CA2103635A1 - Aqueous dispersions of zein and preparations thereof - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Stable aqueous dispersions of zein which may be used as controlled release coatings of pharmaceutical, animal, health/ or food products in an inorganic solvent-free environment are disclosed, as well as methods for preparing the same.

Description

3~ 93 ~:19 AQIJEOUS DISPERSIONS O~F ZEI~J ~JD
C!ONrl'RO~ E!D ~RE~ E_rOi~TlNG~3 DER~VED T}lEREFROM

1131~CKGROU D OF l'HE~ NTION
Coatings have long been applied to pharmaceu-~icals, animal health produc~s, and food products for various reasons, including masking unpleasan~ taste, protecting components from degradation, controlling the site of drug release (enteric coating), controlling the absorption of - lo ~h~ drug compound by retarding release of the drug rom the ~ dosage form, improving the appearance of the produc~l and: changing the physical. surface characteristics o~ the-. ingredients.
The oldest metho~ of coating is perhaps sugar-coatingO
In sugar coating~ the ob~ects to be coated are moistened with an aqueous su~ar solution and tumbled ~for example in a rotating pan), ~nd then dried. The moistening and drying procedures are generally repeated many times before ~atis-,1 factory protectio~ of the object to be coat~d and a sm~oth . 20 sur~ace are obtained.
It is generally considered desirable to apply a seal coat directly over the uncoated tablet, etc~ in ord~r to . separate the object to be coated from the water that is used in the coating process. Many substances have been used as sealing agents in ~his step, including cellulose-. acetate-phthalate, zein, shellac, and other specific , resins. Thereafter, the product may be subcoated, syrup ;~ coated, Pinished, and polished, although many variations of these procedures are used. The sealing coat is applied as ~, 30 a dilute, nonaqueous solution, and not more than two or three thin coats are used to seal the tablets.
More recently, film-coating techniques that have used a wide variety of materials of coating agents have been ,: develop~d, in order to overcome the host of problems that ~,J,~ 35 can be encountered in attempting to sugar coat a tablet, .

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2 ~ c,,~ 3~ 93~ 19 - such as color spotting, cracking of the coatiny, degrada-tion of the drug in the tablet, and excessive suboGatillgs ; which cause retaYdation of disint~gration and bioavail-abil.ity.
Most film-coats are prepared by depositing one or more ; film-forming polymers onto the object to ~e coated, result-: ing in coatings that represent usually from about 2 to 10%
by weight of the coated tablet. Such film coatings tend to have better resistance to chipping of the coating, in-creased tablet st~ength, and decreased production C0i5it as compared to sugar coating. The polymers used in ilm-`~ coating are generally water soluble or water dispersible cellulose derivatives such as hydroxypropyl methylcellulo~e and carboxymethylcellulose.
Hydrophobic polymers such as certain cellulose deriva-tives, acrylic resins, waxes, higher aliphatic alcohols, and polylactic polyglycolic acids have been used in the - development of controlled release pharmaceutical dosage :, forms, such as tablets, capsules, suppositoxies, spheroids, ,` 20 beads or microspheres by, e.g., overcoating the individual dosage units with t}lese hydrophobic polymers.
,, It is known in the prior art that these hydrophobic coatings can bé applied either from a solution, suspension or as dry powders. Since most of hese polymers have a low solubility in water, they are usually applied by dissolving the polymer in an organic solvent and spraying the solution onto the individual drug forms (such as beads or tablets) ~1 and evaporating off the solvent.
~ ', The use of organic solvents in the preparation of : 30 polymer coatings is considered problematic as the I formulations have inherent problems with regard to :,~ flammability~ carcinogenicity, and safety in general. In addition, the use of organic solvents is not favored due to environmental concerns.

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~ost commercially available aqueo~ls clispersions of pre-formed polymers (e.g., ethylcellulose-Aqu~co~t~, Surelea~e~) are prepared via emulsifi~aticn of organic polymer solutions or polymer melts into a~ ~queo~ls ph~se followed by homogeniza~ion. 3rganic solvents used in this process are w~ter-immiscible.
While co~tings for pharmaceutical formulations, etc., comprising zein are ~onsidered desirable, the use o~ such coatings has b~en limited because zein is not soluble in water-immiscible organic solvents and therefore canrlot be prepare~ by the traditional emulsification techniques . described above.
~; Wi~h regard to confectionery coatings, U.SO ~atent No.
2,791,509 (Cosler) describes a coating for non-cereal con-feckionery articles which comprises zein and acetylated glycerides which are appl ied ~o ~he food articles in an edible organic solvent vehicle, such as 90~ ethanol, or ethanol denatured with a minor amount of ethyl acetateO
However, it is stated therein that virtually any o~ganic solvent can be used which is edible, nontoxic, and in whioh the zein and acetylated monoglyceride are solubleO The coating is said to form a continuous barrier against the penetration of water into the confectionery and against penetration of fat, oil and moisture from the interior of the confectionery to the outside.
U.S. Patent No. 4,931,29S (Courtright, et al.) is related to methods for producing a chewing ~um with a zein , ., : coated "delayed release" high-potency swee~en~r. The term .~ "delayed releasel' as used therein is intended to infer a delayed release of the high-potency sweeten~r during chewing of the gum and during storage. In this process, th~ zein is mixed with a solvent or the zein, and a water ' soluble modified cellulose compound such as HPMC to form a i modified zein solution. This modified zein solution is ~ 35 applied tQ a high-potency swee~ener and then dried to .~ ,, .

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4 ~ 3 3 93 419 produce ~he delayed release sWee~ener particles. The particles are then added to a chewing gum ~or~ulation. In a preferred embodiment, the zein is ~issolved in wa~er having a pH of between abou~ 11. 5 and about 12 . 1 and ; 5 contains about 13 weight percent zein. The zein is said ts be either completely dissolved or a major portion of the ; zein is dissolved and a minor portion is suspended in the water. In a second prefer~e~ method, ~he zein is dissolved in ethanol, to between about 10-15% by weight of the ~ 10 solution. The zein is said to comprise about 1-15% of the : coated high-pot~ncy sweetener, the zein, and the HPMC.
~ U.S. Patent No. 3,371,QlS (Sjogren, et al.) describes : tablet coatings comprising an inner layer of a polyethylene glycol which i5 soluble in water and in cPrtain organic solvents, and an outer layer of a film~forminy thermo-plastic substancP which is water insoluble but solubl~ in volatile organic solven~s. Substances which are considered to be suitable for the oUter layer include oellulose , acetates, acrylic resins, silicone resins, as well as ~, 20 shellac and zein.
~` U.S. Patent No. 3,365,365 (Butler, et al.) describes : pharmaceutical composi~ions in ~he form of beadlets suit-:~, able for filling into hard shell capsules, wherein the ,~ beadlets are enteric coated with a coating containing zein and an abietic acid type rosin. The enteric coating which is used for preparing chlordiazepoxide beadlets are ~: :3 produced by mixing the abietic acid type rosin with zein, :3 a wetting agent, an anhydrous lower aliphatic alcohol, and i -a plasticizer.
`I 30 U.S. Patent No. 3,370,054 (Loew~ describes deaminated ~: zein dispersible in solutions having a pH of at least 6.5 which is prepared by hydrolyzing zein with strong alkalies, ~, and thereater removing the alkali by precipitation.
U.S. Patent No. 4,983,403 (Ardaillon, et al.) .1 35 describes a bio~ogically active substance for the feeding .i ,,~ , , ~

~ 3 93 ~19 of ruminants. The composi~ion consists of a ruminant feed additive coated wi~h a mix~ure consisting o~E 2ein in combination wi~h a non-wa~er-solu~le polymer; a hydrophobic substance; a non-wa~e~-soluble polyme~ and a plasticizing agent; or a hydrophobic substance and a non-water-soluble polymer. The coating mixture is said to b~ ob~ained by dispersing or dissolving zein in a solution or dispersion of the non-water soluble polymer and/or of the hydrophobic substance, and optionally, the plasti~iæing agent, in an organic solvent or in a mixture of suitable organic 501v-ents. The coating mixture is obtained afte~ evaporation of the solvent or solvents.

