B2 - Enzymatically debranched starch as a tablet excipient - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to tablet excipients and more particularly to the manufacture of tablets, pellets, capsules or granules for the delivery of drugs, chemicals or other active agents. It relates to an effective starch binder and / or filler.
The tablet excipient of the present invention comprises alpha- 1,6-D-
It is prepared by enzymatic treatment with glucanohydrase to debran starch and at least 20% by weight of short chain amylose. The starch can be fully or partially debranched and will be composed of amylopectin, partially debranched amylopectin, long chain amylose or mixtures thereof in addition to short chain amylose.

[0002]

Tablets and capsules usually contain several excipients in addition to the active ingredient present in an amount sufficient to achieve the desired pharmaceutical, nutritional or chemical effect. It is composed of an inert material that is exposed. These excipients are generally classified according to their function, such as diluents (also called bulking agents and fillers), binders that hold the components together. Tablets include disintegrants that help the tablet break down or release the active ingredient when placed in a flowing environment, lubricants that improve release of tablets compressed from a die or punch, glidants and punches that improve flowability. It may contain an anti-adhesion agent which inhibits the film formation above. Other optional ingredients include moisture absorbers, surface brighteners and / or hardeners, dyes, flavors, sweeteners, antioxidants and / or sorbents.

Different properties are required for the starch used as the binder and the starch used as the degrading agent. The most important property required of the binder is compressibility. Granular starch and conventional pregelatinized starch (ie steamed or cold water dispersible starch) are:
Does not bond well under direct compression.

Tableting and some capsule filling operations are based on the property that certain powders combine under compression. Compressed tablets are produced by wet granulation, dry granulation (eg sludging) or direct compression. Common dry dose capsule fills use materials that can be formed into capsules or plugs and then fed by gravity or force to the materials that can be used to fill the capsules. For the former, materials that improve the flowability of the powder mixture are desirable. For the latter, a binder diluent is required that readily compresses under low pressure to form a soft plug. Since different functional properties are required for these different operations, starch-based excipients will not be effective for all operations or will present different challenges in different operations.

As a typical step involved in wet granulation, the ingredients are mixed to prepare a granulated binder solution, and the ingredients are mixed well with the above granulated solution to form a dough, which is then wetted by a sieve. The steps include coarse screening of the mass, drying, grinding, adding a lubricant and compressing the tablets.

The steps involved in sladding are to mix the powdered ingredients into compacts into hard sludge, grind the sludge to the desired particle size, add other excipients and compact the mixture into tablets. The step of doing is included.

Direct compression, which is the most preferred and economical tableting method, requires only two steps: mixing the dry ingredients and compressing the mixture into tablets. .

The binders or binder diluents used in the above tabletting or capsule filling operations are free-flowing powders which are stable, non-reactive, non-hygroscopic and to some extent miscible. Should be. Binders used for direct tableting require good binding properties.

Typical wet granule binders include starch paste, conventional pregelatinized starch, gelatin, polyvinylpyrrolidone, methylcellulose, sucrose, dextrose and natural gums.

Pregelatinized, modified and stabilized waxy maize starch, pregelatinized tapioca, potato starch, stable modified amylopectin, low viscosity tapioca dextrin, dextrinized corn starch and / or Or conventional starch binders such as cold water swellable pregelatinized cornstarch are water soluble and have limited direct compressibility, if any, and are typically used for direct compression tableting. Although not, it is suitable for wet granulation. Such wet granule binders are used in blends with another binder (s) that have direct compatibility. Such blends are useful in a hybrid wet granulation-direct compression tableting process.

Representative direct compression binders include microcrystalline cellulose, compressible sucrose, certain calcium salts, lactose and dextrose. Of these, microcrystalline cellulose is the preferred binder and it also exhibits good degrading properties. However, tablets made with this binder are
It is not preferable because it tends to have a rough surface. Also, microcrystalline cellulose is very expensive. Other preferred binders include calcium phosphate (di- or tri-basic) and compressible sucrose, each of which has drawbacks. That is, calcium salts are unable to prepare tablets with high levels of active ingredients, and generally require the use of disintegrants. Sucrose, which consists primarily of sucrose, has the drawback of becoming brown and prone to hardening over time, and can react with drugs. Lactose has limited binding properties and exhibits a browning reaction when exposed to heat or moisture. Mannitol and sorbitol show certain taste benefits,
It lacks binding properties and requires degradants or is too hygroscopic or too expensive.

[0012] Physically engineered, partially cold water swellable, compressed starch is reported to be effective as a binder decomposer for direct compression tableting (each by RWShort et al. 23 November 1971 and 1978
See U.S. Pat. Nos. 3,622,677 and 4,072,535, issued Feb. 7, 2012), and effective as free-flowing fillers for dry dose capsules. (See US Pat. No. 4,072,535, supra). The modification is done by passing the starch through closely spaced steel rollers with or without supplemental heat energy, and disintegrating or breaking at least some of the granules. , Resulting in a mixture of fragments of birefringent and non-refractive granules, and starch (typically about 10-20%) being completely solubilized. The compacted mass is crushed and sized into particle size fractions. The obtained starch is
Although direct compression bonding is limited, the loading potential is low and the use of auxiliary binders is often required.

