Sustained release pharmaceutical formulation

It has been found that indoprofen can be used in increased safety at its effective anti-inflammatory dose in humans and that the activity of indoprofen is greatly prolonged by microencapsulating microparticles of indoprofen in a solid protective coating of a cellulose ether such as ethylcellulose.

This invention relates to sustained release pharmaceutical formulations. 
More particularly this invention relates to microencapsulated indoprofen 
most preferably in the form of tablets. 
Indoprofen is a relatively new and important drug having anti-inflammatory 
and analgesic properties described in Girraldi et al British Pat. No. 
1,344,663 (1974) and various articles, such as Pedronetto et al, The 
Journal of International Medical Research, Vol. 3, No. 1, pages 16-20 
(1975). The drug has the following structural formula 
##STR1## 
and can be named alpha-[4-(1-oxo-2-isoindolinyl)-phenyl]propionic acid. 
While indoprofen exhibits excellent anti-inflammatory and analgesic 
properties, its short plasma half-life (t 1/2=2.1-5.4 hours) in humans is 
a drawback. 
Sustained release forms of medication are known in the art. They provide 
for prolonged action of a drug in the gastro-intestinal tract by slow 
release over an extended period of time. One way of achieving sustained 
release of a drug is the use of a tablet wherein the core containing the 
active ingredient is surrounded by a layer of inert material, such as an 
enteric substance which allows the tablet to pass unchanged through the 
stomach and disintegrate in the intestinal tract. Such enteric coated 
tablets often suffer from the disadvantage of not providing a uniform and 
constant drug release. 
A recent patent, i.e., U.S. Pat. No. 3,155,590, discloses a process of 
encapsulating minute aspirin particles with a polymeric wall material that 
is ingestible in living creatures and prolongs the activity of the aspirin 
double or triple the time of the unencapsulated drug. 
The analgesic dose for indoprofen in man is low in comparison to the 
anti-inflammatory dose, i.e., in the order of 100 to 600 mg. per day. At 
this dosage regimen, indoprofen exhibits its maximum analgesic effect and 
has minimal or negligible side effects. 
However, the dose necessary for indoprofen to exert an anti-inflammatory 
activity is higher than the analgesic dose, i.e., in the order of 800 to 
1200 mg. per day. At 800 mg. per day, indoprofen is effective in the 
treatment of osteoarthritis. At this dose gastrointestinal ulceration and 
other side effects are minimal. At 1200 mg. per day, indoprofen is 
effective in the treatment of rheumatoid arthritis, but the incidence of 
gastrointestinal ulceration and other side effects are recognized. Based 
upon clinical studies, up to 800 mg. per day is classified as a safe dose, 
however, above 800 mg., especially 1200 mg., per day has not been shown to 
be safe for prolonged therapy. 
The clinical studies show that as the indoprofen dose is increased, the 
plasma peak height and the bioavailability as measured by total area under 
the plasma curve increases in a linear fashion. For instance, humans given 
100 mg. and 200 mg. indoprofen showed peak heights of 8.3.+-.1.6 .mu.g per 
ml. and 15.1.+-.4.6 .mu.g per ml., respectively. Also, the total area 
under the plasma curve for the corresponding doses were 28.7.+-.7.6 .mu.g 
ml. per hr. and 56.2.+-.15.1 .mu.g ml. per hr., respectively. 
The study in mice reported in Table I shows indoprofen given as the pure 
drug and in microencapsulated form have equivalent bioavailability. For 
instance, with the pure drug, the area under the plasma curve can be 
calculated as 24.5 .mu.g ml. per hr.; whereas, when microencapsulated, it 
can be calculated as 23.3 .mu.g ml. per hr. However, note the plasma peak 
height with the pure drug is 2.5 .mu.g per ml.; whereas when 
microencapsulated, it is only 1.1 .mu.g per ml. In other words, the peak 
height with the pure drug is two times that of the microencapsulated drug. 
It has now been found that the action of indoprofen can be prolonged up to 
eight-fold if it is microencapsulated by certain specific procedures and 
can even be further prolonged by compressing the microcapsules into 
tablets. In accordance with this invention sustained release idoprofen 
tablets are produced by encapsulating micro-particles of indoprofen in a 
solid protective coating of a cellulose ether and then compressing the 
microcapsules into tablets. 
