Multiple-units drug dose

A controlled release multiple-units drug dose is described, which comprises a tablet or a capsule enclosing a plurality of subunits, each containing a therapeutically active agent and being enclosed in an insoluble membrane allowing for diffusion of the juices of the gastrointestinal tract, at least some of the subunits being of increased specific weight as compared with the specific weight of the active agent.

This invention relates to oral drug depot formulations of the multi-units 
type with a controlled release action of short or long duration of the 
active agent or agents. A multiple-units dose consists of a great number 
of subunits, usually in the form of pellets or microencapsulated crystals 
contained in a capsule or tablet. 
Oral depot products can be formulated according to two different 
principles: The controlled release single-unit dose or the multiple-units 
dose. 
A single-unit dose, e.g. a matrix tablet or a tablet enclosed in a 
diffusion membrane, is a depot which releases a drug during the passage of 
the entire alimentary canal without disintegrating. The empty core or 
shell is discharged. 
A multiple-unit dose consists of a large number of mini-depots, e.g. 
pellets or microencapsulated crystals, contained in a capsule or a tablet. 
These many subunits are dispersed and distributed throughout the 
gastrointestinal tract when the capsule or tablet disintegrates. 
An adjustment of the release rate of the depot according to its transit 
time through the small intestine is essential to the achievement of a 
satisfactory bioavailability, as the greatest absorption capacity is 
generally possessed by this part of the gastrointestinal tract, 
particularly the jejunum and the proximal ileum. 
Single-unit doses tend to follow the food having a normal transit time 
through the small intestine that varies between 3 and 8 hours. 
Accordingly, 6-10 hours are recommended by many authors as the maximum 
duration of in vitro release from depot formulations. 
In some cases it is desirable, however, to retain the drug depot in the 
upper gut in order (i) to assure optimal absorption or (ii) to 
additionally extend the absorption phase. The latter applies e.g. to drugs 
with biological half-lives requiring an absorption period of more than 
6-10 hours to facilitate a lower dosage frequency (once daily) and thus a 
more secure therapy. 
As the subunits of the multiple-units formulations are distributed freely 
throughout the gastrointestinal tract, their transport is to a greater 
extent independent of the transit time of food. Hence the bioavailability 
of these products is less vulnerable to variations in both gastric 
emptying and intestinal transit time, providing a more secure interaction 
between in vitro release and bioavailability and thus a better 
reproducible effect. 
Accordingly, the multiple-units dose principle is expected to facilitate 
the production of drug depots with a reproducible and predetermined 
prolonged intestinal transit time. 
Obviously, it would be advantageous if the absorption period could be 
extended in order to reduce the frequency of drug administration to, for 
example, once daily, thus improving patient compliance and reducing the 
risk of erroneous administration. 
The invention is based upon the observation that the specific weight of the 
subunits in a multiple-units dose greatly influences the average transit 
time of the subunits through the gastrointestinal tract. 
A pilot study showed that in the same patient an increase by 0.6 g/ml in 
the specific weight of the subunits (pellets or microencapsulated 
crystals) in a multiple-units dose increased the transit time of the 
subunits through the gastrointestinal tract up to 5 times, irrespectively 
of the size of the subunits. 
An object of the invention is thus to utilize this discovery to obtain a 
reproducible, prolonged transit time, through the gastrointestinal tract, 
of the subunits of a multiple-units dose. 
According to the invention, therefore, a controlled-release multiple-units 
drug dose comprises a tablet or capsule enclosing encapsulated pellets, 
granules or crystals of a therapeutically active agent, the specific 
weight of at least some of which has been increased to a specific weight 
of at least 1.4 by means of a physiologically inert or innocuous substance 
of higher specific weight than that of the therapeutically active agent. 
The said increase of the specific weight ensures that the units get a 
specific weight exceeding that of the normal gut contents. 
The increase can be attained e.g. by incorporating the physiologically 
inert or innocuous substance in the core or the coating material of the 
pellets or the coating material of the microencapsulated crystals, or in 
any other known way. 
Examples of substances, which can be used to increase the specific weight 
of the subunits in a controlled-release multiple-units dose, are barium 
sulphate, zinc oxide, titanium dioxide, and iron powder produced by 
reduction (ferrum reductum). 
The use of a controlled-release multiple-units dose is also advantageous 
because dispersal of the subunits along the gastrointestinal tract results 
in lower local concentration of the active substance, thus causing less 
irritation of the mucosa in case of irritative drugs. 
Since a greater specific weight tends to increase the transit time of the 
subunits, obviously a combination of lighter and heavier subunits in a 
multiple-units dose has the effect of further dispersing the units along 
the gastrointestinal tract. Mixing of subunits of different specific 
weight and/or with different active agents could also be advantageous in 
the formulation of a controlled-release multiple-units combined product. 
