Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL PHARMACEUTICAL COMPOSITIONS
The present invention relates to novel pharmaceutical compositions such as
oral
formulations for once a day administration of a drug/medicament and to novel
solid dose units for incorporation therein. The solid dose units provide a
phased
release of drug to target or prolong the pharmaceutical effect. The
compositions
are particularly useful for multiphase delivery of proton pump inhibitors such
as lansoprazole, pantoprazole, omeprazole, perprazole, etc.
The treatment of certain medical conditions requires an effect to be achieved
over a 24 hour period, e.g. in conditions such as duodenal ulcers, peptic
ulcers
and reflux oesophagitis there is a need to control gastric pH. Similarly in
the
treatment of rheumatoid arthritis there is a need to control pain and ease
mobility difficulties and in the treatment of patients with high blood
pressure
there is a need to control blood pressure. Immediate release dosing regimes
often result in periods during the day where the desired effect is not
achieved
and so such conditions are often treated with multiple doses of drug each day,
but this is inconvenient and can lead to reduced patient compliance. These
conditions are often treated with sustained release formulations but if there
is
not a constant requirement for the drug during the 24 hour period this can
lead
to the use of more drug than necessary. Frequently there is not a constant
requirement for the drug, i.e. when an initial dose of the drug is capable of
achieving the desired effect and it is only as this effect begins to diminish
that
2S further drug is required. Another example is when symptoms may only occur
intermittently, perhaps at particular times of the day, e.g. during the night
or
early in the morning.
In the treatment of conditions such as duodenal ulcers, peptic ulcers and
reflux
oesophagitis with proton pump inhibitors there are benefits in increasing the
time that the intragastric pH is maintained above 3.0, preferably above 4.0,
in
particular there are benefits in maintaining the pH above 3.0, preferably
above
4.0, over a 24 hour period. Current immediate release dosing regimes often
result in periods during the day where this is not achieved and this may
become
particularly acute at night where "breakthrough pH" occurs. There is not a
constant requirement for the inhibitor because it is postulated that the
initial
dose inhibits the receptors and it is only when the receptors begin to
regenerate
that further inhibitor is required. The use of sustained release formulations
therefore involves the use of more inhibitor than necessary. It is desirable
to
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provide pulsed release formulations capable of releasing a second dose of
inhibitor when the effects of the first dose begin to diminish.
There is a need for pharmaceutical formulations capable of delivering drug at
timed periods during 24 hours when a condition and/or symptom occurs or
reoccurs, in particular formulations capable of providing pulsed release of a
drug, where the drug is released in at least two pulses, the second pulse
releases
drug when the effect of the first release is at least partially diminished
and, if
applicable, any further pulses also release drug when the effects of the
previous
pulse are at least partially diminished. There is also a need for
pharmaceutical
formulations capable of providing a single daily dose of a drug affecting
gastric
pH such as a proton pump inhibitor, in particular formulations capable of
maintaining the gastric pH above about above 3.0, preferably above 4.0, for a
period of about 24 hours after a single daily dose, e.g. formulations capable
of
delivering drug at timed periods during 24 hours when an increase in pH is
expected.
In the treatment of conditions where symptoms occur at a known period of the
day, e.g. during the night, as the patient wakes or as the patient gets out of
bed,
it is desirable to treat the symptoms in advance so that they can be avoided
or at
least minimised. Again sustained release formulations can be used, e.g. before
the patient goes to bed, but they often result in the use of more drug than
required. There is therefore a need for delayed release formulations capable
of
releasing drug in anticipation of symptoms. A formulation which could be
taken at night and which would release the drug the following morning so that
its effects are achieved before the patient wakes would be particularly
advantageous. The formulation could suitably include multiple doses such that
it can be taken to provide immediate relief followed by further relief after a
predetermined period of time. One condition which could be treated with such
a formulation is rheumatoid arthritis. Patients suffering from rheumatoid
arthritis experience difficulty in moving when they wake and so it would be
advantageous to provide a formulation which could be taken at night and which
would release the drug the following morning so that its effects are achieved
before the patient wakes. The formulation could suitably include multiple
doses
such that it can be taken during the day to provide immediate relief in
addition
to relief the following morning.
