(12) United States Patent
`Chowhan et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006224911Bl
`US 6,224,911 B1
`May 1, 2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) PROCESS FOR THE PREPARATION OF
`ENTERIC COATED PHARMACEUTICAL
`DOSAGE FORMS
`
`(75)
`
`Inventors: Zakauddin T. Chowhan, Sunnyvale;
`Patrick H. Vo, San Diego, both of CA
`(US)
`
`(73) Assignee: Syntex (U.S.A.) LLC, Palo Alto, CA
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 08/375,049
`
`(22) Filed:
`
`Jan. 18, 1995
`
`(Under 37 CFR 1.47)
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 08/038,597, filed on Mar.
`16, 1993, now abandoned.
`
`Int. Cl? ....................................................... A61K 9/32
`(51)
`(52) U.S. Cl. .......................... 424/490; 424/462; 424/474;
`424/475; 424/482; 424/497; 427/2.21
`(58) Field of Search ..................................... 424/474, 475,
`424/482, 490, 497, 462; 427/2.21
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,017,647 * 4/1977 Ohno et a!. .......................... 424/482
`
`3/1983 Chopra .
`4,377,568
`4,556,552 * 12/1985 Porter et a!. ......................... 424/482
`4,704,295 * 11/1987 Porter et a!. ......................... 424/482
`4,816,259 * 3/1989 Matthews et a!. ................... 424/463
`4,837,030 * 6/1989 Valorose, Jr. et a!. ............... 424/456
`4,857,337 * 8/1989 Miller et a!. ......................... 424/482
`4,970,081 * 11/1990 Frisbee ................................. 424/482
`5,047,258 * 9/1991 Belanger et a!. .................... 424/482
`5,102,668 * 4/1992 Eichel et a!. ......................... 424/490
`5,167,964 * 12/1992 Muhammad et a!.
`............... 424/482
`5,213,794 * 5/1993 Fritsch eta!. ........................ 424/482
`5,229,134 * 7/1993 Mention eta!. ..................... 424/482
`5,330,759 * 7/1994 Pagay eta!. ......................... 424/462
`5,851,579 * 12/1998 Wu eta!. ............................ 427/2.21
`
`FOREIGN PATENT DOCUMENTS
`
`0 072 021
`59-193382A
`
`2/1983 (EP) .
`11/1984 (JP) .
`
`OTHER PUBLICATIONS
`
`Rowe, R.C.., (1981) J. Pharm. Pharmacal. 33: 423.
`* cited by examiner
`
`Primary Examiner-Robert H. Harrison
`(74) Attorney, Agent, or Firm---Heller Ehrman White &
`McAuliffe LLP
`
`(57)
`
`ABSTRACT
`
`This invention is directed to a process for the preparation of
`enteric coated pharmaceutical dosage forms. This invention
`is further directed to the aqueous enteric coating dispersions
`suitable for use in the process and the enteric coated phar(cid:173)
`maceutical dosage forms prepared by the process.
`
`13 Claims, No Drawings
`
`

`
`US 6,224,911 Bl
`
`1
`PROCESS FOR THE PREPARATION OF
`ENTERIC COATED PHARMACEUTICAL
`DOSAGE FORMS
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation of our application Ser.
`No. 08/038,597, filed Mar. 16, 1993, and now abandoned.
`
`FIELD OF THE INVENTION
`
`This invention relates to a process for preparing enteric
`coated pharmaceutical dosage forms, to the aqueous enteric
`coating dispersions suitable for use in the process, and to the
`enteric coated pharmaceutical dosage forms prepared by the
`process.
`
`BACKGROUND OF THE INVENTION
`
`The absorption of a drug as it passes through the alimen(cid:173)
`tary canal can be controlled by coating the pharmaceutical
`with a substance which will at certain pH values retard
`release of the drug while at other pH values promote
`disintegration and/or leaching of the drug from the dosage
`form. For example, a coat comprised of an anionic polymer
`such as cellulose acetate phthalate prevents premature dis- 25
`integration of the pharmaceutical in the acidic environment
`of the stomach and promotes rapid release of the drug in the
`intestine. Such a coat is commonly called an enteric coat
`(e.g., see U.S. Pat. No. 4,857,337 for a description of enteric
`coated aspirin dosage forms).