A microencapsulated formulation for indoprofen has now been discovered 
which can be used safely at its effective anti-inflammatory dose for the 
treatment of both osteoarthritis and rheumatoid arthritis in humans. 
Because indoprofen given in the form of pure drug and microencapsulated 
form are bioequivalent, but the plasma peak height obtained from the pure 
drug is two times that of microencapsulated form, it is now possible to 
use indoprofen at its effective doses of 800 and 1200 mg. per day without 
encountering the incidence of systemic side effects. 
Also, by microencapsulation there now is a delivery system by which the 
release of indoprofen in the gastrointestinal tract can be controlled, 
thereby preventing localized high concentrations. Indoprofen, like other 
drugs in this category, is a weak acid and is unionized in the acidic pH 
of the stomach and thus poorly soluble. The cellulose ether coating of the 
microencapsulation process forms a gel in the stomach pH from which 
indoprofen diffuses slowly, minimizing the possibility of high local 
concentration. 
It is important that the particle size of indoprofen be below 20 microns 
and the nominal coating thickness by microencapsulation be approximately 
50-250 microns to adequately provide the acceptable properties necessary 
to minimize the side effects associated with 80 and 1200 mg. of 
indoprofen which is indicated in the treatment of osteoarthritis and 
rheumatoid arthritis. 
The specific process used to microencapsulate the microparticles of 
indoprofen comprises warming and then cooling the particles while 
dispersed in specific immiscible liquids, one of which is a solvent for 
the cellulose ether when warm but not when cool. In particular, the 
process requires the use of three immiscible phases: 
(1) a liquid mixture of which a major part by volume is a low-viscosity 
liquid which acts as a solvent for the cellulose ether at warm 
temperatures and a minor part by volume of a polymer which acts to force 
the cellulose ether out of solution at cool temperature; 
(2) A cellulose ether which will form a solid protective coating, is 
incompatible with the polymer of (1) but is soluble in the low-viscosity 
liquid solvent (1) at warm temperature, and which with the solvent forms a 
separate phase (the cellulose ether being used in an amount such that the 
warm solution has a viscosity of from about 4,000 to about 10,000 
centipoises and may by agitation be dispersed as minute liquid entities 
ready to coat the indoprofen particles); and 
(3) micro-particles of indoprofen, below 20 microns, which are immiscible 
with (1) or (2) but are wettable by the warm solution of cellulose ether 
in the low-viscosity solvent. 
Only those cellulose ethers which conform to certain specific criteria may 
be used to prepare the microencapsulated indoprofen of this invention. 
First, the cellulose ether must be capable, when in warm solution, of 
wetting the indoprofen particles so as to form a complete liquid shield 
around the particles which when cooled solidify without retention of the 
solvent. Second, the cellulose ether must be soluble when warmed in the 
low-viscosity liquid solvent, capable of forming a separate phase in the 
warm solvent in the presence of the polymer and insoluble in the cool 
solvent in the presence of the polymer. Typical of the cellulose ethers 
which fit the above criteria are ethyl cellulose and ethyl hydroxyethyl 
cellulose. 
The liquid mixture used to prepare the microencapsulated indoprofen of this 
invention will contain two essential ingredients: (1) a major part of a 
low-viscosity liquid, which will act as a solvent for the cellulose ether 
at warm temperatures and form a separate phase containing the cellulose 
ether and (2) a minor part of a polymeric ingredient with which the 
cellulose ether is immiscible and which forces the cellulose ether out of 
solution at cool temperatures. Typical of the low-viscosity liquids which 
can be used are cyclohexane and toluene. Typical of the polymeric 
ingredients are polybutadiene and butyl rubber. 
Various amounts of the indoprofen, cellulose ether an liquid mixture can be 
used in the preparation of the encapsulated indoprofen of this invention, 
depending upon the specific ingredients used and the thickness of the 
encapsulating coating desired. In general, however, the liquid mixture 
will constitute at least 70% by weight of the three immiscible phases, of 
which the low viscosity liquid will constitute the major part. The 
cellulose ether will be present in an amount such that the warm solution 
has a viscosity of from about 4,000 to about 10,000 centiposes. The 
indoprofen which constitutes the remaining immiscible phase will be 
present in the form of minute particles smaller than 50 microns, most 
preferably smaller than 20 microns. 