O~JECT8 AND SUM~A~ OF THE INVENTION
It is therefore an object of the present invention to prepare aqueous dispersions of z~in ~o be used in the coating of pharmaceutical, animal, health, or food products in an organic solvent-free environment.
It is a further object of the pr~sent invention to prepare a solid powder o zein in a redispersible form `~ which thereafter may then be dispersed by the consumer prior to the coating process.
It is a further object of the present invention to provide a stable aqueous dispersion of zein which ~ay ~e stored, e.g., at room temperature, for an extended period ;~' of time.
I It is a further object of the present invention to provide a ~ontrolled release coating of an aqueous dispersion of zein for a substrate comprising an active agent, such as a tablet core, which coating provides a ' controlled release of the active agent at a desired rate ; when the coated substrate is exposed to aqueous solution.
~i It is a further object of the present invention to provide a method for obtaininq a controlled release coating J 35 of an aqueous dispersion of zein for coating a substrate . ~

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comprising an active agent, which coating provides a reproducible controlled release of the active agent at a desired rate when the coated substrate is exposed to an aqueous solution.
In ~iew of the above objects and o~hers, the preser,t invention is related to an aqueous dispersion of ~ein, the aqueous dispersion comprising from aibout 0.1 to about 10 - percent zein. The aqueous dispersions of the pr2sent invention prefera~ly have a pH from about 4 to about 6.
Generally, the particle size of the zein in the aqueous dispersion is ~rom about 0.01 to about 10 ~m. The aqueous .. dispersion is essentially free of organic solvents~
- Th~ present invention ii~ also related to a method for preparing an aqueous dispersion of zein, wherein a solvent mixture comprising water and from about 60 to about 90 percent of an organic solve~t is prepared, zein is added to I the solvent mixture in such a proportion to the solvent ~............... mixture that the zein dissolves in the solven~ mixture, and -~ 1 the zein is precipitated as fir,e particles o obtain an aqueous dispersion comprising from about 0.1 to about 10 percent w/v of zein. The organic solvent may be, eOgO, i ethanol, ace~one, and mixtures thereof.
.~ In a preferred embodiment, the method furth~r com-j prises the steps of pouring the solution of zein as a thin stream into an aqueous phase under continuoUs stirring to .~ thereby precipitate the zein as fine particles. The organic solvent is then evaporated from the mixture, and the resulting aq~eGus phase is concentrated to a zein ~`~ concentration from about 0.1 to about 10% w/v.
~: !30 The present invention is also related to a powdered, j.~
i~ redispersi~le form ~f zein. This zein powder may be redispersed prior to use in a coating process.
In further embodiments, the present invention is related to a stabilized agueous dispersion of zein ~:~; 35 comprisir,g from about 0 .1 to about lO percent zein w/v : '' :' l :~:
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~ 93 ~9 having a particle size from about 0.01 llm to about 10 ~m, and an effective amount of a pharmaceutically acceptable preservative in an amount effective to prevent sedimen-tation.
In preferred embodiments, the pharmaceutically acceptable preservative is preferably selected from the group consisting of benzalkonium chloride, benzoic acid, benzyl alcohol, methyl paraben, propyl paraben, ethyl ~; paraben, butyl paraben, sorbic acid, a quaternary a~monium ~ 10 salt, phenol, cresol, mercury-contai~ing preservatives, and ;; mixtures of any of the foregoing.
Other further embodiments of the prese~t invention a~e directed to a method of preparing ~ stable aqueous disper-sion of zein, comprising adding a pharmaceutically accept-able preservative to an aqueous dispersion of zein com-~ prising from about 0.1 to about 10 percent zein w/v i~ a~
- amount effective to prevent sedimentation of the zein when -~ ~ said stabilized aqueous dispersion of zein.
~ In yet other e~bodiments, the present invention is directed to a solid controlled release formulation, such as a tablet, comprising a substrate comprising an activ~
agent, said substrate coated with a controlled release .j coating to ~ weight gain from about 0.5 to about 100 3 percent, said controlled rel~ase coating compri~ing (i) an :~ 25 aqueous dispersion of from about 0.1 to about 10 percent -~ zein w/v having a particle size from about 0.01 ~m to about 10 ~m, and preferably from about 0.1 ~m ko about 2 ~m, said aqueous dispersion obtained ~y precipitating zein by pouring a solution of zein in a solvent comprising water :`:330 and from about 60 to about 90 percent organic solvent as a ~ i thin stream into an aqueous phase under continuou~ ~tir-ring, the organic solvent thereafter being substantially removed and the resulting aqueous phase concentrated; tii) a pharmaceutically acceptable preservative; (iii) a pharma-. 35 ceutically acceptable plasticizer, the preservative and the . .j `~ J
~ 1 8 ~ tf~ 93-~19 plasticizer each being in~ludPd in an amount n~cessary toO
provide a continuous film capable of releasing the active agent at a desired rate when the formul~tion is exposed to an aqueous solution.
The active agent may be, e~y., a systemically a~tiv~
therapeut.ic agent, a locally active therapeutic agent, a disinfecting and sanitizing agent, a cleansin~ agent, a `~ ~ragrance agent and a fertilizing agent. Other applica~
tions for the controlled release formulations include agricultural, food and household products.
The controlled release coating of the present in-vention may further comprise a rate-controlling agent selected from thP group consisting of water soluble hydrophilic polymers, semi-permeable polymers, selectively permeable polymers, pore-forming materials, microporous material, erosion promoting agents, and mixtures of any of the foregoing. Instead of or in addition to the rat~-controlling agent, the controlled release coating may -~ further comprise one or morP release-modifying passageways formed therein.
;; The present invention is further related to a method for preparing a controlled release formulation comprising coating a substrate comprising an active agent with a sufficient amount of the preserved, plasticized aqueous dispersion of zein of the present invention to obtain a ; j predetermined controlled release of the active agent when the coated substrate is exposed to aqueous solutions.

BRIEF DESCRIPTION OF THE D~WINGS
~he following drawings are illustrative of embodiments of the invention and are not meant to limit the scope of . . .i!
the invention as encompas~ed by the claims.
Figure 1 is a graphical representation of the dis-solution profiles obtained by Examples 29 and 30;

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- ` 93--419 Figure 2 is a graphical representation o:E the dissolution proflles obtained by Example 31;
Figure 3 is a graphical representation of the dissolution profiles obtai~ed by ~xamples 33 36;
Figure 4 is a graphical r~p~esentation of the dissolution profiles obtained by Examples 37 - 39;
F`igure 5 is a graphical represent~tion of the dissolution profiles obtained by Ex~n~pl2s 40 - 42;
Figure 6 is a graphical representation of the - 10 dissolution profiles obtained ~y Fxampl~s 44 and 45:
Figure 7 is a graphical representation o~ the dissolution profiles obtained by Example ~3, and Figure 8 is a graphical representation oP the dissolution profiles obtained by Examples ~6 and 47.
D~TAI~ED DESCRIRTION
Zein is a protein of the prolamine class which is a fraction of a protein contained in corn~ Commercially, it has been obtained, for example, by extractinq corn gluten with a 60-80% isopropyl alcohol under alkaline conditions.
~! After neutralization and concentration, the extra~t con-taining the æein is sprayed into cold water, causing the zein to precipitate. See, e.g., U.S. Patent No. 2,676,169 (Baldoni) and the patents cited therein.
In the past, zein has found many uses as a coating ~l material. However, the use of zein as a coating material has been considered problematic because zein does not bar the migration or transfer o~ moisture, and has been known to form a relatively hard coating having a low tensile ~,30 strength and is easily fractured. As a coating material for food products, zein coatings are known to form relatively hard and crunchy coatings.
Zein is soluble in aqueous alcohols, glycols, and acetone~ water mixtures. The preparation of zein dis-persions is governed by the solubility properties of this ~, .. 1 .

10 ~ 3 9~-~19 natural polymer. Zein is not soluble in water~immiscible organic solvents (e.g., me~hylene chloride) which are commonly used to prepare pseudolatexes ~y emulsification techniques.
In accordance with preferred embodiment of the present invention, zein dispersions are pr~pared by dissolving zein in a mixture of water with either ethanol and/or ac~tone.
Preferably, in order to maximize the amoun~ of zein in the dispersion, the solvent mixtures used in the present invention have a volume percentage of ethanol, acetone or mixtures thereof from about 60 to about 90 percent. How-ever, it is p~ssible to obtain an aqueous dispers.ion according to the present inva~tion with a l~wer a~ount of the organic solvent.
Instead of ethanol ~nd/or a~etone, other organic solvent/water systems may be used to dissolve the zein.
For ~xample, the solvent mi~tures of the present invention may comprise isopropanol, methanol, and the likeO Isopro panol and/or methanol in a ratio of 7:3 (oryanic solvent~
water) work up to a zein concentration of about 10% zein w/v. At higher percentages ~e.g., 15% zein w/v~ a gel is :' formed. Other solvent systems, such as ethyl aceta-te, DMF
and DMS0 may also work but have undesirable properties relative to the preferred embodiments wherein the organic solvent comprises ethanol/water and/or acetone/water.
It has been discovered that more ~han 40~ w/v zein can ` be dissolved in solvent mixtures with a volume percentage -~ I of ethanol and/or acetone between from about 60 to about so. The viscosity of these concentrated solu~ions is , 30 relatively high.
In a preferred embodiment of the invention, the "~
solution of zein is added to an agitated aqueous phase.
Zein precipitat~s as ~ina parti~les resulting in a dispersion. These dispersions are then preferably ;l 35 concentrated, e.g., by evaporating water.

