WO1980000659A1

WO1980000659A1 - Food and pharmaceutical coating composition,method of preparation and products so coated

Info

Publication number: WO1980000659A1
Application number: PCT/US1979/000787
Authority: WO
Inventors: G Banker
Original assignee: Purdue Research Foundation
Priority date: 1978-10-02
Filing date: 1979-09-26
Publication date: 1980-04-17
Also published as: BE879132A; DE2966893D1; JPS55500709A; EP0020496B2; JPH027925B2; IT7926134A0; JPH0339490B2; DK162507C; IT1125424B; DK233080A; JPH02167221A; EP0020496A1; DK162507B; EP0020496A4; IE791870L; IE48699B1; EP0020496B1

Abstract

Pharmaceutical coatings in the form of aqueous dispersion of a water insoluble polymer prepared by dissolving the polymer in a water immiscible organic solvent, emulsifying the organic solution in water, optionally with the aid of additives, and stripping the organic solvent from the system to provide a colloidal, or near colloidal, aqueous dispersion or latex of small, even sized polymeric particules which are applied to pharmaceutical dosages from highly loaded latices. The latexes, which display resistance to bacterial and mold growth and, when combined with selected additives, provides convenient, attractive coating compositions which afford excellent protection and varied release properties to pharmaceutical dosages.

Description

._.^ FOOD AND PHARMACEUTICAL COATING COMPOSITION, METHOD OF PREPARATION AUD PRODUCTS SO COATED

The invention relates generally to food and pharma¬ ceutical coating compositions, a process for producing 5 the coating compositions, and more particularly to a pharmaceutical tablet, capsule, bead or particulate coating in the form of an aqueous latex of water in¬ soluble polymeric compositions, and to solid food or pharmaceutical products coated with such materials.

10 The use of various coatings to seal pharmaceutical

(including vitamins and food supplements) dosages and food products has been known for some time. Many ends have been served by such coatings. For instance, tablet coatings provide a more attractive appearing dosage, pro-

15 tect the dosage from attack, such as by moisture during storage, provide a more acceptable feel, and often taste, to the user of the dosage, and, with selected com¬ pounding, provides either gastric and/or enteric dissolu¬ tion at varying rates to determine the time and rate at 20 which the dosage is released.

Early coatings include natural and synthetic poly¬ mers such as cellulose acetate phthalate and shellac to, as the primary purpose, delay release of the dosage thus providing enteric dosage. Sugar coating of the dosage is

25 a classic example of an early pharmaceutical tablet coat¬ ing affording gastric release, but has the drawback of being a very involved process requiring highly skilled operators. As a result of the various advantages and disadvantages of known coatings for pharmaceutical do-

30 sages, film coatings applied to the dosages from organo- sols (that is), from solutions of plasticized polymers and organic solvents, have become the most utilized pro¬ cedure. Film coatings from organosols provide rapid, simple, effective coating of the dosage and control over

35 the dosage size, coating disintegration and dissolution rates, and generally results in an attractive and de¬ sirable dosage coating. Generally, the organic solvents -^*ar curtailed bacterial and mold growth.

A number of disadvantages have also been attendant to the organosol coatings of pharmaceutical dosages. Often the vapors of the organic solvents are toxic or flammable thereby providing a hazard to the operators - though the solvents may be fully or substantially driven from the tablet coating providing no hazard to the user of the pharmaceutical dosage. Also, organic solvents present an environmental hazard and, accordingly, require recovery systems which are both expensive and compli¬ cated. As a result, in an effort to reduce the amount of solvents employed in film coating, fillers and extenders are often added to the film coating formulations. While this results in an increased solids loading of the coat- ing dispersion, the additives and extenders often com¬ promise the performance of the tablet coating in terms of mechanical properties and permeability. Except in high volume operations, the cost of recovery equipment for the organic solvents often proves prohibitive despite the high cost of the solvents recovered by such systems for recycling. Independent of the fundamental economics of such recovery systems, the demands of environmentally responsible manufacturing often mandate such solvent recovery systems with resulting adverse impacts on the economics of many film coating operations.

While the European pharmaceutical industry has em¬ ployed two aqueous based synthetic polymer dispersions for the coating of pharmaceutical dosages, i.e., Eudragit E-30D^m, a 70:30 ratio of ethylacrylate-methyl meth- acrylate copolymers with a preferred molecular weight of about 800,000; and Eudragit L-30D¹", a 50:50 ratio of ethacrylic acid-ethyl acrylate copolymers with a pre¬ ferred molecular weight of 250,000, which are produced by emulsion polymerization, these compounds are subject to bacterial and mold growth while in the aqueous form.