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There is a need for delayed release formulations capable of releasing drug
after a
predetermined delay, preferably being such that the delayed release of the
drug
coincides with and/or anticipates the occurrence or reoccurrence of the
symptom or condition to be treated.
S
The present invention addresses one or more of the problems discussed above.
It has been found that the inclusion of a disintegrant in the core of a solid
dose
unit, surrounded by an outer semi-permeable membrane comprising a
permeable water insoluble polymer and at least 50 % by weight glidant
surprisingly provides the desired delay and subsequent release profile. The
novel formulation is capable of delaying the release in a largely pH
independent
manner. After the period of delay, drug release is immediately initiated.
The delay and the subsequent release profile can be manipulated by the
selection of the composition and/or thickness of the semi-permeable membrane
and/or the composition and/or amount of disintegrant included in the core.
The arrangement of the disintegrant in the core can also be adapted to
influence
the delay and subsequent release profile, e.g. it can be included as a
separate
outer layer of the core.
A first aspect of the invention provides a solid dose unit for the delayed
release
of a drug comprising:
a) a core comprising the drug and at least one disintegrant
and b) an outer semi-permeable membrane surrounding the core which
comprises a permeable water insoluble polymer and at least 50 % by weight
glidant.
The solid dose units may suitably be pellets, mini-tablets, granules, tablets
etc.
which are well known in the art. The drug may be included in the units by any
suitable conventional means, e.g. it may be incorporated in the core material
or it
may be applied to a seed core as a coat, with or without other constituents
which
make up the unit. The drug and the disintegrant may be included as separate
layers of the core or they may be mixed together in the core.
The units are preferably such that when they are subjected to in-vitro
exposure
to simulated intestinal fluid minimal drug is released until after at least
four
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hours exposure and substantially all of the drug is released after 24 hours
exposure. Preferred embodiments are those wherein minimal drug is released
until after at least six hours in-vitro exposure to simulated intestinal
fluid.
Further embodiments of the invention are those which provide minimal drug
release until after at least 8, 9, 10, 11 and 12 hours in-vitro exposure to
simulated
intestinal fluid respectively. For each of these embodiments substantially all
of
the drug is released after 24 hours in-vitro exposure to simulated intestinal
fluid,
more preferably substantially all of the drug is released after 22 hours in-
vitro
exposure to simulated intestinal fluid.
The in-vitro dissolution profile may be determined by techniques known in the
art, for example using USP apparatus IV at 16 ml/min in 0.5M phosphate buffer
pH 6.5, temperature 37°C. The results should vary only a little
depending on the
method of measurement.
Theoretically one should be able to measure 100% release of the drug after in
vitro exposure to simulated intestinal fluid. However, in practice this if
often
not attainable and no more than, e.g. 85 % of the drug can be measured after
even a very long period of time. This is due in part to limitations inherent
in the
detection equipment, but also to the fact that certain drugs may break down to
other chemicals and hence go undetected or a small proportion may take a very
long time to release. The point at which "substantially all the drug has been
released" is therefore taken to be the point at which no further increase in
the
amount of drug released is seen, i.e. when minimal further release is seen.
All
other measurements, i.e. percentages are measured against the total drug
included in the formulation.
In another embodiment of the invention less than 10% of the drug is released
after four hours in-vitro exposure to simulated intestinal fluid, at least 30%
is
released after ten hours exposure and at least 70% is released after 24 hours
exposure, preferably at least 70% is released after 20 hours exposure. These
measurements are cumulative, i.e. the term "is released after" indicates the
total
amount of released drug that is measured at the stated time, i.e. after 4, 10
or 20
hours in-vitro exposure to simulated intestinal fluid.
In a further embodiment less than 5% of the drug is released after four hours
in-
vitro exposure to simulated intestinal fluid, at least 35% is released after
ten
hours exposure and at least 75% is released after is released after 24 hours
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exposure, preferably at least 75% is released after 20 hours exposure. In a
further embodiment less than 5% of the drug is released after four hours in-
vitro
exposure to simulated intestinal fluid, at least 40% is released after ten
hours
exposure and at least 80% is released after 20 hours exposure.