`The enteric coat surrounds the core dosage form with a
`film which is hydrophobic at acidic pH values. At pH values
`below 4, the monolayers of the film are arranged in a
`compact alignment resistant to penetration by water and
`ions. However, at pH values of 5.8 and more basic the
`monolayers expand allowing the penetration of water and
`lOllS.
`The enteric coat is applied by coating the pharmaceutical
`dosage form with a liquid enteric coating mixture in the
`presence of a sufficient amount of heat to vaporize the
`solvents. The mixture usually contains, in addition to an
`anionic polymer, a plasticizer or a combination of plasticiz(cid:173)
`ers. The plasticizers cross-link the polymer molecules
`together by hydrogen bonding which results in a lattice 45
`structure that adds tensile strength to the esoteric coat and
`promotes adhesion to the surface of the dosage form. The
`enteric coat can contain other ingredients such as
`surfactants, pigments, and fillers.
`Organic solvents or aqueous mixtures of organic solvents
`are often used to prepare the enteric coating mixtures (e.g.,
`see U.S. Pat. No. 4,377,568 for a description of aqueous
`alcoholic enteric coating dispersions). However, organic
`solvents have to be recycled and can result in contamination
`of the enteric coat. When water is used to prepare an enteric 55
`coating dispersion, a detackifier and glidant (e.g., talc) may
`be needed to avoid sticking or clumping of the pharmaceu(cid:173)
`tical dosage forms during the application process. Constant
`and vigorous stirring is usually required to prevent the
`anionic detachifier/glidant from settling out. Because of the
`stirring, foaming may occur and antifoam agents may be
`necessary.
`The solubility of an anionic polymer in an aqueous
`solvent can be increased by adding base (e.g., see Japanese
`Kokai No. 15 9193-382-A for a description of an aqueous 65
`enteric coating solution of carboxymethylethyl cellulose and
`base). However, the free base that is present in the solvent
`
`2
`will also then be present in the resulting enteric coat and the
`capacity of the coat to resist disintegration in an acidic
`environment is reduced.
`In addition to the various process-related problems which
`5 can occur during the application of the enteric coat, other
`problems may become apparent after the coat has dried (e.g.,
`see Rowe, R. C. (1981) J Pharm Pharmacal 33: 423). A
`sufficient amount of enteric coating material must be applied
`to the uncoated dosage form to assure the formation of an
`10 adequate enteric coat. However, as the amount of the enteric
`coating material is increased, problems may occur as a result
`of the internal stress that develops in the coat as it dries. For
`example, a common problem associated with enteric coated
`tablets is logo-bridging (i.e., the enteric coat pulls away from
`15 a tablet surface and the legibility of the monogram is lost).
`Typically, logo-bridging occurs when the weight gain due to
`the enteric coat exceeds 2-3% of the uncoated tablet weight.
`The disclosure of the above and other documents referred
`to throughout this application are incorporated herein by
`20 reference.
`
`SUMMARY OF THE INVENTION
`
`30
`
`This invention comprises a process for preparing enteric
`coated pharmaceutical dosage forms, which process com(cid:173)
`prises combining in water one or more anionic polymers,
`one or more plasticizers, one or more optional excipients,
`and a volatile base to form an aqueous enteric coating
`dispersion; and coating an uncoated pharmaceutical dosage
`form with the aqueous dispersion.
`This invention also comprises an aqueous enteric coating
`dispersion suitable for use in the preparation of enteric
`coated pharmaceutical dosage forms, the dispersion com(cid:173)
`prising one or more anionic polymers, one or more
`35 plasticizers, one or more optional excipients, and a base
`which promotes the dispersion of the anionic polymers in
`water but readily vaporizes during the coating process.
`This invention also comprises an enteric coated pharma(cid:173)
`ceutical dosage form prepared by the process of this inven-
`40 tion.