Hydrolyzed starch, eg about 0.5
Dextrinized starch having a dextrin equivalent weight of -50 is used in the hybrid wet-direct compression tableting process to produce non-flying, water-soluble tablets, such as tablets for sweetened or unsweetened beverages. Melting point raising agent "(see U.S. Pat. No. 4,384,005 issued May 17, 1983 by DRMc Sweeney). An aqueous wetting agent consisting of corn syrup and optionally glycerin is added to the dry mixture containing the acid and optional ingredients, and the hydrolyzed starch acts as a melting point raising agent and the wet mixture is added directly. It is added in an amount sufficient to be added to a free flowing mixture suitable for compression. The above melting point raising agents increase the melting point of the mixture such that the tablet often melts or forms a hard core during the drying step following tablet formation.

Starch fractions, such as non-granular amylose, have also been reported to be effective as binder decomposers in direct compression or double compression (dry sludging) tabletting methods (GK Nichols et al. 19
U.S. Pat. No. 3,490,74 issued Jan. 20, 1970
No. 2 specification). This amylose fraction is non-granular because the inducing starch is generally solubilized to release amylose. This material gelatinizes starch, then high molecular weight (long chain)
It is produced by fractionating amylose from gelatinized starch in water at elevated temperature. The binder degradant must contain at least 50% negative (eg, long chain) amylose, which is present in starch.

US Pat. No. 4,551,177 issued Nov. 5, 1985 to Trubiano et al., As a binder for tablets made by direct compression or dry granulation, or in capsules. Effective as a bond decomposer for and
A free-flowing granular starch derived from compressible granular starch that is cold water soluble by treatment with an alpha -amylase enzyme at a temperature below the gelatinization temperature of the starch, wherein the treated starch is a dense starch. Disclosed is a compressible starch consisting essentially of starch that binds when the starch powder is compressed, characterized in that it is a modified, weakened granule with a low interior and a degraded surface.

[0016]

None of these starch products exhibit all of the desirable binder properties of microcrystalline cellulose in direct compression tableting. Due to the high cost of microcrystalline cellulose, there is a need for a compressible starch that is suitable as a binder in tableting processes, especially direct compression, and is also effective as a binder for capsule filling operations. Additionally, a glossy and smooth surface often belongs to tablets, which is desirable and there is a need for binders that create such a surface appearance.

[0017]

Means for Solving the Problems Alpha- 1,6-D-
De starching the starch by enzymatic treatment with a glucanohydrolase, such as plulunarase or isoamylase,
And it has been found that starch, which gives at least 20% by weight of short-chain amylose, is an excellent direct compression tablet binder that provides tablets with a glossy, smooth surface. Additionally, the debranched starch is selected such that its functional properties favor various tablet shaping functions.

Consisting of starch which has been enzymatically treated with an alpha- 1,6-D-glucanohydrase, such as, for example, plurnalase or isoamylase to debran the starch and yield at least 20% by weight of short chain amylose. Tablet excipients, and especially tablet binders, are provided herein. The present invention also provides a method for producing crystalline amylose from the above debranched starch. The debranched starch can be composed of amylopectin, partially debranched amylopectin, long chain amylose or combinations thereof.
Such tablet excipients are useful for direct tabletting or other tabletting operations.

The term "tablet" used in the present invention includes tablets, capsules, pellets, granules and the like used as an excipient for delivering the active agent (s). Also, the term "excipient" means
Includes binders and other excipients described herein.

The term "short chain amylose" as used in the present invention refers to a linear polymer containing about 15 to 65 units linked by alpha- 1,4-D-glucosidic bonds. Also, the term "long chain amylose"
Refers to the naturally occurring linear fraction of starch, which generally consists of 250 or more anhydrous glucose units.

The fully debranched starch can consist of up to 100% by weight of short-chain amylose, depending on the type of starch used, and virtually all amylopectins, as well as the enzymatic activity of short-chain amylose. It will be pruned so that it does not result in a measurable percentage change. Such starch may be modified by derivatization, crosslinking or conversion.

As the starch suitable in the present invention,
Result alpha of hydrolysis of 1,6-D- glucoside acid -
Mention may be made of amylopectin-containing starch which is considered to have been attacked by 1,6-D-glucanohydrolase, such as plurnalase or isoamylase. Any starch except amylose as isolated may be utilized. Suitable starches include corn,
High amylose corn, potato, sweet potato, wheat, rice,
Examples include sago, tapioca, sorghum, waxy maize, waxy rice, smooth pea, and Canadian pea.

Those skilled in the art will recognize that the maximum short chain amylose content that can achieve enzymatic debranching depends on the type of starch selected. For example, high amylose corn starch contains up to 70% long chain amylose as well as about 30% amylopectin. Actual short-chain amylose content is typically lower than theoretical.

