United States Patent (19) 11 Patent Number: 4,966,768

Michelucci et al. (45) Date of Patent: Oct. 30, 1990

54 SUSTA NED RELEASE ETOOOLAC (56) References Cited
U.S. PATENT DOCUMENTS
(75) Inventors: John J. Michelucci; Deborah M.
Sherman, both of Plattsburgh; 3,954,959 5/1976 Pedersen ............................... 424/21
Richard J. DeNeale, Willsboro, all of 4,309,404 W1982 DeNeale et al. .
N.Y. 4,309,405 1/1982 Guley et al. .
4,309,406 1/1982 Guley et al. .
4,369,172 1/1983 Schor et al. ........................... 424/19
(73) Assignee: American Home Products 4,389,393 6/1983 Schor et al. ........................... 424/19
Corporation, New York, N.Y. 4,657,757 4/1987 Hanna et al. .
21) Appl. No.: 268,646 Primary Examiner-Shep K. Rose
Attorney, Agent, or Firm-John W. Routh
22 Filed: Nov. 7, 1988 (57) ABSTRACT
A sustained release dosage form of etodolac is provided
Related U.S. Application Data which is a tablet having as essential components etodo
(63) Continuation of Ser. No. 100,501, Sep. 24, 1987, aban lac, hydroxyproplymethylcellulose, ethylcellulose and
doned. a release rate modifying agent such as dibasic sodium
phosphate, the hydroxyproplymethylcellulose having a
(51) Int. Cl. .......................... A61K9/22; A61K9/26 hydroxypropoxyl content of about 7.0% to 8.6% by
(52) U.S. C. .................................... 424/468; 424/469; weight.
424/470; 424/488
58) Field of Search ................ 424/468, 469, 470, 488 3 Claims, 4 Drawing Sheets
U.S. Patent Oct. 30, 1990 Sheet 1 of 4 4,966,768

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hours. Thus after the window period of about 10-12
SUSTA NED RELEASE ETODOLAC hours during which the drug enters the bloodstream,
half of that present is metabolized every half-life and
This application is a continuation of application Ser. hence concentration of the drug in the blood tapers off
No. 100,501, filed Sept. 24, 1987 now abandoned. 5 after about 16-18 hours. Additional formulation prob
BACKGROUND OF THE INVENTION lems are presented when the medication is one having a
relatively short elimination half-life and whose solubil
(a) Field of the Invention ity shows a great degree of pH dependency. Etodolac is
This invention relates to a novel therapeutic dosage a medicine with a half-life of about eight hours and an
form of etodolac which provides drug plasma levels 10 aqueous solubility which is very low and pH indepen
over a twenty-four hour period. More particularly, the dent below pH 3. The solubility then gradually in
sustained release dosage form is a tablet comprising as creases with rising pH up to 5 and linearly increases
essential ingredients etodolac, hydroxypropylmethyl with increasing pH to 7. A thirty fold difference in
cellulose, ethylcellulose and a release rate modifying solubility between pH 5 to 7 has been observed.
agent such as dibasic sodium phosphate. 15
SUMMARY OF THE INVENTION
(b) Prior Art
The active agent of this invention, 1,8-diethyl-1,3,4,9- According to this invention, novel therapeutic tablet
tetrahydropyrano3,4-bindole-1-acetic acid or a thera dosage forms have been formulated to provide a once-a-
peutically acceptable salt thereof, is disclosed in U.S. day dose of eotdolac. The formulation comprises etodo
Pat. No. 3,939,178. This active agent, hereinafter desig 20 lac and a carrier base material made from a mixture of
nated by its generic name, etodolac, has been reported (i) hydroxypropylmethylcellulose having a hydroxy
to have analgesic and anti-inflammatory properties. It propoxyl content of 7.0 to 8.5% weight percent, a me
. has been further reported to be active in the treatment thoxyl content of 19-24 weight percent, and a number
of adjuvant arthirtis, a model of inflammatory arthritis average molecular weight of less than 50,000, (ii) from
sensitive to treatment with nonsteroidal anti-inflamma 25 15-28% by weight of the mixture of ethylcellulose and
tory drugs, in U.S. Pat. No. 4,533,551. a release rate modifying agent such as dibasic sodium
Hydroxypropylmethylcellulose alone and in combi phosphate. Etodolac is water insoluble to an apprecia
nation with ethylcellulose has been proposed as an in ble extent below pH 3 and the release rate modifying
gredient in a sustained release formulation for twenty agent maintains the etodolac tablet environment such
four hour administration ortherapeutic agents. See U.S. 30 that the pH solubility dependency is minimized
Pat. No. 4,369,172, issued Jan. 18, 1983 which describes throughout the gastrointestinal tract.
