A pharmaceutical oral controlled release multiple-units formulation in which individual units comprise cross-sectionally substantially homogeneous cores containing particles of a sparingly soluble active substance, the cores being coated with a coating which is substantially resistant to gastric conditions, but which is erodable under the conditions prevailing in the small intestine, in particular an enteric coating which is substantially insoluble at a pH below 7 such as Eudragit.RTM. S (an anionic polymerizate of methacrylic acid and methacrylic acid methyl ester), is prepared by a process comprising comminuting an active substance together with a substance which is readily soluble in intestinal fluids such as an anionic detergent to obtain particles containing the active substance in intimate admixture with the readily soluble substance, combining the resulting particles into cross-sectionally substantially homogeneous cores together with components which accelerate the disintegration of the cores and intestinal fluids such as talc and saccharose, coating the individual cores with an erodable coating, and combining a multiplicity of the coated cores into a capsule or tablet formulation. Such a coating may also be used when the active substance is a substance which exerts an irritating effect on the gastric mucosa and/or is unstable in an acidic environment.

The present invention relates to oral pharmaceutical controlled release 
multiple-units dosage forms with important new features. 
TECHNICAL BACKGROUND 
Many physiological factors influence both the gastrointestinal transit time 
and the release of a drug from a controlled release dosage form and thus 
the uptake of the drug into the systemic circulation. Dosage forms should 
therefore be designed so that such variable factors do not compromise the 
efficacy and safety of the product. 
In man, a reproducible gastrointestinal transit time of a depot formulation 
can be achieved only by a controlled release multiple-units dosage form. 
The term "controlled release multiple-units formulation" (Bechgaard & 
Hegermann Nielsen, 1978) indicates a pharmaceutical formulation comprising 
a multiplicity (typically at least 100) of individual coated (or 
"microencapsulated") units contained in the formulation in such a form 
that the individual units will be made available from the formulation upon 
disintegration of the formulation in the stomach of the animal, including 
man, who has ingested the formulation. Typically, the multiple-units 
formulation may be a capsule which is disintegrated in the stomach to make 
available a multiplicity of individual coated units contained in the 
capsule, or a tablet which is disintegrated in the stomach to make 
available a multiplicity of coated units originally combined in the 
tablet. 
Drug release from a controlled release dosage form is generally controlled 
either by diffusion through a coating or by erosion of a coating by a 
process dependent on, e.g., enzymes or pH. The importance of a pH 
independent diffusion with respect to obtaining a reproducible rate of 
availability and to minimizing intra- and intersubject variations is known 
(GB Pat. No. 1 468 172 and Bechgaard & Baggesen, 1980). It is also known 
that controlled drug release in vivo can be achieved through an erodable 
process by enteric coating of a multiple-units dosage form (Green, 1966; 
McDonald et al., 1977; Bogentoft et al., 1978). 
Both above-mentioned types of controlled release multiple-units formulation 
techniques aim at a controlled release of active substance at a 
predetermined pattern to reduce and delay the peak plasma level without 
affecting the extent of drug availability. Due to a lower peak plasma 
level, the frequency of undesired side-effects may be reduced, and due to 
the delay in the time to obtain peak plasma level and the extension of the 
time at the therapeutically active plasma level, the dosage frequency may 
be reduced to once or twice daily dosage in order to improve patient 
compliance. 
A further advantage of the controlled release multiple-units dosage form is 
that high local concentrations of the active substance in the 
gastrointestinal system is avoided, due to the units being distributed 
freely throughout the gastrointestinal tract, independent of gastric 
emptying. If the mucosa of the stomach is more sensitive to the active 
substance than the intestinal mucosa, controlled release formulations 
avoiding release of active substance in the gastric area will be 
preferred; formulations of this type are controlled release multiple-units 
formulations in which the coatings are substantially resistant to gastric 
conditions. 
DISCLOSURE OF INVENTION 
The present invention relates to new developments in controlled release 
multiple-units formulations where the individual units are coated with an 
erodable coating. 
According to the invention, active substances are incorporated in 
pharmaceutical oral controlled release multiple-units formulations in 
which individual units comprise cross-sectionally substantially 
homogeneous cores containing particles of an active substance, the cores 
being coated with a coating which is substantially resistant to gastric 
conditions but is erodable under the conditions prevailing in the small 
intestine. 
The individual units of the multiple-units formulations according to the 
invention will normally be pellets (coated cores) in which the core is 
constituted by a combination of active substance and excipients. A type of 
core which is widely used in the known art (vide, e.g., Eur. Patent 
Application No. 79 850 110) is a substantially spherical particle of a 
size of about 0.5-1 mm consisting of excipient(s) with active substance 
applied to its surface. Typical cores of this type are the so-called 
"non-pareil" cores where the excipients are in the form of spherical 
particles of saccharose. It is also known, e.g., from GB Patent 
Specification No. 1 468 172, to prepare cores which are cross-sectionally 
substantially homogeneous, but these known cross-sectionally substantially 
homogeneous cores were coated with a diffusion coating. It is believed 
that it has not previously been suggested to combine cores which are 
cross-sectionally substantially homogeneous with an erodable coating. In 
the present context, the term "cores which are cross-sectionally 
substantially homogeneous" designates cores in which the active substance 
is not confined to an exterior layer on the core body, in other words 
normally cores which, through the cross-section of the core body, contain 
substantially the same type of composition comprising microparticles 
containing active substance, in contrast to the non-pareil type of cores 
which each consist of an excipient body with active substance applied to 
its surface, and in contrast to coated crystal units which are 
substantially monolithic crystals. From this definition, it will be 
understood that the cores which are cross-sectionally substantially 
homogeneous will normally consist of a mixture of active substance with 
excipient(s), (and in spite of the term "homogeneous", this mixture will 
not necessarily be qualitatively or quantitatively homogeneous through the 
cross-section of the particle but may show, e.g., a concentration gradient 
of one or more of its constituents) or they may consist substantially 
solely of active substance in a non-monolithic form, e.g. as a sintered 
mass of crystalline or amorphous particles of active substance. In the 
following specification and claims, such cores which are cross-sectionally 
substantially homogeneous will, for brevity, often simply be designated 
"cores". 
The erodable coatings used in the formulations of the present invention are 
coatings which are substantially resistant under gastric conditions but 
are eroded during the passage of the unit through the small intestine. 