Water, of course, is an excellent solvent or vehicle for many practical purposes in that it is nonflammable

O ^" -^■*-.- and thus provides no explosion hazard, is low cost, is substantially free of toxic effects and innocuous to the environment. Unfortunately, the use of aqueous solutions of polymers for film coating to provide dosage coatings is quite limited due to the very low solids contents, i.e., on the order of 7% to 15% of known aqueous solu¬ tions. As the concentration of solids rises, the vis¬ cosity of the solution rapidly approaches an inoperable condition. Similarly, an increase in the molecular weight weight of the polymer in an aqueous solution rapidly causes an unworkably high viscosity. Thus, rela¬ tively low molecular weight polymers and low concentra¬ tions are normally required. These characteristics re¬ sult in a need for a plurality of layers of polymer to be built up in order to obtain a coating of adequate thick¬ ness for surface protection. Multiple coatings involve a long processing time which is complicated further by the slow evaporation of water and large amounts of water which must be removed from each coating. Further, many drugs are sensitive to water when exposed to high con¬ centrations for extended periods of time and, accord¬ ingly, require initial sealing with water barriers, such as the shellac coating, prior to coating with the con¬ ventional aqueous film coating. Another serious drawback with existing water-based coating systems is the tendency for bacteria and molds to multiply and grow in aqueous media, either solvent or vehicle. This tendency has been observed in the above- mentioned Eudragit compositions. Thus care in storage and attention to shelflife are of critical importance in avoiding septic conditions in known aqueous based coating systems.

Still another problem with the low solids aqueous film coating techniques now known is the relatively poor film obtained. Few water soluble materials provide the desired film coatings properties. The more desirable film obtainable with the use of longer chains, higher molecular weight polymers cannot be employed in the^" con¬ ventional aqueous coating methods.

In accordance with the present invention there is provided a process for preparing novel coatings for solid food and pharmaceutical products including vitamins and food supplements in which process one or more water in¬ soluble polymers are formed into a colloidal, or near colloidal, aqueous dispersion of such polymers by first dissolving the polymer in an organic solvent more vola- tile than water, emulsifying the solution thus formed in a continuous water phase - optionally with the aid of an emulsifying agent - and thereafter stripping the organic solvent from the emulsion to form very small, i.e., on the order of .1 to 10 microns, and up to 15 to 20 microns, even sized particles of the polymeric compo¬ sition which particles are maintained as a substantially stable dispersion in the aqueous medium, hereafter re¬ ferred to as a latex. Product coating is facilitated by adding selected additives to the latex and applying such dispersion having high solids loading to pharmaceutical dosages by conventional means in a coating pan or by more specialized procedures, i.e., immersion coating, fluid- ized beds, etc. U.S. Letters Patent 3,896,762 issued July 29, 1975 discusses a workable coating apparatus. Water insoluble polymers suitable for use with the instant invention include ethyl cellulose, polyvinyl acetate phthalate, cellulose acetate phthalate, hydroxy propyl methyl cellulose phthalate, maleic anhydride co¬ polymers, including poly(methylvinyl ether/maleic anhy- dride) i.e., the Gantrez Series, ethylene maleic anhy¬ dride, styrene maleic anhydride, and various straight chain and branched alkyl esters of maleic anhydride co¬ polymers, including ethyl, propyl, butyl etc. to C-_g alkyl half esters, and butyl, isobutyl etc. to C._g alkyl quarter esters. Acrylic/acrylate copolymers or acrylate polymers, including Eudragit E-30D™ and Eudragit L-30D", as described above, and biodegradable polymers, including

^ζx

( OM ^''"'*- polyactic acid, d and 1 {+ and -), polyactic/polygiycolic acid copolymer, polypeptides such as glutamic acid/ leucine copolymer, glycolides, ( β-propiolactone, tetra- methylglycolide, β-butyrolactone, γ-butyrolactone, piv- alolactone, and cyclic esters of α-hydroxybutyric acid, α-hydroxyisobutyric acid, α-hydroxyl ^~ -methylvaleric acid, α -hydroxyliquocenic acid, β -phenyl lactic acid, α-hydroxy α-ethylbutyric acid. Many water immiscible solvent systems are appropriate for use in the present invention. Primarily, the solvents or solvent systems must have substantial solvent effect upon the polymers employed, and preferably be quite volatile relative to water in order to leave little residue in the final latex or, alternatively, have permissible residue limits for use in foodstuffs. Typical solvents include chlorinated solvents such as ethylene dichloride, tetrachloroethyl- ene, chloroform, methylene chloride and similar solvents, aliphatic, alicyciic or aromatic hydrocarbons such as hexane and cyclohexene, esters such as ethyl acetate, higher alcohols, ethers, and combinations thereof, or combinations of such solvents with polar water missible solvents such as acetone or lower alcohols in ratios which produce an overall mixed solvent which is water immiscible. Isopropanol and methylene chloride, ethylene dichloride or chloroform, for instance, constitute an excellent water immiscible solvent system for hydroxy- propyl methyl cellulose phthalate. Spice oleoresins are examples of solvents having permissible residue limits in foodstuffs. Numerous other solvent systems will be apparent to those skilled in the art.