`
`ADVANTAGES OF THE INVENTION
`
`The process of this invention produces an enteric coat
`which is free of organic solvents, detackifiers, glidants, and
`antifoam agents. In addition, because a volatile base is used
`in the process to promote the solubility of the anionic
`polymer in the aqueous enteric coating dispersion, the
`resulting enteric coat does not contain free base.
`The process of this invention produces enteric coated
`tablets that at 6 to 15% weight gain pass USP enteric coating
`specifications for disintegration and dissolution and do not
`exhibit logo-bridging.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Definitions
`
`Unless otherwise stated, the following terms used in the
`specification and claims have the meanings given below:
`All percentages refer to percentages by weight.
`The term "volatile base" means a base which which will
`readily vaporize under the conditions used for coating the
`uncoated dosage form.
`The term "aqueous dispersion" or "aqueous enteric coat(cid:173)
`ing dispersion" means a mixture of enteric coating material
`dispersed in a solvent consisting essentially of water.
`
`50
`
`60
`
`

`
`US 6,224,911 Bl
`
`5
`
`4
`Drugs which are useful in this invention include any for
`which enteric adsorption might be desirable. Exemplary
`drugs include naproxen (see U.S. Pat. No. 4,009,197) and
`ketorolac (see U.S. Pat. No. 4,089,969) and the pharmaceu-
`tically acceptable salts thereof. While, suitable pharmaceu(cid:173)
`tically acceptable dosage forms of drugs can be prepared by
`any of the usual and acceptable modes known in the art, the
`preferred dosage form is a tablet (e.g., see Edward Rudnic
`and Joseph B. Schwartz. 1990. Remington's Pharmaceutical
`10 Sciences, ed. A. R. Gennaro, 1633-65, Easton: Mack Pub(cid:173)
`lishing Company, for a description of how to make tablet
`forms of drugs).
`In some instances it may be necessary to apply a sealing
`coat to the tablet prior to applying the enteric coat. A sealing
`coat protects the tablet ingredients from the water in the
`aqueous enteric coating dispersion to assure the stability of
`the dosage form. The sealing coat comprises a resin such as
`shellac, zein, and the like and is applied to the dosage form
`by methods known to those of ordinary skill in the art.
`
`Description
`
`3
`The term "enteric coating material" means the non(cid:173)
`aqueous ingredients that are present in the aqueous enteric
`coating dispersion and the materials which comprise the
`enteric coat. For the process of this invention such materials
`can include anionic polymers, plasticizers, and optional
`excipients.
`The term "pharmaceutically acceptable" means that
`which is generally safe, non-toxic and neither biologically
`nor otherwise undesirable and includes that which is accept(cid:173)
`able for veterinary use as well as human pharmaceutical use.
`The term "pharmaceutical dosage form" means a dosage
`form of a drug (e.g., tablet, powder, capsule, and the like)
`which is pharmaceutically acceptable, as defined above, and
`which possesses the necessary and desirable characteristics
`of a dosage form acceptable for administration to a patient 15
`(e.g., a tablet of acceptable hardness, dissolution, stability,
`and a size and weight practical for oral administration).
`The term "optional excipients" means that excipients may
`or may not be present. For example, "combining in water
`one or more anionic polymers, one or more plasticizers, one 20
`or more optional excipients, and a volatile base" means that
`combining the excipients may or may not be carried out in
`order for the described process to fall within the invention.
`The term "uncoated" when referring to a dosage form
`means that the dosage form does not have an enteric coat. 25
`
`Materials
`Suitable anionic polymers for the enteric coating of this
`invention are insoluble in acidic environments (e.g., gastric
`juice) but are soluble at pH 5.5 and upwards. Such polymers
`include cellulose acetate phthalate, methacrylate-base
`polymers, cellulose acetate, trimellitate, hydroxypropyl
`methylcellulose phthalate, and the like. Suitable
`methacrylate-based polymers include Eudragit® L and
`Eudragit® S, anionic polymers synthesized from meth- 35
`acrylic acid and an acrylate. Specific methacrylate-based
`polymers include Eudragit® L 100, which is synthesized
`from methacrylic acid and methyl methacrylate and has a
`ratio of free carboxyl groups to ester groups of approxi(cid:173)
`mately 1:1, Eudragit® L 100-55, which is synthesized from
`methacrylic acid and ethyl acrylate and has a ratio of free
`carboxyl groups to ester groups of approximately 1:1, and
`Eudragit® S 100, which is synthesized from methacrylic
`acid and methyl methacrylate and has a ratio of free carboxyl
`groups to ester groups of approximately 1:2.
