CA2008005A1 - Microencapsulated taste-masked water-insoluble nsaid drug materials - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
This disclosure is directed to preparation of individual taste-masked, high payload, microcapsules by microencapsulatio of water-insoluble NSAID drug materials in the substantial absence of microcapsule agglomerates. These taste-masked micro-capsules contain a high payload, e.g., about 83-~ wt.~ of said NSAID drug material and can then be formulated into chewable tablets and liquid aqueous suspensions for medicinal use.
Cellulose acetate phthalate is the micro-encapsulating polymer wall material.
Control of pH, controlled addition of a Hofmeister (lyo-tropic) salt, microencapsulation of the water-insoluble NSAID
medicament with a liquid phase of cellulose acetate phthalate microencapsulating material and the subsequent insolubilization of said liquid encapsulating material after it is wrapped around the medicament core with dilute acid are important process parameters to achieving the proper individual microcapsules to obtain taste-masked, water-insoluble NSAID drug materials, esp., naproxen and ibuprofen, by microencapsulation alone.

Description

JN~ r~L)~ E~ KED W~
~N';OlU131E ~S~IO 1)1~13(~ RI/~LS

111~L~ `SC1~lB'l'r_N 01;~L~ _IN ENTION
rl`he presetl~ inve1ltio1l is directed to preparation of i~dividual tclste-masked, hiyl~ payload, microcapsules by micro-enc<11~sulatio1~ of water-ins~luble NS~ID drug materials in the substa1~tial a~sence of microcapsule agglomerates. These taste-mas~ed microcapsules contain a high payload, e.g., about 83+ wt.
Or said l~SAID drùg material and can then be formul~ted into c}lewable tablets and liquid aqueous suspensions for medicinal use. Cellulose acetate phthalate is the micro-encapsulating polymer wall material.
Control of p~1, controlled addition of a ~50~meister (lyo-tropic) salt, microencapsulation of the water-insoluble NSAID
me~ica1ne1lt with a liquid phase of cellulose acetate p1~thalate microencapsulating material and t~le subsequent insolubilization of said liquid encapsulating material after it is wrapped around t~le medicament core with dilute acid are important process para1neters to achieving the proper individual microcapsules to obtain taste-masked, water-insoluble NS~I~ drug ma~erials, e.g., ~apro~en and ibuprofen, by microencapsulation alone.
B~CKGROUND OF T~1E INVENTION ~ND PRIOR ~R' Non-steroidal anti-inflammatory drugs tNS~ID) llaving analyesic and anti-infla1nmatory properties have been widely administered orally in the treatment of mild to severe pain, -2~

~?art:icularly for rheumatoid arthritis and osteoarLIIr:itjs patients. Tolerance or addiction to t~lese drugs is not genercilly a ~roblem witll t~leir continuous use in the treatment of pain or in tlle treatment of acute or chronic inflammatory states.
~lowever, these drugs generally have a hiyher potential for adverse side effects at tlle upper concentrations (limits) of their effective dose ranges. Therefore, it is importallt that such non-steroidal anti-inflammatory drugs be accurately measured and administered orally.

These non-steroidal anti-inflammat~ry drugs, e.g., ibuprofen and naproxen, have been widely prescribed by physicians. These drugs are in general tolerated well by most patients and provide an effective means for control of pain and inflammatory processes, particularly for the rheumatoid arthritis and osteoarthritis patients. However, these non-steroidal anti-inflammatory drugs have severe bitter taste and aftertaste, and have an adverse mouth feel when taken orally.
Therefore, in order to make wider use of them while substantially eliminating the bitter taste, aftertaste and adverse mouth feel and make these druys more pleasant upon taking them orally, there has long been desired a way to insure delivery of -these druys in their desired concentrations while avoiding their extremely bitter taste, ]ingering aftertaste and adverse mouth feel effects referred to above connected with their inges-tion orally thereby encouraging patient compliance.