Erodable coatings may be coatings which are eroded by process dependent 
upon, e.g., enzymes present in the segment of the intestine where the 
erosion is desired, including enzymes generated by the animal, including 
man, to whom the unit is administered and enzymes produced by bacteria, or 
bacterial fermentation of the erodable coating. As has been explained 
above, erodable coatings are distinguished from diffusion coatings which 
are substantially insoluble and non-erodable in gastrointestinal fluids, 
but are permeable, by diffusion, to gastrointestinal fluids and dissolved 
active substance. (For the sake of completeness, however, it should be 
noted that although the quantitatively predominant contribution to the 
absorption from erodably coated units is the phase after the coating has 
been eroded, it cannot be precluded that a certain amount of active 
substance will be released through the uneroded coating by diffusion). 
An important class of erodable coatings for use in the formulations 
according to the present invention are the so-called enteric coatings 
which are coatings that are substantially insoluble under the pH 
conditions prevailing in the stomach but are soluble at a pH prevailing in 
the small intestine, typically a pH of above 4.5. 
DETAILED DESCRIPTION OF INVENTION 
Cores 
According to the invention, the cores are cross-sectionally substantially 
homogeneous cores. The combination of cross-sectionally substantially 
homogeneous cores with a coating which is substantially resistant to 
gastric conditions but is erodable under the conditions prevailing in the 
small intestine offers several advantages compared to the known art 
erodably coated cores. 
Firstly, cross-sectionally substantially homogeneous cores are easy to 
produce in large scale in reproducible manner in, e.g., automatic 
equipment because the components therefor are normally simply mixed in the 
prescribed proportions, which means that the inter-core variation in 
composition, e.g., concentration of active substance, can be kept within 
narrow limits. Secondly, the concentration of active substance in the core 
can be varied within very wide limits (generally between 10-90% by 
weight), which renders it possible to optimize the concentration of active 
substance in the single core in order to minimize capsule sizes for a 
given dosage strength and thereby optimize patience compliance. Thirdly, 
the size of the cores may be easily adjusted as desired, to improve the 
distribution pattern of the units throughout the gastrointestinal tract; 
this is in contrast to the non-pareil technique where the size variation 
is limited by the available standard sizes. Fourthly, the composition of 
the cores may be optimized with respect to the extent of drug 
availability, i.e., to enhance the release of the active substance in the 
small intestine, after erosion of the coating. 
Thus, it is possible to utilize special measures to enhance the absorption 
of the active substances by enhancing the disintegration of the cores and 
the dissolution of the active substance. One such special measure 
according to the invention is to provide the active substance in the cores 
in the form of particles of a size of about 1-10 .mu.m, in particular 
about 2-5 .mu.m, in admixture with components enhancing the disintegration 
of the cores and the dispersion of the active substance in intestinal 
fluids. 
The cores are typically made by granulating these particles together with 
excipients, including bulk agents such as carbohydrates and derivatives 
thereof such as starch and starch derivatives, including microcrystalline 
cellulose, binders such as cellulose derivatives, including 
methylcellulose or hydroxypropylmethylcellulose, polyethylene glycol, 
polyvinylpyrrolidone, agar, or gelatin, such as by treatment in a high 
speed mixer (to directly obtain compact-shaped cores), or by treatment in 
a planet mixer with subsequent extrudation of the mixture into strings of 
predermined diameter close to the desired final cross-sectional dimension 
of the cores and treatment of the strings in a marumerizer or similar 
equipment to obtain compact-shaped cores. The diameter of the cores is 
normally adapted so that the coated core has a diameter of about 0.4-1.2 
mm, in particular about 0.5-1.0 mm, especially about 0.5-0.8 mm, such as 
0.5-0.7 mm. The preferred diameter of the coated cores is about 0.5-0.6 
mm. By incorporating special ingredients in the mixture, an increased 
tendency to disintegrate in contact with intestinal fluids may be imparted 
to the cores. Examples of such materials are solid insoluble materials 
which will tend to counteract excessive compaction of the content of the 
cores during their preparation, and/or to introduce slidability between 
the components in the cores, and/or to geometrically introduce tensions in 
the cores, and/or to interfere with the packing of the content of the 
cores to provide voids between the particles containing active substance, 
such as plate-shaped bodies, e.g., talc, or compact-shaped particles of a 
particle size of about 20-100 .mu.m, in particular about 50-75 .mu.m, such 
as aluminium silicate, zinc oxide, magnesium oxide, titanium dioxide, 
colloidal silica, or magnesium trisilicate. 
According to a particular aspect of the invention, the disintegration of 
the cores is additionally enhanced when particles of a substance which is 
readily soluble in intestinal fluids are incorporated in the mixture from 
which the cores are made. Examples of such substances are saccharose, 
glucose, mannitol, sorbitol, or lactose. 
In particular, it is preferred to enhance the disintegration of the cores 
in intestinal fluids by a combination of the two above-mentioned measures 
that is, by incorporation of both insoluble and a soluble 
disintegration-enhancing component. One example of a combination of this 
kind is the combination of talc and saccharose which is illustrated in the 
examples. 
The possibility of enhancing the disintegration of the cores is especially 
valuable in connection with active substances which are sparingly soluble 
and which, therefore, should be exposed to the intestinal fluids as 
effectively and fast as possible after erosion of the coating. In order to 
obtain maximum disintegration, it is preferred to use only a small amount 
of binder, if any, in the mixture from which the cores are made. 
The weight ratio between the active substance(s) and the excipients may 
vary within wide limits. As a general rule, the cores may contain 10-90% 
by weight of active substance. When the active substance is a sparingly 
soluble substance, the amount of disintegration-enhancing components 
(insoluble and/or soluble) will often be at least 20% by weight, typically 
at least 40% by weight, calculated on the total mixture. 
In accordance with a particular aspect of the invention, the predetermined 
controlled release of the active substance may be changed by changing the 
density of the cores, and thus, the time of appearance of the cores in the 
predetermined segment of the intestine may be varied at will. By 
increasing the density of the cores with resulting increased transit time 
of the coated cores (Bechgaard & Ladefoged, 1978), a more delayed and 
longer lasting absorption phase is obtained, that is a longer period 
during which the absorption of the active substance takes place after the 
substance has been released, and thereby made available for absorption, by 
erosion of the coating. 
Examples of excipients which may be used to increase the density of the 
cores are described in U.S. Pat. No. 4,193,985 and include heavy 
particulate substances such as barium sulphate, titanium oxide, zinc 
oxides, and iron salts. 