dosage forms as a carrier base material a particular The in vitro dissolution of these novel forms shows
hydroxypropylmethylcellulose, i.e. having a hydroxy prolonged drug release profiles through 14 hours. Sur
propoxyl content of 9-12 weight percent, a methoxyl prisingly, the table dosage forms of the invention dis
content of 27-30 weight percent and a number average 35 solve faster and release drug more rapidly as the hy
molecular weight of less than 50,000 with up to 30% by droxypropoxyl content increases within the range
weight of the mixture of ethylcellulose. The patent tested to about 7 to 8.6%
describes comparative dissolution tests run with tablets The in vivo evaluation of these novel dosage forms
made with this carrier base material and with a carrier also confirm that drug plasma levels are maintained
base material made with a hydroxypropylmethylcel 40 over a twenty-four hour period and are bioequivalent to
lulose having a hydroxypropoxyl content of 8% by a conventional dosing regimen.
weight. The dissolution tests shown in Examples 1-4 of DETAILS OF THE INVENTION
the patent indicate that the tablets made from the 8%
hydroxypropxyl content material dissolve faster and The etodolac useful in the invention is of pharmaceu
release drug more rapidly than tablets made from 10.3% 45 tical grade and preferably is micronized.
hydroxypropoxyl material. The hydroxypropylmethylcellulose is the U.S.P.
Another patent, U.S. Pat. No. 4,389,393, describes Substitution Type 2208 having a 2% aqueous solution
controlled release dosage forms having as a carrier base viscosity of 80 to 120 cps, a methoxyl content of 19-24
material a hydroxypropylmethylcellulose having a hy weight percent, and a hydroxypropxyl content of 7.0 to
droxypropoxyl content of 4-32 weight percent, a me 50 8.5 weight percent. A suitable grade is available from
thoxyl content of 16-24 weight percent and a number Dow Chemical Company, Midland, Mich. and mar
average molecular weight of at least 50,000 with up to keted under the trademark Methocel Product Grade
30% by weight of the mixture of ethyl cellulose. K100LV but specifically with a hydroxypropoxyl con
U.S. Pat. No. 3,954,959 issued May 4, 1976 describes tent of 7.0-8.5 weight percent.
dosage forms in which the medicine is admixed with a 55 Ethylcellulose useful in this invention is the National
buffer, shaped into small particles and subsequently Formulary or pharmaceutical grade. Suitable grades are
coated with a film forming material such as ethylcellu the medium type and standard grades marketed by Dow
lose for diffusion of gastrointestinal juices. Chemical Company, Midland, Mich., under the Ethocel
Sustained action medications effective for 24 hours or trademark. Other suitable grades are those marketed by
once-a-day dosage present formulation problems be Hercules, Inc. of Wilmington, Del. and Biddle-Sawyer
cause of the relatively short period of time they are Corp. of New York, N.Y. Ethocel is an organo soluble
present in the gastro-intestinal tract prior to elimination. ethyl ether of cellulose containing between 2.25 and
This is especially true for medications with short half 2.58 ethoxy groups per glucose unit corresponding to an
lives (i.e. less than 6 hours) that normally would be ethoxy range of 45 to 49.5%.
administered in divided doses two or more times a day. 65 The hydroxypropylmethylcellulose and the ethylcel
The window period for medication release into the lulose comprise the carrier base material and the ethyl
patient's system and hence into the blood stream varies cellulose content of the carrier base material can range
from patient to patient but normally averages 10 to 12 from about 15% to about 28% by weight. The weight
 4,966,768 4.
3
percent of the carrier base material in the tablet dosage -continued
forms of the invention can range from about 18% to Ingredient Milligram per Tablet
about 30% by weight.