The temperatures used during the steps of the preparation of the 
encapsulated indoprofen will vary depending upon the specific liquid 
mixture and cellulose ether used. In general, however, the three 
immiscible phases will be heated to a temperature in the range of from 
about 50.degree. C. to about 90.degree. C. and then cooled to about room 
temperature or slightly above room temperature. 
The compression of the microencapsulated indoprofen into tablets will be 
carried out in accordance with well known tableting procedures. 
Besides the above essential ingredients, other conventional tableting 
ingredients can also be included in the tablets. Accordingly, antioxidants 
such as ascorbic acid or sodium metabisulfite; lubricants such as talc, 
magnesium stearate or sodium lauryl sulfate; fillers such as lactose 
calcium diphosphate; and colorants may be added if desired. However, it 
should be understood the inclusion of microencapsulated indoprofen 
constitutes the critical feature of this invention. 
It may also be desirable to include other medicaments in the tablets, such 
as other analgesics, antihistamines, hypoglycemics, antidepressants, 
bronchodilators, sedatives, decongestants, antispasmodics, etc.

Th following examples will serve to illustrate the invention; however, they 
should not be considered as limiting the scope thereof. All parts and 
percentages are by weight unless indicated otherwise. 
EXAMPLE 1 
This example illustrates the microencapsulation of indoprofen in ethyl 
cellulose. 
The following ingredients are used: 
(1) cyclohexane as the low viscosity liquid, 
(2) butyl rubber having a viscosity of 60-75 "Mooney" 8 minute reading at 
212.degree. F., as the polymer component of the liquid mixture, 
(3) ethyl cellulose having an ethoxyl content of approximately 48.5% by 
weight, and a viscosity of 90-94 centipoises as a 5% by weight solution in 
a 20% alcohol/toluene solvent, as the cellulose ether, and 
(4) indoprofen particles having a size of less than 20 microns. 
To 200 parts of a 3% solution of the above described butyl rubber in 
cyclohexane is added 4 parts of the above described ethyl cellulose and 48 
parts of the above described indoprofen particles and the whole heated to 
80.degree. C. with agitation sufficient to produce separate phase droplets 
of ethyl cellulose in cyclohexane of approximately 2 microns average drop 
size. The droplets coat the indoprofen particles. The dispersion is then 
slowly cooled to room temperature with continued agitation. During the 
cooling the ethyl cellulose deposits as a rigid coating on the indoprofen 
particles. The resulting microencapsulated indoprofen is removed by 
centrifuging and dried. The microencapsulated product is suitable for 
placing in capsules or compressing into tablets either alone or in 
combination with conventional pharmaceutical ingredients. 
EXAMPLE 2 
This example illustrates the difference in indoprofen plasma level over a 
time period between mice given pure indoprofen and mice given 
microencapsulated indoprofen. 
Plasma levels of indoprofen are determined in adult mice (22-25 g.) 
following oral gavage of either pure drug or microencapsulated drug. Drugs 
are administered at 1% of the body weight. Each treatment group in a 
single experiment contains four animals and the data is pooled for 
evaluation. Animals are sacrificed by decapitation. Blood from each 
treatment group is collected and pooled in heparinized tubes. Plasma is 
collected and frozen for assay of indoprofen concentration. Plasma 
indoprofen concentration is determined by high pressure liquid 
chromatography fitted with a UV detector; concentration is determined at 
max. 284 nm. 
The results of the experiments are shown in Table I. 
TABLE I 
______________________________________ 
Plasma Level (.mu.g/ml) of Indoprofen in Mice, 
Administered Orally as a Suspension* 
Mean + Standard Error 
Time, hours 
Pure Drug Microencapsulated 
______________________________________ 
2 2.49 .+-. 0.45 
1.10 .+-. 0.39 
4 1.62 .+-. 0.15 
1.03 .+-. 0.24 
8 0.89 .+-. 0.24 
0.89 .+-. 0.16 
16 0.49 .+-. 0.17 
0.57 .+-. 0.29 
32 0.43 .+-. 0.0 
0.66 .+-. 0.47 
K.sub.e, hr..sup.-1.spsp.a 
0.1276 0.0155 
t.sub.1/2, hr..sup.b 
5.4 44.7 
______________________________________ 
*Aqueous suspension containing 0.5% methylcellulose and 0.06% surface 
active agent. 