Active Substance 
The active substance in the formulations according to the invention may be 
any active substance which is advantageously administered in a controlled 
release multiple-units formulation to be made available in the small 
intestine, in particular drug substances, including, e.g., methyldopa, 
morphine, naproxene, prazosin, theophyllin, verapamil, amilorid, and 
disopyramide. 
Especially important formulations according to the invention are 
formulations in which the active substance, apart from being a substance 
about which it is known or indicated from a pharmacokinetic and/or 
clinical point of view that it is advantageously administered in a 
controlled release multiple-units formulation, is a substance which exerts 
an irritating effect on the gastric mucosa such as acetylsalicylic acid, 
indomethacin, and other non-steroid antiinflammatory drugs, and/or is 
unstable in acidic environment such as erythromycin, iron salts, cardiac 
glycosides, e.g., digoxin, and L-Dopa, and/or is sparingly soluble. 
The pharmaceutical formulation according to the invention is of particular 
importance in connection with sparingly soluble active substances, as 
these are difficult to formulate in accordance with known controlled 
release dosage forms based on the diffusion principle. 
In the present context, the term "sparingly soluble substance" designates a 
substance which requires more than 30 parts by volume of water to dissolve 
1 part by weight of the active substance at ambient temperature. Examples 
of sparingly soluble active substances are found among almost all 
therapeutic groups, including diuretics, antiepileptics, sedatives, 
antiarrhythmics, antirheumatics, .beta.-blockers, vasodilators, 
analgesics, bronchodilators, hormones, oral antidiabetics, 
antihypertensives, anti-inflammatories, and antidepressives. 
Among the sparingly soluble substances, important substances belong to a 
group which requires more than 1000 parts by volume of water to dissolve 1 
part by weight of the active substance at ambient temperature, or even 
more than 10,000 parts by volume of water. 
As examples of sparingly soluble active substances which may be formulated 
according to this aspect of the invention may be mentioned indomethacin, 
spironolactone, ibuprofen, furosemide, sulfadiazine, sulfamerazine, 
progesterone, reserpine, pyrvinium embonate, mofebutazone, 
hydrochlorothiazide, tetracycline, tolbutamide, acetaminophen, 
testosterone, valproic acid, estradiol, acetazolamide, erythromycin, iron 
salts, hydralazine, carbamazepine, quinidine, and cardiac glycosides, 
e.g., digoxin. 
As examples of substances among the above-mentioned sparingly soluble 
substances which require more than 1000 parts by volume of water to 
dissolve 1 part by weight of the substance at ambient temperature may be 
mentioned spironolactone, ibuprofen, furosemide, hydrochlorothiazide, 
tolbutamide, and testosterone. 
By utilization of the principle of the invention, it is possible to obtain 
an extent of availability of a sparingly soluble active substance which is 
equal to or better than the extent of availability of plain formulations 
and to reduce and delay the peak plasma level compared to plain 
formulations. This is achieved by utilizing (i) the fact that the units 
are freely distributed throughout the gastrointestinal tract, independent 
of gastric emptying, as the units are small enough to pass the pylorus 
even when the sphincter is closed, and (ii) the fact that there is a 
significant physiological variation along the gastrointestinal tract, 
including variation in pH and qualitative and quantitative composition of 
enzymes and microflora. In the stomach, the pH range is wide, viz. pH 1-6, 
primarily due to increase in pH after intake of food, while the pH in the 
small intestine ranges from 5 to 8. The variation in the physiological 
environment along the small intestine may be utilized by adapting the 
erodable coating to be eroded in a desired segment of the small intestine. 
The above-mentioned measures to enhance the disintegration of the cores 
are preferably used in combination with special techniques for enhancing 
the dissolution of the active substance which are explained below in 
connection with the discussion of the particles containing active 
substance. 
Particles Containing Active Substance 
The active substance is normally present in the cores in the form of 
particles of a size in the range of from about 1 to about 75 .mu.m. 
Normally, the particles are of the conventional sizes in which the 
particular active substances are available. While active substances which 
are readily soluble may be available in any size within the range stated 
above, sparingly soluble substances are typically available as ground 
materials having particle sizes in the range of about 1-10 .mu.m, and this 
range, in particular the range of about 2-5 .mu.m, is normally suitable 
for sparingly soluble active substances for incorporation in the cores of 
the present invention. 
According to a particularly important embodiment of the invention, active 
substances which are sparingly soluble are incorporated in the cores in 
the form of particles in which they are in intimate admixture with a 
substance which is readily dissolved in intestinal fluids and which, 
therefore, enhances the dispersion of the active substance. Such an 
intimate admixture may be obtained, e.g., by co-comminuting the active 
substance together with the dispersion-enhancing substance, both 
substances preferably being in solid form during the comminution. The 
co-comminution may be performed by subjecting a mixture of particles of 
the active substance with particles of the dispersion-enhancing substance 
to grinding, in particular high shear grinding, e.g. in a pinned disc mill 
or a jet mill or other equipment exerting similar stress. The resulting 
intimate mixture will be in the form of particles in the range of 1-10 
.mu.m, in particular 2-5 .mu.m, in which the active substance and the 
dispersion-enhancing substance are intimately combined with each other by 
conglomeration and/or adsorption. The particles in which a sparingly 
soluble active substance is combined with a dispersion-enhancing substance 
show enhanced dissolution of the active substance, which is believed to be 
due to the fact that the dispersion-enhancing substance incorporated in 
the particles enhances the dispersion of the active substance which is 
thereby more efficiently exposed to the intestinal fluids. 
The dispersion-enhancing substance which is incorporated in the particles 
containing active substance may, in principle, by any pharmaceutically 
acceptable excipient which is readily soluble in intestinal fluids. 
Examples of such substances are saccharose, glucose, mannitol, sorbitol or 
lactose. Especially effective dispersion-enhancing substances are 
surface-active substances such as detergents, in particular anionic or 
non-ionic detergents, for instance sodium salts of fatty alcohol 
sulphates, preferably sodium laurylsulphate, sulfosuccinates, partial 
fatty acid esters of sorbitans such as sorbitanmonooleate (SPAN.RTM.), 
partial fatty acid esters of polyhydroxyethylene sorbitans such as 
polyethylene glycolsorbitan monooleate (Tween.RTM. 80), or 
polyhydroxyethylene fatty alcohol ether such as polyhydroxyethylene (23) 
lauryl ether (BRIJ.RTM. 35). 