The release rate modifying agent is chosen so as to Dibasic Sodium Phosphate, USP
Lactose, NF
52.5 mg
27.0 mg
impart an alkaline microenvironment to the dosage 5 Ethylcellulose, NF 26.25 mg
form and minimize the pH solubility dependency of the Magnesium Stearate, N.F 5.25 mg
etodolac as it passes through the gastrointestinal tract. Taic 1.5 mg
The release rate modifying agent should be physiologi Theoretical Tablet Weight =525 mg
cally acceptable and can include primary, secondary or
tertiary salts of phosphoric acid, or salts of phthalic 10
The method of manufacture was the same as that of
acid, citric acid, tartaric acid or mixtures of such buffer Example 1.
salts. The preferred salt is sodium dibasic phosphate.
The following examples illustrate the formulation of EXAMPLE 3
the novel therapeutic tablet dosage forms of the inven This example illustrates the preparation of a tablet
tion. In these examples, the ethylcellulose was obtained 15 with 400 milligrams of etodolac and containing the
from the Dow Chemical Company, Midland, Mich. It following ingredients in the listed amounts per tablet.
was a dry material of the standard type having a viscos
ity designation of 4 cps and an ethoxy content of 48% to
49.5%. The hydroxypropylmethylcellulose was also Ingredient Milligram per Tablet
obtained from the Dow Chemical Company. It also was 20 Etodolac, micronized 400.0 mg
a dry material and was the Methocel Product Grade Hydroxypropyl Methylcellulose, USP 150.0 mg
K100LV having a hydroxypropoxyl content of 7 to 8.6 Dibasic Sodium Phosphate, USP 70.0 mg
weight percent. Lactose, NF 36.0 mg
Ethylcellulose, NF 35.0 mg
The carrier base material concentration in the tablet Magnesium Stearate, NF 7.0 mg
formulae (hydroxypropylmethylcellulose and ethylcel 25 Talc 2.0 mg
lulose) ranges from 21% to 26.4% (weight by weight). Theoretical Tablet Weight =700 mg
The ethylcellulose to hydroxypropylmethylcellulose
weight ratio in the tablet formulae ranges from 1 to 3.2 The method of manufacture was the same as that for
to 1 to 4.2.
30 Example 1.
EXAMPLE 1. EXAMPLE 4
This example illustrates the preparation of a tablet This example illustrates the preparation of a tablet
with 200 milligrams of etodolac and containing the with 600 milligrams of etodolac and containing the
following ingredients in the listed amounts per tablet. 35 following ingredients in the listed amounts per tablet.
Ingredient Milligram per Tablet Ingredient Milligram per Tablet
Etodolac, micronized 200 Ing Etodolac, micronized 600.0 mg
Hydroxypropyl Methylcellulose, USP 75.0 mg
Dibasic Sodium Phosphate, USP 35.0 mg 40 Hydroxypropyl
Lactose, NF
Methylcellulose, USP 168.0 mg
105.8 mg
Lactose, NF 18.0 mg
Ethylcellulose, NF 17.5 mg Dibasic Sodium Phosphate, USP 105.0 mg
Magnesium Stearate, NF 3.50 mg Ethylcellulose, NF 52.5 mg
Talc - 100 mg - Magnesium Stearate, NF 15.75 mg
Talc 3.0 mg
Theoretical Tablet Weight =350 mg Theoretical Tablet Weight = 1050 mg
45

METHOD OF MANUFACTURE The method of manufacture was the same as that for
Example 1.
The etodolac together with ethylcellulose, hydroxy Instead of using alcohol and methylene chloride as
propylmethylcellulose, lactose, talc and the dibasic 50 the granulating liquids, other liquids such as tap water
sodium phosphate is dry blended, and subsequently may be used instead. Example 3 was repeated using tap
granulated with an alcohol, denatured 23A, and methy water as the granulating liquid with satisfactory results
lene chloride solvent mixture. Following wet sizing, in all respects.
drying and dry sizing of the granulate, it is blended with The unique dissolution profile of the novel therapeu
magnesium stearate. The final blend is compressed into 55 tic dosage forms of the invention is illustrated by FIGS.
tablets of the correct weight. Subsequently, an aqueous 1, 2 and 3 of the drawings which chart dissolution pro
film coat color suspension and a gloss solution are ap files of 200400 and 600 milligram etodolac tablets (350,
plied to the tablets. Denatured 23A is a 100:10 blend of 700 and 1050 mg total tablet weight respectively) pre
ethyl alcohol and acetone. pared as described in Example 1 except that the hydrox
EXAMPLE 2 60 ypropymethylcellulose had varying hydroxypropoxyl
This example illustrates the preparation of a tablet contents ranging from 7% and 8.6%. The dissolution
with 300 milligrams of etodolac and containing the data in the profiles shown in FIGS. 1, 2 and 3 establish
following ingredients in the listed amounts per tablet. that the tablet dosage forms of the invention dissolve
faster and release drug more rapidly as the hydroxy
65 propoxyl content increases.