:: 1 ~" ~ ,1 ,, '`, ~ 93-~l9 The upper limit of zein in the zein ~ispersions of the present inven~ion are zein concen~ra~ions of a~ou~ 10% w/v~
Higher concentrations have been found to resul~ in ~he formation of agglomerates. After concentrating the dis~
persions of the present invention, it has been found that the maximum soli~s content obtainable is about 10% w/v.
Agglomeration and sticking to the vessel are observed at higher solids cont~nt.
The pH of the aqueous zein dispersions of the present ~0 invention is generally in the range from about pH 3 to about 7. In preferred embodiments of the present inven-tion, the zein concentration in the aqueous dispersion is from about 6 to about 10 % w~v, and the p~ is rom about 4 to about 6. In most preferred embodiments, the aqueous zein dispersion has a p~ from about 4.5 to about 5.5. When the p~ of an aqueous zein dispersion of 6-10% w/v is adjusted substan~ially a~ove pH 6 or below pH 4 via the use of electrolytes or buffers, the dispersion has been found 3 to become unstable and a fine dispersion of zein is no I 20 longer obtained which would be suitable for commercial -~ applications, such as in spray coatings. For example, at least a portion of the zein particles will no longer be in a desirable nanoparticle size rang~. The zein in the dispersion may precipitate, agglomerate, and/or flocculate at such pH levels. Stability may be achieved at substan-~:~ tially higher pH's, e.g. pH 9-10 or above. As indicated in the Merck Index, zein is solu~le in alXaline solutions of pH 11 5 or greater. Therefore, it is possible at pH 9-lO
and above, a portion of the zein in the aqueous dispersion ¦ 30 is solubilized.
If an adjustment of the pH of the aqueous dispersion ~q; is deemed desirable, it may be possible to do so via the use of an inorganic or organic monomeric or polymeric acidic or basic compound which do not ionize to any sub-stantial degree without causing precipitation, agglomer~
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~q 12 ~ I,r, ~ ~j 93-419 ation and/or flocculatlon in the aqueous pseudolatex dispersio~.
In another embodiment of the present invention, the pH
of the aqueous zein dispersion can be adjusted by adding a suitable buffer system to adjust the pH of the aqueous z~in dispersion to above abou~ pH g. For example, suitable buffer systems include an ammonium carbonate-ammonia buffer, a citric acid~sodium phosphate buffer, and a boric acid-potassium chloride-sodium hydroxide buf~erO
In a preferred embodiment, the particle siz2 of the zein in the aqueous dispersion is from about 0.01 to about 10 ~Lm, although depending upon the desired use of the end product, larger particle sizes may be acceptable. In most preferred embodiments of the present invention, the -- 15 majority of the zein particles in the resultant aqueous - dispersion are from absut 100 t~ about 300 nanometers.
In another embodiment of the present invention, a zein dispersion is prepared as set forth above and then is dried to obtain fine parkicles, preferably smaller than about lO~m. The fine particles of zein which are obtained are preferably in the size range from abou~ 0~1 to about 5.0 ~m. The zein dispersi~ may be dried by any suitable method known to those skilled in the art, such as spray Ij dryingl freeze drying, oven drying, vacuurn dryiny, etc.
j 25 The zein powder may thereafter be redispersed in an aqueous ;I solution when so desired.
The use of a redispersible zein powder is desirable for a variety of reasons. First; microbiological concerns ~! and the necessary addition of preservatives to the aqueous dispersion would be minimized or eliminated. Secondly, the `i; redispersible zein powder of the present invention results in reduced shipping volumes and a greater flexibility at the formulation stage.
The aqueous dispersions of zein used as coatings in the present inv~ntion may be used in virtually any appli~

i cation in which a coa~ing wo~ld be desi:rable, inclucling use in conjunction with food products, animal health products, confectionery products, and various pharmaceuticals, in-cluding tablets, spheroids, granules (or beads), micro-spheres, seeds, pellets, ion~exchange resin beads, and other multi-particulat~ syste~s in order to obtain desired controlled release of the therapeutically active agent. Granules, spheroids, or pellets, etc., prep~red in accordance with the present invention can be presented in a capsule or in any other suitable dosage form.
The coating formulations of the present invention should be capable of producing a continuous ~ilm ~hat is smooth and elegant, capable of suppor~ing pigme~ts and other coating additives, non-toxic, inert, and tack-fr~eO
To achieve this objective, other suitable pharmaceutically acceptable a~ents may be added to the dispersion. For example, the inclusion of a plasticizer may be desirable in - the event that ~he film formed by the zein coating ls otherwise too bri~tle. ThP addition of a surfactant may : 20 also be desirahle. Wa~er-soluble plasticizers, e.g., glycerin, propylene glycol, and PEG 400, ar~ preferred in comparison to the wate~-insoluble plasticizers, eOg., dibutyl sebacate (DBS), triethyl citrate (T~C; sometimes classified as a water-soluble plasticizer), tributyl .~25 citrate (TBC), acetyltributyl citra~e (ATBC), and acetyl~
~ trie~hyl citrate (ATEC). Propylene glycol at a concen-.'' tration from about 20 to about 25%, based on the amount of .! zein, appears to be the best plasticizer. Certain plasti-cizing agents, such as polypropylene glycol and polye~hyl-ene glycol, have been found to solubilize part of the pro-~;~ tein (zein) as well as plasticize the film. The resultant ,.JI product therefore comprises a solution o~ zein as well as a dispersion of zein.
~, In preferred embodiments, the plasticizer is water~
;~;i 35 soluble and is incorporated in a sufficient amount to ~ ,1 ..i . . .

1 4 ~ !,'; .. J 9 3--4 19 provide a desired formation of ~he film to be made from the aqueous zein ~ispersion of ~he present inventi.on~ The amount of plastici2er added is preferably from about 20 to about 40 percent, based on the zein content.
One skilled in the art will recognize that the selec~
tion of such additional pharmaceutical agents and the level of inclusion of these agents in the zein latex should be optimized for the particular use. Also, in the case of pharmaceutical coatings, once the beads, tablets, etc. have been successfully coated, the dissolution properties of the `~ particular formulation can be Gptimized.
Control~ed release coatings obtained from the aqueous dispersions of the p~esent invention have been determined to fail relatively quickly, i.e., the active agent com-prising the substrate is released very quickly due to failure of the film coat. Upon inspection, it was been discovered that the coating had numerous small cracks which allowed rapid hydration of the tablet core. The cause of this rapid disintegration of the continuity of the film coating is not known.
However, in a further embodiment of the present in~
vention, it has now been surprisingly discovered that the i addition of a pharmaceutically acceptable preservative prevents the degradation of the zein dispersion of the present invention. As previously men~ioned, it is there~
fore desired in certain embodiments of the present in~
vention to include a pharmaceutically acceptable preser-vative is selected from ~he group consisting of benzal-konium chloride, benzoic acid, benzyl alcohol, methyl ~; 30 paraben, propyl paraben, ethyl paraben, butyl paraben, ; sorbic acid, a quaternary ammonium salt, phenol, cresol, mercury-containing preservatives, and mixtures of any ~f the foregoing.
With regard to the aqueous dispersions of the present invention, the pharmaceutically acceptable preservative is , ~

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15 93-~l9 included in an amount effective to preven~ sedimentation of the zein (e.g., less than about 20% sedimentation after 30 ~ays). In e~bodiments of the present invention which are directed to controlled release coatings, the preservative is included in an amount whlch is effective to provide a continuous film capable of releasing the active ayen~ at a desired rate when thie formulatlon is exposed to an aqueous solution.
In certain preferred embodlments, methyl paraben in an amount of at least 0.05%, w/v is incorporated into the aqueous dispersion of zein. In another preferred embodi-ment, methyl paraben and propyl paraben in a ratio of about lO:l are incorporated into the aqueous dispersion of zein, the methyl paraben being present in an amount of at least 0.05%, w/v. In an especially preferred embcdiment, the preservative comprises about 0~2% methyl paraben and about 0.02% propyl paraben, w/v.
The release of the active agent from the controlled - release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the i addition of one or more pore-formers which can be .inorganic -~, or organic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. Upon exposure to fluids in the environment of use, ~5 the pore-formers are, e.g., dissolved, and channels and pores are formed that fill with the environmental fluid.
~;l For example, the pore-formers may comprise one or more ;l water-soluble hydrophilic polymers in order to modify the release characteristics of the formulation. Examples of suitable hydrophilic polymers include hydroxypropylmethyl-., cellulose, cellulose ethers and protein-derived materials.
; Of these polymers, the cellulose ethers, especially ~; hydroxyalkylcelluloses and carboxyalkylcelluloses, are ; .~! preferred. Also, synthetic water soluble polymers may b used, such as polyvinylpyrrolidone, cross-linked polyvinyl , '~