The amount of dispersion-enhancing substance which is incorporated in the 
particles containing active substance is normally less than 100%, 
calculated on the active substance, typically at the most 70%, calculated 
on the active substance. Thus, for instance, when the readily soluble 
substance is saccharose or another dispersion-enhancing carbohydrate, it 
is normally co-comminuted with the active substance in an amount of about 
40-60% by weight, calculated on the active substance. When the 
dispersion-enhancing substance is a surface-active substance such as a 
detergent, it is preferably co-comminuted with the active substance in an 
amount of at the most 10% by weight, calculated on the active substance, 
preferably about 5% by weight. 
Coating 
The erodable coating applied to the cores according to the invention is 
preferably an enteric coating which is applied from a solution and/or 
suspension in an organic solvent and/or water. The application of the 
coating is typically performed in a fluidized bed or by pan coating. 
Examples of enteric coating materials which may be used for the purpose of 
the present invention are coatings selected from the group consisting of 
acrylic polymers and copolymers, e.g. a polymerisate of methacrylic acid 
and methacrylic acid methyl ester such as Eudragit.RTM. S 12,5, 
Eudragit.RTM. S 12,5 P (which corresponds to Eudragit.RTM. S 12,5 but 
contains 1.25% of dibutylphthalate), Eudragit.RTM. 30 D or Eudragit.RTM. L 
12,5, shellac, cellulose acetate esters such as mixed partial esters of 
cellulose-containing phthalate groups, acetyl groups and free acid groups 
(cellulose acetate phthalate), polyvinyl acetate esters such as polyvinyl 
acetate phthalate, hydroxypropylmethyl cellulose esters such as 
hydroxypropylmethylcellulose phthalate, or alkyleneglycolether esters of 
copolymers such as partial ethyleneglycol monomethylether ester of 
ethylacrylate-maleic anhydride copolymer, propyleneglycol monomethylether 
ester of ethylacrylate-maleic anhydride copolymer, dipropyleneglycol 
monomethylether ester of ethylacrylate-maleic anhydride copolymer or 
diethyleneglycol monomethylether ester of methylacrylate-maleic anhydride 
copolymer, N-butylacrylate-maleic anhydride copolymer, 
isobutylacrylate-maleic anhydride copolymer or ethylacrylate-maleic 
anhydride copolymer. 
The coating material may be admixed with various excipients such as 
plasticizers, inert fillers, e.g. talc, pigments, in a manner known per 
se. 
The type and amount of enteric coating applied is adapted so as to obtain 
resistance to gastric environments and release in the desired segment of 
the small intestine. Normally, the amount of the coating will be about 
2-25% by weight, calculated as dry coating weight on the total weight of 
the cores, typically about 4-12% by weight. 
In accordance with one aspect of the present invention, the coating is 
selected so that it will be preferentially eroded in the distal part of 
the small intestine. An example of such a coating is an enteric coating 
which is substantially insoluble at pH below 7. 
In the present context, the term "an enteric coating which is substantially 
insoluble at pH below 7" designates an enteric coating which, under the 
experimental conditions defined under MATERIALS AND METHODS below, 
releases less than 15% of the active substance contained in the coated 
core within one hour at pH 6.5. 
Preferably, the coating which is substantially insoluble at pH below 7 
will, at the same time, effectively release a high proportion of the 
active substance, typically more than 90% of the active substance 
contained in the core, within one hour at pH 7.5. 
Preferred materials for enteric coatings which are substantially insoluble 
at pH below 7 are polymerisates of methacrylic acid and methacrylic acid 
methyl ester or mixtures thereof. A specific example of such a coating 
material is Eudragit.RTM. S. 
The use of a coating which is selectively or preferentially eroded in the 
distal part of the small intestine offers several advantages: 
Firstly, due to the longer travel of the units through the small intestine 
to reach the distal section of the small intestine in which the pH is in 
the range of 7-8, the time to reach peak plasma concentration is 
increased. 
It is known that physiological pH variations in the distal segment of the 
small intestine are small. Furthermore, pH variations caused by food 
intake are also low in the distal segment. Due to these very stable pH 
conditions, controlled release formulations of the invention in which the 
coating is one that is substantially insoluble at pH below 7 will yield a 
highly reproducible absorption phase, both within and between subjects and 
are therefore preferred. 
As appears from Example 5, the standard deviations of the bioavailability 
parameters of a formulation according to the invention where the coating 
was an enteric coating which is substantially insoluble at pH below 7 were 
of the same order of magnitude when the formulation was administered with 
food or after a fast, respectively. The administration of the coated cores 
concomittant to food intake did not influence the extent of availability. 
The aspect of the invention comprising controlled release multiple-units 
formulations in which the coating is an erodable coating which is 
selectively eroded in the distal part of the small intestine, in 
particular an enteric coating which is substantially insoluble at pH below 
7, is of general importance and advantage in connection with any type of 
units, including units which are not cross-sectionally substantially 
homogeneous. 
Therefore, one aspect of the present invention relates to a pharmaceutical 
oral controlled release multiple-units formulation in which individual 
units comprising an active substance are coated with a coating which is 
selectively eroded in the distal part of the small intestine. The coating 
is preferably an enteric coating which is substantially insoluble at a pH 
below 7, and especially a coating which will release at least 90% of the 
active substance within one hour at a pH of 7.5 under the experimental 
conditions defined under MATERIALS AND METHODS below. 
Hence, according to this aspect of the invention, the units may be any type 
of units used in multiple-units formulations. Interesting units, apart 
from the cross-sectionally substantially homogeneous cores discussed 
above, are units of the non-pareil type (including such units with a 
concentration gradient of the active substance along the radius of the 
core), and crystals. The active substances which are formulated according 
to this aspect of the invention are typically the same as mentioned above. 
The preparation of the units according to this aspect of the invention is 
performed by coating the desired unit types in the same manner as 
described above.

The invention is illustrated in greater detail in the following 
experimental section. 
MATERIALS AND METHODS 
In the examples, the following materials were used: 
Indomethacin: 
(2-[1-(4-Chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid); BP 80. 
Sodium laurylsulphate: 
Ph Eur 
Microcrystalline cellulose: 
BPC 79. 
Saccharose powder: 
Ph Eur 
Talc: 
Ph Eur 
Purified water: 
Ph Eur 
Eudragit.RTM. S 12,5: 
An anionic polymerisate of methacrylic acid and methacrylic acid methyl 
ester having a dry matter content of 12.5%, a density D.sup.20 of 0.84, a 
viscosity at 20.degree. C. of 100 cP; supplied by Rohm Pharma GmbH, 
Darmstadt, Germany. 