`Generally, the anionic polymers useful in this invention
`are dissolved in organic solvents before being used in a film
`coating process. For example, the solvents recommended by
`the manufacturer for dissolving Eudragit® LandS polymers
`include methyl alcohol, ethyl alcohol, ethyl alcohol/water, 50
`isopropyl alcohol, isopropyl alcohol/water, n-butyl alcohol,
`propylene glycol, ethyleneglycol monobutyl ether, acetone,
`acetone/isopropyl alcohol, and the like. However, base will
`promote the dispersion of these anionic polymers in water;
`and a suitable volatile base (e.g., ammonium hydroxide) will 55
`readily vaporize under the conditions used for the film
`coating process of this invention.
`Suitable plasticizers impart sufficient tensile strength to
`the coating to prevent film cracking and logo-bridging. Such
`plasticizers include triethyl citrate, dibutyl phthalate, poly- 60
`ethylene glycols, propylene glycol, diethylphthalate, acetyl
`triethyl citrate, and the like.
`Suitable optional excipients include surfactants (e.g.,
`polysorbate 80, sodium lauryl sulfate, and the like), colo(cid:173)
`rants (e.g., iron oxide, lakes, dyes, titanium dioxide, and the 65
`like), and fillers (e.g., microcrystalline cellulose and the
`like).
`
`30
`
`An anionic polymer or a combination of anionic polymers
`is dispersed in water and the dispersion is stirred. A volatile
`base is slowly added and the dispersion is further stirred.
`A plasticizer or a combination of plasticizers is emulsified
`in water and the emulsion is stirred. The emulsion is then
`added to the dispersion of polymer and base. One or more
`optional excipients are then added. The aqueous dispersion
`is then passed through a #80 mesh screen to produce the final
`aqueous dispersion which is suitable for use in the prepa(cid:173)
`ration of an enteric coated pharmaceutical dosage form. The
`preparation of an aqueous enteric coating dispersion of this
`invention is described in Example 1.
`Preferably the anionic polymer is polymethacrylate-
`based, preferably Eudragit® L 100-55 alone or in combina(cid:173)
`tion with Eudragit® L 100; the plasticizer is triethyl citrate
`and dibutyl phthalate either alone or triethyl citrate in
`combination with dibutyl phthalate or polyethylene glycol
`40 400; and the base is ammonium hydroxide. Preferably the
`dispersion comprises 7 to 18% Eudragit® L 100-55, 0 to 8%
`Eudragit® L 100, 0 to 6% triethyl citrate, 0 to 6% dibutyl
`phthalate, and 0.3 to 1.0% ammonium hydroxide; more
`preferably 7 to 8% Eudragit® L 100-55, 7 to 8% Eudragit®
`45 L 100, 2 to 3% triethyl citrate, 1 to 2% dibutyl phthalate, and
`0.3 to 0.9% ammonium hydroxide.
`The enteric coat can be applied by coating a cascading bed
`of the uncoated pharmaceutical dosage form with the aque(cid:173)
`ous enteric coating dispersion in the presence of a sufficient
`amount of heat to vaporize the water and base. Unless a
`water-insoluble excipient (e.g., iron oxide) has been
`included, the dispersion does not require stirring during the
`application process. Thus, without relying upon organic
`solvents, lubricants, or antifoam agents, the enteric coating
`material is delivered to the pharmaceutical dosage form with
`uniform coverage and the coating material dries without
`adjacent dosage forms adhering together.
`The aqueous enteric coating dispersion of this invention is
`particularly suited for application by spray coating.