The controlled, prolonged drug release means also that unnecessary peak 
concentrations in the blood with their inherent risks of exaggerated drug 
action or enhanced side effects of both are avoided and that adequate 
treatment over extended time periods is ensured. 
Clinical investigations have shown that the transit time of the individual 
units of a multiple-units dose can easily be extended over a 24 hours 
period by suitably increasing the specific weight of the subunits. 
Thus, according to the invention, a substantial proportion, e.g. at least 
5% and preferably at least 20%, and sometimes at least 50%, by weight of 
the total composition is in the form of subunits having specific weight 
greater than the specific weight of the entire drug composition. The 
amount by which the specific weight of some of the subunits is above the 
average can vary widely, but preferably it is at least 5% above the 
average and preferably at least 20%. Expressed in another way at least 25% 
by weight of the subunits preferably have a specific weight at least 25% 
above the specific weight of other subunits in the composition. 
Although the drug release from the subunits of the multiple-units dose can 
be controlled in various known ways, the preferred manner of controlling 
is by coating the subunits with a diffusion membrane which is insoluble in 
and not degradable by the gastrointestinal juices. 
The subunits can be composed as follows. An inactive, heavy core can be 
provided with a layer of the active agent by means of a suitable adhesive, 
and then provided with a diffusion membrane. 
Alternatively, the active agent can be mixed with the innocuous heavy 
substance, the mixture being formed to pellets or granules, and coated 
with the diffusion membrane. 
A third possibility is using crystals of the active agents as cores in the 
subunits. 
In all cases, the amount and specific weight of the inactive substance 
determines the increase in specific weight of the subunits. 
A pilot study was aimed at observing the influence on transit time of 
variations in specific weight and size of the subunits. Four 
ileo-colostomy patients, three females and one male, aged between 24 to 40 
years, three with part of the small intestine resected, volunteered for 
the study. The post-operative period was from 2 to 6 months. As determined 
the day before the investigation, each patient had a gastrointestinal 
transit time of at least 21/2 hours. 
Coated pellets were used, prepared either with barium sulphate (specific 
weight of pellets 1.6 g/ml) or with paraffin wax (specific weight of 
pellets 1.0 g/ml). In both cases, the diameters were 0.3-0.7 mm and 
1.2-1.7 mm, respectively. 
After a 12 hours fasting period, a transparent colostomy bag was fitted to 
the patient, and 1850 pellets suspended in a standard meal were 
administered. After this meal, the patients resumed the usual hospital 
meal routine. 
The investigation period was 36 hours. During the first 12 hours, the 
colostomy bag was totally emptied every 3 hours, during the next 12 hours 
intermittently as needed, and during the final 12 hours again every 3 
hours. 
The contents from each emptying were investigated separately, counting the 
contents of the four different types of pellets to determine the transit 
time. 
The following tables illustrate the results of the investigations. 
Table 1 
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Number, size, and specific weight of the pellets 
Number of Diameter 
pellets 0.3-0.7 mm 1.2-1.7 mm Total 
______________________________________ 
Light pellets 
sp.w. 1.0 g/ 
ml 800 125 925 
Heavy pellets 
sp.w. 1.6 g/ 
ml 800 125 925 
1600 250 1850 
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Table 2 
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Recovery of pellets 
Diameter 
Patient Sp. weight 0.3-0.7 mm 1.2-1.7 mm 
______________________________________ 
EBO 1.0 87.9% 98.4% 
1.6 95.6% 96.0% 
IMC 1.0 88.9% 95.2% 
1.6 64.9% 64.8% 
MH 1.0 76.1% 67.2% 
1.6 71.3% 41.6% 
PKB 1.0 89.8% 95.2% 
1.6 72.5% 77.6% 
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Table 3 
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Average transit time for pellets in hours 
EBO IMC MH PKB.sup.1) 
0.3- 1.2- 0.3- 1.2- 0.3- 1.2- 0.3- 1.2- 
Sp.w. Diam. 
0.7 1.7 0.7 1.7 0.7 1.7 0.7 1.7 
______________________________________ 
1.0 3.2 1.8 6.5 7.9 12.9 16.9 9.0 9.8 
1.6 13.5 9.5 23.7 27.3 16.0 19.3 10.7 10.1 
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.sup.1) One colostomy bag was lost during the 5th interval of the 
investigation period. The number of each type of pellets in the lost bag 
has been calculated on the assumption that the probability of recovery 
would be equal to that of EBO. 
The extension of the transit time attained by an increase of the specific 
weight of the pellets is clearly demonstrated by Table 3. 
Continued clinical investigations comprised six ileocolostomy out-patients, 
five females and one male, aged between 25 and 50 years. Two of the 
patients had part of the ileum resected. 