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16 ~;~, $ . `1, ,i, .f~ 3 J 93-~l9 pyrrolidone, polyethylene oxide, etc., water-soluble polydextrose~ s~ccharides and polysaccharides, such as pullulan, d~xtran, sucrose, glucose, fructose, mannitol, lactose, mannose, galactose, sorbitol and the like In certain preferred embodiments of the present invention, the hydrophilic polymer comprises hydroxypropylmethylcellulose.
Other examples of pore-formers includ~ alkali metal salts such as lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, and the like.
The pore-forming solids may also be polymers which are soluble in the envlronment of use~ such as Carbowaxes~, Carbopol~, and the like. The pore-formers embrace diols, polyols, polyhydric alcohols, polyalkylene glycols, poly-glycols, poly-alkylenediols, and the like.
Semipermeable polymers may also be incorporated in the controlled release coating as a pore-former to change the release characteristics of the formulation. Such semi-permeable polymers include, or example, cellulose acylates, acetat~s, and other semipermeable polymers such as those described in U.S. Patent No. 4,285,987 (hereby incorporated by reference), as well as the selectively permeable polymers formed by the coprecipitation of a polycation and a polyanion as ~isclosed in U.S. PatO NosO
3,173,876; 3,276,586; 3,541,005; 3,5~1,006 and 3,546,142 (hereby incorporated by reference).
Other pore-formers which may be useful in the formu-lations of the present invention include starch, modified starch, and starch derivatlves, gums, including but not lim.ited to xanthan gum, alginic acid, other alginates, bentonite, veegum, agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed, okra gum, arabinogalactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylo-pectin, dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange resins, such as potassium polymethacrylate, ;J

,'`1, 17 93 ~19 carrageenan, kappa-carrageerlan, lambdacarrageenan, gum karaya, biosynthetic gum~ etc. Other pore-formers include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer ch5ain, microporous materials such as bisphenol, a microporous poly(vinylchloride), microporous polyamides, microporous modacrylic copolymers, micropor~us styrene-acrylic and its copolymers~ porous polysulfones, halogenated poly~vinylidene), polychloro-ethers, acetal polymers, polyesters prepared by esteri-~i fication of a dicarboxylic acid or anhydride with an .
alkylene polyol, poly(alkylenesulfides), phenolics, poly-esters, asymmetric porous polymers, cross linked olefin polymers, hydrophilic microporous homopolymers, copolymers or interpolymers having a reduced bulk density, and other r similar materials, poly(urethane), cross-linked chain-extended poly~urethane), poly(imides), poly(benzimida-; zoles), regenerated proteins, semi-solid cxoss-linked j 20 poly(vinylpyrrolidone).
;~ In general, the amount of pore-former included in the ~j controlled release coatings of the present invention may be from about 0.1% to abou~ 80%, by weight, relative to the combined weight of hydrophobic acrylic polymer and pore-~5~ former.
The controlled release coatings of the present invention may also include an -exit means comprising at least one passageway, orifice, or the like. The passageway may be formed by such methods as those disclosed in U.S.
~3 30 Patent Nos. 3,845,770; 3,916,889; ~,063,064; and 4,088,864 all of which are hereby incorporated by reference). The .?
passageway can have any shape such as round~ triangular, square, elliptical, irregular, etc. The passageway may be included instead of, or in addition to, the inclusion of ,~, ~^3 35 ~ permeability-enhancing compounds, hydrophilic monomers, pH-~ ~ , ~ - f ~ ~

18 2 ~ ~ ~i J~3~ 93-~lg sensitive polymers, alld/or pore-formers, in order to obtain a release of the active agent(s) included in the formulation.
A wide variety of therapeutically active agents can be used in conjunction with the present invention. The thera peutically active agents (e.y. pharmaceutical agen~s) which may be used in the compositions of the present invention include both water soluble and water insoluble drugi,~
Examples of such ~herapeutically active agents include antihistamines (e~g., dimenhydrinate, diphenhydramin~, chlorpheniramine and dexchlorpheniramine maleate), anal-gesics (e.g~, aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.), anti-infla~matory agents (e.g., naproxyn, diclofenac, indomethacin, ibuprofen, acetaminophen, aspirin, sulindac), gastr~-intestinals and anti-emetics (e.g., metoclopramide), anti-epileptics (e.g., phenytoin, meprobamate and nitrezepam), vasodilators (e.g., nifed-- ipine, papaverine, diltiazem and nicardirine), anti-tussive agents and expectorants (e.gO, codeine phosphate), anti-~0 asthmatics (e.g. theophylline), anti-spasmodics ~eOg.
atropine, scopolamine), hormones (e.g., insulin, leparin), diuretics (e.g., eltacrymic acid, bendrofluazide), anti ~ hypotensives (e.g., propranolol, clonidine), broncho-; dilators (e.g., albuterol), anti-inflammatory s-teroids (e.g., hydrocortisone, triamcinolone, prednisone), anti~
biotics (e.g., tetracycline), antivirals, antihemorrhoid-als, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, antacids, vitamins, stimulants (including appetite suppressan~s such as phenylpropanolamine). The above list is not meant to be ~` exclusive.
~, In another preferred embodiment of the present inven-tion, the active agent is disinfecting aqent, e.g. chlorine compound, calcium hypochlorite and the aqueous solution is ~'!
.' I
` .`'.' ' `
, 19 ~ 93-~ls an environment of use, e.g., a surrounding body of ~later such as a recreational pool.
In ~till another preferred embodiment of the pre~ent invention, the active ayent is a cleansing agent, e.g., germicides, deodorants, surfactants, fragrancest perfumes, sanitizers, dye and the environment of use is an aqueous solution, e.g. a urinal or toilet bowl~
In yet another preferred embodiment of the present in-vention, the active agent is a chemical impregnant, e.g., fertilizer, animal repellents, pesticides, herbicides, fungicides, plant growth stimulants, and the environment of use is anywhere around the home, e.g. soil, trees etc.
.
DETAI~D DESCRIPTION OF T~ PREFERRED EMBODIMENT8 The following examples illustrate various aspects of the present invention. They are not to be construed to -~ limit the clai~s in any manner whatsoever.
'' . ' _~-2 D~terminin~ h2 ~lubility of_Zein The approximate solubilities of zein in different ethanol: water and acetone:water (v/v~ mixtures are determined. In Example l, dehydrated ethanol USP
1 obtained from a commercially available source (Midwest ;~ ~125 Grain Products Co., Pekin, IL) is add~d in different 1~ proportions ~0/lO, 2/8, ~/6~ 5/5, 6/4, 7/3, 8/2, 9/l, lO/0) to water. Next, a commercially available zein-granular powder (Freeman Industries, Inc. Tuckahoe, NY) is added to lO ml of each of the solvent ~ixtures in a glass vial. The mixtures are then agitated in a ~, horizontal shaker. The solubility (w/v) is then determined. The results arP set forth in Table l below.
.~
Example 2 is prepared in similar fashion to Example l, with acetone from a commercially available source : 35 (MallincXrodt Inc., Paris KY) being substituted for the ~:

` !

~ 3 93-419 ethanol. The res~lts are similar to those set forth for Example 1.
Table 1 Solubility of Zein in Ethanol/Water Mixtures Inqredient Amount ethanol/
water (v/v) 0/10 2/8 4/6 5/5 6/q zein (g in 10 ml) 0.20 0.20 0.20 1.0 0O40 solubility ` lw/v) ~0.1% <2% <2~ ~10% ~40%