Eudragit.RTM. L 12,5: 
An anionic polymerisate of methacrylic acid and methacrylic acid methyl 
ester having a dry matter content of 12.5%, a density of D.sup.20 of 0.84, 
and a viscosity at 20.degree. C. of 75 cP; supplied by Rohm Pharma GmbH, 
Darmstadt, Germany. 
Eudragit.RTM. L 30 D: 
An anionic polymerisate of methacrylic acid and methacrylic acid methyl 
ester having a dry matter content of 30% as an aqueous dispersion, 
supplied by Rohm Pharma GmbH, Darmstadt, Germany. 
Acetyltributylcitrate: 
Citroflex.RTM. A-4; supplied by Pfizer A/S, Copenhagen, Denmark. 
Isopropanol: 
BP 80. 
Polyvinylpyrrolidone: 
BP 80 Add 81. 
Furosemide: 
(4-Chloro-N-furfuryl-5-sulfamoylantranilic acid) BP 80. 
Acetylsalicylic acid: 
Ph Eur 
Triacetin: 
(1,2,3-propanetrioltriacetate) USP XX. 
Determination of in vitro dissolution of pellets or cores: 
In vitro dissolution rates were determined according to Baggesen et al 
(1981). The rotation speed was 30.+-.1 r.p.m. and the dissolution medium 
was 250 ml of 0.1M hydrochloric acid (pH 1.2) or citrate buffer (0.05M, pH 
4.5 or 0.02M, pH 6.5) or phosphate buffer (0.05M, pH 7.5), maintained at 
37.+-.0.1.degree. C. Release of active substance into the dissolution 
medium was determined by measuring the absorbance spectrophometrically at 
320 nm (indomethacin), 271 nm (furosemide) or 278 nm (the isobestic point 
of acetylsalicylic acid/salicylic acid). 
Example 1 
Preparation of Indomethacin-Containing Cores to be Coated with an Enteric 
Coating 
Cores (containing 24% talc) were prepared from 2.9 kg indomethacin, 0.2 kg 
sodium laurylsulphate, 0.5 kg microcrystalline cellulose, 4.0 kg 
saccharose powder and 2.4 kg talc. 
The indomethacin and the sodium laurylsulphate were co-comminuted by 
passage through a grinder using a 0.5 mm sieve. 
The ground mixture was mixed with the microcrystalline cellulose, the 
saccharose and the talc in a planet mixer. 
10 kg of the resulting mixture were moistened with 0.8 kg purified water 
and were mixed in a planet mixer until the mixture was a little lumpy. 
The moist mixture was extruded through a 0.5 mm sieve. The first kgs of 
extrudate passing the sieve were powdery and were reextruded. The 
resulting extrudate were strings breaking off in lengths of 10-30 cm. 
2 kg of the extruded strings were formed into compact-shaped cores in a 
marumerizer, and the resulting compact-shaped cores were dried in a 
fluidized bed dryer and sieved through a separator, the upper sieve being 
0.71 mm, and the bottom sieve 0.46 mm. 
In a similar manner as described above, cores (containing 10% talc) were 
prepared from 2.9 kg indomethacin, 0.2 kg sodium laurylsulphate, 1.0 kg 
microcrystalline cellulose, 4.9 kg saccharose powder, and 1.0 kg talc. 
The release of the indomethacin was measured, at pH 7.5, as described under 
MATERIALS AND METHODS, for the cores containing 24% talc and 10% talc, 
respectively. The amount of indomethacin released at pH 7.5 after 10 
minutes appears from Table I. 
Table I 
______________________________________ 
Percentage of indomethacin released at pH = 7.5 after 10 min 
(n = 2) 
______________________________________ 
Cores with 24% talc 
98.4% 
Cores with 10% talc 
60.0% 
______________________________________ 
It appears from Table I that the increase of the talc content from 10% to 
24% results in an increase of the release of indomethacin to practically 
quantitative release within 10 minutes. 
Coating of Cores with Enteric Coating 
An enteric coating suspension was prepared by homogenizing 9.0 kg 
Eudragit.RTM. S 12,5 together with 0.135 kg acetyltributylcitrate, 0.9 kg 
talc and 7.965 kg isopropanol. 
10 kg of the above-described cores containing 24% talc were coated with 
4.167 kg of this coating suspension in a fluidized bed, and the resulting 
pellets were covered with talcum. 
For the preparation of a pharmaceutical dosage form, more than 1000 of 
these pellets were filled in a capsule No. 1. Each capsule contained 75 mg 
indomethacin. 
Example 2 
The Effect of Dispersion-Enhancing Agents with Respect to Improving the 
Dissolution of the Active Substance 
In a similar manner as described in Example 1, (but without cocomminution 
of the indomethacin with any dispersion-enhancing agent), cores were 
prepared from 3.2 kg indomethacin, 1.0 kg microcrystalline cellulose, 5.7 
kg saccharose powder and 0.1 kg polyvinylpyrrolidone. These cores are 
designated cores, type 0. 
Another portion of cores, designated cores, type SACH, was prepared from 
the same ingredients in a similar manner, except that in this case the 
indomethacin and the saccharose powder were co-comminuted by passage 
through a grinder using a 0.5 mm sieve. 
In the same manner as described in Example 1, cores were made from 3.2 kg 
indomethacin, 0.2 kg sodium laurylsulphate, 1.0 kg microcrystalline 
cellulose, 5.5 kg saccharose powder and 0.1 kg polyvinylpyrrolidone. These 
cores are designated cores, type NaLS. 
The release of the indomethacin was measured, at pH 7.5, as described under 
MATERIALS AND METHODS for these 3 types of cores. 
The amount of indomethacin released at pH 7.5 after 10 minutes appears from 
Table II. 
Table II 
______________________________________ 
Percentage of indomethacin released at pH = 7.5 after 10 min 
(n = 2) 
______________________________________ 
Cores, Type 0 71.0% 
Cores, Type SACH 92.8% 
Cores, type NaLS 97.1% 
______________________________________ 
It appears from Table II that the release of indomethacin is considerably 
increased when a dispersion-enhancing agent is co-comminuted with the 
indomethacin, and that the detergent type of dispersion-enhancing agent 
results in the fastest release. 
EXAMPLE 3 
The Influence of Coatings Soluble at Different pH on the Dissolution of 
Indomethacin 
An enteric coating suspension was prepared as described in Example 1 from 
2.08 kg Eudragit.RTM. L12.5, 2.08 kg Eudragit.RTM. S12.5, 0.0625 kg 
acetyltributylcitrate, 0.417 kg talc and 3.69 kg isopropanol. 