The starch is pregelatinized to show sufficient and uniform enzymatic debranching. It is used in dry form or in aqueous dispersion fluidized gelatinization. Various methods of pregelatinizing starch, such as jet-steaming, drum-drying,
Direct or indirect heating by spray drying and steam injection atomization as well as chemical (eg NaOH) or mechanical (eg extrusion) gelatinization processes are known in the art. Any method can be used in the present invention. In a preferred embodiment, such starch is slurried in water and about 300 °.
Jet steamed at F (149 ° C).

Converted starch may be used in the present invention. The conversion degrades the starch and reduces the viscosity of the cooked starch dispersion. Conversion of starch to thin-boiling or free-flowing starch useful in the present invention is accomplished by standard oxidation, heating, acid or alpha -amylose enzyme conversion techniques known in the art. can do. A method of starch conversion using alpha -amylose enzyme is described in US Pat. No. 4,726,957 to Lacourse et al. And is known in the art. Dextrinized starch can also be used in the present invention.

Acid-, oxidative- or enzyme-conversion can be carried out on either derivatized or derivatized starch, but derivatized on acid- or oxidative-conversion and on dextrinization. One of ordinary skill in the art will recognize that the use is well known in the art.

Derived starches and converted and derivatized starches are suitable for debranching,
It is also suitable for use in tableting binders. Suitable derivatives include acetic acid esters and half-esters such as succinate and octenyl succinate prepared by reaction with esters such as anhydride, succinic acid and octenyl succinic acid (“OSA”), respectively; orthophosphoric acid or tripolyester. Phosphoric acid derivatives prepared by reaction with sodium or potassium phosphate; ethers,
For example, hydroxypropyl ether prepared by reaction with propylene oxide; and other suitable starch derivatives. Those approved for use in foods and / or pharmaceuticals are preferred.

Each modified starch has a suitable degree of substitution (DS) to provide a balance of fat-bonding, flowability, heat stability, molecular size, etc. and compression properties as desired by those skilled in the art. ) And / or the degree of conversion should be indicated. The amount of derivatizing agent used depends on the type of reagent, the amylose content of the starch or starch mixture, the amount of conversion and debranching. Typically, as conversion, crosslinking or derivatization increases, debranching must be controlled to provide the proper balance of properties and maintain compressibility. Those skilled in the art will also recognize that the compression properties required will depend on the compressibility of the active agent, the loading of the ingredients in the tablet, the other ingredients in the tablet and the method of making the tablet.

OSA starch derivatives are preferred when better emulsification or fat-binding properties are required. The person skilled in the art will recognize that the emulsification properties required depend not only on the fat content of the tablet, but also on the intended use of the tablet (eg broth). A preferred starch derivative for fat-binding or emulsifying formulations is a jet-prepared by treatment with up to 3% octyl succinic anhydride.
Cooked, debranched starch derivatives or jet-cooked, acid-converted OSA starch derivatives having a water flow of 85 or less.

Such starch may be cross-linked before and after debranching to provide heat and shear resistance in the manufacture, use and storage of tablets.

The crosslinked starch which can be used in the present invention can be produced according to the methods described in the prior art. The reaction conditions used will vary with the type of crosslinker used as well as the starch size, batch size, etc.

Preferred cross-linking agents for food and pharmaceutical starches include epichlorohydrin, phosphorus oxychloride, sodium trimetaphosphate and adipic acid-acetic anhydride. Treatment with sodium trimetaphosphate which gives up to 0.4% residual phosphoric acid calculated as phosphoric acid gives up to about 2.5% bound acetyl. Phosphorus oxychloride is preferred at a treat level of about 0.1% by weight of starch. Such starches may also be derived by treatment with up to about 25% propylene oxide or up to about 4% succinic anhydride to give the corresponding starch derivative. These treatment levels or OSA treatment levels are preferred as they are within the food and drug dosing control limits. Other processing levels are preferred for non-food products.

The above-mentioned starch-forming method, slurry pre-gelatinization, conversion, dextrinization and cross-linking are well known,
Known in the art, eg MW Rutenberg
Handbook of Water-Soluble Gums and Resins, by Robert L. Davidson (ed.), MacGraw Hill Book C
o., New York, New York, 1980, pp. 22-36 "Starch
and Its Modifications ".

In the production of modified starch, conversion or dextrinization is typically carried out before the pregelatinization step. However, it is also possible to pregelatinize the starch prior to such treatment. Similarly, derivatization or cross-linking is typically done before the pregelatinization step, although this order can be reversed. Branch cutting
Pre-gelatinization is performed on modified (ie derivatized, cross-linked, dextrinized or converted) or unmodified starches to ensure a uniform product. Must be done before the pruning process.

In a preferred embodiment, the next step after producing the modified starch is to gelatinize the starch, thereby disrupting the association of the starch molecules in all or part of the granular structure and rendering the molecule enzymatic. Is more compatible with and makes the enzyme easier and uniform to debranch starch molecules. After the starch has been gelatinized, the solids content, temperature and pH of the aqueous dispersion are adjusted to provide maximum enzyme activity.