In~r~dient ~mount ethanol/
water (v/v) 7~3 8/2 9/1 10/0 zein (g in 10 ml~ 4.00 4.00 4.00 0.20 solu~ility (w/v) ~40% ~40% ~40% <0.1%
l As can be seen from the results set forth in Table 1, i,~ more than 40% w~v zein can be dissolved in solvent mixtures with a volume percentaye of ethanol or acetone between 60 and 90. The viscosity of these concentrated solutions is high.
:
' ~X~MPLES 3-5 ~ l . . . _ Preparat~on of Aqu~ou~
Dispersion of Zein - Precipitation Method ~, In Example 3, solutions of zein in ethanol/water or acetone/water are added into an aqueous phase under contin-;' uous stirring. In Example 3, ~he solvent mixture used is .`!'~
3~ ethanol:water (8:2 v/v), whereas in Example 4 the solvent mixture used is acetone:water (8:2 v/v).
~ . ~
i: In Examples 3-4, 200 ml of the solvent mixture ~:1, (ethanol/water and acetone/water, each in a ratio of 8:2 . ~, . ~ .
., ,~
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2 ~ ( 3 ~ 93-~19 v/v, respectively) is prepared, and then 10% w/v zeirl is added. The resul~ant ~ein solution is pour~d as a thin stream into 200ml water. The zein precipitates immediately as fine particle~ resulting in dispersions. Stirring is continued to evaporate the organic solvent and concentrate the a~ueous phase, the alcohol and some water are evapor-ated off at room temperature to provide an aqueous dis-persion of zein (e.g., 6-10% w/v zein, and preferably 6-8%
zein).
The average particle size of the zein latex obtained by the evaporative method is from about 240 nm to about 300 nm, as determined by photon correlation spectroscopy (BI-200SM goniometer, BI-~030 digital correlator, Melles Griot lO mW ~e-Ne laser, Brookhaven Inistruments Corporakion, Holtsville, ~Y). Latexes are formed at zein concentrations of 6% w/v and 3% w~v.
In Example 5, zein dispersions are prepared by dis-solving zein in ethanol/water (6/4~ v/v). The resulting `~ solution is poured onto an aqi~ated aqueous phase. Zein precipitates as fine par-ticles resulting in dispersion~.
These dispersions are then concentrated.
Further investigations considered formulation vari ables such as the zein concentration, the volume of the zein solution, the volume of the external aqueous phase, and the addition of surfactants. From the results ob~
tained, it was determined that the upper limit of zein concantration in the aqueous zein dispersions is about 10%
w/v; higher concentrations of zein result in lump forma~
. tion. Moreover, after concentrating the dispersions, the maximum solids content obtainable by this method is about 8% w/v.
., :
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22 9~-~19 AM _ ES 6-7 Prepara~ion o~ ~queous ~isper~ion of Zein - Evaporation M~thod In Example ~, zein is added to solverlt mixtures com-prising ethanol/wat~r and acetone/w~ter (8:2 v/v~. The ; resultant zein solutions are placed in a beaker and stirred with a maqnetic stirrer.
In Example 6, the zein precipitates from solution after evaporation of the organic solvent until a 2ein concentration of 30% w/v is obtained. The product obtained in Example 6 did not have a pseudolatex formation, and large agglomerates/viscous lumps formed.
In ~xample 7, the organic solven~ is evaporated over a period of 48 hours in a one liter beaker, and a zein con-- 15 centration o 3% w/v is obtained~ The pH range of the pro-duct was 5-7. The product of ~xample 7 did have pseudo~
: latex formation~ Howev~r, in addition to small nanopar~
ti~les, some la~ger lumps and agglomerates were formed.
The results indicate that the precipitation method is superior to the evaporation method. TablP 2 below is a :' comparison of results obtained by these two rnethods.
.
:.:. T~ble 2 Comparison of Results Obtained by Evaporation and Precipitation Methods :
;.~ Evapo_a ion Precipitation Zein conc. ~%w/v) 30 3 6 3 , Pseudolatex `' 3C formation (Y/N) N Y Y Y
*Dispersion agglomerated ~: ' Red;sper~ability ~f Zein Parti¢les 35In Examples 8-9, zein latexes prepared according to Example 4 are spray-dried using a Buchl Mini Spray dryer (Model 190, BrinkMann Instruments, Inc., Westbury, NY; in let temperature = 90C~. In Example 8, a 5% w/v ~ein .~
i, 23 ~ ),J 93-~19 solutio~ was prepared in acetone/water (7/3 ~/v). In Example 9, i~ 10~ w/v zein solution ~ s prepared in ethanol/water (6/4 v/~r).
: In each of Examples 8 and 9, flne zein particles smaller than about 10 ~m are obtained. Most of the ~ein particles are smaller than about 5 ,umO

~X~MPL~ lg : ~ec~ o~ h~n~e~
In Examples lOa d, zein pseudolatexes ~re prepared according to Example 4~ A solvent mixtur~ of ethanol and water (6/4~ is prepared, and 6% zein W/V iS addedO 20 ml of the mixture is then added to an external aqueous phase~
In Example 10a, the external aqueous phase comprises a 20 ml buff~r solution prepared according to USP at different pH. The different buffer solutions and results are set forth in Table 3. From these results, it .is con cluded that a dispersion OL' zeln c:an be formed in bu:Efers of hi~h pH.
i20 Table 3 Stirring pH pH pi~ p~l time ~ L~ pH 5 7.4 9 lQ
0 large aggre pseudolatex .~ aggre- gates ~ little :~ gates aggregates :~l over large aggre- ps~udolatex ~;, 30 night aggre- gates & little - ~ gates agqregates pH 1.1: 0 . lM HCi 3: pH 3: 0.2M potassium hydrogen phthalate and 0.2h HCl pH 5: 0.2M potassium biphthalate and O.~M NaOH
pH 7 O 4: 0 . 2M monobasic potassium phosphate and 0.2M NaO~
pH 9 and pH 10: 0 . 2M boric acid + potassium chloride and ~- 3 o. 2M NaOH
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. ~

~d. ~. . - ., -2~ t~ 3,~ C3 3 ~
In Example lOb, tlle external aqueous phase comprises a 20 ml buffer solution prepared according to USP of o.
citric acid and 0.2M Na2HP04 at pH 3.5, pH 5, and pH 7.4.
At each pH, large aggregates form when the zein solution is added.
In Example lOc, the external aqueous phase comprises a 20 ml solution with a pH 7.4 buffer with different ionic streng~hs using NaCl to adjust ionic strength to 0.144, -~ 0.25, 0.5, 0.75 and 1Ø At each o~ ~hese ionic s~rengths, aggregates form when the zein solution is added.
`~ In Example lOd, the external aqueous phase comprises a 20 ml solution with a p~ 9.5 bu~fer made ~rom ammonium carbonate-ammonia. An accep~able pseudolatex is produced after stirring overnight.
EXA~IPLE 11 In Example 11, a zein pseudolatex is prepared accord-ing to the procedure se~ ~or~h in Example 4. The solid content of the latex is S~ zein (w/v). The zein pseudo-; latex is then plasticized hy adding 20~ propylene glycol, based on the zein conten~. Thereafter, the zein latex is ~` applied as a coating onto substrates.
In Example lla, Nu pareil beads are loaded with chlorpheniramine maleate, and thereafter coated with the ~ zein latex in a Uni-Glatt fluidized bed coater equipped `~ with a Wurster column. An inlet temperature of 60C is `~ used. An approximate 10% weight gain is applied to the ; beads. The pseudolatex is found to be easy to use and does `'30 not contain any undispersed zein. No sticking or congeal-~;~ ing is noted.
'','7 While the zein pseudolatex as prepared above was useful as a coating, it did not provide a slow release of the chlorpheniramine maleate from the zein coated beads '~35 (the drug was released at the same rate as the uncoated ~," ;~, .', :
i~' ' !`~. ` 1~

25 2 @ i .~ 9 3 419 beads). Examinat.ion uslng scanning electrorl microscopy revealed numerous crack~ in the film coat.
n ~ample llb, DSC analysis was performed on the zein latex ilm samples tha~ were cast at room temperature and at 60C. The Tg of the room temperature sample was 327K
and the Tg of the 60C film sample was 370K, indicating that the film formed at the lower temperature was plasti-cized to a greater degree, possibly due to residual moisture in the film and the loss of the propylene glycol ~t ~O~C.
In Example llc, a second batch of zein latex (5%
solid) is used to coat chlorpheniramine malea~e-loaded :~ beads under different operating conditions, with an inlet ~ temperature of 35C. The results of Example llc were ;: 15 similar to those of Examples lla and llb, with scanning electron microscopy reveal ing nUmerous cracks in the coating.
In Example lld, further studies are conducted to determine the effect of increasing amounts of plasticiz~r in the aqueous zein dispersion, and ko determine the effect ~ of relative humidity. A zein film containing equal amounts .~ of propylene glycol and zein on a weight basis is deter-mined to be flexible at about 0% relative humidity, but . becomes very sticky at 50% rela~ive humidityO For a zein film containing 35% propylene glycol on a weight basis o zein, at 50% relative hum.idity the film remains flexible.
1 At higher relative humidities, the film becomes more . sticky, and at lower relative humidities it slowly becomes :l more brittle as the film dried and moisture is lost from the film. From these studies, it is concluded that a propylene glycol range of about 10-40% would b~ suitable, with a propylene glycol range of 20-25~ being most `. preferred.
~:, l .

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2 6 2 ; ~ 3 9 3 'i 1 9 E:a~AMPLE :L2 ~e~ ion o~ zeln Film~
In Example 12, zein solutions are prepa~ed with and without plasticizer, and cast into aluminum petri dishes and dried at room ternperakure. In each of Examples 12a-12, the ~ein is added to 5-7 ml of a solvent mixture o ethanol/water (Examples 12a and 12b) or acetone/water ,~ (Examples 12c and 12d) in a ratio of 8:2 v/v. In Examples 12a and 12c, the resultant solution comprises 20% zein w/v, in Examples 12b and 12d the resultant solution comprises 30% zein w/v. Propylene glycol 20-40% is incorpoxated in~o the solutions as a plasticizer prior to casting. Smooth, transparent, flexible films are formed from 25% or 30% w/v zein solutions in ethanol or acetone/water mixtures (8O2 v/v~. However, the fil~3s became brittle after a few days and after storage of the fil~s in a desiccator, possibly due to further water evaporation or evaporation of the propylene glycol. In order to improve the flexibility of ~ the film, different plasticizers are added to the polymer ^.20 solution. The results indicate that water-soluble plasti-clzers, e.g., glycerin, propylene glycol, and PEG 400, pro~
; vide flexible films when compared to the water-.insoluble plasticizers, e.g., dibutyl sebacat~ (DB~), triethyl citrate (TEC3 r tributyl citr~te (TBC), acetyltributyl citrate (ATBC), and acetyltriethyl citrate (ATEC). Propyl~
~, ene glycol a~.-a concentration from about 20 to about 25%, i, based cn the amount of zein, appears to be the best plasti-;, cizer of those studied.
!