It is often desirable to include surfactants or emulsifiers to assist in producing a stable emulsion. The emulsifiers may be anionic such as sodium lauryl sulfate (USP), cationic such as the quaternary- ammonium halides (such as cetyl pyridinium chloride) or non- ionic, such as linear fatty alcohol ethoxylates (exem-

________

/,, WIPO . plified by Alkasurf" LA3, LA7, LA9 or LA12 available from Alkanol Chemical Ltd. of Mississauga, Ont., Canada) or the polyoxyethylene condensation products (exemplified by Spans and Tweens or polyoxyethylene-polypropylene glycol as Pluronic F68, available from Wyandotte Chemicals Corp., Wyandotte, Michigan, U.S.A.). Other agents in¬ cluding materials such as polyglycerol esters of fatty acids, polyoxethylene sorbitan onolaurate, polyoxethyl- ene sorbitan tristearate, polyoxethylene sorbitan mono- stearate, polyoxyethylene sorbitan monoleate, propylene glycol mono and diesters of fats and fatty acids, sodium lauryl sulfate and sorbitan mόnostearate are useful to serve such functions. Generally, the emulsions and lattices of the instant invention can be formed without surfactants or emulsifiers, but in many instances, finer particle size and greater stability are attained with such additives. The particularly above-listed biode¬ gradable polymers form emulsions and resulting latices without benefit of additives. Various other additives, such as cetyl alcohol, beeswax (yellow, bleached or white and white natural), candelilla wax, carnauba wax, cocoa butter, fatty acids such as .those in the food additives, mono, di and tri glycerides (including glyceryl monostearate, monooleate, etc. and self-eipμlsifying glyceryl monostearate), gly- cerol-lacto stearate, oleate or palmitate (other self- emulsifying waxes), glyceryl-lacto esters of fatty acids (also self-emulsifying) lauric acid, lauryl alcohol, linoleic acid, octyl alcohol and acetate, and paraffin may be advantageously included to enhance the properties of the emulsion. _*• number of additives such as carnauba wax and chlorowax improve the appearance of the tablet coating. These, of course, can be added to the latex as polishing agents. Preferably, the resulting latex includes between 10 percent to 60 percent solids, optionally 40 to 50 per¬ cent, or more, solids with low, workable viscosities and non-Newtonian dilatant flow. Concentration of the water insoluble polymer in the organic solvent generally is in the range of 10 percent to 50 percent by weight, but higher concentrations are sometimes workable and de- sirable, provided unduly high viscosities are not pro¬ duced. Surfactants/emulsifier concentrations in the emulsions may of course be zero in some instances, but when included are within the general range of 0.1 percent to 10 percent by weight, and preferably 0.5 to 2 percent. Other additives including pharmaceutically active ingre¬ dients may be included in amounts between 0 percent and 20 percent by weight of the emulsion, but usually between 0 percent and 10 percent by weight of the emulsion. The resulting latex of water insoluble polymers does not in itself usually yield the desired dosage coating composition. Annealing agents, particularly water solu¬ ble polymers such as hydroxypropyl cellulose., hydroxy- propyl methylcellulose, methyl cellulose, methyl ethyl cellulose, polyvinylpyrrolidone and/or sodium carboxy- methylcellulose are often desirable additives. Gums, including official gums, such as pectin acaeia-USP, tragacanth-USP, as well as non-official gums such as karaya, locust bean, chondrus, and alginic acid deriva¬ tives, etc. may also be employed as annealing agents, though generally the aforementioned annealing agents are preferred. Other materials of possibly desirable appli¬ cation, though believed to be less desirable than those first listed, include high molecular weight carboxyvinyl polymer such as Carbopol 934 available from B.F. Goodrich Company, provided it is employed in amounts not above 2 or 3% concentration and is neutralized with a sodium hydroxide to be solubilized as a sodium salt. Hydroxy- ethyl cellulose, available as Cellosize from Union Carbide Company, sodium alginate, propylene glycol ester of alginic acid, available as Kelgin, and Kelcoloid respectively from the Delco Chemical Company, polyvinyl alcohol. Also, as an example of a low molecular weight annealing agent which is not polymeric, dioctyl sodium sulfosuccinate-USP, may, in some instances, be employed. In general, annealing agents are recognized by those skilled in the art for the properties of being water soluble, suitable for ingestion, and compatible with the basic latex. Often, plasticizers are necessary to pro¬ vide workable coatings. Typical plasticizers include propylene glycol, glycerin, glyceryl triacetate, poly¬ ethylene glycol, triethylcitrate, tributylcitrate, diethylphthalate and dibutylphthalate.

Therefore, an advantage of this invention is it pro- vides aqueous dispersions for tablet coatings utilizing high molecular weight, water insoluble polymers hereto¬ fore applicable primarily by means of organosols. It is a further advantage of this invention to pro¬ vide more economical dosage coatings utilizing water as a dispersing medium.

It is another advantage of the present invention to provide environmentally acceptable dosage coatings. It is still another advantage of the present inven¬ tion to provide aqueous vehicle dosage coating composi¬ tions having resistance to the growth of bacteria, molds and other such objectionable matter therein.