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Various ways ancl delivery systems hclve l>een attemE~ted in the ~Iior art to aocomplisl~ these and other objectives.
II~S. Patent No. ~,755,532, issued to ~ Sunshine et al, is directed to analgesic and anti-inflammatory compositions compris-- ing dipilellllydramine and analgesically and anti-inflammatorily effective amounts of sulindac, diclofenac, fenclo~enac, alclo-fenac, ibufenac, iso~epac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac or oxipinac, or a pharmaceutical-ly acceptable salt thereof. The Sunshine et al patent apparently relies UpOIl sweeteninq and flavoring agents to counter the very bitter taste and lingering aftertaste o~ ibuprofen and naproxen when these two drugs are incorporated into the Sunshine et al compositions and they are administered orallyO
U.S. Patent 4,7G6,012, issued to Valenti, teaches the microencapsulation of ibuprofen and naproxen. The micro-encapsulation method employed by Valenti dissolves a coating agent in water by salification to form an aqueous solution, dispersing the medicament particles first in water, then in the solution of salified coating agent to for~ a suspension, and adding an acidifying agent thereof to precipitate the coating aqent onto the particles of medicament and recovering the micro-capsules thus formed.
U.S. Patent 4,460,563, issued to Massimo Calanchi, dis-closes that ibuprofen can be microencapsulated with hydroxy-propylmethylcellulose phthalate.

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U.S. ~1te1lt ~,726,966, issued to Kawashima et al, disso1ves ibu~ro~en with acrylic acid resin in ethanol and mixes this solution w;th water while stirring to deposit the coating.
~ccording to Kawashima et al, the appropriate granular ibuprofen g1^ai1l size thus salvaged ranges from lO to 2,000 micrometers.
~`hese particles are termed to be microspheres by Kawa~hima et al.
U.S. Patent 4,762,702, issued to Gergely et al, is directed to a phannaceutical preparation containing ibuprofen coated with a hydrocolloid/fumaric acid coating, e.g., xanthan gum and/or maltodextrin-fumaric acid. Gergely et al rely heavily on sweetening and flavoring agents to alleviate the very bitter taste of ibuprofen. It is noted in Example l that lO to 15 times the quantity of sugar as compared with ibuprofen is employed in addition to citric acid present in an amount equal to twice the quantity of ibuprofen in order to obtain what Gergely et al term a mixture which "could be made into a pleasant tasting beverage". Note Example l of Gergely et al.
U.S Patent 4,571,333, issued to 11siao et al, is directed to a controlled release tablet for once-daily oral administration of about 500 to 1200 mg of naproxen or naproxen sodium, utilizing a homogeneous matrix comprising about 4 to 9 weight percent of hydroxpropylmethylcellulose having a number average molecular weight in the range of from about 80,000 to about 130,000, about 81 to 96 weight percent naproxen or naproxen sodium, 0.l to about 2 weight percent of a pharmaceutically acceptable lubricating agent, and 0 to about 8 weight percent of other pharmaceutically acceptable excipients.

-5~ 9t-u.~ dtents ~,~3s,l~G; 4,~35,187, al-d ~,$35,18~ are ~irecte(l to makillg taste~neutral (taste-masked) ib~lpro~`en in dr-y pot~der form. U.S. Patents 4,835,1~6 and U.S. 4,~35,1n7 involve obtalning this taste-neutral ibuprof~-n in powder form by spray dryillg suspensions of colloidal silica in organic solvent solu~
tions of ibuprofen and a cellulose material In U.S. Patent 4,835,1~6, issued to Gerald L. Reuter et al, the organic solvent is a mixture of lower alkanol, e.g., isopropanol, and ethyl acetate, and the cellulose material is cellulose acetate phthalate. This product is stated to contain about 40% to 70% by weight ibuprofen, about 15-~ to 50% by weiyht of cellulose acetate phthalate and about 5% to 40% by weight col-loidal silica.
In U.S. 4,835,187, issued to Gerald L. Reuter et al, the organic solvent is a lower alkanol, e.g., isopropanol, or con-tains at least 50% lower alkanol, and the cellulose material is ethyl cellulose, hydroxyethyl cellulose, or hydroxypropylmethyl cellulose, alone or in admixture. The lower alkanol solvent has a colloidal silica suspended therein. Tllis product is stated to con~in about 40% to 70% by weight ibuprofen, about 15% to 50% of a cellulose material selected from the group consistiny of etllyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose and admixtures thereof and about 5% to ~0% by weight colloidal silica.
In U.S. 4,835,188, issued to Ying T. R. Ho et al, the taste-neutral powder form of ibuprofen is obtained by spray drying a dispersion of ibuprofen and ethyl cellulose in water ~6--havitlg a pla~ticizer dissolved or suspendecl therein. This product is stated to contain about 63~ to 77% by weight ibupro-en~ about ~5% to 40% by wei~ht ethyl cellulose and about 2% to 7% weight plasticizer.
DETAII,ED DESCXIPTION OF TI~E INVENTION
This invention enables the preparation of individual taste-masked microcapsules by microencapsulation o~ water insoluble NS~ID drug materials in the substantial absence of microcapsule agglomerates, viæ., agglomerates of individual microcapsules. These taste-masked individual microcapsules can then be formulated into chewable tablets and liquid aqueous suspensions of the appropriate dosage for medicinal use. Cel-lulose acetate phthalate is the microencapsulating polymer microcapsule wall material.
Control of pH, controlled addition of a Hofmeisker (lyo-tropic) salt, microencapsulation of the wat~r-insolubl~ NSAID
medicament with a liquid phase of cellulose acetate phthalate polymer material and the subsequent insolubilization of said liquid microencapsulating material, after it has wrapped around the medicament core, with dilute acid are important process parameters to achieving the proper individual microcapsules to obtain these taste-masked water-insoluble NSAID drug materials by microencapsulation alone. These individual microcapsules thus obtained are bland tasting, however, and use of flavoring agents to impart pleasant tastes to the already effectively taste-masked X~