In another embodiment of the invention less than 10% of the drug is released
after six hours in-vitro exposure, at least 30% is released after ten hours
and at
least 70% is released after 24 hours, preferably at least 70% is released
after 20
hours. In a further embodiment less than 5% of the drug is released after six
hours in-vitro exposure, at least 35% is released after ten hours and at least
75%
is released after 20 hours. In a further embodiment less than 5% of the drug
is
released after six hours in-vitro exposure, at least 40% is released after ten
hours
and at least 80% is released after 20 hours.
In yet another embodiment of the invention less than 10% of the drug is
released
after 8 hours in-vitro exposure, at least 30% is released after 12 hours and
at least
70% is released after 24 hours, preferably at least 70°ro is released
after 20 hours.
In a further embodiment less than 5% of the drug is released after 8 hours in-
vitro exposure, at least 35% is released after 12 hours and at least 75% is
released
after 20 hours. In a further embodiment less than 5% of the drug is released
after 8 hours in-vitro exposure, at least 40% is released after ten hours and
at
least 80% is released after 20 hours.
In yet another embodiment of the invention less than 10% of the drug is
released
after 10 hours in-vitro exposure, at least 30% is released after 14 hours and
at
least 70% is released after 24 hours exposure, preferably at least 70% is
released
after 22 hours. In a further embodiment less than 5% of the drug is released
after 10 hours in-vitro exposure, at least 35% is released after 14 hours and
at
least 75% is released after 22 hours. In a further embodiment less than 5% of
the
drug is released after 10 hours in-vitro exposure, at least 40% is released
after 14
hours and at least 80% is released after 22 hours.
In yet another embodiment of the invention less than 10% of the drug is
released
after 12 hours in-vitro exposure, at least 30% is released after 16 hours and
at
least 70% is released after 24 hours. In a further embodiment less than 5% of
the
drug is released after 12 hours in-vitro exposure, at least 35% is released
after 16
hours and at least 75% is released after 24 hours. In a further embodiment
less
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than 5% of the drug is released after 12 hours in-vitro exposure, at least 40%
is
released after 16 hours and at least 80% is released after 24 hours.
Suitable disintegrants include croscarmellose sodium, crospovidone, sodium
starch glycolate etc. These materials result in swelling and disintegration of
the
dosage unit.
The semi-permeable membrane comprises a permeable water insoluble polymer
and at least 50 % by weight glidant. The weight of the glidant accounts for at
least 50% of the total weight of the membrane. The semi-permeable membrane
may optionally comprise further components, but preferred embodiments are
those wherein the membrane comprises the permeable water insoluble polymer
and the glidant only.
The semi-permeable membrane preferably comprises at least 55% glidant, more
preferably at least 60% glidant and most preferably at least 65% glidant.
Particular embodiments of the invention include a semi-permeable membrane
which comprises at least 66 % glidant.
Suitable glidants include talc, silicon dioxide, kaolin, glycerol
monostearate,
metal stearates such as magnesium stearate, titanium dioxide and starch.
preferred glidants are talc, silicon dioxide and kaolin. The most preferred
glidant is talc. Pharmaceutical compositions usually comprise less than 30%
glidants such as talc, however the function of the glidant in the present
2~ invention is completely different from the conventional function, the high
level
of glidant included in the semi-permeable membrane affects the mechanical and
physical properties of the membrane. Suitable polymers include methacrylic
acid polymers such as Eudragits, addition polymers such as PVAP, PVP and
PVA, cellulose derivatives such as cellulose acetate, ethylcellulose,
cellulose
acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose
and
suitable resins such as shellac. Preferred polymers are methacrylic acid
derivatives, ethylcellulose and cellulose acetate. The most preferred polymers
are methacrylic acid polymers such as Eudragits, particularly Eudragit ILS.
The
membrane preferably lacks a plasticiser.
The semi-permeable membrane is surprisingly capable of resisting pressure
from the swelling of the disintegrant material until a critical point at which
it
ruptures and drug release immediately commences.
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The units preferably release the drug in a non-osmotic, largely pH independent
manner. The units preferably lack protection from the environment of the
stomach, e.g. they lack an enteric coat. The units preferably lack osmotic
modifiers.