These and other advantages of the instant invention will become evident upon further consideration of the specification and the appended claims.

According to the instant invention, high solids loading latices suitable for formulating dosage coating compositions are formed by dissolving one or more rela- tively high molecular weight, water insoluble polymers, in a water immiscible organic solvent or solvent system. The thus formed organic solvent solution is emulsified to form an aqueous emulsion having a continuous water phase. Generally, emulsification is accomplished by initial mixing by physical agitation and then fine dispersion by sonication and/or homogenization to form the emulsion. Optionally, additives, surfactants and emulsifying agents

- TjR OM ^"*"" may be added to aid in establishing and stabilizing the emulsion, but such agents tend to be of relatively low volatility. Thus, in many instances, such additives must be acceptable in the. tablet coating ultimately formed. 5 Many acceptable agents for these purposes are known. Sufficiently stable emulsions are generally formed by subjecting the organic solvent solution and water to com¬ minuting forces by means of devices such as colloid mills, ultrasonic vibrators, homogenizers, etc. These 0 are well known in the art of emulsification. Preferably, the emulsion is subjected to such treatment promptly upon formation of the crude emulsion.

It is not absolutely necessary that the emulsion be stable for extended periods since it is desirable that 5 the organic solvent be promptly stripped from the emul¬ sion. This, in the case of marginally stable emulsions, can be carried out promptly. While it is preferred that a vacuum distillation process be employed, particularly in the instance of unstable emulsions, steam distilla- 0 tion, either with or without vacuum, may be employed to • remove the more volatile organic solvents from the emul¬ sion.

As the organic solvent is removed, the polymer initially dissolved therein forms discrete solid parti- 5 cles. These particles generally are on the order of .1 to 20 micron average particle size, and generally below 10 microns. Also, the particles generally are of con¬ sistent size as a result of the homogeneous nature of the emulsion from which the particles are formed, though 0 minor amounts of particles up to 15 or 20 microns may be present.

The essentially submicron size of the polymeric par¬ ticles in the remaining aqueous phase gives rise to a latex having on the order of 10 percent to 60 percent 5 solids and preferably 40 to 50 percent and most pref¬ erably 25 to 35 percent solids loading with low vis¬ cosities and non-Newtonian dilatant flow.

OMPI A number of additives may be incorporated in the latex according to the instant invention to provide en¬ hanced coating characteristics. For instance, plasti¬ cizers such as triacetin, propylene glycol, glycerine, triethylcitrate, diethylphthalate, tributylcitrate or dibutylphthalate and annealing agents such as water soluble polymers often are incorporated individually or in combination depending upon the film characteristics desired. Pigments, release agents, and polishing agents may also be included to vary the properties, i.e., gastric release, enteric release, rapid dissolution and appearance of the coating.

The various advantages and properties of the dosage coatings in accord with the latex forming process above- described will be apparent from the following examples. Example 1

A basic latex was formed by dissolving 60 grams of ethyl cellulose having a degree of substitution of be¬ tween 2.44 and 2.58 and an ethoxyl content of 48 to 49.5 percent in 240 grams of an 85 to 15 ratio of benzene ethanol solvent. The solution was allowed then to stand overnight and was then filtered through surgical gauze. 3.3 grams of n-decane was then added. The resulting solution of the water insoluble ethyl cellulose in the water immiscible solvent system was added drop by drop at 55°C to an aqueous solution of 4 grams of sodium laurylsulfate in 600 grams of water. A reflux condenser was attached to the flask in which the crude emulsion was formed and a marine propeller type agitator was employed to mix the solutions. The resulting emulsion was promptly submitted to ultrasonic agitation at the rate of 120 watts for 5 minutes and passed through a two stage laboratory homogenizer at 6000 psi. Thus a direct emulsification of the ethyl cellulose and water immis- cible solvents was produced. Thereafter, the organic solvent was removed by vacuum distillation in a rotary evaporator at 25 inches of mercury and 45°C after .0.5 grams of a silicone antifoa . As the organic solvent was removed, a stable pseudolatex of' essentially sub- micron particles of ethylcellulose was formed in the aqueous vehicle. Example 2

Sixty grams of ethylcellulose was dissolved in 440 grams of ethylene dichloride, filtered through surgical gauze and 13 grams of cetyl alcohol was then added to the solution. The resulting solution of a water insoluble 0 ethyl cellulose polymer in a water immiscible organic solvent was placed in a 2000 ml. 3 neck flask equipped with a reflex condenser and a marine propeller type agi¬ tator. Four grams of sodium lauryl sulfate was added to 600 grams of water and the thus formed aqueous solu- 5 tion was added drop by drop to the organic solution through a separatory funnel to form a continuous aqueous phase emulsion by inverse emulsification. The thus formed crude emulsion was subjected to ultrasonic agita¬ tion and homogenization as described in Example 1 , and 0 the organic solvent was similarly removed to form a latex of micron or submicron size of ethyl cellulose particles in an aqueous vehicle. Example 3

