Note: Descriptions are shown in the official language in which they were submitted.
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NOVEL DOS~~GE FORM
This invention relates to means fir oral delivery of a drug, aad
specifically to means of avoiding changes in the rate of absorption of an
s orally-delivered drug in the gastrointestinal tract due to the presence of
co-
administered food material.
The oral route of administration of drugs is a popular means of therapy.
Many drugs are well absorbed from the small intestines as well as the
to large intestines, and such absorption is unaffected by the co-
administration
of foods. However, the absorption of a number of drugs is affected by the
presence of food that is administered either with the dosage form or
immediately after or before dosage foam administration. Such food effects
have been well documented in the scientific literature, particularly by
is Welling and colleagues (e.g. Welling 1977, J. Pharmacokinet. Biopharm.
5, 291-334; Welling 1989, Pharmac~. Ther. 43, 425-4.1; Williams et al.
1996, Eur. J. Drug Metab. Pharmacokin. 21, 201-11).
For some drugs the presence of food can increase the absorption of the
2o drug into the systemic circulation, wl0ereas for other drugs the food
effect
is associated with a reduction in absorption. Several different mechanisms
are known to be responsible for such food effects. For example, food
may increase the absorption of certain drugs due to improved dissolution
of the drug, an effect which is promoted by a longer residence time of the
25 drug in the stomach, and by stimulation of bile which acts as a surface
active agent thereby improving drug dissolution. Alternative mechanisms
include the preferential transport of a drug into the lymphatic system in
the presence of fats and fatty acid;>, and the inhibition or reduction of
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efflux systems, in particular p-glycoprotein, by specific food materials.
An example of this latter case is the enhanced absorption of drugs such as
cyclosporin in the presence of grapefruit juice.
s The opposite effect, i. e. food causing a reduction in drug absorption, can
also occur through a number of different mechanisms. For example, some
drugs physically interact or complex with particular food types. This
phenomenon is well known for the bisphosphonates and tetracyclines,
which can interact with calcium present in dairy products. Drugs can also
io be physically or chemically attached to food through various absorption
processes. In addition, the drug and food (or digestion products thereof)
may compete for the same absorption pathway. Indeed, some drugs are
transported in the gastrointestinal tz~act, not by a process of passive
diffusion, but by the exploitation o1.-' the pathways responsible for the
is absorption of dietary peptides. Drugs in this class include the ~3-lactam
antibiotics and several drugs useful in the treatment of cardiovascular
diseases, such as captoprii. For the latter example, it has been clearly
shown that if captopril is administered with foodstuffs high in protein,
then the amount of drug reaching the; systemic circulation can be greatly
2o reduced. Another category of drugs known to be affected by foods is the
peptidic thrombin inhibitors.
One simple strategy for avoiding food effects on drug absorption is to
provide labelling for the patient that directs that the drug should not be
2s taken together with food, and preferably should be administered on a well-
fasted stomach. While this may be possible in some clinical situations, it
creates problems in certain patient groups and limits the utility of certain
therapeutic products. From the standpoint of patient compliance,
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WO 99137290 PCT/GB99/00193
marketing and the avoidance of inappropriate levels of drugs, it would be
advantageous if a drug could be administered with a food, or shortly
before or after a meal, without the rate; of drug absorption being altered.
s The present invention seeks to provide a means of orally administering a
drug which avoids or reduces the effects of co-administered food material
on the rate of absorption of said drug.
In particular, the present invention provides an orally administrable
io pharmaceutical dose unit of a size greater than 7 mm comprising a drug
and an outer coating which is adapted to prevent release of said drug into
the stomach or the small intestine whE;n the pharmaceutical dose unit is in
the presence of food.
Zs The present invention further provides an orally administrable
pharmaceutical dose unit of a size greater than 7 mm which comprises a
drug and an outer coating wherein the coating is made of a material that is
soluble at pH values below 5.0 and is adapted to provide a separation of
the pharmaceutical dose unit from co-administered food material.