The optimum parameters for enzyme activity depend on the enzyme used. Thus, the starch debranching rate depends on factors such as enzyme concentration, substrate concentration, pH, temperature, the presence or absence of initiator, and other factors. Depending on the type of enzyme or its source, various parameters may need to be adjusted to achieve optimal digestion rates. In general, the preferred enzymatic debranching is one that is performed at the highest feasible solids content to facilitate subsequent drying of the starch composition while maintaining optimal reaction rates. For example, for pullulanase used in the present invention, 28%
Pre-cooked starch dispersions ranging up to solids are preferred.

Those skilled in the art will appreciate if higher solids starch systems (eg, about 50% solids) are gelatinized in the process to provide sufficient mixing to uniformly mix the starch and enzyme at high solids. It will be appreciated that the higher solids starch system described above is utilized. Furthermore, those skilled in the art will also recognize that temperature, treatment time and other parameters in the enzymatic debranching process must be adjusted to higher solids content. Processes utilizing high solids dispersions are within the scope of this invention and can be used to produce the debranched starches of this invention.

The method of the present invention is described using pullululanase (EC 3.2.1.41, pullulan 6-glucanohydrolase) as the enzyme component, such as isoamylase (EC 3.2.1.68) or the like. Endo- alpha- 1,6-D-glucanohydrolase, which shows selectivity in the degradation of 1,6-bonds of other starch molecules, virtually completely eliminates 1,4-bonds and gives short-chain amylose. The debranched starches of the present invention can be produced using a class of compounds.

In a preferred embodiment, the enzyme used is a thermostable debranching enzyme obtained from a new species of Bacillus . This enzyme belongs to the group of debranching enzymes known as pullululanases. It catalyzes the hydrolysis of alpha -1,6-bonds in pullulan and amylopectin, provided that there are at least two glucose units in the side chain. Pullulan consists essentially of D-glucopyranosyltriose units linked by an alpha -1,6-linkage.

Optimal concentrations of enzyme and starch substrate are determined by the level of enzyme activity and the enzyme source.
Enzyme activity is determined by the source and type of enzyme and the concentration of enzyme in the commercial batch.

While the process of the present invention uses the enzyme in solution, it is within the scope of the present invention to use the enzyme immobilized on a solid support.

Debranching proceeds in the presence of a buffer to give p
Ensure that H is at the optimum pH level throughout the degradation. Buffers such as acetate, citrate or other weak acid salts are applicable. Other agents can be used to optimize enzyme activity. This reaction is Bacillus
(60) for pullulanase obtained from Bacillus
PH range from 3 to 7.5, preferably 4.
It is carried out in the pH range of 5-5.5, optimally at pH 5.0.

The aqueous starch dispersion is a Bacillus ( Bacill)
us ) for pullulanase 25 at pH 5.0
It must be maintained during enzymatic digestion at temperatures of ~ 100 ° C, with a preferred temperature range of 55-65 ° C, optimally 60 ° C. However, if shorter treatment times are desired, a temperature range of 60-65 ° C or higher enzyme concentrations can be used. Alternatively, higher temperatures may be used when a thermostable enzyme that gives short chain amylose from starch is selected in the present invention. With respect to other parameters defining enzyme activity, the preferred and optimum temperature ranges will vary with other parameters such as substrate concentration, pH and other factors, and can be determined by one of ordinary skill in the art.

The enzymatic reaction is continued until the desired level of debranching is reached. The progress of the enzymatic reaction can be measured by various methods. If all critical parameters are established for achieving a particular starch composition, the reaction will eventually proceed to a predetermined relative end point. The endpoint can also be monitored and defined by measuring the number of reducing groups released by alpha -1,6-glucanohydrolase activity by this method known in the art. Other techniques can be used to define the reaction endpoint, such as changes in viscosity, iodine reaction or monitoring changes in molecular weight. If the starch is sufficiently debranched, the short-chain amylose will precipitate from the debranched starch dispersion on standing (in the preferred starch solids range, eg 28%) and will reach the end point when no further precipitation occurs. To reach. The precipitate can be resuspended and the dispersion can be spray dried, preferably at temperatures above 60 ° C., to give a product containing at least 70% by weight of short chain amylose. it can. In addition, the short chain amylose can be recovered by filtering and washing the precipitate and spray drying the washed precipitate, preferably at temperatures above 60 ° C.

The short-chain amylose content is preferably measured by gel permeation chromatography. After separating the starch by gel permeation chromatography into fractions of different molecular weight, the percentage of short chain amylose was
It is determined by calculating the percentage by weight of the partially debranched starch eluted in the low molecular weight fraction. It will be appreciated by those skilled in the art that these percentages are approximately equal to the amount of short chain amylose released from amylopectin by debranching enzyme. Experimental errors in gel permeation chromatography (for example, due to contamination by enzymes or by contamination with sugar or dextran added with starch, enzyme solutions, buffers, or other process components) are more likely than short-chain amylose in starch samples. Also results in short-chain amylose that is as large as about 5%.

The degree of starch debranching required for tableting applications depends on the function of the starch in the tablet, the type of starch used and its extent and activity when converted, derivatized, crosslinked or dextrinized. It depends on the type and amount of ingredients, tablet formulation, physical properties (capsules, pellets, granules, tablets) and other tablet manufacturing requirements.