- l Btabilizing ~qu~ou ~ein Disper3ions With Different Pre~ervatives In Examples 13-18, different preservatives are added ~3 ~5 to zein dispersions made according to the present inven~
33 tion, and the effect of the preservative on the zein ~3 ~3 3 ~, 3 '3 27 93-~19 dispersiorl was noted upon stora~e. For each of Examples 13-18, the zein dispersion is prepared in accord~nce ~ith Example 3, i.e., 6% zein in ETOH/water solutiorl (6/4, ~o ml) was added to the same amount of water to maXe the ~ein dispersion. Thereafter, the pre~ervatives were added and the dispersion was continuously stirred for two days.
In Example 13, the preservative is benzalkonium chloride 0.25~ w/v. In Example 14, the preserva~ive is benzoic acid 0.5% w/v. In Example 15, the preservative is sodium benzoate 0.5% w/v. In Example 16, the preservative is benzyl alcohol 1% w/v. In Example 17, the preservative is methyl paraben, 0.2% w/v. In Example 18, the preserv-;~ ative is propyl paraben, 0.02~ w/v. The zein dispersions of Examples 13-18, along with a control (~ein dispersio~
without preservative) were then stored at room temperature for 5 days, and then examined at O days, 2 days; 5 days, 15 days, 30 days, 45 days and 90 days. The r~sults are set forth in Table 40 ~', Table 4 , Examples 13-18 Effect Of Preservatives On The Preparation Of Zein Dispersions Storage Time Amount Solid 0 2 5 Preservative %, _ ~ Content % ~y~ days days*
~-~ Benzalkonium chloride 0.25 6.3 good good good ;, 30 Benzoic acid 0.5 6.35 good good good Sodium rapid aggregation benzoate 0.5 and sediment ' ~' J, Benzyl alcohol 1 5.95 good good goocd ;, Methyl paraben 0.2 5.55 good good good 35Propyl paraben 0.02 5.05 good good good control 0 5.6 good good goocl ~. .

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28 ~ , 3 ~ 9 3 - q l g Table 4 Continued:
Preservative 15 days 30 days 45 days so days Benzalkonium 10%
chloride unchanged sediment unchanged 20~ sediment 2.5%
Benzoic acid unchanged sediment unchanged 10% sediment Sodium ; benzoate 1%
Benzyl alcohol unchanged sediment un~hanged 8% sediment Methyl paraben unchanged unchanged unchanged 4~ sediment Propyl paraben unchanged uncha~ged unchanged 4% secliment : 15 control all bad sediment smell bad bad * 5 days later, all samples had a little sediment.

:; 20 EXAMPLEs 19-23 In Examples 19-23, plasticizers, triethyl citrate ~TEC) 20~ w/v and propylene ylycol (PG) 20~ w/v w~re add--~ ed to the zein dispersions along with a preservative. In ~:. Example 19, the pres~rvative was benzalkonium chloride 0.25~ w/v. In Example 20, the preservative was benzoic acid 0.5% w/v. In Æxample 21, the prese~vative was sodium benzoate 1~ w/v. In Example 22, the preservative -~, was methyl paraben 0.2% w/v. In Example 23, the pre-servative was propyl paraben 0.02% w/v. The plasticized zein dispersions of Examples 19-23 were then stored at room temperature along with a control sample ~2ein dispersion without plasticizer or preservative) for 13 days, and examined at 0 days, 4 days, 6 days, 10 days and 13 days. The results are set forth in Table 5 below:
, ,~
~, :, ~.,1 . -`1 ~ ' : ,~

29 ~3''~ 93~419 Table 5 Examples 19-23 Effect Of Preservatives On The Storaqe_Of Zeln Dispersions Storage Time Preserva- Amount o 4 6 ti.ve %, w/v days days days :~: 10 Benzalkonium chloride 0.25 good good good Benzoic acid 0.5 good good good : 15 ^ rapid aggre-Sodium gation benzoate 0. 5 and - 20 sediment .~. Benzyl alcohol 1 good good good ~- 25 Methyl :. paraben O. 2 good good good .``~ Propyl paraben o. 02 good good good Control 0 good good some sed-.~ iment .': ' ',1 ' :::

., ~, : :

93-~19 Storage Time Preserva- Amount 10 13 tive %, w/v days days Benzalkonium very little chloride 0.25 good sediment Benzoic bad little acid 0~5 smell sediment Sodium benzoate 0.5 _ ._ _ _ Benzyl very little -;~ alcohol 1 good sedi~ent Methyl lit~l e paraben 0.2 sediment unchanged Propyl little paraben 0.02 sediment unchanged bad smell and all Control o sediment sedimented : `
-~, The results for the unplastioized zein dispersions (Examples 13-18) and the plasticized ziein dispersion (Examples 19-23) were simila~. l'he addition of s~dium benzoate, an anionic preservative, resulted in rapid aggregation, possibly suggesting a positive charge of ~he zein particles. The other preservatives ~benzalkonium chloride, benzoic acid, benzyl alcohol, methyl paraben and propyl paraben) significantly improved the stability when compared to a preservative-free dispersion which sedimented an unpleasant odor after approxi~ately one week.
~;~ The results indicate that only very little i40 sedimenta~ion was observed with the preserved dispersions and that the preservatives provide ~ stabilizing effect upon thP aqueous zein dispersion.

, ,.j:
''I
''~

~ ~'l 93-~lg EX~MPLES 24~28 Ca~tina Films ~'ro~ Preserved ~ein Di~p~r~io~is In Examples 24-28 the effect of different pre-i~ervatives on the ~ein films and caisting conditions are istudied. In each of Examples 24-28, a zein dispersion is .~ prepared in accordance with Example 4 (10 ml, 6.25~
solids) ~nd plasticized and a preservative added, with 20% triethyl citrate and 20% propylene glycol. In ~xample 2~, the preservative is b2nzalkonium chloride 0.25% w/v. In ~xample 25 the preserva~ive was benzoic acid 0.5% w/v. In Example 26, the preservative was ; sodium benzoate 1~ w/v. In Example 27, ~he preserva~ive was methyl paraben 002% w/v. In Example 28, the i preserva~ive was propyl paraben 0.02~ w/v. Zein films are then cas~ from the zein dispersions of Examples 24-2g and then for each Example, the zein films are dried at : 60~C overnight and at room temperature for three days.
~;. The results are provided in Table 6 below:
Table 6 Effect Of Different Pre~ervatives On 'rhe Zein Films ~: Amo~nt Preservative %, w/v 60 C
., , Benzalkonium chlor.ide 0.25 brittle, clear Benzoic acid 0.5 brittle, clear Sodium benzoate 0.5 brittle, cloudy '~ (rapid aggregation) Benzyl alcohol 1 brittle, clear Methyl paraben 0.2 brittle, clear :! Propyl paraben 0.02 brittle, cloudy 1 30 control 0 brittle, cloudy ;~`
' .. . .
, "
~,, 32 ~J ' ~c~ ~3~ 93-~19 Table l Contirluecl) Amount Preservative %, w/v Room Temperature Benzalkonium chloride 0.25 flexible, clear Benzoic acid 0.5 flexible, clear Sodium benzoate 0.5 flexible, clear (r~pid aggregation) Benzyl alcohol 1 Elexible, clear Methyl paraben 0.2 flexible, clear Propyl paraben 0.02 flexible, cloudy .; control 0 flexible, cloudy : .~
... As can be ascertained from the results reported in Table 6, all of the zein films were clear and flexible when stored at room temperature, except for propyl parabe~. A plasticizing effect of the parahens could not be detected by this method when compared to preservative-free films.
.~.
: 20 BXAMPLE5 23-32 ~. Theophylline Tabl~ts : In Examples 29-32, four different aqueous disper-.. sions of zein prepared in accordance with Example 3 are applied to directly compressible theophylline tabl.ets.
The theophylline tablets each weigh 300 mg, have a hard-ness of 9.5 kg, an~ have the ingredients set forth in ~I Table 7 below:
:'~, Table 7 Theophylline Tablets Inqredients Amount Theophylline Granules 225 mg Fast Flow Lactose #316 73.5 mg Magnesium $tearate 1.5 mq Total Weight 300 mg ~ ,1 .';, ~