This coating, which is soluble at pH above 6.5, was called Coating A. 
An enteric coating suspension was prepared as described in Example 1 from 
4.16 kg Eudragit.RTM. S12.5, 0.0625 kg acetyltributylcitrate, 0.417 kg 
talc and 3.69 kg isopropanol. 
This coating, which is soluble at pH above 7.0, was called Coating B. Cores 
containing sodium laurylsulphate and 24% talc, prepared as described in 
Example 1, were coated with 10% Coating A or 10% Coating B (% dry matter 
of coating, calculated on the weight of the core). The dissolution of 
indomethacin from the resulting two types of pellets was determined as 
described under MATERIALS AND METHODS. The results are stated in Table 
III. 
Table III 
______________________________________ 
Percentage of indomethacin released at pH 6.5 and pH 7.5 
(n = 3) 
pH = 6.5 pH = 7.5 
10 m 30 m 60 m 60 m 
______________________________________ 
Coating A 17.4 64.0 76.5 98.6 
Coating B 6.5 9.0 9.8 100.7 
______________________________________ 
It appears from Table III that cores coated with Coating A and Coating B 
quantitatively released the indomethacin at pH 7.5 within 60 minutes and 
that cores coated with Coating B only released about 10% indomethacin 
after 1 h at pH 6.5. The possibility of adjusting the enteric coating is 
very important because it makes it possible to tailor-make formulations to 
be disintegrated in a predetermined segment of the small intestine. 
Example 4 
Bioavailability of Indomethacin from two Multiple-units Controlled Release 
Formulations 
Drug formulations: 
The two types of indomethacin-containing pellets prepared in Example 3 
(designated Coating A and Coating B, respectively) were formulated into 
hard gelatin capsules designated Coating A and Coating B capsules, 
respectively. Each capsule of each formulation contained 75 mg 
indomethacin. Instant release capsules of indomethacin (Indocid.RTM., 
Merck, Sharp and Dohme Ltd.) were used as the reference formulation. Each 
capsule of the reference formulation contained 25 mg indomethacin. 
Indomethacin was almost completely released from this capsule formulation 
during 10 minutes at pH 6.5. 
Drug administration: 
Eight healthy normal adult male subjects of age range 21-24 years and 
bodyweight range 60-80 kg were selected for this study. 
Each subject fasted for 12 hours before drug administration and remained 
fasting for 4 hours afterwards. Administration was conducted in a 
three-way complete crossover with one week between dosing, in which each 
subject received orally one Coating A or B capsule or three capsules of 
the reference formulation (75 mg total dose) together with 100 ml water. 
Blood samples (10 ml) were withdrawn before dosing and at intervals during 
24 hours afterwards. 
Measurement of indomethacin in plasma: 
Concentrations of indomethacin in plasma were measured using a high 
performance liquid chromatographic (HPLC) method. Plasma (200 .mu.l for 
concentrations between 0.1 .mu.g/ml and 4 .mu.g/ml or 100 .mu.l for 
concentrations above 4 .mu.g/ml containing 1 .mu.g mefenamic acid as an 
internal standard) was mixed with phosphate buffer (1 ml, 1M pH 5.0), and 
extracted with freshly distilled diethyl ether (5 ml) for 10 minutes on a 
rotary mixer. The phases were separated by centrifugation and the organic 
phase was removed and evaporated to dryness under nitrogen at 37.degree. 
C. The residue was washed to the bottom of the tube with a small amount of 
ether which was then evaporated to dryness. 
The drug residues were dissolved in methanol (50 .mu.l), portions (20 
.mu.l) of which were injected into the HPLC system which consisted of an 
automatic injector and pump (Waters Associates Ltd., U.K.), fitted with a 
variable wavelength ultra-violet monitor (Pye Unicam Ltd., U.K.) operated 
at 260 nm (.lambda.max for indomethacin in methanol). The stainless steel 
column (30 cm.times.0.4 cm i.d.) was prepacked with .mu. Bondapak C.sub.18 
(mean particle size 10 .mu.m, Waters Associates Ltd.) and a stainless 
steel precolumn (7 cm.times.0.2 cm i.d.) drypacked with pellicular 
Co:Pell.RTM. ODS (particular size 25-37 .mu.m, Whatman Ltd., UK) was 
installed to protect the analytical column. Chromatography was performed 
in reversed-phase mode with a mobile phase of acetonitrile (62%, v/v) in 
phosphate buffer (0.1M, pH 4.0) at a flow rate of 2.5 ml/min. Indomethacin 
and the internal standard (mefenamic acid) were eluted with retention 
times of 2.7 and 3.6 minutes respectively. 
Linear calibration curves of peak area ratio of indomethacin to internal 
standard were constructed by analysis of plasma containing these compounds 
over the concentration range 0.1 .mu.g/l-4 .mu.g/l. The standard error of 
taking the calibration line as a measure of indomethacin concentration 
over this range was 0.12 .mu.g/ml. The recovery of the internal standard 
at the level added of 5 .mu.g/ml was 100%.+-.4 S.D. (n=5), and the mean 
recovery of indomethacin over the concentration range 0.5 .mu.g/l-4 
.mu.g/l was 103%.+-.3 S.D. (n=5). No peaks were present on chromatograms 
of extracts of predose plasma in the position of the internal standard, 
but in some samples of predose plasma, interfering material was present at 
the position of indomethacin and equivalent to a maximum of 0.1 .mu.g/ml. 
The limit of detection was therefore arbitrarily set at 0.1 .mu.g/ml. The 
precision of measurement was assessed by the coefficients of variation of 
the means of replicate measurements (n=6) of .+-.17% at 0.1 .mu.g/ml, 
.+-.2% at 2 .mu.g/ml and .+-.4% at 4 .mu.g/ml. Known metabolites of 
indomethacin did not interfere with the measurement of the unchanged drug 
above a limit of 0.1 .mu.g/ml. 
Data processing: 
Areas to 24 h (AUC) under the plasma concentration-time curves were 
calculated by the trapezoidal rule. Since plasma drug levels at 24 h after 
dosing were close to the limit of detection, these areas were considered 
to be equivalent to infinite time. Since drug administration was 
unbalanced with respect to the dosing sessions, AUCs, peak plasma levels 
and their times of occurrence, times to reach a plasma level of 1.0 
.mu.g/ml were subjected to analysis of variance by regression techniques. 
Overall formulation-related effects were examined by the F-test and 
formulation means were tested pair-wise by the method of least significant 
differences (Snedecor & Cochran, 1967). 