wat~r-insoluL~l~ NS.~ID druq materials is pre~erred W~lell formulat-il~g same into c}lewable tablets and liq~lid suspension oral dosage 1: orms .
Usually the average/mean microcapsule diameter ranges from about 25 to about 600 microns. The process of this invention involves the principal steps of preparing an aqueous dispersion of the water-insoluble non-steroidal, anti-inflammatory drug (NS~ID) material within an aqueous solution of cellulose acetate phthalate, said water-insoluble NSAID drug material particles having a particle size ranging from about 25 to about 500 microns at a p~ of about 6 or higher wherein said solution contains from about 2 to about 8 wt.% of cellulose acetate phthalate; gradually adding with continued agitation a solution containing an inor-ganic Hofmeister (lyotropic) salt to form cellulose acetate phthalate in liquid phase separate from the equilibrium liquid;
slowly adjusting the pH of the resulting solution by slow addi-tion of a dilute acid to a pH of about ~ or lower which renders said cellulose acetate phthalate polymer insoluble; and recover-ing the individual microcapsules thus formed.
The term inorganic Hofmeister (lyotropic) salt as used herein refers to the sulfate, citrate, tartrate, acetate chlor-ide, nitrate, bromide and iodide anion salts of sodium, potas-sium, ammonium, rubidium, cesium, magnesium, calcium, silicone, barium and lithium cations. Sodium sulfate is preferred.
While various dilute acids can be used to insolubilize the cellulose acetate phthalate polymer cell wall material, e.g., citric acid, acetic acid, fumaric acid, tartaric acid, etc., the ~a~ 7 u~e c,~ citric acid is p~err~d ~-~r t~ purpose in a concentra-tiC)Il of about 10 to about ~0 wt.~ in water.
Suitable water-insoluble NSAID drug materials which can be used in accordance with this invention include, but are not necessarily limited to, the following: naproxen, ibuprofen, sulindac, dicolofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxipinac, zomepirac, sodium (Zomax) and pharmaceutically acceptable water-insoluble salts thereof.
The taste-masked individual microcapsules of water-insoluble NS~ID drug material produced in accordance with this invention contain a high payload of the water-insoluble NSAID
drug core material, e.~., about 83-~ wt.%, based on total micro-capsule weigh-t.
This invention will be illustrated in greater detail in the examples which follow.

(Preparation of Cellulose Acetate Phthalate (CAP) micro-encapsulated Naproxen) In a 4-liter beaker there are added 3,280 grams of de-ionized water. With agitation, ~5 grams of sodium bicarbonate were added to adjust the pH so as to solubilize the cellulose acetate phthalate polymer. 175 grams of particulate cellulose acetate phthalate having a particle size of about 14 mesh to 200 mesh, and more particularly about 1200 microns to about 50 microns, were added in small increments with continued agitation over 3-4 hours until all of the cellulose acetate phthalate (CAP) 2~ C~

is aclded aTld (~issolved. Tl~e resu~in~ solution contairs 5 weigllt percent cellulose acetate phthalate alld has a pEI of about 7.0 or slightly above.
200 grams of tllls 5~ cellulose acetate phthalate aqueous bical-bollate solution and 200 ~rams of deionized water were added to a 1500 ml beaker. Then 100 grams of the naproxell (to be microencapsulated) having a particle si~e of 25 to 400 microns was added and dispersed with agitation. With continued agita-tion, there was added slowly dropwise from a separatory flask 250 ml of a 20% by weight aqueous solution of sodium sulfate. This sodium sulfate solution acts as a coacervating agent permitting the cellulose acetate phthalate polymer to come out as a liquid phase microencapsulatiny material wrapping the naproxen drug particles.
After the CAP liquid microcapsular walls are formed, the CAP polymer is rendered insoluble by slow addition of a citric acid solution until the total solution p~l is approximately 4.0, thus rendering the CAP insoluble at that pH. Once this has been accomplished the agitation is stopped and the microcapsules are allowed to settle from solution so that the supernatant liquid may be decanted so as to rid the batch of the sodium sulfate.
These individual microcapsules of naproxen are then washed with an acidified aqueous solution to further remove sodium sulfate.
The washed CAP microencapsulated naproxen microcapsules are then filtered by a vacuum filter and dried for further use. These individual microcapsules contained approximately 91 wt.% naproxen for a 91% payload of the active drug.