Preferred starches include waxy maize, potatoes, tapioca, waxy rice and other starches containing high percentages of amylopectin. In a preferred embodiment, the starch is debranched to 100% by weight of short chain amylose. Typically, starches containing large percentages of amylopectin yield about 75-90% short chain amylose. Partially debranched starch containing about 20-75% short chain amylose is also preferred for use in the present invention.

After the desired degree of starch debranching has been achieved, the enzyme can be inactivated. Purululanases are immediately inactivated at temperatures above about 70 ° C,
The reaction can therefore be conveniently stopped by raising the temperature of the starch dispersion to at least 75 ° C for about 15 minutes. If the starch is fully debranched, it is not necessary to inactivate the enzyme. This debranched starch is recovered by separating the short chain crystalline product precipitate from the mother liquor, which contains the reaction system with soluble starch fragments, enzymes and other products, and dehydrating the short chain amylose. You can

When purification of the debranched starch composition is required, reaction impurities and byproducts are dialyzed,
It can be removed by filtration, centrifugation or other methods known in the art to isolate and concentrate the starch composition. The fully debranched starch is centrifuged,
Dehydration can be done by filtration and other methods known in the art.

If a dried starch composition is desired,
The starch may be dried by spray drying, flash-drying or any other method known in the art.

This debranched starch can be used in blends that are effective as tablet binders.
For example, starch binders effective for wet granulation typically have some degree of water solubility or dispersibility and are limited in their direct compressibility.
Such starch is used in the wet granulation stage of the hybrid tablet manufacturing process. Typically following this stage,
The step of compressing the wet granules (bound by a water soluble starch binder) into dry final tablets is performed. Debranched starch is effective as a binder for direct compression in the drying stage. Therefore, a blend of two starches is effective in such a formulation. Wet granulating binders useful in binder mixtures are known in the art and have been described above. Pregelatinized starch, such as corn starch, is useful in the present invention.

A variety of starch miscible active agents can be used in the tablets of the present invention. The specific nature of the active ingredient is not critical, and pharmaceutically and non-pharmaceutical active ingredients such as milled detergents, dyes, pesticides, agricultural chemicals, enzymes and foods can be used. Typical products include pills, drug and vitamin capsules and tablets, fertilizers, pesticides, rodenticides, animal feed, briquette,
Examples include broth and other seasoning tablets. The term "tablet" is used in its broadest sense in the present invention and is meant to encompass all of the above products.

If necessary, a decomposing agent can be used. As such decomposition, a raw starch, a modified starch, a gum, a cellulose derivative, a fine crystalline cellulose,
Clays, effervescent mixtures and enzymes.

A binder (or a mixture of binders),
The amounts of active ingredient and lubricant, disintegrant and / or diluent, if present, are not only the desired potency but also the compatibility of the ingredients, the tableting method used, the amount of debranching, the percentage of short chain amylose, And further, the flight properties of the final tablet,
Depends on degradability, solubility and / or stability. The amount of binder diluent used in dry dose capsules likewise depends on various factors. Once given the minimum and preferred properties desired in the final product, the acceptable limits of weight ratio of the components will be readily determined by one of ordinary skill in the art. Anti-adhesives, glidants, flavours, colorants and the like may be used. These are incorporated into the tablets of the invention in a suitable effective amount.

As readily determined by one of ordinary skill in the art,
Particular embodiments of the debranched starch disclosed in the present invention include binder (s), moisture absorber (s) (eg,
Starch dried to 2-3% water), binder decomposer (s), filler (s) or gradient (s),
It can be selected as a tablet excipient that acts as a lubricant (s) or flow agent (s), tablet surface gloss or hardening agent (s) or combinations thereof.

[0056]

The following examples fully explain the embodiments of the invention. In the examples below, all parts and percentages are by weight and all temperatures are in degrees Celsius unless otherwise noted.

The following methods were used to characterize debranched starch useful in the present invention, to monitor its manufacturing process, and to manufacture and evaluate tablets containing such compressible starch. did.

Water Fluidity Measurement The water fluidity of starch is 10
Requires 23.12 ± 0.05 seconds between 0 revolutions 2
30 with standard oil having a viscosity of 4.73 cps
Thomas Rotational Shear-Type standardized at ℃
Viscometer (Arthur H. Thomas Co ,. Philadelphia, P
Manufactured by A 19106). An accurate and reproducible measurement of water fluidity depends on the extent of starch conversion (viscosity decreases as conversion increases).
It is obtained by measuring the time elapsed for 100 revolutions at different solids levels. The method used is to slurry the required amount of starch (eg 6.16 g on a dry basis) in 100 ml of distilled water in a coated copper cup and heat the slurry in a boiling water bath with occasional stirring. Including that. The starch dispersion is then diluted with distilled water to a final weight (eg 107
g). 1 of the dispersion obtained at 81-83 ° C
The time required for 00 revolutions is recorded and converted to water fluidity as specified in the table below.