.sup.a The apparent rate of elimination, K.sub.e is calculated using a on 
compartment open model system as described by J. G. Wagner 
Biopharmaceutics and Relevant Pharmacokinetics, page 180, Hamilton Press 
(1971) 
##STR2## 
It can be seen from the above that the encapsulated drug has a plasma 
half-life eight times longer than the unencapsulated drug. 
EXAMPLE 3 
This example illustrates the dissolution rate of the microencapsulated 
indoprofen of this invention as compared with the non-encapsulated drug. 
The in vitro dissolution analysis is done using the United States 
Pharmacopeia apparatus at 100 rpm (The United States Pharmacopeia, 19th 
rev., page 651, 1975, Mack Publishing Co.). 
Capsules are prepared by placing 50 mg. of pure indoprofen or 
microencapsulated product containing 50 mg. of indoprofen into hard 
gelatin capsule shells, size No. 2. Tablets are prepared by compressing 
microencapsulated product contaning 100 mg. of indoprofen on a tablet 
machine using 9/32" flat, face tooling. Each capsule and tablet is placed 
in a rotating basket and immersed in 900 ml. of simulated intestinal fluid 
(no pancreatin). At 10, 20, 30, 60, 120 and 180 minutes, 5 ml. samples are 
withdrawn, filtered through a 0.6 micron membrane filter and assayed for 
absorbance in a UV spectrophotometer at .lambda. max. 284 nm. The percent 
of indoprofen dissolved is calculated, each value being an average of two 
analyses. The results of the analyses are shown in Table II. 
TABLE II 
______________________________________ 
Percent Dissolved (Minutes) 
Product 10 20 30 60 120 180 
______________________________________ 
Pure drug capsule 
36.7 92.8 96.3 97.2 96.3 -- 
Microencapsulated 
capsule 4.2 9.3 8.9 17.3 28.6 -- 
Microencapsulated 
tablet 2.3 3.5 4.0 5.7 10.0 11.6 
______________________________________ 
EXAMPLE 4 
This example illustrates the use of microencapsulated indoprofen in 
prolonged release formulations containing other medicaments. 
In each case the ingredients are blended in a twin shell blender for 5 
minutes and then compressed into tablets. Formulations 1 and 2 are 
compressed into 530 mg. tablets on a tablet machine using 1/2" flat face 
tablet tooling. Formulations 3-5 are compressed into 330 mg. tablets on a 
tablet machine using 7/16" flat face tablet tooling. The ingredients are 
set forth below: 
______________________________________ 
Mg. per Tablet 
% 
______________________________________ 
Formulation 1 
Microencapsulated indoprofen 
118.0 22.3 
Aspirin, USP 325.0 61.3 
Lactose Fast flo, USP 
79.5 15.0 
Magnesium stearate, USP 
7.5 1.4 
530.0 100.0 
Formulation 2 
Microencapsulated indoprofen 
118.0 22.3 
Acetaminophen, USP 325.0 61.3 
Lactose Fast flo, USP 
79.5 15.0 
Magnesium stearate, USP 
7.5 1.4 
530.0 100.0 
Formulation 3 
Microencapsulated indoprofen 
118.0 35.8 
Indoprofen, Pure drug 
50.0 15.1 
Lactose Fast flo, USP 
157.0 47.6 
Magnesium stearate, USP 
5.0 1.5 
330.0 100.0 
Formulation 4 
Microencapsulated indoprofen 
118.0 35.8 
Propoxyphene hydrochloride USP 
65.0 19.7 
Lactose Fast flo, USP 
142.5 43.2 
Magnesium stearate, USP 
4.5 1.3 
330.0 100.0 
Formulation 5 
Microencapsulated indoprofen 
118.0 35.8 
Phenobarbitol Sodium, USP 
15.0 4.5 
Lactose Fast flo, USP 
192.5 58.3 
Magnesium stearate, USP 
4.5 1.3 
330.0 100.0 
______________________________________