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F.XAMPLE_2 (Forlllul~tiotl of chewable tablets cont.lirlin~ tl~e CAP Microerlccl~su-l~ted llaE~roxen prepared according to Example 1.) One thousancl 250 mg. active chewable naproxen tables were prepared as follows:

PROCEDURE FOR P~EPARATION OF 1000 - 250 mg ACTIVE
CHEWABLE NAPROXEN TABLETS
The following materials were added to a laboratory V-blender and blended for twenty minutes:
a. 275 grams of taste-masked naproxen microcapsules -(91.0% active), b. 600 grams of Mannitol USP granules, c. ~00 grams of Avicel PH-101, d. 100 grams of Di Calcium Phosphate, e. 30 grams of Tartaric Acid, f. 4 grams of Tartaric Acid, and g. 20 grams of Peppermint Flavor.
After blending the above materials for 20 minutes, a small portion of the blend was removed into a container and 2.5 grams of magnesium stearate were added thereto. The materials were mixed by hand and returned to the V-blender and blended for 10 minutes.
Tablets were compressed from this mixture on a Stokes RB2 rotary press with 9/16 inch round, beveled edge, scored tooling.
These tablets had the following physical properties:
Hardness - 14.0 Strong-Cobb units Friability - 1.0% (20 tablets at 25 rpm - 4 min.) ~v~
-ll-~ VeL-a~3~ W~i~ht - 1230 milligrams ~ EX~MPLE 3 (~'reparation of a liquid suspension containing the C~l' micro-encapsulate(3 naproxen prepared according to Example 1) The C~P microencapsulated naproxen microcapsules prepared in accordance with Example 1 above were then formulated into a liquid suspension dosage form. The preparation of the liquid suspension dosage form was accomplished as follows:
Four (4) liters of liquid suspension vehicle were prepared by the following procedure:
All of the following ingredients were dry blended:
800 grams of sucrose, 20 grams of sodium carboxymethylcellulose, 4.8 grams of xanthan gum, 4.8 grams of sodium saccharin, 46.5 milligrams of ~D&C Yellow #5, and 103.5 milligrams of FD6C Yellow #6 The above dry blended materials were then dissolved in approximately 1500 ml of purified water in a 4-liter beaker with agitation. Then 4.8 grams of methyl paraben and 1.2 grams of propyl paraben were dissolved in 40 ml of USP propylene glycol and added to the above water solution. Then the following materials were added sequentially in their noted amounts:
1200 grams of light corn syrup, 8 ml of orange flavor oil, 2 grams of Tween 80, and 40 ml of a 20% (W/V) aqueous solution of citric acid.
All ingredients were allowed sufficient time to mix and then there was added a sufficient quantity of purified water to bring the volume to 4 liters.

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2.75 gran~s of the high payload (91~) CAP microencapsulate~
individual l~aproxen microcapsules prepared in accordance with Example 1 wele added to 100 ml of the liquid suspensioll vehicle produced as indicated above to form a liquid suspension dosaye orm of microencapsulated naproxen.
This liquid suspension dosage form of microencapsulated naproxell was evaluated in a 10-person taste panel studied side by side along with the raw drug naproxen in the same liquid suspen-sion vehicle and further compared ~ith a commercial suspension bein~J marketed under the trade designation NAPROSYN SUSPENSION
(25 mg/ml). This N~PROSYN SUSPENSION 25 mg/ml contains 25 mg/ml active ingredient of naproxen in a vehicle of FD&C yellow #6, fumaric acid, imitation orange flavor, imitation pineapple flavor, magnesium aluminum silicate, methyl paraben, purified water, sodium chloride, sorbital solution, ar.d sucrose.
The results of this 10-person taste panel were that the CAP microencapsulated naproxen suspension dosage form was the preferred one compared with the other two dosage forms as it was best in taste-masking of the drug naproxen, mouth feel, and aftertaste. The term "mouth feel" includes the presence or absence of various texture sensations, e-g-, including slimy, gritty, burning, etc. The term "aftertaste" as used herein refers to a lingering objectionable taste sensation which per-sists after swallowing and can be characteri~ed as a numbing, burning or bitter sensation.