One hundred grams of cellulose acetate phthalate was ⁵ added to 700 grams of an 80 to 20 ratio of ethyl acetate- isopropanol solvent. The solution was filtered and 14 grams of cetyl alcohol added. Thereafter, a solution of six grams of sodium lauryl sulfate in 1000 grams of water was added to form an emulsion as set forth in Example 2, ° and a latex was formed by removing the organic solvent in the manner set forth in Example 2. The resulting latex was stable and of micron or submicron particle size. Example 4

A solution of 10 grams of polymethyl vinyl ether- maleic anhydride copolymer (Gantrez AN 169™ available from GAF Chemical Company) was added to 100 grams of an ethyl acetate solvent. A latex of micron or submicron REAIT

OMPI IPO sized particles of the copolymer was formed in conjunc¬ tion with a solution of 1.5 grams of sodium lauryl sulfate in 300 grams of water by the emulsification pro¬ cess and removal of the organic solvents as described in Example 2. Example 5

Ten grams of a polymer of 90 percent L-Lactic Acid and 10 percent glycolic acid having a molecular weight of 15,000 was added to 90 grams of chloroform. A stable, micron or submicron latex of the polymer was formed in conjunction with the solution of 1 gram of fatty alco¬ hol ethoxylate (Alkasurf LA 3^W) and 200 grams of water in the manner described with reference to the emulsifica¬ tion and separation described in Example 2. Example 6

Ten grams of L-Polyactic acid having a molecular weight of 15,000 was added to 90 grams of chloroform. A stable, micron or submicron latex of the polymer was formed in conjunction with an aqueous solution identical to that utilized in Example 5 by utilizing the emulsifi- cation and organic solvent removal step described in Example 2.

All of the latices produced as described at Exam¬ ples 1 through 6 were stable, micron or submicron sized latices of water insoluble polymers in aqueous vehicles. Formulation of other latices utilizing water insoluble polymers which do not form latices by more conventional emulsification of colloid forming methods can be pro¬ duced by methods essentially similar to those described above. Of course, differing polymers may require appro¬ priate organic solvent systems, and such solvent systems would be water immiscible, and may require the addition of emulsifying agents and other additives. However, the nature of such solvents and additives are well recognized in the art and may be identified without undue experimen¬ tation. *. «_

•--__- However, though the latices as produced in Examples 1 through 6 have the properties of stable, high solids loading in an aqueous vehicle and are resistant to bac¬ terial and mold growth, such latices are not necessarily

⁵ appropriate for producing tablet coatings. The suspended polymers are, of course, water insoluble and thus not readily dissolvable in gastric liquids, though this quality can be put to advantage for enteric release in many instances. Further, such latices generally form

10 marginal films, and in many cases are not film forming at all. When film is formed, often the films are not of sufficient physical integrity or attractiveness to func¬ tion as a tablet coating.

To produce a dosage coating as is the object of

15 the present invention, plasticizers, annealing agents, usually in the form of water soluble polymers which may be incorporated into the water phase of the latex, and/ or pigments and other additives may be added to the lat¬ ices. Such other additives, which include polishing

20 agents, release agents, etc. may be incorporated at var¬ ious points in the formulation process, i.e., prior to emulsification or after formulation of the latex. Example 7

Latices formed as set forth in Example 1 were

25 placed in petri dishes and the solvents evaporated, at 30°C, both without and with plasticizers in varying amounts to form films. The plasticizers added were U.S.P. Grade propylene glycol, glycerin, glyceryl tri¬ acetate (triacetin), and polyethylene glycol. The re-

30 suits obtained are shown in Table I. TABLE I

Plasticizer %Plasticizer on %Total Film Polymer Weight Polymers Characteristics

None 44 Hard, brittle, glass like and transparent Discontinuous.

Polyethylene 67 22.3 Discontinuous, hard glycol and brittle.

Propylene^' 40 Hard divided into glycol 60 22.3 small pieces.

80 Discontinuous

Glycerin 55 25.5 Translucent, soft and discontinuous.

Glycerin 67.5 24.6 Translucent, soft. Continuous. The film has a waxy texture.

Triacetin 49 25.3 Transparent. Continuous

While the film forming properties are improved by the addition of plasticizer, and particularly when using triacetin, still transparent and soft, waxy, films are not ideal tablet or other dosage coatings. Example 8

In addition to plasticizers, water soluble poly¬ meric materials were also slowly added with gentle mixing and in various amounts to latices essentially as prepared in Example 1. The results are shown in Table II. TABLE II

.Plasti-

Poly¬ Water , cized Based mers Soluble Plasti¬ .Total on Polymer Film Char¬

Patio Polymer cizer Polymers Weight acteristics

1:1 Methyl¬ Propylene 10.6 80 Translucent, cellulose Glycol flexible.

50 cps

2:1 Methyl¬ Propylene 13.0 92 Translucent, cellulose Glycol hard and

50 cps brittle.