Ingredient Milligram per Tablet The in vivo performance of the novel dosage forms of
Etodolac, micronized 300.0 mg this invention has been evaluated in bioavailability stud
Hydroxypropyl Methylcellulose, USP 112.5 mg ies in comparison with equivalent immediate release
 4,966,768
5 6
dosage forms. A tablet containing 600 milligrams of TABLE I-continued
etodolac prepared generally according to Example 4 RELATIVESTEADY STATE BOAVAILABILITY
was given once a day and evaluated in a 3 day steady AND OOSE PROPORTIONALITY OF ETOOOLACSR
COMPARED TO EQUIVALENT DAILY DOSE
state bioavailability study in comparison with capsules OF IMMEDIATE RELEASE ETODOLAC
containing 300 milligrams of conventional immediate Parameters 300 mg b.i.d. 600 mg S.R.
release etodolac given twice a day. The 600 milligram timax - SEM (hr)*
% of Reference
1.7
m
0.3 7.8 - 0.7
458.8
tablet demonstrated equivalent bioavailability to its P ver .0001
reference capsules. The pharmacokinetic parameters O Cmax/Cnin SEM
% of Reference
7.47 0.86 7.43 - 1.02
99.5
measured in the study are listed in Table 1 below. Com P 9388
parison of the AUC (0-24) in the table for each of the Maximum plasma concentration
'Area under plasma profile curve
600 milligram tablet and the reference capsules shows a "Maximum time to plasma peak
90% bioavailability for the 600 milligram tablet. The 15
(max and timax values, as would be expected, are lower We claim:
and later respectively for the 600 milligram tablets. 1. A sustained release dosage form useful in providing
once-a-day medication which consists essentially of an
There is shown in FIG. 4 the mean etodolac plasma admixture of a carrier base material with etodolac and a
level for each of the 600 milligram tablets and the 300 20 release rate modifying agent and shaped and com
milligram capsules administered in the bioavailability pressed to a solid unit dosage form having a regular and
study. Each of the 600 milligram tablet and 300 milli prolonged release pattern upon administration, the car
gram capsule doses showed similar average etodolac rier base material comprising about 18 to 30 weight
percent of the solid dosage form and being hydroxy
plasma levels from this study, i.e. ~ 6-7 mcg per milli 25 propylmethylcellulose in admixture with 15 to 28
liter. weight percent of the admixture of ethylcellulose,
TABLE I
wherein the hydroxypropylmethylcellulose has a hy
droxypropoxyl content of about 7.0 to about 8.6 weight
RELATIVE STEADY STATE BOAVAILABILITY percent, a methoxyl content of about 19-24 weight
AND DOSE PROPORTIONALITY OF ETODOLACSR 30 percent, a 2% aqueous solution viscosity of 80 to 120
COMPARED TO EQUIVALENT DAILY DOSE cps, and an average molecular weight of less than
OF MIMEDIATE RELEASE ETOOOLAC 50,000, the release rate modifying agent being an effec
Parameters 300 mg b.i.d. 600 mg S.R. tive amount of a physiologically acceptable buffer acid,
buffer acid salt or mixture thereof.
Cmax - SEM (mcg/mL) 20.84 153 186 - 1.08 35 2. The composition according to claim 1 wherein the
% of Reference ww. 57.2 release rate modifying agent is dibasic sodium phos
P W 000 phate.
AUC (0-24) - SEM 1622, 11.7 146.0 - 14.4 3. The composition of claim 1 wherein the carrier
(mcg X hr/ml) base material is within the range of about 18% to about
% of Reference 90.0 30% by weight of the solid unit dosage form.
P m .0222 t XE

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