-13~ 8 EXAMPI,E ~
(Micl-oellc.lpsulation of ibuprofen with cellulose acetate phthalate (C~P) ) Ibuprofen was microencapsulated with cellu~ose acetate phtllalate using the same procedure and concentrations as set forth in Example 1 except that ibuprofen was used in place of naproxen. The ibuprofen individual microcapsule core payload was approximately 91 wt.~ with the remainder being cellulose acetate phthalate microcapsule wall material.

, lO EXAMPLE 5 (Preparation of chewable tablets dosage form of ibuprofen micro-encapsulated with CAP) Chewable tablets containing individual microcapsules having approximately 90.3 wt.% (Formulation ~), and 90. b wt.~
(Formulations B and C) of the active ibuprofen microencapsulated with CAP were prepared (as in Example 1) using the same basic chewable tablet making procedure set forth above in Example 2, but using the below formulations, which differ depending upon the particular targeted patient population, as follows: Formulation A was prepared so that each chewable tablet had 50 mg of ibupro-fen. Formulation B was prepared to contain 100 mg of ibuprofen in chewable tablet form and Formulation C was prepared to contaln 200 mg of ibuprofen/chewable tablet.

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(I'ROCEDURE ~OR PREr~RATION OF 2000 - 50 mg Ac~rIvF
CIIEWABLE IBUPROFEN TABLETS ) The following materials were added to a laboratory V-blender and blended for twenty minutes:

a. 110.7 grams of taste-masked ibuprofen microcapsules -(90.3% active), b. 400 grams of Mannitol USP granules, c. 200 grams of Avicel*PH-101, d. 0.6 grams of FD&C Yellow #6, e. 30 grams of Aspartame, f. 6 grams of Citric Acid, and, g. 30 grams of Orange Flavor.
After blending the above materials for 20 minutes, a smail portion of the blend was removed into a container and 2.6 grams of magnesium stearate was added. The materials were mixed by hand and the mixture was returned to the V-blender and blended for 10 minutes.
Tablets were compressed on a Stokes RB2 rotary press with 3/8 inch round, beveled edge, tooling.

The following resulting tablets had the following physical properties:
~ lardness - 7.5 Strong-Cobb units Friability - 0.47% (20 tablets at 25 rpm - 4 min.) Average Weight - 395 milligrams * Denotes Trade Mark ~ 3t~

_ O I' il ~ i O Tl U

(~'ROC`~I)tll~E lOI~ PRE~ 'I`ION 0~: 1000 - 100 mq AcrrIvr~
CIIIJ~ULE :1 ~3UPROI;EN '1`A11LETS

The iollowing materials were added to a laboratory V-blender alld blended for twenty minu-tes:

a. 110.5 grams of taste-masked ibuprofen microcapsules -(90.6~ active), b. 300 grams of Mannitol USP granules, c. 100 grams of Avicel PH-101, d. 50 grams of Di Calcium Phosphate, e. 15 grams of Aspartame, f. 2 grams of Tartaric Acid, and g. 10 grams of Peppermint Flavor.
After blending the above materials for 20 minutes, a small portion of the blend was removed into a container and 1.25 grams of magnesium stearate was added. The materials were mixed by hand and the mixture was returned to the V-blender and blended for 10 minutes.
Tablets were compressed on a Stokes RB2 rotary press with 3/8 inch round, beveled edge, tooling.
The resulting tablets had the following physical proper-ties:
Hardness - 10.3 Strong Cobb units Friability - 0.38% (20 tablets at 25 rpm - 4 min.) Average Weight - 595 milligrams e ~

F~?rmulatlon c OCI.I)U~E FO~ l'REPARATION OF 1000 - 200 mg ~CTIVE
Cl~ \BI,I~ IBUPROFEN TAULI~TS

'l`he following materials were added to a laboratory V--blender foI twenty minutes:

a. 221 grams of taste-masked ibuprofen microcapsules -(90.6% active), b. 600 grams of Mannitol USP granules, c. 200 grams of Avicel PH-101, lQ d. 100 grams o Di Calcium Phosphate, e. 30 grams of Aspartame, f. 4 grams of Tartaric Acid, and g. 20 grams of Peppermint Flavor.
After blending the above materials for 20 minutes, a small portion of the blend was removed into a container and 2.5 grams of magnesium stearate was added. The materials were mixed by hand and the mixture was returned to the V-blender and blended for 10 minutes.
Tablets were compressed on a Stokes RB2 rotary press with 9/16 inch round, beveled edge, tooling.