3:1 Methyl¬ Propylene 18.88 69 Translucent, cellulose Glycol hard and

50 cps brittle.

1:1 Hydroxy Triacetin 20.0 25-50 Transparent

3:1 prcpyl or trans¬

4:1 . methyl¬ lucent.

6:1 cellulose Flexible methyl¬ cellulose cps

2:1 Hydroxy Glycerin+ 20.0 50 Translucent,

3:1 propyl Triacetin flexible.

4:1 methyl¬ cellulose 15 cps

From Table II, it is apparent that the film charac¬ teristics are substantially improved utilizing annealing

- JREΛ

OMPI agents in conjunction with plasticizers. Further it was found that such films displayed desirable dosage coating characteristics with regard to dissolution in gastric liquids, water absorption, water barrier, properties and appearance. However, certain of the plasticizers, par¬ ticularly glycerin, appear to evaporate in a matter of days. Triacetin plasticizers appear to be permanent. Example 9

To 1 part of a 24.5 percent ethyl cellulose latex also containing therein two parts of a 5 percent methyl¬ cellulose annealing solution and between 25 to 50 per¬ cent triacetin plasticizer was added 20 percent (on a weight to weight basis of total polymer) of titanium dioxide. Films were cast by evaporating the solvent at 30^βC on a glass substrate. The addition of the titanium dioxide improved general film quality substantially in that the films were flexible and tougher than similar films without the opacifying agent. Also, the appear¬ ance and texture of the film were also improved. The addition of titanium dioxide to similar formulations utilizing glycerin in place of the triacetin decreased the "oily" surface appearance of the resulting films attributed to the presence of glycerin.

From the above results it becomes apparent that the latices of water insoluble polymers can be utilized to form excellent dosage coating compositions with the in¬ clusion of plasticizers, annealing agents, particularly water soluble polymeric materials and various other essentially conventional constituents utilized generally with more conventional tablet coating compositions, such as opacifying agents, polishing agents, carnauba wax and chlorowax.

A particularly important quality of this invention will be appreciated with reference to Example 10. Example 10

In the manner essentially as set forth in Example 2, a number of latices were prepared utilizing, as a fixed ^{■ :~}3_ portion, ten parts of ethyl cellulose, 10 cps, 1 part cetyl alcohol, and .5 parts of sodium lauryl sulphate. Varying amounts of ethyl dichloride and water were em¬ ployed, with the ethyl dichloride being present in the

5 amount of 150 grams and water employed in the amount of 200 grams. Various solutions of between 20% and 30% by weight of ethyl cellulose relative to ethylene dichloride were prepared. After emulsification, the water and ethylene dichloride were removed from each sample until

10 the resulting latex contained 34.5% ethyl cellulose in all instances. The viscosity of the ethyl cellulose in ethylene dichloride solutions increased rapidly from the 10,000 cps at 20% solutions, to 20,000 cps at the 30% solution. Initially, the final viscosity of the latex

15 after removing the organic solvent and some water to pro¬ duce the 34.5% ethyl cellulose latex increased rapidly in viscosity, particularly at the 25% and the 27.5% solu¬ tions, but ultimately it was found that the 30% initial solution provided a final latex of relatively low vis-

20 cosity, i.e., approaching that of the 20% initial solu¬ tion and substantially below that of the 22.5% solutions. Investigation of the particle size disclosed that the 30% initial solution produced particles on the order of 5 to 10 microns in size which was substantially equiva-

25 lent to the particle size and distribution of the 20% initial solution. This was surprising since the inter¬ mediate initial solutions, i.e. about 25% and 27.5%, produced less desirable latices having not only sub¬ stantially greater particle size, i.e., up to 20 to 30

30 microns, but also a wider distribution of sizes. Thus it is preferred that the 30% initial solution be em¬ ployed since the particle size is desirable and sub¬ stantially less water need be removed to provide a latex of equivalent solids loading. Similar procedures may

35 be employed to produce optimum initial solutions from other water insoluble polymers.

- REXO

OMPI Example 11

Four petri dishes containing Difco Nutrient Agar were processed as described below and stored for three days .at 37^βC. One milliliter samples of ethyl cellulose and cellulose acetate phthalate latices, substantially as prepared in Examples 2 and 3, were spread over the surface of the agar prior to storage of two of the dishes. The samples of the cellulose latices were be¬ tween 1 and 1 1/2 years old and had been repeatedly opened during this period. However, no growth appeared on the agar, indicating that the samples were completely devoid of bacterial contamination. An Eudragit latex was similarly cultured on another agar dish and produced heavy growth of bacteria during storage indicating con- tamination. Finally, a control dish containing agar was exposed to the air prior to storage and also developed growth.