Participation in the study was conditional upon the patient having 
terminated a post-operative period of 2 months and having a transit time 
at least 3 hours, as determined on the day before the examination. 
Coated pellets identical to those in the pilot study were used. 
In the morning of the day of examination, the fasting (12 hours) 
ileo-colostomy patient had a transparent colostomy bag fitted, and at the 
same time 250 pellets of each of the four kinds, or a total of 1000 
pellets, were administered, suspended in a standard meal. 
After the test meal, the patient resumed the usual meal and locomotive 
routine. The colostomy bag was emptied completely every 2 hours during the 
first 14 hours, and then every 4 hours during the following 8 hours of 
night. The pattern of emptying was repeated the following day in order to 
complete a 48 hours' observation period. 
The collected fractions were analysed by manually picking off the pellets 
from thin layers of the visceral contents. 
The frequency of pellets in the colostomy bags during the first day, 
defined as the period from 8 a.m. to 2 a.m., is shown in Table 4. The 
difference in frequencies of the four types of pellets having passed the 
small intestine during the first day is seen to be caused mainly by the 
differences in specific weight of the pellets, the influence of the 
different diameters of pellets being less important. 
Table 4 
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Frequency (%).sup.(1) of pellets during the first day of observation 
Spe- 
Size cific Patients Ave- 
mm weight BMM VN AS.sup.(2) 
HB JPL IO.sup.(3) 
rage 
______________________________________ 
0.3-0.7 
1.0 100.0 100.0 91.9 90.4 100.0 
97.7 97.6 
1.6 17.2 6.3 77.0 9.8 16.4 
16.6 13.3 
1.2-1.7 
1.0 99.1 99.6 99.2 77.2 96.8 
87.6 92.1 
1.6 10.9 4.4 68.8 2.1 3.4 5.4 5.2 
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.sup.(1) Relative to recovered pellets. The average of recovered pellets 
of all four kinds in the total observation period was 90% (range 84-95%). 
.sup.(2) The patient AS is atypical, owing to a very large consumption of 
liquid, totalling 5900 ml (thereof 5000 ml of beer), during the test 
period. 
.sup.(3) The figures for the patient IO is the average of two replicate 
studies. 
The figures shown that the specific weight is of significant importance 
(p&lt;0.05) for the prolongation of the transit time of the subunits, whereas 
it is doubtful whether an increase in size if of importance.

The following Examples illustrate different ways of preparing pellets with 
increased specific weights for use in controlled-release multiple-units 
doses. 
EXAMPLE 1 
The components of the core of a pellet are: 
______________________________________ 
Parts by weight 
______________________________________ 
Ferrum reductum 80 
4-(2-Hydroxy-3-isopropylaminopropoxy)-indole 
6 
Microcrystalline cellulose 
6 
Talcum 2 
Hydroxypropylcellulose 3 
Sodium hydrogen carbonate 
3 
______________________________________ 
The components are mixed and moistened with 20 parts by weight of water, 
after which the mass is extruded to form strings of 1 mm diameter, from 
which balls of approximately 1 mm diameter are formed. After drying, the 
specific weight of the balls is 3.7. 
The balls are coated with a solution of an acrylic polymer, marketed under 
the registered trade mark Eudragit RS, the specific weight being 3.4 after 
the coating. 
EXAMPLE 2 
The core components of a pellet are: 
______________________________________ 
Parts by weight 
______________________________________ 
Zinc oxide 95 
Polyethylene powder 5 
______________________________________ 
The components are mixed, moistened with 16 parts by weight of water, and 
extruded to strings of 0.8 mm diameter, from which balls with about the 
same diameter are formed. After drying, the specific weight of the balls 
is 3.0. 
The cores are then coated with 15 parts by weight of ethylphenylephrine 
hydrochloride (.alpha.-[(ethylamino)methyl]m-hydroxybenzyl alcohol 
hydrochloride) by alternatively moistening with a 3% solution of 
ethylcellulose in isopropanol and coating with the powdered drug. 
Finally, an external coating is applied, consisting of ethylcellulose with 
10% by weight of acetyltributyl citrate admixed as a softening agent. 
The specific weight of the resulting pellets is 2.7. 
EXAMPLE 3 
The components of the subunits are: 
______________________________________ 
Parts by weight 
______________________________________ 
Acetylsalicylic acid crystals 
65 
Titanium dioxide 32.5 
Acrylic polymer (Eudragit.RTM. RS) 
2.5 
______________________________________ 
In a coating pan, the crystals of acetylsalicylic acid (specific weight 
1.37) are alternatively moistened with a 3% solution of the acrylic 
polymer, and dusted with titanium dioxide powder. 
The specific weight of the resulting coated crystals is 1.6.