~ f f ~ ? ?r~ ~ j 33 ~ J -- 93-~19 The theophylline tablets are prepared by comprfessing a granulation of the theophylline granules, lactose and magnesium stearate on a stokes rf~ftary pre~s into tablets weighing 300 mg. When tested in-vitro, the ta~iflets release theophylline over a period of 30 minutes. In Example 29, the theophylline tablets are coated with a zein pseudolatex dispersion including benzoic acid as a preservative and having the ingredients set forth in Table 8 below:
lO Table ff~
Example 29 - Benzoic Acid : Inqredients Amofunt Zein 18 g Effenzoic Acid 1.8 g Final Volume of ~fatex 360 ml Propylene Glycol 25% ~of solids) Solids content 5%
'' In Example 30, the theophylline tablets are coated with a zein pseudolatex dispersion having benzalkonium HCl as a preservative, as in Table 9 belo~:
, Table 9 i Example 30 - Benzalkonium HCl , Inqredients Amount `~ 25 Zein 18 g Bfenzalkonium HCl 0.9 g Final Volume of Latex 34fD ml .f Propylene Glycol 25% (of solids) l Solids Content 5.35%
i In Example 31, the theophylline tablets are coated with a zein pseudolfatex dispersion having methyl paraben and propyl paraben as prPservatives, and also include ~: lactose as set forth in Table lf~' below:

.:lf:
, '~' 3 ~ , 3 J~ 93-~19 Table 10 Example 31 - P~rabel~s and L~ctose ~ Inqredients ~mount : Zein 18 g Lactose 2.0 g Propyl Paraben 0. 02%
Methyl Paraben 0, 2%
Propylene Glycol 25% (of solids) ~ Solids Contents 5. 67%
', 10 In Example 32, the theophylline tablets are coated with a zein pseudolatex dispersion having methyl and - propyl paraben as preservatives, and further inclllde hydroxypropylmethylcellulose (HPMC), as set forth in ~ 15 Table 11 below:
:~ Table 11 ' Example 32 - Parabens and HPMC
-` Inqredients Amount ' Zein 18 g ;~ 20 HPMC 2.0 g Propyl Paraben 0.02%
Methyl Paraben 0.2 ~ Propylene Glycol 25% (of so~ids~
.. ~ Solids Contents 5.5~%
:^l 25 In each of Examples 29-32, the thPophylline tablets are coated using a Hi-Coater at an inlet temperature of ~,~ 60C, an outlet temperature of 28C, and a pan rotation :': speed of 20 rpm. The coated ta~lets are then cured for ;;'~! 30 24 hours in a 40C oven~
~,; : The cured coat~d theophylline tablets of Examples 29-32 are then subjected to dissolution testing according : to USP method II in 900 ml deionized water maintained at 37C.

;1:
.7 :3:

~,.

35 ~ 93-~l9 Figure l shows the dissolution results of Exarnples 29 and 30 as compared to uncoated theophylline kable-ts.
The dissolution profiles in Figure l indicate that zein with benzoic acid (Example 29) provides no release of theophylline within an 8 hour time span, and that the zein with benzalkonium HCl (Example 30) provic1es a slow - incremental release of theophylline from 0~ to 6% in the span of 8 hours. In comparison, the uncoated theophyl~
line tablets release substantially all of the theophyl-line within one hour. The results provided in Figure l show that the drug release from the zein coated tablets ~-~ is effectively closed down.
A similar result as illustrated in Figure 2 is obtained with zein dispersions containing lactose and - 15 parabens (Example 31~. Similar to Example 29~ no theophylline is released from the tablets of Example 31 (zein dispersion with lactosP and methyl and propyl ' paraben). Zein with lactose shows no release within the ; span of 8 hours.
; 20 The inclusion of ~PMC in the zein/methyl and propyl ,~, paraben dispersion (Example 32~ results in an increas~ in ;` drug release rate over time, and the HPMC increases the ' permeability of the film coat as indicated by the drug release profile shown in Figure 2.
The results indicate that parabens and benzoic acid ~I play a significant role in ~he preservation of the zein ~, dispersions of the present invention.
~,..`~, ~,1 EX~MPLES 33-36 ; 30 Zein Coatin~ ~pplied To A~P Tabl~t A zein pseudolatex (6.1% solids) is prepared in accordance with Example 3, and preserved with a combina-1; tion of propyl and methyl paraben (0.02% and 0.2% w/v, , respectively). The preserved pseudolatex is plasticized : ~ .
' ~';1 ~ ' 3 ~ ~ ~ c~ ~j 3,3 93-41g with 25% w/v pr~pylene glycol and stirred gently for fou~
hours.
APAP tablets are prepar~d by compressing compap Coarse L (90~ acetaminophen) comrnercially available from Mallinckrodt, Inc. to a weiqht of 500 mg.
The plasticized latex was applied to 300 mg aceta minophen (APAP~ tablets in a Hi-Coater, inlet temperature ~0C, outlet 28~C, pan rotation speed main~ained at 20 rpm.
lo In Example 33, ~he APAP tablets are coated to a weight gain of 0.67%. In Example 34, the ~PA~ tablets are coated to a weigh~ gain of 2.67%. In Example 35, the APAP tablets are coated to a weight gain of 5.29%. In Example 36, the APAP tablets are coated to a weight gain of 7.64%. Samples are taken at regular intervals and percent weight gain is determi~ed. All isiamples are then allowed to cure in a 40c oven for 2~ hou~s.
Next, the dissolution of the coated APAP tableks of Examples 33-36 (3 samples of each) is tested in 0.1 N
HCl, deionized (DI) water, and 0.1 N phosphate buffer at 37C, in accordance with USP Method II. As a control, ' the dissolution of uncoated APAP tablets is also exam ;~ ined. The results are provided in Figure 3. The ',~ dissolution data provided in Figure 3 indicate that by ~25 increasing the percentage of the coating on the APAP
tablets, the release of the APAP was reduced.