`Preferably, the pharmaceutical dosage form is a tablet. The
`tablet is loaded into a coating pan (e.g., Freund model
`HCT-30 Hicoater) which is preheated by inlet air tempera(cid:173)
`ture until the target exhaust temperature is reached. While
`the pan is rotating, the aqueous enteric coating dispersion is
`sprayed onto the tablets using a spray gun (e.g., a Freund
`model HM with a 1.5 mm fluid nozzle). After the spraying
`is completed the tablets are dried for an additional period.
`
`

`
`US 6,224,911 Bl
`
`5
`The preparation of an enteric coated tablet by the process of
`this invention is described in Example 2.
`The disintegration characteristics of the enteric coated
`tablets of this invention can be determined using the in vitro
`methods described in The United States Pharmacopeia 5
`(USP XXII). Rockville, Md.: United States Pharmacopeia!
`Convention, Inc., 1990, pp 1577-1578. Dissolution charac(cid:173)
`teristics can be determined by in vitro methods described in
`USP XXII, pp 1578-1579. In vitro disintegration and dis(cid:173)
`solution tests of enteric coated tablets prepared by the 10
`process of this invention is described in Examples 3 and 4,
`respectively.
`Enteric coated tablets prepared by the process of this
`invention pass USP enteric coating specifications for disin(cid:173)
`tegration and dissolution at as low as 6 to 8% film coat 15
`weight gain. No logo-bridging occurs at as high as 15% film
`coat weight gain.
`
`EXAMPLES
`
`The following examples are not intended to limit the
`scope of the invention. While the process parameters pro(cid:173)
`vided are meant to reflect a certain level of accuracy, some
`experimental error and deviation should be tolerated.
`
`Example 1
`
`Preparation of Aqueous Enteric Coating Dispersion
`
`Eudragit® L 100-55 (70.0 gms) and Eudragit® L 100 (70
`g) were dispersed in purified water (500 g) and the suspen(cid:173)
`sion was stirred for approximately 10 minutes. Strong
`ammonia solution, NF (8.4 g; 9.3 mL of 28-29% NH3 in
`water) was slowly added to the dispersion and the mixture
`was stirred for 30 minutes. Triethyl citrate, NF (28 g) and
`dibutyl phthalate (11 g) were emulsified in water (269 g) and
`the emulsion was stirred for 10 minutes. The emulsion was
`added to the dispersion containing the Eudragit® polymers
`and base, and the resulting dispersion was moderately stirred
`for 20 minutes. The dispersion was passed through a #80
`mesh screen to produce an aqueous enteric coating disper(cid:173)
`sion comprising the following:
`
`Dispersion 1
`
`Eudragit ® L 100-55
`Eudragit ® L-1 00
`Triethyl Citrate, NF
`Dibutyl Phthalate
`Strong Ammonia Solution, NF
`Purified Water, USP
`
`%
`
`7.32
`7.32
`2.93
`1.17
`0.88
`80.4
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`6
`
`-continued
`
`Iron Oxide
`Purified Water, USP
`Dispersion 3
`
`Eudragit ® L 100-55
`Eudragit ® L 100
`Triethyl Citrate, NF
`Strong Ammonia Solution, NF
`Purified Water, USP
`Dispersion 4
`
`Eudragit ® L 100-55
`Eudragit ® L 100
`Triethyl Citrate, NF
`Polyethylene Glycol 400, NF
`Strong Ammonia Solution, NF
`Purified Water, USP
`Dispersion 5
`
`Eudragit ® L 100-55
`Dibutyl Phthalate
`Strong Ammonia Solution, NF
`Purified Water, USP
`Dispersion 6
`
`Eudragit ® L 100-55
`Dibutyl Phthalate
`Strong Ammonia Solution, NF
`Purified Water, USP
`Dispersion 7
`
`Eudragit ® L 100-55
`Triethyl Citrate, NF