We have found that coating the pharmaceutical dose unit with a suitable
material which is insoluble or only sparingly soluble at pH values above
5.0 can allow for retention of the intact dose unit in the upper regions of
the gastrointestinal tract, thereby resulting in its separation from co-
2s administered food material. Thus, die co-administered food is permitted
to proceed along the gastrointestinal tract and so becomes located in the
distal regions of the intestine, while the dose unit is retained in the
stomach or proximal small intestines where it is subsequently broken down
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WO 99137290 PCT/GB99/00193
to release its contents. By this means, the system provides effective
separation of the dose unit from co-administered food, thereby minimising
any effect of such food material on the rate of absorption of important
pharmacological agents.
Accordingly, a preferred embodiment of the present invention provides a
pharmaceutical dose unit for oral delivery of a drug comprising said drug
and an outer coating wherein the pharmaceutical dose unit has a size
greater than 7 mm and wherein the coating is insoluble at pH values above
to 5Ø
By "a pharmaceutical dose unit" we include the meaning of a
pharmaceutical formulation or system containing a known amount of a
drug. Preferably, the pharmaceutical <iose unit is in the form of a tablet or
is capsule.
When the single dose unit is a tablet, it will have a core comprising the
drug and typically one or more furttler ingredients of the type that are
conventionally blended with drugs, ;such as an excipient, and an outer
2o coating or Iayer which surrounds the core and comprises a material which
prevents release or any substantial release of the drug when the dose unit
is in the presence of food, e.g. a material which is insoluble at pH values
above 5Ø
25 When the single dose unit is a capsule, it will have a casing which
encloses a compartment containing the drug and typically one or more
further ingredients of the type that am conventionally blended with drugs,
such as an excipient, and a barrier coating or layer on the outer surface of
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the casing which comprises a material which prevents release or any
substantial release of the drug when the dose unit is in the presence of
food, e.g. a material which is insoluble at pH values above 5Ø
When the drug is filled into a capsule, any of the capsules which have
been fabricated to deliver medicaments to the human body may be
employed. Suitable capsules include Those made of hard gelatin, starch or
hydroxypropyimethyl cellulose.
to Starch capsules, e.g. as described i;a the United States Pharmacopoeia
(USP), are preferred since these offer advantages in coating, i. e. in the
storage and stability of the coating layer (PCT/GB95/01458).
By "starch capsules" we include capsules made from starch as well as
~s capsules made from modified starches or starch derivatives. By the term
"derivatives" we particularly mean esters and ethers of the parent
compound that can be unfunctionali,~ed or functionalised to contain, for
example, ionic groupings.
2o Suitable starch derivatives include hydroxyethyl starch, hydroxypropyl
starch, carboxymethyl starch, cationic starch, acetylated starch,
phosphorylated starch, succinate derivatives of starch and grafted starches.
Such starch derivatives are well lc~iown and described in the art (for
example Modified Starches: Properties and Uses, O. B. Wurzburg, CRC
25 Press Boca Raton (1986)).
The starches used should be of food or pharmaceutical quality.
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WO 99137290 PCTIGB99100193
The starch capsules can be made by an injection moulding process and
typically comprise a body and a cap. 'The body is felled with the drug and
the cap is then attached and sealed. Methods for making starch capsules
are well known and are described, for example, in EP-A-118240, WO-
s 901OS 161, EP-A-0304401, W O-92104408 and GB-2187703.