Results: 
Peaks of mean plasma concentrations of indomethacin of 4.9 .mu.g/ml, 3.0 
.mu.g/ml and 2.3 .mu.g/ml occurred after single oral doses of 75 mg of the 
reference formulation and the Coating A and B capsule formulations 
respectively and these peaks of mean levels occurred at 1 h, 2 h and 3 h 
respectively, vide FIG. 1. 
Indomethacin was more slowly absorbed from both Coating A and B capsules 
than from the reference capsules, and was more slowly absorbed from the 
Coating B capsules than it was from the Coating A capsules. 
The bioavailability parameters appear in Table IV. The differences between 
formulations within these parameters are highly significant except for the 
AUC. 
TABLE IV 
______________________________________ 
Mean values of bioavailability parameters of indomethacin after 
administration of the reference and coating A and B capsules, 
respectively. Standard deviations are in parentheses 
Reference 
Coating A Coating B 
______________________________________ 
Area (.mu.g h/ml) 
12.2 (4.0) 
13.7 (4.3) 
11.8 (2.4) 
Peak plasma level (.mu.g/ml) 
5.5 (1.2) 3.8 (1.2) 2.9 (0.8) 
Time of peak level (h) 
1.0 (0.3) 2.1 (0.6) 3.5 (0.9) 
Time to 1 .mu.g/ml.sup.a (h) 
0.4 (0.2) 1.2 (0.3) 2.4 (0.7) 
______________________________________ 
.sup.a Time after dosing required to reach a plasma level of 1 .mu.g/ml, 
by interpolation. 
These data imply a considerable slower absorption rate after administration 
of the Coating B capsules compared with Coating A and the reference 
formulations. The extent of bioavailability, however, was similar after 
administration of each preparation. 
Discussion: 
Formulation of indomethacin as multiple-units controlled-release capsules 
comprising enteric-coated pellets of different sensitivity to an alkaline 
environment did not affect the extent of drug bioavailability, and drug 
absorption was slower after administration of these pellets when compared 
with the standard reference formulation. Rates of absorption were in the 
order: reference formulation&gt;Coating A capsules&gt;Coating B capsules (Table 
IV); thus it was demonstrated that these absorption rates are ranked in 
order of their observed dissolution rates in vitro (Table III). The 
present formulation technique takes into account the transit time and 
distribution of the pellets throughout the gastrointestinal tract 
(Bechgaard & Ladefoged, 1978) and the characteristic of a strictly 
alkaline-dependent erosion of the coating of pellets. The data confirm 
that the drug release from these pellets in vivo was dependent on an 
alkaline pH and that dissolution probably occurred in the distal part of 
the gastrointestinal tract, where the pH is relatively high (pH 6.5-7.5) 
and less variable than that in the proximal small intestine, which factor 
is more important in the non-fasting state. This finding is further 
supported by the low observed standard deviations of the bioavailability 
parameters after administration of the Coating A and B capsules (Table 
IV). These standard deviations were of the same order of magnitude as 
those after administration of the standard reference formulation. Thus the 
present multiple-units controlled release formulations represent a 
reliable and reproducible source of indomethacin. 
Example 5 
The Effect of Food on the Bioavailability of Indomethacin from a 
Multiple-units Controlled Release Formulation 
Drug formulation: 
Coating B capsules each containing 75 mg indomethacin, as described in 
Example 4. 
Drug administration: 
Nine healthy adult male subjects, age range 22-36 years and bodyweight 
ranges 63-70 kg, were selected for this study. 
Administration was conducted as a complete crossover with one week between 
doses, in which each subject received a single oral dose of one capsule 
(75 mg) together with 100 ml water, once after a 12 hours fast, and once 
after the subject had received a breakfast consisting of cereal, egg, 
bacon and sausage, one slice of toast and one cup of coffee, within 15 
minutes of drug administration. Blood samples were withdrawn before 
dosing, and at intervals during 24 hours afterwards. 
Measurement of indomethacin in plasma: 
Concentrations of indomethacin in plasma were measured by a high 
performance liquid chromatographic method, as described in Example 4. 
Data processing: 
Areas to 24 h (AUC) under the plasma concentration-time curves were 
calculated by the trapezoidal rule. Peak plasma levels and times of their 
occurence, AUC, and times to reach a plasma level of 1 .mu.g/ml were 
subjected to analyses of variance for crossover designs (Snedecor & 
Cochran, 1967), with subjects, dosing sessions, treatments and residual as 
factors in the analysis. The statistical significance of treatment 
differences was tested by the method of least significant differences. 
Results: 
A peak of mean concentrations of indomethacin in plasma of 1.9 .mu.g/ml 
occurred at 5 hours after administration of 75 mg after a 12 h fast, and 
indomethacin was present (0.2 .mu.g/ml) in plasma withdrawn 24 h after 
dosing. When 75 mg was administered within 15 min of ingestion of a 
substantial breakfast, the peak of mean plasma levels of indomethacin (1.8 
.mu.g/ml) occurred at 6 h and thereafter mean plasma indomethacin 
concentrations declined to 0.4 .mu.g/ml at 24 hours, vide FIG. 2. 
Two peak levels of indomethacin concentrations were present in plasma of 
most subjects after administration with fasting and also with food, but 
this effect was more noticeable when the doses were administered with 
food. Indomethacin is thought to undergo enterohepatic recirculation in 
man, and the secondary peak plasma levels may have been an expression of 
this recirculation. 
The overall major peak plasma concentrations and AUC were not significantly 
different (P&gt;0.05) after administration of Coating B capsules either after 
a 12 h fast or with food (Table V) 
Table V 
______________________________________ 
Mean bioavailability parameters of indomethacin. Standard 
deviations in parentheses (n = 9) 
Fasting With food 
______________________________________ 
Area (.mu.g.h/ml) 
13.8 (3.8) 12.5 (2.6) 
NS 
Peak level (ng/ml): 
First 2.7 (0.8) 2.2 (1.0) 
NS 
Second .sup. 0.5.sup.a 
(0.2) .sup. 1.1.sup.b 
(0.8) 
NS 
Time of peak level (h): 
First 4.2 (1.4) 6.4 (2.2) 
P&lt;0.05 
Second 12.7 (1.0) 14.4 (6.8) 
NS 
Time (h) to reach 1 .mu.g/ml.sup.a 
3.0 (1.3) 5.5 (2.6) 
P&lt;0.05 
______________________________________ 
.sup.a Secondary peak levels were present in the plasma of 6 subjects 
.sup.b Secondary peak levels were present in the plasma of 7 subjects 
Significance levels refer to treatment differences from the analysis of 
variance. NS = not significant (P&gt;0.05) 
The time of occurrence of the first peak plasma level after administration 
with food (6.4 h) was later than, and significantly different from 
(P&lt;0.05), that after administration after a 12 h fast (4.2 h), but 
corresponding times of occurrence of the second peak levels were not 
statistically significantly different. The time required to reach a plasma 
concentration of 1 .mu.g/ml after administration with food (5.5 h) was 
longer than, and significantly different from (P&lt;0.05), that after 
administration after fasting (3.0 h), as seen from Table V. 