Time required for 100 revolutions (seconds) Amount of starch used (anhydrous, g) 6.16 ^a 8.80 ^b 11.44 ^c 13.20 ^d Water fluidity 60.0 5 39.6 10 29.3 15 22.6 20 20.2 25 33.4 30 27.4 35 22.5 40 32.5 45 26.8 50 22.0 55 24.2 60 19.2 65 15.9 70 13.5 75 11.5 80 10.0 85 9.0 900 For a, b, c, and d, the final weight of the starch solution is
Weigh 107, 110, 113 and 115 g respectively.

Gel Permeation Chromatography Slurry 5 mg of starch in 4 ml of dimethylsulfoxide ("DMSO") containing 0.3 M sodium nitrate and the slurry for at least 30 minutes
The starch for analysis was prepared by heating to ° C. A sample (200 μl) was added to ALC / GPC-15
0C Chromatograph (Water Associates, Milford, Mas
Sachusetts (Nelson 3000 Series Chromatography Data System and PL Gel Mix 10 μl Column)
(Polymer Laboratory, Amherst, Massachusetts)) as the mobile phase using DMSO containing 0.03 M sodium nitrate and 1 ml / ml.
Elution was performed at a rate of minutes. This column was loaded with a dextran standard (Pharmacia Chemicals, Piscataway, NJ, Mw 2,000; 20,000; 80,000;
500,000; and 2,000,000)
Was measured using. The percentage of short chain amylose was calculated from the relative areas of the peaks obtained within the molecular weight range of about 500-200,000.

Example 1 This example illustrates the production of debranched starch.

Preparation of Debranched Starch Starch was added as applicable prior to gelatinization and treatment with pullululanase. To add the starch, 100 parts of a slurry in 150 parts of water was heated to 52 ° C, the indicated amount of hydrochloric acid (1.75%) was added and the mixture was stirred at 52 ° C for 16 hours. . Hydrolyze this mixture with alkali (3% sodium hydroxide solution)
It was stopped by neutralizing to pH 5.5 at pH 5.5. The converted starch was collected by filtration, washed and dried.

To produce the octenylsuccinate derivative, 100 parts of starch are slurried in 150 parts of water, the pH-value is adjusted to 7.5 with sodium hydroxide and a certain amount of octanier amber is prepared. Sample anhydride was added slowly while maintaining the pH at 7.5 with alkali. The reaction was complete when it was no longer necessary to add more alkali. The pH was adjusted to 4.0-6.5 and the resulting derivative was collected by filtration, washed and dried.

To produce the acetate derivative, 10
Slurry 0 parts starch in 150 parts water to pH
Was adjusted to 8.0 with 3% sodium hydroxide, and the specified amount of acetic anhydride was added slowly, the pH being
Was maintained at 8.0 with the above alkali. The reaction was complete when it was no longer necessary to add more alkali. pH
Was adjusted to 4.0-6.5, and the resulting derivative was collected by filtration, washed and dried.

100 parts of starch were slurried in 150 parts of water and cross-linked by adding 0.8 parts of sodium hydroxide, 1.0 part of sodium chloride and then the specified amount of phosphorus oxychloride. Starch was produced. The slurry was stirred at room temperature for 3 hours. When the reaction was complete, the pH was adjusted to 5.5 with acid. The starch was collected by filtration, washed and dried.

Aqueous slurry (20-30% solids) was added to
Produced using one of these modified starches or, where applicable, native starch. The aqueous starch slurry was jet steamed at about 300 ° F (149 ° C) to gelatinize the starch. The steamed starch dispersion was placed in a constant temperature bath at 60 ° C. with constant stirring. The pH was adjusted to 5 with 3% hydrochloric acid.

Depending on the type of starch used and its amylopectin content, a value of 0.
5-10.00 ml of pullulanase was added to this cooked starch dispersion. Used pullulanase
(EC 3.2.2 41 pullplan 6-glucanohydrolase) is a starch debranching enzyme produced from a new species of Bacillus . This enzyme [Promozyme®] is obtained from NOVO Industri A / S, Denmark. The enzyme activity of the 1.25 g / ml solution of Promozyme is
Normalized in 200 PUN / ml solution. 1P
UN (pullulanase unit NOVO) is the amount of enzyme that, under standard conditions, hydrolyzes pullulan to eliminate reducing hydrocarbons with a reducing power equal to 1 micromol glucose per minute. The method of measuring PUN is NOVO I
Obtained from ndustri A / S. Thus, for example, in a starch dispersion using corn starch, 125 PUN of pullululanase is added to the dispersion per 100 g of corn starch. For the waxy mize starch dispersion (which shows a higher amylopectin content), 750 PUN per 100 g of waxy mize starch,
Add to the dispersion.

The starch was debranched until the desired short-chain amylose content was reached by pullulanase. The fully debranched starch forms a crystalline precipitate on standing which is either filtered and washed before spray drying as described below, or 71-
Flash dried at an inlet temperature of 110 ° C and an outlet temperature of 50-85 ° C. The pullululanase was inactivated by heating the dispersion to at least 80 ° C. The starch dispersion was spray dried at an inlet temperature of 200-210 ° C and an outlet temperature of 120-90125 ° C.
The spray dried starch was screened with a # 40 mesh screen.