We have found that in human subjects it is possible to retain coated dose
units intact within the stomach following their co-administration with a
meal. The tablet or capsule only breaks up to release the drug contained
to therein when the bulk of the food material within the stomach has emptied
into the small intestine. The coating material selected for the invention is
not an enteric material. Enteric coatings are defined as those materials
that are insoluble in the acid conditions present in the human stomach but
begin to dissolve at a higher pH that is typical of the small intestine
is (i.e. pH 6.0 and above). Suitable coating materials for use in the present
invention are those that dissolve ill the acid conditions of the fasted
stomach (i. e. around pH 2.0), but are. insoluble or dissolve more slowly in
the presence of food, where the pH of the stomach is increased to about
pH 4.5 to 5.5 due to the slight buffering effect of food material. Since the
2o coating material does not dissolve, or dissolves slowly, in the fed
stomach,
the coated dose unit (tablet or capsule) retains its integrity, and does not
break up and disperse its contents in the presence of food.
Conveniently, the coating material is a polymer, preferably a methacrylate
2s polymer. In a preferred embodiment of the present invention, the coating
is Eudragit E100, a polymer of butylmethacrylate, (2-dimethyl
aminoethyl} methacrylate, and methylmethacrylate in the weight ratio
1:2:1 (available from Rohm Pharma, Darmstadt, Germany), which
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WO 99137290 PCT/GB99100193
dissolves when the pH falls below :5. Other polymers that would be
suitable for use in the present invention include, but are not limited to,
polyamino acids and polymeric materials, such as chitosan and poly-
galactosamine, the solubility of which increase with a decrease in pH.
s
Separation of an orally-administered pharmaceutical dose unit from co-
administered food can be achieved for pharmaceutical dose units greater
than about 7 mm in size. By "a size greater than 7 mm", we mean that
the unit can be of any shape, preferably a conventional shape for a
io pharmaceutical dose unit (such as a tablet or capsule), which has at least
one linear dimension (i. e. length, width or depth) of greater than 7 mm,
for example over 10 mm. Conveniently, the largest linear dimension is
less than 20 mm. Units having a largest dimension of over 30 mm are
generally unsuitable for oral delivery.
~s
During the normal process of dige;>tion, food is mixed with acid and
enzymes present in the stomach, and is subsequently broken down into
small particles. These small particles of food are expelled through the
pylorus into the small intestine. In contrast, a dose unit in the form of a
2o coated capsule or tablet greater than '~ mm in size is not removed from the
stomach in the fed condition because the pylorus is in a constricted state.
The pylorus remains in a constricted state until the bulk of the food has
been removed from the stomach sunk that the stomach again reaches a
fasted state. The mechanisms involved in emptying food from the fed
2s stomach into the intestine and preventing the emptying of large, intact
single units from the fed stomach have been well discussed in the
literature. It is known, for example:, that an indigestible single unit will
remain in the stomach until the food has been removed to the small
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WO 99/37290 PCTIGB99/00193
intestine. In man, a physiological process known as the migrating
myoelectric complex is known to control this process (Szurszewski 1969,
Am. J. Physiol. 217, 1757-63). Hence, after the stomach is empty of
food, there will be a period of approximately 1 - l lh hours before phase 3
s of the migrating myoelectric complex removes an intact coated tablet or
capsule into the intestines. Thus, provided the drug is contained in a non-
disintegrating single unit for a suitable period of time, the stomach will
effectively permit separation of the encapsulated drug from the co-
administered food.
to
For many drugs that are vulnerable to food effects, it would be
advantageous if the food were to be removed to the small intestines and
for release of the drug to occur in the stomach. This is particularly the
case for those drugs that exploit the d.i- and tri-peptide pathway, which is
is known to be located in the upper ref;ions of the small intestine. In this
case it would be most advantageous for the food to have passed the
preferred absorption site in the intestines and for the capsule or tablet to
break up in the stomach, thereby releasing the drug upstream from the
preferred absorption site. We have found that this break up in the
2o stomach during the period between the emptying of the food and the onset
of the clearance mechanism of the migrating myoelectric complex, can be
achieved by the careful choice of size of the administered single unit and
the coating polymer. We have particularly found that a polymer coating
that is soluble within the pH range 2..i - 4.0 can provide the desired effect.
2s We believe that this effect is achieved because the polymer is poorly
soluble in the stomach contents when, in food is present. However, as the
food is removed from the stomach, the pH decreases and the polymer
therefore begins to dissolve.