The units are particularly suitable for the controlled release of proton pump
inhibitors, preferably lansoprazole, pantoprazole, omeprazole, perprazole,
etc.
They may be included in formulations suitable for the treatment of duodenal
ulcers, peptic ulcers and reflux oesophagitis. The units are also suitable for
the
controlled delivery of other drugs, e.g. drugs that are conventionally
administered in multiple doses or when timing is important for the reasons
discussed above. Drugs which may be included in the units include, e.g. proton
pump inhibitors, anti-inflammatories, antihypertensives, antibiotics, hormonal
1 ~ drugs and drugs which are active on the endocrine system. The term proton
pump inhibitor when used herein refers not only to the active compounds but
also to appropriate prodrugs and derivatives. The term also covers appropriate
salts of the compounds, prodrugs and derivatives.
The cores may suitably comprise one or more of the following: a stabiliser
such
as magnesium carbonate; a binder such as hydroxypropylcellulose LF grade or
EXF grade; a disintegrant such as hydroxypropylcellulose (low substituted) 1-
hpc 31; a binder or diluent such as sucrose, maize starch; and/or a lubricant
such as magnesium stearate.
A second aspect of the invention provides a plurality of solid dose units as
described above which collectively exhibit the following in-vitro dissolution
profile when subjected to in-vitro exposure to simulated intestinal fluid:
i) after four hours exposure less than 10% of the drug is released
ii) after ten hours exposure at least 30% drug is released
and iii) after 24 hours exposure at least 70% drug is released.
After four hours in-vitro exposure to simulated intestinal fluid less than 10%
of
the drug is released, preferably less than 7% is released, more preferably
less
than 5% is released and most preferably less than 2% is released. Preferred
embodiments are those wherein after six hours in-vitro exposure to simulated
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_g_
intestinal fluid less than 10% of the drug is released, preferably less than
7% is
released, more preferably less than 5% is released and most preferably less
than
2% is released. Further embodiments of the invention are those wherein after
at
least 8, 9, 10, 11 and 12 hours in-vitro exposure to simulated intestinal
fluid
respectively less than 10% of the drug is released, preferably less than 7% is
released, more preferably less than 5% is released and most preferably less
than
2% is released. For each of these embodiments after ten hours in-vitro
exposure
to simulated intestinal fluid at least 50% of the drug is released, preferably
at
least 55% is released, more preferably at least 60% is released and most
preferably at least 65% is released. For each of these embodiments after 24
hours
in-vitro exposure to a simulated intestinal fluid at least 70% of the drug is
released, preferably at least 75% is released, more preferably at least 80% is
released.
1 ~ In one embodiment of the invention less than 10% of the drug is released
after
four hours in-vitro exposure, at least 30% is released after ten hours and at
least
70% is released after 20 hours. In a further embodiment less than 5% of the
drug
is released after tour hours in-vitro exposure, at least 35% is released after
ten
hours and at least 75% is released after 20 hours. In a further embodiment
less
than 5% of the drug is released after four hours in-vitro exposure, at least
40% is
released after ten hours and at least 80% is released after 20 hours.
In another embodiment of the invention less than 10% of the drug is released
after six hours in-vitro exposure, at least 30% is released after ten hours
and at
2~ least 70% is released after 20 hours. In a further embodiment less than 5%
of the
drug is released after six hours in-vitro exposure, at least 35% is released
after
ten hours and at least 75% is released after 20 hours. In a further embodiment
less than 5% of the drug is released after six hours in-vitro exposure, at
least 40%
is released after ten hours and at least 80% is released after 20 hours.
In yet another embodiment of the invention less than 10% of the drug is
released
after 8 hours in-vitro exposure, at least 30% is released after 12 hours and
at least
70% is released after 20 hours. In a further embodiment less than 5% of the
drug
is released after 8 hours in-vitro exposure, at least 35% is released after 12
hours
and at least 75% is released after 20 hours. In a further embodiment less than
5%
of the drug is released after 8 hours in-vitro exposure, at least 40% is
released
after ten hours and at least 80% is released after 20 hours.