Preparation of Crystalline Short-Chain Amylose A 28% solids slurry of waxy mize starch in water was jet steamed at 149 ° C. (300 ° F.) to give a 25% solids starch dispersion. The dispersion was placed in a constant temperature water bath at 60 ° C., the pH was adjusted to 5.0, and 8 ml of Promozyme purpurnase per 100 g of starch was added to the dispersion. The enzymatic reaction was carried out by stirring for 88 hours with continuous stirring.

On standing, a crystalline precipitate formed in the milky starch dispersion. The precipitate was filtered, washed 3 times and air dried to give crystalline short chain amylose in about 85% yield. Gel permeation chromatography showed that the product contained 84% short chain amylose.

A second dispersion of waxy maize starch was debranched in a similar manner except that the enzymatic reaction was continued for 48 hours and the filtration and washing steps were omitted. The dispersion was then spray dried at 26% solids in a Nirolaboratory spray dryer with an inlet temperature of 210 ° C and an outlet temperature of 125 ° C. The product was composed of 78% short chain amylose and was recovered in about 75% yield.

Tablet Production Using a laboratory scale tablet press (Stokes, Model B-2,16 3/8 "standard concave punch, Stokes Co., Warminster, PA), tablets were formed from the following formulations: did.

[0073] Ingredients wt% functional acetaminophen (APAP) ^a 64.00 active ingredient Binder 34.75 Binder Magnesium stearate ^b 1.00 lubricants amorphous fumed silica ^c 0.25 fluidizing agent. a. USP from Mallinckrodt, St, Louis, Missouri
Powder. b. NF powder obtained from Ruger Chemical Co., Irvigton, New Jersey. c. Obtained from Cabot Corporation, Tuscola, Illnois
Cab-O-Sil (registered trademark).

All ingredients except the binder were dry blended, screened on a 10 mesh screen and blended with the binder.

Tablets weighed 360-460 mg were formed in a tablet press at pressure settings from A (low) to I (high) by adjusting the weight setting for each compression setting. Compressibility is expressed as the profile obtained by increasing the pressure setting until the associated hardness measurement levels off. The tablet hardness was measured using a hydraulic hardness tester (Delamar, Model PT 1000, Va
Kel Industries, Edison, New Jersey) kg / cm ²
Was measured in units of.

Acetaminophen (APAP), the active ingredient
Tablets are formed in the absence of binder even under high pressure without compression. Thus, binders effective in formulations containing acetaminophen, especially the very high loading tablets used in the present invention, were effective in virtually all commercial tablet formulations.

Example 2 This example illustrates that the fully debranched starches of this invention are superior binders as compared to commercial binders in direct compression tableting.

Direct compression tablets were made according to the formulation of Example 1 using the starch debranching and tabletting method of Example 1. The commercial binders used as controls are set forth in Formulas 1 and 2 below. Visual observations of compression profiles, structurally weak, capped or broken tablets are set forth in Tables 1 and 2.

[0079] a. Not compressible. b. Incompressible; structurally weak, capped or broken tablets. c. Incompressible; structurally weak, capped or broken tablets. A modified starch binder produced by the method of US Pat. No. 3,490,742. d. Incompressible; structurally weak, capped or broken tablets. Modified starch binder ("Star" produced by the method of U.S. Pat. No. 4,072,535).
ch 1500, "Colorcon Inc. West Poingt, PA). e. Modified starch binder produced by the method of US Pat. No. 4,551,177. Tablets were structurally intact when removed from the tablet press. .

[0080] Incompressible; structurally weak, capped or broken tablets. ForemostWhey Products, Baraboo, Wisc
Fast # 316, hydrous lactose obtained from onsin; Edwar
Emcompr obtained from d Mendell Co., Carmel, New York
ess, dibasic calcium phosphate dihydrate. b. Obtained from FMC Corporation, Newark, Delaware
Avicel pH 101, microcrystalline cellulose. c. Fully debranched waxy maize starch obtained by the method of Example 1 (77.0% short chain amylose content). d. Fully debranched waxy maize starch obtained by the method of Example 1 (84.3% short chain amylose content). e. Fully debranched waxy maize starch obtained by the method of Example 1 (85.2% short chain amylose content).

The results show that the native starches (Waxywise, corn and potato) form structurally weak tablets, most of which break or cap (the top part (cap part) is peeled off during molding). Destruction). Although the compressibility (weight to hardness) profile showed some binding capacity, the disruption of tablet integrity made the native starch unsuitable as a binder, especially for high load (64%) APAP formulations. Similar results were obtained using isolated potato amylose (US Pat. No. 3,490,742) and starch modified by the method of US Pat. No. 4,072,535.

Some binding capacity is observed in 1) modified starch produced by the method of US Pat. No. 4,55,177, 2) hydrous lactose; and 3) dibasic phosphate dihydrate. It was However, only the processed starch of U.S. Pat. No. 4,551,177 formed tablets, which were intact, crushed, and showed no capping when removed from the press. . Lactose- and calcium phosphate-containing tablets were structurally weak, capped and broken. The best compressibility and structural integrity is achieved by microcrystalline cellulose and well debranched waxy maize starch (77.0-85.2% short chain amylose).
Were observed in tablets manufactured from The debranched starch had excellent compressibility. Additionally, tablets made from debranched starch had a smooth, glossy surface and remained intact when the tablets were removed from the tablet press.