'rhe resulting tablets had the following physical proper-ties:
llardness - 13.5 Strong-Cobb units Friability - 1.6% (20 tablets at 25 rpm - 4 min.) Average Weight - 1178 milligrams ~17-~ X M_,E 6 ("repalatioll of: a liquid suspension of C~P microencapsulclted i~lpl~Lell lndividucll microcapsules having approximately 91 wt.~6 payload of ibuprofen) Utilizing the procedure of Example 3 above, the CAP
microencapsulated ibuprofen microcapsules (prepared as in Example 4) were formulated into liquid suspension dosage forms, depending upon the particular targeted patient population.
Formul~tion A was prepared using 2.2 grams of individual ibuprofen mic~ocapsules per 100 mls of the liquid suspension vehicle prepared in Example 3 for a 100 mg per 5 ml active ibuprofen dose.
~ ormulation B was prepared using 4.4 grams of individual ibuprofen microcapsules per 100 mls of the Example 3 liquid sus--pension vehicle for a 200 mg per 5 ml active ibuprofen dosage.
~ ormulation C was prepared using 8.8 grams of individual ibuprofen microcapsules per 100 mls of the Example 3 liquld sus-pension vehicle for a 400 mg per 5 ml active ibuprofen dose.

(Preparation of Cellulose Acetate Phthalate (CAP) Micro-encapsulated Ibuprofen) Into a 3-liter beaker fitted with a birdcaye baffle and a stirring motor with a 3" turbine blade, were added 30 grams of CAP into 600 ml. of deionized water.
With agitation, a sufficient quantity of sodium bicar-bonate was added to ad~ust the pH so as to solubilize the CAP.
The CAP has a particle size of about 40 mesh to 200 mesh. The C.~' particl~s were well disp~rsed to facili-tate di.ssolvincJ t~e C~ polymer-. r~ e resultillg solution contains 5 wt.% CAP and has a pil of about 7.0 or slightly above.
Next, 150 g of ibuprofen were dispersed into the CAP
solution. The ibuprofen particles had a particle size of approx-imately 25 to 5QO microns. 900 g of a ~0% (wt/wt~ aqueous sodium sulfate solution were added slowly (dropwise) with continuous agitation at about 150 rpm. This addition takes place over approximately 1-1/2 hours. ~his sodium sulfate aqueous solution acts as a coacervating agent permitting the CAP polymer to come out as a liquid phase microencapsulating material wrapping the ibuprofen drug particles.
After the CAP liquid microcapsule walls are formed, the CAP polymer was rendered insoluble by slow addition of 20% wt/wt citric acid solution until the final solution pH is approximately 4, thus rendering the CAP insoluble at that p~ for water. Once this has been accomplished, the agitation is stopped and the microcapsules are allowed to settle from solution so that the supernatant liquid may be decanted so as to rid the batch of sodium sulfate.
These individual microcapsules of ibuprofen were then washed two times with 800 ml of water. The washed CAP micro-encapsulated ibuprofen microcapsules were then filtered by a vacuum filter and dried for three hours in an oven whose tempera-ture is held at 45 deg. C. These individual microcapsules contain approximately 83-1/3 wt.%

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F.XAMPI.F 8 (Prepar,ltioll o~ Cellulose ~cctate ~'hthalatc (C~P) Micro-encapsulat~d Ibuprofen) Into a 3-liter beaker fitted with a birdcage baffle and stirring motor with a 3" turbine blade, were added 30 grams of CAP into 600 ml. of deionized water.
~ ith agitation, a sufficient quantity of sodium bicar-bonate was added to adjust the p}l so as to solubilize the CAP.
The CAP has a particle size of about 40 mesh to 200 mesh. The CAP particles were well dispersed to facilitate dissolving the CAP polymer. The resulting solution contains 5 wt.~ CAP and has a pH of about 7.0 or slightly above.
Next, 300 g of ibuprofen were dispersed into the C~P
solution. The ibuprofen particles had a particle size of approx-imately 25 to 500 microns. 900 g of a 20% (wt/wt) aqueous sodium sulfate solution were added slowly (dropwise) with continuous agitation at about 350 rpm. This addition takes place over approximately 3 hours. This sodium sulfate aqueous solution acts as a coacervating agent permitting the CAP polymer to come out as a liquid phase microencapsulating material wrapping the ibuprofen drug particles.
After the CAP liquid microcapsule walls are formed, the CAP polymer was rendered insoluble by slow addition of 70 ml of a 20% wt/wt citric acid solution over a period of approximately 30 minutes until the final solution pH is approximately 4, thus rendering the CAP insoluble at that pll for water. Once this has been accomplished, the agitation is stopped and the microcapsules -20- 2 ~ S