`Strong Ammonia Solution, NF
`Purified Water, USP
`Dispersion 8
`
`Eudragit ® L 100-55
`Triethyl Citrate, NF
`Dibutyl Phthalate
`Strong Ammonia Solution, NF
`Purified Water, USP
`Dispersion 9
`
`Eudragit ® L 100-55
`Dibutyl Phthalate
`Strong Ammonia Solution, NF
`Purified Water, USP
`Dispersion 10
`
`Eudragit ® L 100-55
`Dibutyl Phthalate
`Strong Ammonia Solution, NF
`Purified Water, USP
`
`%
`
`0.40
`80.0
`
`7.30
`7.30
`4.17
`0.87
`80.3
`
`7.38
`7.38
`3.69
`0.53
`0.88
`80.1
`
`14.9
`2.97
`0.38
`81.8
`
`17.8
`5.09
`0.80
`76.3
`
`14.6
`4.18
`0.65
`80.5
`
`14.6
`2.09
`2.09
`0.66
`80.5
`
`16.4
`3.32
`0.68
`79.6
`
`14.7
`4.19
`0.65
`80.5
`
`Example 2
`
`Preparation of Enteric Coated Tablets
`
`Proceeding similarly, the following aqueous enteric coat- 55
`ing dispersions were prepared:
`
`Dispersion 2
`
`Eudragit ® L-100-55
`Eudragit ® L-1 00
`Triethyl Citrate, NF
`Dibutyl Phthalate
`Strong Ammonia Solution, NF
`
`%
`
`7.31
`7.31
`2.93
`1.17
`0.87
`
`In this Example, naproxen sodium tablets were chosen as
`the model pharmaceutical dosage form. Uncoated naproxen
`sodium tablets pretreated with a sealing coat were loaded
`into a Freund model HCT-30 Hicoater coating pan which
`had been preheated at an inlet air temperature of 70° C. until
`the exhaust temperature was 44 o C. While the pan was
`60 rotated at 10 rpm, Dispersion 1 was sprayed onto the tablets
`using a Freund model HM spray gun with a 1.5 mm fluid
`nozzle at an atomizing pressure of 2.8 kg/cm 2 and a flow rate
`of 6.0 mL/min.
`After spraying was completed, the tablets were dried for
`65 an additional10 to 20 minutes. The enteric coated naproxen
`sodium tablets prepared from Dispersion 1 had 5.5% weight
`gain.
`
`

`
`US 6,224,911 Bl
`
`8
`was removed and a perforated plastic cylinder (9.5 mm in
`length and 20.7 mm in diameter) was added to each tube.
`The rack was imersed in simulated intestinal fluid test
`solution (see USP XXII, p 1789) maintained at 37° C. and
`the apparatus was operated for 2 hours.
`The enteric coated naproxen sodium tablets prepared by
`the process of this invention and tested by the above
`methods were in compliance with USP specifications for
`disintegration of enteric coated tablets.
`
`Example 4
`
`In Vitro Dissolution Test
`
`5
`
`10
`
`7
`Proceeding as above, but at a pan speed of 20 to 22 rpm,
`inlet temperature of 50° C., exhaust temperature of 33° C.,
`atomizing pressure of 2.2 kg/cm2
`, and a flow rate of 6.5
`mL/min, enteric coated naproxen sodium tablets were pre(cid:173)
`pared from Dispersion 2.
`Proceeding as above, but at a pan speed of 10 rpm, inlet
`temperature of 80° C., exhaust temperature of 42 to 43° C.,
`atomizing pressure of 2.6 kg/cm2
`, and a flow rate of 6.0
`mL/min, enteric coated naproxen sodium tablets with 7.8%
`weight gain were prepared from Dispersion 3.
`Proceeding as above, but at a pan speed of 10 to 12 rpm,
`inlet temperature of70° C., exhaust temperature of 42 to 43°
`C., atomizing pressure of 2.5 to 3.0 kg/cm2
`, and a flow rate
`of 6.0 to 6.3 mL/min, enteric coated naproxen sodium tablets
`with 6.1% weight gain were prepared from Dispersion 4.
`Proceeding as above, but at a pan speed of 15 rpm, inlet
`temperature of 75° C., exhaust temperature of 43° C.,
`atomizing pressure of 2.6 kg/cm2
`, and a flow rate of 6.2
`mL/min, enteric coated naproxen sodium tablets with 8.0%
`weight gain were prepared from Dispersion 5.