Example 3 This example shows that partially debranched starch (about 20
˜60% short chain amylose) is an effective tablet binder.

The formulations and methods of Example 1 were used to test the partially debranched starches shown in Table 3 below. The results are shown in Table 3.

Table 3 Binder profile Direct compression APAP formulations Tablet hardness expressed in kg / cm ² for partially debranched starch Machine position 24.5% SCA ^a 28.0% SCA ^a 32.6% SCA ^a 52.4% SCA ^a 60.1% SCA ^a A B 2.0 2.5 2.5 C 2.0 2.0 3.0 D 2.0 2.5 3.0 E 2.0 3.3 2.5 3.3 2.5 F 3.0 3.0 3.0 3.0 2.8 G 2.0 3.0 2.5 2.8 3.3 H 2.0 3.3 2.0 2.5 5.3 I 1.5 2.0 2.0 2.0 2.0 a. Short-chain amylose content of waxy maize starch that has been debranched.

This result is commercially viable in that the tablet binder performance is that the tablets are compressible (but less miscible than microcrystalline cellulose) and retain their structural integrity when removed from the press. It is shown that the binder is similar to that of the modified starch of US Pat. No. 4,551,177 and is better than that of the lactose and calcium phosphate binders (see Tables 1 and 2). The partially debranched starch also formed tablets with a smooth, glossy surface.

Example 4 This example illustrates that various raw starches can be used in the present invention.

The formulations and methods of Example 1 were used to test the partially debranched starches shown in Table 4 below. The results are shown in Table 4.

TABLE 4 Binder Profile Direct Compression APAP Formulation Tablet Hardness Expressed in kg / cm ² Machine Position Partially Debranched Cone Partially Debranched Tapioca Starch 32.5% SCA ^a Starch 42.9% SCA ^a A B C D E 2.0 4.5 F 2.5 4.0 G 3.0 4.5 H 2.5 4.0 I a. Short chain amylose content of partially debranched waxy maize starch.

The results show comparable tablet binder performance of partially debranched starch from different sources. The positive attributes of partially debranched waxy maize starch were also observed for partially debranched corn and tapioca starch.

Those skilled in the art will recognize that the conditions used in these examples (eg, weathered APAP formulations) are more severe than those encountered in industrial operation. Thus, the performance of debranched starch under such conditions indicates that such starch is effective in virtually all tableting operations requiring binders by direct compression.

[0092]

INDUSTRIAL APPLICABILITY A compressible starch excipient which is suitable as a binder in a tableting method comparable to expensive microcrystalline cellulose, particularly in direct compression, and is effective as a binder for a capsule filling operation is a main object of the present invention. Provided by the invention. The binder according to the invention also creates a glossy, smooth surface.

Claims (4)

[Claims] 1. A starch is debranched by enzymatic treatment with alpha-1,6-D-glucano-hydrase and selected from the group consisting of amylopectin, partially debranched amylopectin, long chain amylose and mixtures thereof. About 15% by weight of the starch component and at least 20% by weight of alpha-1,4-D-glucoside linkages.
A tablet excipient consisting of starch in a mixture of short chain amylose from ~ 65 anhydroglucose units, said tablet excipient being a binder degrading agent, a binder diluent, a filler or diluent, a water absorbing agent. Tablet excipients which are agents, glidants, lubricants or flow agents, surface brighteners or hardeners or combinations thereof. 2. A starch is debranched by enzymatic treatment with alpha-1,6-D-glucano-hydrase and selected from the group consisting of amylopectin, partially debranched amylopectin, long chain amylose and mixtures thereof. About 15% by weight of the starch component and at least 20% by weight of alpha-1,4-D-glucoside linkages.
Tablets of starch in a mixture of short chain amylose from ~ 65 anhydroglucose units. 3. A starch is debranched by enzymatic treatment with alpha-1,6-D-glucano-hydrase and is selected from the group consisting of amylopectin, partially debranched amylopectin, long chain amylose and mixtures thereof. About 15% by weight of the starch component and at least 20% by weight of alpha-1,4-D-glucoside linkages.
A tablet excipient consisting of starch in a mixture of short chain amylose from ~ 65 anhydroglucose units, the tablet starch being a binder,
Tablets that are binder decomposers, binder diluents, fillers or diluents, moisture absorbers, glidants, lubricants or flow agents, surface brighteners or hardeners or combinations thereof. 4. A. Starch is alpha-1,6-D
A starch component selected from the group consisting of amylopectin, partially debranched amylopectin, long-chain amylose and mixtures thereof by enzymatic treatment with glucano-hydrase to debran starch and at least 20
A mixture consisting of wt% short chain amylose from about 15-65 anhydroglucose units linked by alpha-1,4-D-glucosidic bonds, b. A method of making a tablet, comprising the steps of drying the starch mixture, c) blending the starch mixture with at least one active agent to form a blend, and d) compressing the blend into tablets.