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In yet another embodiment of the invention less than 10% of the drug is
released
after 10 hours in-vitro exposure, at least 30% is released after 14 hours and
at
least 70% is released after 22 hours. In a further embodiment less than 5% of
the
drug is released after 10 hours in-vitro exposure, at least 35% is released
after 14
hours and at least 75% is released after 22 hours. In a further embodiment
less
than 5% of the drug is released after 10 hours in-vitro exposure, at least 40%
is
released after 14 hours and at least 80% is released after 22 hours.
In yet another embodiment of the invention less than 10% of the drug is
released
after 12 hours in-vitro exposure, at least 30% is released after 16 hours and
at
least 70% is released after 24 hours. In a further embodiment less than 5% of
the
drug is released after 12 hours in-vitro exposure, at least 35% is released
after 16
hours and at least 75% is released after 24 hours. In a further embodiment
less
than 5% of the drug is released after 12 hours in-vitro exposure, at least 40%
is
released after 16 hours and at least 80% is released after 24 hours.
A third aspect of the invention provides an oral formulation for the
controlled
release of a drug which comprises solid dose units as described above. These
include oral formulations for the controlled release of a drug which comprises
a
first population of solid dose units comprising the drug and a second
population
of solid dose units comprising the drug wherein the first population comprises
units which exhibit the following in-vitro dissolution profile when subjected
to
in-vitro exposure to simulated intestinal fluid:
i) after two hours exposure at least 60°ro of the total drug included
in the
first population is released
and ii) after three hours exposure at least 80% of the total drug included in
the
first population is released
and the second population comprises units as described above.
The units of the first population are preferably such that after two hours in-
vitro
exposure to simulated intestinal fluid at least 65% of the total drug included
in
the first population is released, more preferably at least 70% is released,
most
preferably at least 75% is released. The units of the first population are
preferably such that after three hours in-vitro exposure to simulated
intestinal
fluid at least 80% of the total proton pump drug included in the first
population
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is released, more preferably at least 85% is released, most preferably at
least 90%
is released.
The units of the invention may be included in any suitable oral formulation,
e.g.
tablets, capsules and microcapsules. Other examples will be apparent to a
person of skill in the art, as will suitable excipients and for inclusion in
the
formulations.
The units of the first population preferably release the drug when the
formulation or the units pass from the stomach into the intestine as a result
of
the change in pH. This may be achieved by known means, e.g. by coating the
units with an enteric coat. The change in pH when the environment of the
duodenum is reached causes the enteric coat to dissolve and release the drug.
Suitable materials from which enteric coats may be prepared are well known in
the art, e.g. cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate,
Preferred materials are Eudragit S100, Eudragit L 100, Eudragit L 100.55 and
Eudragit L30D-55, most preferably Eudragit L30D-55.
The formulations are suitable for the multiphase delivery of proton pump
inhibitors, preferably lansoprazole, pantoprazole, omeprazole or perprazole.
These formulations are suitable for the treatment of duodenal ulcers, peptic
ulcers and reflux oesophagitis. The formulations are also suitable for the
phased
delivery of other drugs, e.g. drugs that are conventionally administered in
multiple doses or at as sustained release formulations for the reasons
discussed
above. Drugs which may be included in the formulations include, e.g. proton
pump inhibitors, anti-inflammatories, antihypertensives, antibiotics, hormonal
drugs and drugs which are active on the endocrine system. The drug included
in the first and second populations of units may be different or identical.
Preferred formulations are those in which the drug included in the first and
second populations of units are identical. The amount of drug included in the
first and second populations of units may be different or identical.
The units may suitably be incorporated in a delivery system which provides
multiphased delivery of a drug, i.e. which provides at least two phases of
delivery from a single dosage formulation. Further phases of delivery can be
provided by including further populations of solid dose units adapted to
deliver
drug after a different period of delay. The time interval between phases can
be
manipulated by the selection of the composition of the units, i.e. the
selection of
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the composition and/or thickness of the semi-permeable membrane and/or the
composition and/or amount of disintegrant included in the core and/or the
arrangement of the disintegrant in the core of each population.
The formulations are preferably suitable for once daily administration. They
are
preferably suitable for controlling gastric pH over a 24 hour period.
Particularly
preferred formulations are those capable of controlling gastric pH over a 24
hour
period so as to prevent the pH falling below 4.0 over this period.