Thus, though the latices, according to the instant invention, are aqueous vehicle formulations, and though for all practical purposes the organic solvents have been removed, the latices still display a most surprising resistance to bacteria and mold growth. On the other hand, other latices, such as Eudragits prepared by more conventional emulsion polymerization processes, were particularly prone to bacterial spoilage thereby re¬ quiring extremely careful handling. Though the precise reason for this quality of the instant invention is not entirely understood, it is believed to relate to the method of formation of the latex, i.e., initial dis- solution in a water immiscible organic solvent, and then stripping the organic solvent to form the latex. Also, the smooth surface of the polymer particles in latex may not afford a forceable environment for growth of bac¬ teria or molds. Systems employing cellulose polymers are preferred since these are known to have a greater resistance to bacteria and mold growth and thus enhance the desirable characteristics of the instant invention.

OMPI Certain additives, such as polyethylene glycol, pre¬ ferably of a molecular weight 4,000 and 6,0Q0, but oper- ably between 400 and 20,000, may serve dual purposes. Such, polyethylene glycols have been found to be desirable annealing agents while concurrently lending high gloss to resulting tablet coatings. In most instances, polyethyl¬ ene glycol would replace but a part of the annealing agents discussed above. However, worthwhile results are obtained when one or two parts of the polyethylene glycol is included on the basis of about 5 parts of ethyl cell¬ ulose in a typical formulation. Example 12 - Enteric Coated Tablets

A latex solution was prepared by diluting 333.3 grams of ethylcellulose latex (30% solids) prepared according to example 1 and 19 grams of tributylcitrate with 147.7 grams of water to produce 500 grams of coating solution. 1.9 kg of blank lactones tablets were air sus¬ pension coated with this coating solution. Twenty four of the coated tablets were evaluated by the USP method for enteric coatings and the results set forth in Table III, arranged in order of increasing disintegration times in intestinal fluid.

Table III Disintegration Time in Minutes

Pound 1 #1 #2 *3 #4 #5 #6

PH 1.2 X X X X X X a b a b a b a b a b a pH 7.5 17 - 37 25 - 46 29 - 49 29 - 52 36 - 58 38 -

Round 2 ∑fi 1.2 X X X X X X

pH 7.5 28 - 47 32 - 48 32 - 56 35 - 56 40 - 61 41 -

Round 3 EH 1.2 X X X X X X

^•pH 7.5 20 - 47 28 - 55 28 - 58 32 - 55 35 - 54 39 -

Pound 4 pH 1.2 X X X X X X

P⁹ 7.5 29 - 51 29 - 48 33 - 51 34 - 58 36 - 57 41 -

Note: x - no change in pH 1.2 a - start to disintegrate at pH 7.5 b - complete disintegration at pH 7.5

--£- Example 13 - Resistance to Bacteria

Ethylcellulose latices of this invention of 20 and 35% solids content (samples Nos. 1 and 2), prepared ac¬ cording to Example 1 were compared with commercially available coating compositions for resistance to bac¬ teria. The pour-plate method of counting living bac¬ teria or groups of bacteria was used. A measured or known amount of liquid latex was mixed with molten agar medium in a Petri-dish. After setting and incubation the number of colonies were counted. Counts were made on plates which we^'re inoculated to yield between 30 and 300 colonies to ensure test precision and accuracy; the counts are recorded as the means of the most appro¬ priate dilution. Detailed Description of the Experiment

Using a fresh sterile pipette three dilutions of each latex sample (1, 1/10, 1/100) are prepared. One ml of each dilution is pipetted into each of 3 sterile tubes which contain 3 ml of molten agar at 45°C. The medium and inoculum are immediately mixed by shaking the tubes which are then poured to the ready made agar plate which contains approximately 15 ml of setting agar. Care is taken that the plate is kept flat on the bench during this operation. Each plate was then swirled in a circular movement lasting 5-10 seconds. After allow¬ ing the plates to set, they were inverted and incubated at room temperature for 4-5 days. After incubation a plate was selected containing between 30 and 300 colo¬ nies, the number of colonies are counted and the colony 0 count per ml of initial latex sample is calculated from the dilution made for the preparation of the plate that was counted. Table 4 Viable bacteria colony count normalized to 0.1 ml latex samples following inoculation with E. Coli.

Sample. 0 hr 8 hr 1 day 2 days 1 15,400+529 0+0 9+9 q+o 2 16,000+200 0+0 0+0 o+p

A 15,000+200 14,867+305 18,867+902 33,667+3215 Water con¬ 15,133+305 14,733+416 15,400+200 14,333+416 taminated B 4 cps 2,533+104 2,917+104 1,483+104 2,217+76 B 13-18 cps 2,550+50 2,827+64 2,100+100 1,350+50 B 40-60 cps^' 2,550+50 ^*• .2,867+76 2,017+104 1,250+50 C 2,583+76 2,883+76 1,317+76 2,483+104 Water con¬ 2,600+50 2,833+76 2,317+76 1,533+104 taminated Sample A Acrylic based latex (Eudragit'" E30D Rohm Pharma GmbH

Postfach 4347, D6100 Dormstadt, W. Germany) Sample B Hydrcxypropyl methylcellulose (Methocel" front Dow Chemical Company, Midland, Michigan) E5 viscosity of 2% solution 2-6 centipoises (cps) , E15 2% solution 13-18 cps and E50 2% solution 40-60 cps Sample C Hydroxypropyl methylcellulose (Pharmacs-at'" Shin - Etsu

Chemical Company Ltd. Japan) Example 14 - Non-Enteric Coated Tablets

40 parts of the ethylcellulose latex , 30% solids , prepared by the method of example 1 was mixed with 50 parts of a 1 5% solids solution of HPMC , 5 cps viscos ity , and 10 parts of diethylphthalate. Blank tablets con¬ sisting of equal parts of microcrystalline cellulose and unmilled dicalciu phosphate dihydrate were air suspen¬ sion coated .