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By using a coating thickness of a suitable size, it is possible to achieve the
desired release of the drug in the stomach when the food is in the small
intestine. Coating thickness may be determined by known methods, such
s as by sectioning dose units and measuring the coat thickness by light or
election microscopy. In practice, coat thickness may be determined by
measuring dose unit weight gain during or following the coating process
and calculating the coat thickness therefrom. A preferred thickness for the
coating is between 20 and 200 ~cm, and more preferably between 40 and
to 100 ~cm. As a further consequence of the pH buffering effect of food, in
the event that the patient takes a second meal shortly after the first, then
the capsule will not release its contents until the second meal has also been
discharged into the small intestine. In effect, the tablet or capsule is able
to discriminate as to whether it is in die presence of food in the stomach or
1s not.
A further aspect of the present invention provides a method for separating
an orally administrable pharmaceutical dose unit from co-administered
food comprising coating said pharmaceutical dose unit with a material that
2o is soluble at pH values below 5Ø
An additional aspect of the present invention provides pharmaceutical dose
units for use in medicine. The present invention may be used to orally
deliver a variety of drugs that suffer from food effects on administration.
2s These include, but are not limited to, the following examples;
amoxicillin, ampicillin, antipyrine, clodronate and other similar
bisphosphonates, captopril, cephalexin, ketoconazoie, lysinopril,
oxytetracycline, tetracycline, levodopa, methyldopa, methacycline,
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WO 99/37290 PCT/GB99/00193
nafcillin, penicillamine, rifamycin, theophylline, peptidic thrombin
inhibitors and Sampatrilat.
We believe the invention to be especially useful for the administration of
s drugs that are negatively influenced by the presence of food; that is, the
absorption is decreased in the presence of food. These include, but are
not limited due, the ~i-lactam antibiotics, peptide-like drugs such as
lysinopril and captopril, as well as the peptidic thrombin inhibitors.
Examples of the latter class of drug can be found in Bernatowicz et al.
to (I996), J. Med. Chem. 39, 4879.
Thus, the invention further provides the use of a drug and a coating
material that is soluble at pH values below 5.0 in the preparation of an
orally administrable pharmaceutical dose unit of a size greater than 7 mm
1s which is adapted to prevent release of the drug into the stomach or the
small intestine when the pharmaceutical dose unit is in the presence of
food.
The invention is now described, bw: not limited, with reference to the
2o following examples:
Example 1 - Preparation of coated starch capsules
Starch capsules (size 0) were obtained from Capsugel (Switzerland) and
2s were filled with pharmaceutical exc:ipients together with a radiolabelled
marker used to demonstrate capsule break up. The marker chosen was
erbium oxide, that can be converted to a y-emitting material in a nuclear
reactor. The contents of each capsule; were:
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WO 99/37290 PCT/GB99100193
227 mg captopril
66.5 rng microcrystalline cellulose (Avicel Pfi 102)
5.5 mg erbium oxide
s 5.0 mg magnesium stearate
The preparation of the Eudragit E100 coating solution was as follows:
50 g Eudragit E100
to 25 g talc
20 ml water
730 ml isopropanol
Initially, 50 g of Eudragit E100 was weighed into a plastic weighing boat.
is A solvent mixture comprising 730 ml of isopropanol and 20 ml of
ultrapure water was prepared in a 1 litre measuring cylinder. Into a 1 litre
glass bottle was transferred 600 rril of the isopropanol/water solution
(130 ml of the ispropanol/water mixture was retained in the measuring
cylinder). The Eudragit E100 was then slowly added to the
2o isopropanol/water solution while mixing vigorously with an overhead
stirrer. Into a 250 ml beaker was weighed 25 g of talc, to which 80 ml of
the retained isopropanollwater solution was added while mixing with a
glass rod until a smooth paste was foamed. The talc paste was then added
to the Eudragit solution, and the remaining isopropanol/water solution was
25 used to rinse the beaker before being added to the Eudragit/talc mixture.