EXAMPLES 37~39 In Examples 37-39, the effect of 0.1 N HCl (pH
' 30 1.02), and 0.1 N Phosphate buffer (pH 7.4) on the release of APAP from zein-coated APAP tablets prepared in accord-ance with Examples 33-36 and coated to a weight increase ~j of 4~39~ is investigated. ~he dissolution results are " reported in Figure 4. The results indicate a negligi~le~! 35 ef~ect on release of the APAP due to the pH of the dis-~; !
```~;
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~ 11 ;~

37 ~ ,,', ~" t~ 93-419 solution ~edia. The tablets are tested for dissolution in 0.1 N HCl (pH = 1.2; Example 37); O.lN phosphate buffer (pH = 7.4, Example 38) and deionized water (~xample 39).

EXAMP~S 4 0 ~ 4 ?
Di~fer~nt Concentration~ o~ Paxab~n In Examples 40-42, the effect of varying the amount of methyl paraben incorporated in the zein pseudo~latex on the release of AP~P from coa~ed APAP tablets is investigated.
In each of Examples 40-42, APAP tablets prepared in accordance with Examples 33-36 are coated with z~in pseudo-latex plastlcized with propylene glycol (25% w/v).
In Example 40, preservative is 0. 02% propyl paraben (no methyl parabPn included). In Example 41, the preserva-tive is 0O05% methyl paraben and 0.02% propyl paraben.
In Example 42, ~he preservative is 0.~% methyl paraben and 0.02% propyl paraben. The coated tablets of Examples 40~42 and a control (uncased APAP tablet~ are then sub-jected to dissolution testing in accordance with USP
, Method II in deionized water at 37Co The results are -' set forth in Figure 5.
As indicated by Figure 5, the tablets containing no , 25 methyl paraben dose-dump very quickly due to failure of ;-~`,, the film coat. Inspection of these tablets reveals ; numero~s small cracks in the coating which allow rapid hydration of the tablet core. The addition of methyl ~, paraben at a 0.05% level substantially improved the ., .~
coating. The release of APAP is virtually shut down at 0.2% concentra~ion of methyl paraben>
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E~MPLES ~3-~5 E~ect o~ Di~eren~ Tempera~ur~ on _q~_Zein__atex In ~xample ~3, a zein pseudolatex (6.1% solids) is prepared in accordance with Example 3 and is preser-ved with a combination of p~opyl and methyl paraben at con-centrations of 0.02% and 0.2~, respectively. A porti~n of the prese~ved æein pseudolatex equivalent -to 15 g solids was plasticized with 25% propylene glycol and stirred gently for 2~i hours. The plasticized z~in pseudolatex is then applied to APAP tablets in accordance with Examples 33-36 to a 5% weight gain. The remaining portions of the preserved zein pseudolatex is divided into two lots and stored at room temperature and at 4C, respectively, for a two week period. The stored zein pseudolatex is ~hen plasticized with propylene glycol 25%
and is sprayed onto APAP tahlets in the same manner to a 5% weight gain. In Example 44, the tablets coated with the aged zein pseudolatex are held at room temperature -~ for two weeks. In Example 45, the aged zein pseudolatex is held at 400C for two weeks.
Thereafter, dissolution tests are performed on khe tablats of Examples 44-45 in 900 ml deioni~ed water a-t 37C, the results of which are provided in Figure 6. The results indicate that the tablets coated with the aged s 25 zein pseudolatex (Examples 44 and 45) displayed surfa~ecracks and imper~ections, as compared to the smooth, s, continuous surface of tablets coated with fresh zein pseudolatex (Example 43), which is 5 days old at the ~ime of spraying. This 5 day time period is necessary for the ~' 30 evaporation of the water and alcohol to concentrate the;.~ dispersion to the 6.1% solids level.
Next, the tablets of Example ~3 are placed in closed containers and held for two weeks at room temperature and t~ at 40C. Dissolution tests are performed and the results I

: ~ :s ~ Ss ~ '~s ~ 9 ~, ~, ., w ~ 9 3 -4 1 9 show no differenc~s in th~ releas~ profile, as sh~wn in Figure 7O

Addition of a Pore-Former In Example 46, two batches of zein pseudolatex are :~ prepared (16 g solids each) in accordance wi~h Example 430 Two grams o~ hydroxypropylmethylcellulose (HPMC~ is ~ added to one batch (Example 46) and two grams of lactose : 1o is added to the other (Example 47). The zein pseudo~
latexes of ~xamples 46 and 47 are then plasticized, preserved with polyethylene glycol (25% w/v); methyl - parahen (0.2% w~v)i and propyl paraben ~0.02$ w/v); and sprayed onto APAP tablets to a weight gain of 5%.
Dissolution tests are performed in 900 ml of deionized water at 370C~ The results are shown in Figure 8.
, The results indicate that drug release profiles can . be regulated with the use of pore-forming materials in the zein pseudolat~xes of the present invention. The APAP tablets used in this study tended to swell and disintegrate rapidly. The zein pseudolatex formations ~:~, that include pore-formirlg materials would be more sùited .;i to a non-disinkegrating tablet formation where the drug release would ideally be diffusion-controlled.
The examples provided above are not meant to be exclusive. Many other variations of the present invention would be obvious to those skilled in khe art, and are contemplated to be within the scope of the appended claims.

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Claims (32)

1. An aqueous dispersion of zein comprising from about 0.1 to about 10 percent zein w/v, and having a pH
from about 3 to about 7.

2. The aqueous dispersion of claim 1, comprising from about 5 to about 10 percent zein w/v, and having a pH
from about 4 to about 6.

3. The aqueous dispersion of claim 1, wherein the particle size of the zein in said aqueous dispersion is from about 0.01 to about 10 µm.

4. The aqueous dispersion of claim 2, wherein the average particle size of the zein in said aqueous disper-sion is from about 100 to about 300 nanometers.

5. A method for preparing an aqueous dispersion of zein, comprising preparing a solvent mixture comprising water and from about 60 to about 90 percent of an organic solvent selected from the group consisting of ethanol, acetone, and mixtures thereof, adding zein to said solvent mixture in such a proportion to said solvent mixture that the zein dissolves in the solvent mixture, and precipitating the zein as fine particles and removing the organic solvent to obtain an aqueous dis-persion comprising from about 0.1 to about 10 percent w/v of zein.

6. The method of claim 5, further comprising precipitating the zein by pouring said solution of zein as a stream into an aqueous phase under continuous mixing, such that the zein precipitates as fine particles, thereafter evaporating said organic solvent from the mixture, and concentrating the resulting aqueous phase.

7. The method of claim 6, further comprising drying the resultant aqueous dispersion to obtain a zein powder which is redispersible in aqueous solutions.

8. The method of claim 6, further comprising spray-drying said resultant aqueous dispersion to obtain a redis-persible zein powder having a particle size ranging from about 0.1 to about 10 µm.

9. The method of claim 8, further comprising redispersing the zein powder in an aqueous solution prior to use in a coating process.

10. The method of claim 6, further comprising adding an effective amount of a plasticizer to said aqueous dis-persion of zein to provide a flexible film when said aqueous dispersion is applied to a substrate.

11. The method of claim 6, further comprising adding a solubilizing agent to said aqueous dispersion of zein.

12. The method of claim 6, further comprising adding a suitable buffer system to adjust the pH of said aqueous dispersion of zein to above about pH 9.

13. The method of claim 6, further comprising adding an ammonium carbonate-ammonia buffer to said aqueous dis-persion of zein to adjust the pH to above about pH 9.

14. The aqueous dispersion of zein produced by the method of claims 5-13.

15. A zein powder having a particle size ranging from about 0.1 to about lo µm which is redispersible in an aque-ous solution to provide an aqueous dispersion of zein.

16. An aqueous dispersion of zein comprising from about 0.1 to about 10 percent zein w/v, and a buffer in an amount effective to adjust the pH of the aqueous dispersion to above about pH 9.

17. The aqueous dispersion of claim 16, wherein said buffer is selected from the group consisting of an ammonium carbonate-ammonia buffer, a citric acid-sodium phosphate buffer, and a boric acid-potassium chloride-sodium hydroxide buffer.

18. A stabilized aqueous dispersion of zein, comprising an aqueous dispersion comprising from about 0.1 to about 10 percent zein w/v having a particle size from about 0.01 µm to about 10 µm, and an effective amount of a pharmaceutically acceptable preservative.

19. The stabilized aqueous dispersion of claim 18, wherein said pharmaceutically acceptable preservative is selected from the group consisting of benzalkonium chloride, benzoic acid, benzyl alcohol, methyl paraben, propyl paraben, ethyl paraben, butyl paraben, sorbic acid, a quaternary ammonium salt, phenol, cresol, mercury-containing preservatives, and mixtures of any of the foregoing.

20. The stabilized aqueous dispersion of claim 18, wherein said pharmaceutically acceptable preservative about 0.2% methyl paraben and 0.02% propyl paraben, w/v.

21. The stabilized aqueous dispersion of claim 18, further comprising an effective amount of water-soluble plasticizer to provide a flexible film when said aqueous dispersion is applied to a substrate.

22. The stabilized aqueous dispersion of claim 18, which has less than 20% sedimentation after 30 days.

23. The stabilized aqueous dispersion of claim 18, wherein said pharmaceutically acceptable preservative comprises methyl paraben and propyl paraben in a ratio of about 10:1, said methyl paraben being present in an amount of at least 0.05%, w/v.

24. The method of claim 5, further comprising preserving the resulting aqueous dispersion of zein by adding an effective amount of a pharmaceutically acceptable preservative.

25. The aqueous dispersion of claim 1, further comprising an effective amount of a pharmaceutically acceptable preservative.

26. A solid controlled release formulation, comprising a substrate comprising an active agent, said substrate coated with a controlled release coating to a weight gain from about 3 to about 15 percent, said controlled release coating comprising (i) an aqueous dispersion of from about 0.1 to about 10 percent zein w/v having a particle size from about 0.01 µm to about 10 µm, said aqueous dispersion obtained by pre-cipitating zein by pouring a solution of zein in a solvent comprising water and from about 60 to about 90 percent organic solvent selected from the group consisting of ethanol, acetone, and mixtures thereof as a thin stream into an aqueous phase under continuous stirring, the organic solvent thereafter being substantially removed and the resulting aqueous phase concentrated;
(ii) a pharmaceutically acceptable preservative;
(iii) a pharmaceutically acceptable plasticizer, the preservative and the plasticizer each being included in an amount necessary to provide a strong, continuous film cap-able of releasing the active agent at a desired rate when the formulation is exposed to an aqueous solution.

27. The controlled release formulation of claim 26, wherein said active agent is selected from the group con-sisting of a systemically active therapeutic agent, a locally active therapeutic agent, a disinfecting and sanitizing agent, a cleansing agent, a fragrance agent and a fertilizing agent.

28. The controlled release formulation of claim 26, wherein said therapeutically active agent is selected from the group consisting of antihistamines, analgesics, non-steroidal anti-inflammatory agents, gastro-intestinals, anti-emetics, anti-epileptics, vasodilators, anti-tussive agents, expectorants, anti-asthmatics, hormones, diuretics, anti-hypotensives, bronchodilators, steroids, antibiotics, antivirals, antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics, sedatives, decongestants, laxatives, vitamins, and stimulants.

29. The controlled release formulation of claim 26, wherein said controlled release coating further comprises a pore-former.

30. The method of claim 10, further comprising coating a substrate comprising an active agent with a sufficient amount of the preserved, plasticized aqueous dispersion of zein to obtain a predetermined controlled release of said active agent when said coated substrate is exposed to aqueous solutions.

31. The method of claim 30, further comprising further controlling the release of said active agent by adding a pore-former to said aqueous dispersion of zein.

32. The method of claim 30, further comprising forming one or more release-modifying passageways in said coating.