Discussion: 
Administration of Coating B capsules with food did not affect the extent of 
drug bioavailability, but the presence of food decreased the rate of 
bioavailability as indicated by the later, and statistically significantly 
different, time of occurrence of the first peak plasma level and the time 
to achieve a plasma concentration of 1 .mu.g/ml. The phenomenon of the 
double peak level was also exaggerated after administration with food. 
Apparently, the extent to which a concomitant meal influences the 
bioavailability of indomethacin from Coating B capsules is equal to that 
from a plain indomethacin capsule. It should be emphasized that the 
observed standard deviations of the bioavailability parameters were of the 
same order of magnitude when the drug was administered with food or after 
a fast, as seen from Table V. Thus, the controlled release multiple-units 
formulation according to the invention represents a reliable and 
reproducible source of indomethacin when administered with food. 
Example 6 
Preparation of Furosemide-Containing Cores to be Coated with an Enteric 
Coating 
Cores were prepared from 40 g furosemide, 10 g saccharose powder, 10 g 
microcrystalline cellulose, 25 g saccharose powder and 15 g talc. The 
furosemide and 10 g of the saccharose were passed through a grinder using 
a 0.5 mm sieve. 
The powder was mixed with the microcrystalline cellulose, the rest of the 
saccharose and the talc in a planet mixer. 
100 g of the resulting mixture was moistened with 12 g purified water and 
was mixed until the mixture was a little lumpy. 
The moist mixture was extruded through a 0.5 mm sieve. 
The resulting extrudate was formed into compact-shaped cores in a 
marumerizer, and the cores were dried in a fluidized bed; the dried cores 
were sieved, the upper sieve being 0.71 mm, and the bottom sieve 0.46 mm. 
Coating of Cores with Enteric Coating 
An enteric coating suspension (C) was prepared by homogenizing 11.4 g 
Eudragit.RTM. L 30 D together with 0.6 g triacetin and 8 g purified water. 
Another enteric coating suspension (D) was prepared by homogenizing 25.0 g 
Eudragit.RTM. S 12.5 together with 0.375 g acetyltributylcitrate, 2.5 g 
talc and 22.1 g isopropanol. 
Portions of each 100 g of the cores obtained above were coated with coating 
suspension C and D, respectively, in a fluidized bed, and the resulting 
pellets were covered with talcum. 
The release of furosemide from the resulting pellets was determined as 
described under MATERIALS AND METHODS. The results are stated in Table VI. 
TABLE VI 
______________________________________ 
Percentage of furosemide released at pH 4.5 and at pH 7.5 (n = 2) 
pH 4.5 
pH 7.5 
120 m 30 m 
______________________________________ 
Coating C 16.9 95.4 
Coating D 14.3 96.5 
______________________________________ 
It appears from Table VI than the release of furosemide is practically 
quantitative at pH 7.5, and that the furosemide is released very slowly at 
pH 4.5. 
Example 7 
Preparation of Enteric Coated Acetylsalicylic Acid Crystals 
An enteric coating suspension was prepared by homogenizing 59.4 g 
Eudragit.RTM. S 12.5 together with 0.9 g acetyltributylcitrate, 11.7 g 
talc and 46.8 isopropanol. 
100 g of acetylsalicylic acid crystals having a size from 0.3 to 0.7 mm 
were coated with 20% (% dry matter of coating, calculated on crystals) of 
this enteric coating suspension in a fluidized bed. 
The dissolution of acetylsalicylic acid from these coated crystals was 
determined as described under MATERIALS AND METHODS. The results are 
stated in Table VII. 
TABLE VII 
______________________________________ 
Percentage of acetylsalicylic acid released at pH 1.2, pH 6.5 and 
pH 7.5 (n = 3) 
pH = 1.2 pH = 6.5 pH = 7.5 
60 m 60 m 60 m 
______________________________________ 
3.2 5.7 100.0 
______________________________________ 
It appears from Table VII that the release of acetylsalicylic acid is 
practically quantitative at pH 7.5, and that there is only a very slow 
release at pH 1.2. 
For the preparation of a pharmaceutical dosage form, 500 g of the coated 
crystals obtained above were filled into a capsule No. 00. 
LITERATURE 
GB Pat. No. 1,468,172 
Eur. Patent Application 79 850 110, Publication 0 013 262 
U.S. Pat. No. 4 193 985 
Baggensen S, Bechgaard H, & Schmidt K (1981) Content and dissolution 
uniformity testing of controlled-release products: The Repro-Dose.RTM. 
quality control procedure. Pharm. Acta Helv 56, 85-92 
Bechgaard, H & Hegermann Nielson, G (1978) Controlled release 
multiple-units and single-units doses. A literature review. Drug Develop 
Ind Pharm 4, 53-67. 
Bechgaard, H & Ladefoged, K (1978) Distribution of pellets in the 
gastrointestinal tract. The influence on transit time exerted by the 
density or diameter of pellets. J. Pharm Pharmacol 30, 690-692. 
Bechgaard, H & Baggesen, S (1980) Propoxyphene and norpropoxyphene: 
Influence of type of controlled release formulation on intra and 
intersubject variations. J. Pharm Sci 69, 1327-1330. 
Bogentoft, C, Carlsson, I, Ekenved, G & Magnusson, A (1978) influence of 
food on the absorption of acetylsalicylic acid from enteric-coated dosage 
forms. Eur J Clin Pharmacol 14, 351-355. 
Green, DM (1966) Tablets of coated aspirin microspherules-A new dosage 
form. J. New Drugs 6, 294-303. 
McDonald, P. J., Mather, L. E. & Story, M. J. (1977) Studies on absorption 
of a newly developed enteric-coated erythromycin base. J. Clin Pharmacol 
17, 601-606. 
Snedecor, G. W. & Cochran, W. G. (1967) Statistical Methods, Iowa State 
University Press, Iowa, 271-275.