`Proceeding as above, but at a pan speed of 13 rpm, inlet
`temperature of 70° C., exhaust temperature of 40.5° C.,
`atomizing pressure of 2.5 kg/cm2
`, and a flow rate of 6.2
`mL/min, enteric coated naproxen sodium tablets with 6.5% 25
`weight gain were prepared from Dispersion 6.
`Proceeding as above, but at a pan speed of 12 to 15 rpm,
`inlet temperature of70° C., exhaust temperature of 44 to 45°
`C., atomizing pressure of 2.8 kg/cm2
`, and a flow rate of 6.0
`mL/min, enteric coated naproxen sodium tablets with 8.0% 30
`weight gain were prepared from Dispersion 7.
`Proceeding as above, but at a pan speed of 12 to 15 rpm,
`inlet temperature of 68° C., exhaust temperature of 42 to 44°
`C., atomizing pressure of 3.0 kg/cm2
`, and a flow rate of 5.0
`mL/min, enteric coated naproxen sodium tablets with 6.0% 35
`weight gain were prepared from Dispersion 8.
`Proceeding as above, but at a pan speed of 18 rpm, inlet
`temperature of 70° C., exhaust temperature of 40° C.,
`atomizing pressure of 2.5 kg/cm2
`, and a flow rate of 6.2
`mL/min, enteric coated naproxen sodium tablets with 7.5% 40
`weight gain were prepared from Dispersion 9.
`Proceeding as above, but at a pan speed of 12 rpm, inlet
`temperature of 75° C., exhaust temperature of 40.5° C.,
`atomizing pressure of 2.5 kg/cm2
`, and a flow rate of 6.2 45
`mL/min, enteric coated naproxen sodium tablets with 7.2%
`weight gain were prepared from Dispersion 10.
`
`15
`
`An enteric coated naproxen sodium tablet was placed in
`a round bottom, 1000 mL vessel containing a dissolution
`fluid which was maintained at 37° C. and continually stirred
`at 50 rpm by a paddle held in a horizontal position near the
`bottom of the container. The dissolution fluid was 0.1 N HCl
`for the first two hours and 0.1 M phosphate buffer (pH 7.4)
`20 for a third hour. Samples of the dissolution fluid were
`removed at various intervals, filtered through a 8.0,u filter
`and the amount of dissolved drug was determined by ultra(cid:173)
`violet spectrophotometry at 272 nm.
`The enteric coated naproxen sodium tablets demonstrated
`excellent physical resistance to the acid medium (e.g., no
`dissolution occurred after 2 hours). At pH 7.4, all tablets
`were in compliance with USP specifications for dissolution
`of enteric coated tablets.
`While the process of this invention has been described
`with reference to a general description and to specific
`embodiments by example, it should be understood that
`various modifications and/or substitutions are possible with(cid:173)
`out departing from the true spirit and scope of the invention.
`We claim:
`1. A process for preparing an enteric coated pharmaceu(cid:173)
`tical dosage form comprising:
`(1) combining in water one or more anionic polymers
`being synthesized from methacrylic acid and an acrylic
`acid ester, one or more plasticizers selected from tri(cid:173)
`ethyl citrate and dibutyl phthalate, and ammonium
`hydroxide to form an aqueous enteric coating disper(cid:173)
`sion free of organic solvents, detackifiers, glidants, and
`antifoam agents; and
`(2) spray coating an uncoated pharmaceutical dosage
`form with the dispersion.
`2. The process of claim 1 in which the polymers are a first
`polymer alone, the first polymer being synthesized from
`methacrylic acid and ethyl acrylate and having a ratio of free
`50 carboxyl groups to ester groups of approximately 1:1, or the
`first polymer in combination with a second polymer, the
`second polymer being synthesized from methacrylic acid
`and methyl methacrylate and having a ratio of free carboxyl
`groups to ester groups of approximately 1:1.
`3. The process of claim 2 in which the dispersion com(cid:173)
`prises 7 to 8% of the first polymer, 7 to 8% of the second
`polymer, 2 to 3% triethyl citrate, 1 to 2% dibutyl phthalate
`and 0.8 to 0.9% ammonium hydroxide.