The present invention also provides a composition comprising a permeable
water insoluble polymer and at least 50 % by weight of glidant which is
suitable
in the preparation of the solid dose units described above. The composition
more preferably comprises at least 55% by weight glidant, even more preferably
at least 60% glidant and most preferably at least 65% by weight glidant.
1 ~ Particular embodiments of the invention include at least 66 % by weight
glidant.
Preferred glidant materials include talc, silicon dioxide, kaolin, glycerol
monostearate, magnesium stearate and other metal stearates, the most preferred
glidant is talc. The polymer may suitably be a methacrylic acid polymers, e.g.
a
Eudragit.
The present invention still further provides a method for the preparation of
the
solid dose units described above which comprises coating a core comprising a
drug and a disintegrant with a composition comprising a permeable water
insoluble polymer and at least 50 % by weight glidant. The present invention
2~ also provides a method for the preparation of the oral formulations
described
above which comprises bringing solid dose units as described above into
association with suitable components to provide a pellet, mini-tablet, granule
or
tablet.
The present invention will now be exemplified with reference to the following
Examples, by way of illustration only.
Figure 1. is a graph showing the in-vitro release profile of the type A
lansoprazole pellets of Example 1 in pH 6.5 phosphate buffer.
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Figure 2. is a graph showing the in-vitro release profile of the type B
lansoprazole pellets of Example 1 in pH 6.5 phosphate buffer.
Figure 3. is a graph showing the in-vitro release profile of lansoprazole
formulations A and B of Example 2 in pH 6.5 phosphate buffer.
Figure 4. is a graph showing the in-vivo release profile of lansoprazole
formulations A and B of Example 2.
Figure 5. is a graph showing the in-vitro release profile of a single
lansoprazole
minitablet of Example 3 in pH 6.5 phosphate buffer.
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Example 1: Preparation of pellets containing lans~razole
Sugar spheres were loaded onto a Glatt granulator and were sprayed with a
binder solution of hydroxypropylcellulose in isopropylalcohol. At the same
time a powder blend of hydroxypropylcellulose (low sub), magnesium
carbonate, lansoprazole, sucrose and corn starch was added to provide drug
containing cores having the following composition:
w w
Sugar spheres 30.6
HPC 1.8
Lansoprazole 17.7 %
Magnesium carbonate 13.2
Hydroxypropyl cellulose (Iow sub) 8.3
Sucrose 17.7
Corn Starch 10.6
The resulting drug containing cores were sieved and returned to the rotor. A
suspension of hydroxypropylcellulose in isopropylalcohol and croscarmellose
sodium and was sprayed onto the cores to provide disintegrant layered cores
having the following composition:
w w
Croscarmellose sodium 22.9
Hydroxypropyl cellulose 5.7 %
Drug containing core 71.4
The disintegrant coated cores were sieved and placed in a fluidisation chamber
operating in a Wiirster mode. A polymer coat consisting of Eudragit RS and
suspended talc was sprayed onto the cores continuously to provide pellets
having the following compositions:
Tie A w w
Eudragit RS 14.0
Talc 28.1 %
Disintegrant layered core 57.9
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T-ape B W 4~~
Eudragit IZS 17.1
Talc 34.1
Disintegrant layered core 4g_g %
The in-~~itro dissolution profile of the two types of pellets was determined
using
USP apparatus IV at 16 ml/min in 0.5M phosphate buffer pH 6.5, temperature
37°C. The results are presented in Table 1.
Table 1: Dissolution profiles for delayed release pellets
Release:
Time (min) Type A Pellet Type B Pellet
0 0 0
60 0 0
120 0.2 0
180 0.3 0
240 1.0 0
300 4.9 0
360 18.6 0,2
390 29.6 2.6
420 39.4 6
450 49.1 11.5
480 56.5 18.7
510 62.4 2g
540 67.1 38.3
570 70.4 47
600 73.7 54.5
630 76.6 61.1
660 79.4 66.7
690 81.8 71.1
720 83.9 74.3
750 85.7 76.7
780 87.5 78.8
810 89.1 80.6
90.5 82.3
870 91.8 83.9
900 93.0 85.8
930 94.2 g7,3
960 95.4 gg,6
These results are presented in Figures 1 and 2.