The resulting coated tablets were uniformly coated with a continuous film, which had a smooth glossy ap¬ pearance. Twenty-four tablets were tested by the USP disintegration test and all passed . ^{~ ~}- In summary, the instant invention, while making use of components, constituents and individual procedures which per se have been heretofore employed in the forma¬ tion of films, and occasionally for coating of tablets, provides unique results. For instance, while the water insoluble polymers employed in the instant invention may have heretofore been utilized in organosols for coating tablets, the instant invention provides for coating from latices. Many of the plasticizers, annealing agents, polishing agents, etc. have been heretofore employed with tablet coatings, but certainly not in conjunction with a latex of a water insoluble polymer which, in itself, is only marginally film forming. In no instance has there been any suggestion of a tablet coating composition utilizing an aqueous vehicle which is highly resistant to bacterial and mold growth. However, by combining the rather improbable pseudolatices, and more conventional additives, a dense, high gloss dosage coating may be formed which displays healing of initial coating imper- feetions upon application of subsequent layers. Such coatings display low water vapor transmission rates and are, depending upon the specific blend, suitable for gas¬ tric or enteric release. Of particular significance is the most surprising characteristic of being sterile and resistant to bacterial growth and mold growth, though utilizing a water vehicle. High ratios of coating materials to water may be obtained, thereby greatly facilitating the formation of dosage coatings without unduly subjecting the dosages to attack by water, or requiring a great number of individual coatings with substantial amounts of solvent to be driven off. Further, given the disclosure of the instant invention, the basic mechanism, i.e., direct or inversion emulsi- ^• fication in a continuous water phase of a water insoluble polymer dissolved in an organic solvent, and formation of a pseudolatex therefrom with further addition of appropriate plasticizers, annealing agents, polishing agents and other such conventional additives to form a coating, may be readily varied and tailored for specific uses employing relatively conventional skills of the art. Thus, the advantages in many respects, and par¬ ticularly the very unusual resistance to bacterial growth and mold growth, are intrinsic in the process and do not require deviations or compromises beyond the rather straightforward formation of the pseudolatex.

Claims

"~-~ Claims:

1. A process for forming aqueous based coatings for food or pharmaceutical products characterized by:

. dissolving at least one substantially water in- soluble polymer in a volatile water immiscible organic solvent for the polymer; forming a fine dispersion of the water insoluble polymer solution in a continuous aqueous phase by agita¬ tion of the water and the polymer solution, optionally in the presence of an emulsifier or surfactant; forming solid particles of the water insoluble polymer in the water phase by distillation of the organic solvent from the dispersion; optionally adding a water soluble polymer, or an additive to enhance the proper- ties of the dispersion and/or improve the appearance of the tablet coating; forming a film coating on a pharmaceutical dosage by applying the aqueous dispersion of water insoluble polymer to the dosage and removing the water therefrom.

2. A process for forming an aqueous based coating as set forth in Claim 1 characterized in that the average particle size of the water insoluble polymer in the dispersion is substantially between .1 and 20 microns.

3. A process for forming an aqueous based coating as set forth in Claim 1 characterized in that the solids content of the dispersion is between 10 percent and 60 percent by weight.

4. A coated pharmaceutical dosage produced as set forth in Claim 1.

5. A process for forming an aqueous based coating composition as set forth in Claim 1 characterized in that the aqueous dispersion includes a polishing agent.

- υϊTEΛ c OMPI ■ - 6. A process for forming an aqueous based 'coating composition as set forth in Claim 1 characterized in that the emulsion of organic solvent solution and water is formed with the benefit of an emulsifying agent.

7. A coating composition for food or pharmaceu¬ tical products characterized by: an aqueous dispersion of at least one water insol¬ uble polymer having an average particle size between .1 and 20 microns, the solids content of the dispersion com¬ prising about 10 percent to 60 percent by weight of the dispersion and optionally containing an -annealing agent, ^_ or a plasticizing agent or an emulsifier, or an additive to enhance the properties of the dispersion or improve the quality, performance or appearance of the product coating.

8. A coating composition for pharmaceutical do¬ sages as set forth in Claim 7 characterized in that additional solid constituents comprising annealing agents, plasticizers and additives are included in an amount not exceeding about 60 percent by weight of the water insoluble polymer.

OMP WIP