`4. The process of claim 3 in which the pharmaceutical
`60 dosage form is a pharmaceutically acceptable naproxen or
`naproxen sodium tablet.
`5. The process of claim 3 in which the pharmaceutical
`dosage form is a pharmaceutically acceptable ketorolac
`tablet.
`6. An aqueous enteric coating dispersion free of organic
`solvents, detackifiers, glidants, and antifoam agents and
`suitable for use in the preparation of an enteric coated
`
`Example 3
`
`In Vitro Disintegration Test
`
`Six open-ended transparent tubes (7.5 em in length and
`21.5 mm in diameter) were assembled in a rack such that the
`bottom of each tube was positioned against a 10-mesh No.
`23 (0.025-inch) W. and M. gauge woven stainless-steel wire 55
`cloth. The rack was suspended in a 1000 mL low-form
`beaker in such a manner so that the tubes could be raised and
`lowered in the imersion fluid at a rate of 29 to 32 cycles per
`minute through a distance of 5.3 to 5.7 em. The volume of
`the imersion fluid was such that the wire mesh is 2.5 em
`from the surface of the fluid at the top of the upward stroke
`and 2.5 em from the bottom of the beaker at the bottom of
`the downward stroke.
`An enteric coated naproxen sodium tablet was placed in
`each of the six tubes. The rack was imersed in simulated 65
`gastric fluid test solution (see USP XXII, p 1788) maintained
`at 37° C. and the apparatus was operated for 1 hour. The rack
`
`

`
`US 6,224,911 Bl
`
`5
`
`9
`pharmaceutical dosage form, the dispersion prepared by
`combining in water one or more anionic polymers being
`synthesized from methacrylic acid and an acrylic acid ester,
`one or more plasticizers selected from triethyl citrate and
`dibutyl phthalate, and ammonium hydroxide.
`7. The dispersion of claim 6 in which the polymers are a
`first polymer alone, the first polymer being synthesized from
`methacrylic acid and ethyl acrylate and having a ratio of free
`carboxyl groups to ester groups of approximately 1:1, or the
`first polymer in combination with a second polymer, the 10
`second polymer being synthesized from methacrylic acid
`and methyl methacrylate and having a ratio of free carboxyl
`groups to ester groups of approximately 1:1.
`8. The dispersion of claim 7 comprising 7 to 8% of the
`first polymer, 7 to 8% of the second polymer, 2 to 3% triethyl 15
`citrate, 1 to 2% dibutyl phthalate and 0.8 to 0.9% ammonium
`hydroxide.
`9. An enteric coated pharmaceutical dosage form prepared
`by a process comprising:
`(1) combining in water one or more anionic polymers 20
`being synthesized from methacrylic acid and an acrylic
`acid ester, one or more plasticizers selected from tri(cid:173)
`ethyl citrate and dibutyl phthalate, and ammonium
`hydroxide to form an aqueous enteric coating disper-
`
`10
`sian free of organic solvents, detackifiers, glidants, and
`antifoam agents; and
`(2) spray coating an uncoated pharmaceutical dosage
`form with the dispersion.
`10. The enteric coated dosage form of claim 9 in which
`the polymers are a first polymer alone, the first polymer
`being synthesized from methacrylic acid and ethyl acrylate
`and having a ratio of free carboxyl groups to ester groups of
`approximately 1:1, or the first polymer in combination with
`a second polymer, the second polymer being synthesized
`from methacrylic acid and methyl methacrylate and having
`a ratio of free carboxyl groups to ester groups of approxi(cid:173)
`mately 1:1.
`11. The enteric coated dosage form of claim 10 in which
`the dispersion comprises 7 to 8% of the first polymer, of the
`second polymer, 2 to 3% triethyl citrate, 1 to 2% dibutyl
`phthalate and 0.8 to 0.9% ammonium hydroxide.
`12. The enteric coated dosage form of claim 11 in which
`the pharmaceutical dosage form is a pharmaceutically
`acceptable naproxen or naproxen sodium tablet.
`13. The enteric coated dosage form of claim 11 in which
`the pharmaceutical dosage form is a pharmaceutically
`acceptable ketorolac tablet.
`
`* * * * *