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-15-
Example 2: Preparation of a mixture of vellets accordin to Example 1 and
immediate release pellets
The method described above was repeated to provide drug containing cores
having the following composition:
w w
Sugar spheres 36.7
HPC 0.5
Lansoprazole 10.0
Magnesium carbonate ~.5 %
Hydroxypropyl cellulose (low sub) 13.3
Sucrose 19.9
Corn Starch 12.1
Is
An enteric coat was added to the drug containing core in the following
proportions:
~~ w
Drug containing core 81.2 %
Eudragit L30D-55 12.1
Talc 3.g %
Polyethylene glycol 6000 1.2
Titanium dioxide 1.2
Polvsorbate 80 0.5
2>
The in-vitro dissolution profile of the resulting immediate release pellets
was
determined using USP apparatus IV at 16 ml/min in 0.5M phosphate buffer pH
6.5, temperature 37°C. The immediate release pellets were then mixed
with the
pellets prepared according to Example 1 and incorporated into capsules to
provide two formulations:
Formulation A: Type A pellets and Immediate release pellets
Formulation B: Type B pellets and Immediate release pellets
The in-vitro dissolution profile of the two formulations was determined using
USP apparatus IV at 16 ml/min in 0.5M phosphate buffer pH 6.5, temperature
37°C. The results are presented in Table 2.
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Table 2: Dissolution profiles for formulations comprising immediate release
pellets and dela~~ed release pellets
Time Mind Mean Drug
Release (%)
Formulation Formulation
A B
60 27 33
120 39 44
180 44 46
240 47 48
300 ~ 53 49
360 64 51
420 74 54
480 81 62
540 85 71
600 89 80
660 92 87
720 95 93
780 98 98
These results are presented in Figure 3.
In-vivo mean concentrations of lansoprazole concentrations were measured in
healthy male adults aged 18 to 45 and within 10% of desirable weight. A five
~~ay open, randomised, placebo controlled, cross over study was performed and
the results obtained from the subjects treated with capsules comprising
approximately two hundred pellets, equivalent to a total dose of 30 mg. The
results are presented in Figure 4. In addition to the results for formulations
A
and B the graph includes data for Zoton TM (a lansoprazole formulation having
a
conventional enteric coat) and formulation C (formulation A pellets coated
with
an enteric coat). These additional formulations were tested for comparative
purposes.
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Example 3: Preparation of delayed release minitablets containine
lansoprazole
A dry granulation was prepared from lansoprazole, lactose, microcrystalline
cellulose and magnesium stearate by mixing and dry granulation. A second
granulation containing magnesium carbonate, crospovidone and
hydroxyporpylcellulose was prepared by wet granulation . The wet granulation
product was dried and milled to an appropriate size before mixing with the
product of the dry granulation. The resultant blend was compressed into
minitablets of 4 mm diameter using standard tooling on a Kilian LX tablet
press.
i~ w w
Magnesium carbonate 2.24 7.47
I ~ Croscarmellose sodium (AcDisol) 1.2 4.00
Hydroxypropyl cellulose 0.9 3.00
Lansoprazole 3.0 10.0
Lactose Fast Flo 11.225 37.42
Microcrystalline Cellulose (Avicel 11.225 37.42
PH101)
Magnesium stearate 0.21 0.70
The uncoated minitablets were coated, as described in Example l, with Eudragit
and talc:
w w
2~ Eudragit RS 7.5°0
Talc 15.2
Uncoated minitablets 77.3%
The in-vitro dissolution profile of a single minitablet was determined using
USP
apparatus IV at 16 ml/min in 0.5M phosphate buffer pH 6.5, temperature
37°C.
The results are presented in Table 3.
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Table 3: Dissolution profile for a single minitablet
Time ~Mins~ Mean Drug Release (,%)
240 0
270 0
300 p
330 p
360 0
390 0
420 4,7
450 29.9
480 30.6
510 48.7
540 54.4
570 58.1
600 60.7
630 63.1
660 65.5
690 67,2
720 69.9
750 72.2
780 73.7
840 79.0
900 81.7
960 85.1
These results are presented in Figure 5.