aIe all owe(l t~ settle from solution so ~ t the supernatant ui~l may L~e clecanted so as to rid the batch of sodium su]fate.
Tllese lndividual mlcrocapsules of ibuprofen were then washed two times with ~00 ml of water. T}le washed C~P micro-encapsulated ibuprofetl microcapsules were then filtered and dried for 2-1~2 hours in an o~:n whose temperature is held at 45 deg.
C. Tlle semi-dry microcapsules were then passed through a 20-mesh sieve to break apart the agglomerates. The batch of micro-encapsulated ibuprofcn is then placed in a tray and air driecl at room temperature overnight. These individual microcapsules contain approximately 90.9 wt.% ibuprofen as payload of the active drug.

F.X~MPI!F 9 (l're~al-atl~l~ o~ C~llulo e Acetate Phtl~ late (C~P) Microencapsu-lated Ibupl-ofell) Into a 1-liter breaker fitted with a birdca~e baffle and a stirring motor with a 3" turbine blade/ were added 7.5 grams of C~P into 150 ml. of deionized water.
With agitation, a sufficient quantity of sodium bicar-bonate was added to adjust the pH so as to solubilize the CAP.
The C~P has a particle size of about 40 mesh to 200 mesh. The CAP particles were well dispersed to facilitate dissolving the C~P polymer. The resulting solution contains ~% (wt/wt) CAP and has a p~ of about 7.0 or slightly above. This CAP solution was diluted with 150 ml of water.
Next, 75 g of ibuprofen (granulated with ethylcellulose) were dispersed into the CAP solution. The ibuprofen granules had a particle size of approximat~ly 150 to 500 microns. 225 ml of a 20% (wt/vol) sodium chloride buffer solution (USP 7.2 pH buffer was used) were added slowly (dropwise) with continuous agitation at about 150 rpm. This addition took place over approximately 1 hour. This aqueous sodium chloride buffer solution acted as a coacervating agent permitting the C~P polymer to come out as a liquid phase microencapsulating material wrapping the ibuprofen drug particles.

~q~ 3'~
-2~-~ ftel~ the C~l' liquid microcapsule walls were f`ormed, the C~l~ polylller ~ s relldered insoluble by slow addition of 15 ml of a 20~wt/wt)citr;c acid aqu~ous solution over a period of approxi-mately 10 minutes ulltil the final solution pH was approximately 4, thlls rendering the C~P insoluble at that pH for water. Once this had been accomplished, the agitation was stopped and the microcapsules were allowed to settle from solution so that the supernatant liquid could be decanted so as to rid the batch of sodium chloride buffer~
These individual microcapsules of ibuprofen were then washed two times with 200 ml of water. The washed CAP micro-encapsulaed ibuprofen microcapsules were then filtered and dried for 2-l/2 hours in an oven whose temperature was held at 45 deg.
C. The batch of microencapsulated ibuprofen was then placed in a tray and air dried at room temperature overnight. These indi-vidual microcapsules contained approximately 90.9 wt~ ibuprofen as payload of the active drug. The dry microcapsules were then passed through a 20-mesh sieve to break apart the agglomerates.

_:X~M _~ 10 (rreE~alatioll of Cellulose ~cetate Phthalate (C~P) Microencapsu-lat:~!(3 7,omepirac, Sodium. (Tl~e commercial trade name for this drug is Zomax).

Into a 3-liter beaker fitted with a birdcage baffle and a stirring motor with a 311 turbine blade, were added 30 grams of CAP into 60 ml. of deionized water.
With agitation, a sufficient quantity of sodium bi-carbonate was added to adjust the pll so as to solubilize the CAP.
The CAP had a particle siæe of about 40 mesh to 200 mesh. The CAP particles were well dispersed to facilitate dissolving the CAP polymer. The resulting solution contained 5 wt.~ CAP and had a p~l of about 7.0 or slightly above. Next there was added 6 ml of a 1.3% (wt/vol~ aqueous solution of diocty' sodium sulfosuc-cinate material. The CAP solution was diluted with 600 ml of deionized water.
Next, 300 g of Zomax were dispersed into the CAP solution.
The Zomax particles had a particle size of approximately 25 to 400 microns. 1000 ml of a 20% (wt/vol) aqueous sodium sulfate solution were added slowly (dropwise) with continuous agitation at about 150 rpm. This addition took place over approximately 2 hours. This sodium sulfate aqueous soluti.on acted as a coacer-vating zgent permitting the CAP polymer to come out as a liquid phase microencapsulating material wrapping the Zomax drug par-ticles.

~6~ t~

~ tel~ the C~l' liquid microcapsule walls we~e formed, t.lleC~ )ol~rmel w.3s relldered insoluble by 510w addition of a suffi-cient ~luantity of 20~(wt/wt:)citric acid soluti.on over a peri.od ~f approximately lO minutes until the final solution pll was approxi-mately ~1, tllus rendering the C~P insoluble a-t that pll for water.
Once this had been accomplished, the agitation was stopped and the microcapsules were allowed to settle from solution so that the supernatarlt liquid may be decanted so as to rid the batch of sodium sulfate.
Tilese individual microcapsules of Zomax were then washed three times with 530 ml of a 1.75~ (wt/vol) solution of aqueous citric acid. The washed CAP microencapsulated Zomax micro-capsules were then filtered and dried for one hour in a fluid bed dryer whose temperature was held at 40 deg. C. The dry micro-capsules were then passed through a 20-mesh sieve to break apart the agglomerates~

Claims (19)

1. A taste-masked, microencapsulated, non-steroida1, anti-inflammatory, water-insoluble NSAID drug material comprising individual microcapsules microencapsulated with cellulose acetate phthalate and having a high payload of active drug and charac-terized as free flowing, individual, taste-masked microcapsules in the substantial absence of microcapsule agglomerates and having a microcapsule particle size distribution ranging from about 25 to about 600 microns.

2. A taste-masked microencapsulated water-insoluble NSAID
drug material as in claim 1 wherein said drug is naproxen.

3. A taste-masked microencapsulated water-insoluble NSAID
drug material as in claim 1 wherein said drug is ibuprofen.

4. A taste-masked microencapsulated water-insoluble NSAID
drug material as in claim 1 wherein said payload of active drug is about 83+ wt.%.

5. A process for preparing microencapsulated non-steroidal, anti-inflammatory water-insoluble NSAID drug material which comprises preparing an aqueous dispersion of said NSAID
material having a particle size distribution ranging from about 25 to about 500 microns within an aqueous solution of cellulose acetate phthalate at a pH of about 6 or higher and containing from about 2 weight percent to about 8 weight percent of cellu-lose acetate phthalate; gradually adding with continued agitation a solution containing an inorganic salt of the Hofmeister (lyo-tropic) series, to form cellulose acetate phthalate in liquid phase separate from the equilibrium liquid; slowly adjusting the pH of the resulting solution to a pH of about 4 or lower; while rendering said cellulose acetate phthalate polymer insoluble by slow addition of a dilute acid material; and recovering the individual microcapsules thus formed.

6. A process as in claim 5 wherein said water-insoluble NSAID drug material is naproxen.

7. A process as in claim 5 wherein said water-insoluble NSAID drug material is ibuprofen.

8. A process as in claim 5 wherein said Hofmeister (lyotropic) salt is sodium sulfate.

9. A process as in claim 5 wherein said dilute acid material is citric acid.

10. A taste masked, microencapsulated, water-insoluble non-steroidal, anti-inflammatory drug (NSAID) in chewable tablet form containing microcapsules as in claim 1 and pharmaceutically acceptable excipient materials.

11. Chewable tablets as in claim 10 wherein said water-insoluble NSAID drug material is naproxen.

12. Chewable tablets as in claim 10 wherein said water insoluble NSAID drug material is ibuprofen.

13. Chewable tablets as in claim 10 wherein the individual microcapsule payload of active water-insoluble NSAID drug material is about 83+ wt.%.

14. A liquid suspension comprising individual taste-masked microcapsules as in claim 1 and pharmaceutically accep-table excipient materials.

15. A liquid suspension as in claim 14 wherein said water-insoluble NSAID drug material is naproxen.

16. A liquid suspension as in claim 14 wherein said water-insoluble NSAID drug material is ibuprofen.

17. A liquid suspension as in claim 14 wherein the in-dividual microcapsule payload of active water-insoluble NSAID
drug material is about 83+ wt.%.

18. A taste-masked microencapsulated water insoluble NSAID
drug material as in claim 1 wherein said payload of active drug is about 90+ wt.%.

19. A taste-mask microencapsulated water-insoluble NSAID
drug material as in claim 1 wherein said drug is Zomax.