The capsules were then coated with Eudragit E100 solution using an
Aeromatic STREA-1 fluidised bed coater, as follows:
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Into the chamber of the Aeromatic STREA-1 coater (standard column)
(available from Niro Limited) were placed 55 drug-containing capsules
and 450 g of placebo capsules. The Eudragit E100 coating solution was
s applied to the starch capsules using tb~e following coating conditions, with
minor modifications as appropriate:
Drying temperature 250"C
Fan speed 6
to Atomisation pressure 1 ba.r
Pump speed Start at 1, increase to 2 as run proceeds
To determine the weight gain of the capsules at intervals throughout the
coating process, the drug-containing capsules were weighed and the
is amount of Eudragit E100 coating applied per capsule was calculated. This
weight gain figure was then used to calculate the coat thickness on the
capsule. When the capsules had gained 65 mglcapsule in weight, the
coating process was terminated andu the capsules were allowed to dry
overnight.
Coating thickness can be calculated fi-om the weight gain as follows:
(i) The surface area of the capsule was calculated according to the
equation:
2s
Surface area (cm2) _ ~ x diameter (cm) x length (cm)
For capsules of size 0, the surface area is 5 cm2.
:~2
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WO 99/37290 PCT/GB99/00193
(ii) Given that 1 mg of Eudragit E100 coating solution applied to a surface
area of 1 cm2 yields a layer of 8 ~crn in thickness, a coat thickness was
calculated using the weight gain of the capsule according to the
s equation:
Coat thickness (gym) = weight gain ~mg]. x 8
surface area (cm2)
to Hence, in the present example:
Coat thickness = (65/5) x 8 = 104 ~,m
Dissolution testing:
is
Three Eudragit E100-coated capsules were dissolution tested using the
Van Kel dissolution apparatus (United States Pharmacopoeia dissolution
method 2, using a basket) prior to neutron irradiation. A further five
Eudragit E100 coated capsules were dissolution tested after neutron
2o irradiation. Eudragit E100-coated capsules were dissolution tested in pH 5
citric acid-disodium hydrogen phosphate buffer (McIlvaine's buffer).
Dissolution buffer samples (5 ml) were withdrawn at 15-minute intervals
for a duration of 180 minutes. Each. dissolution sample was placed in a
ml screw-top glass bottle for analysis of captopril content by HPLC, as
2s described in Kirschbaum and Perlma.n (1984) J. Pharm. Sci. 73, 686-7.
Results indicated that the capsules did not dissolve at pH 5.0 aad that
neutron irradiation did not affect dhe solubility of the Eudragit E100
coating.
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WO 99/37290 PCTIGB99/OOI93
Example 2 - Preparation of coated gelatin capsules
The procedure described in Example 1 for preparation of starch coated
s capsules may also be used to coat capsules made from gelatin. Suitable
gelatin capsules (size 0) include those obtained from Capsugel,
Switzerland.
Example 3 - Preparation of a coated tablet
io
A tablet was prepared from microcrys~alline cellulose, containing the same
radiolabel (erbium oxide) as described in Example 1, and 250 mg of
captopril. The tablets were circular with a diameter of 15 mm, and were
made by compression using the Manesty F3 machine with concave
is punctures. The tablets were coated using a solution of polymer Eudragit
E100, as described in Example 1.
An increase in weight of the tablets o~f 55 mg was used as an indication of
suitable coating thickness. Tablet coating thickness can be calculated
2o using the same method as that described in Example 1, with the following
equations being used to calculate surf~~ce area:
For circular (discoidal) tablets:
Surface area (cm2) _ (7c x diameter (cm) x height (cm))
2s + (~ x radius2 (cm2))
For oblong tablets:
Surface area (cm2) = n x diameter (cm) x length (cm)
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Example 4 - In vivo evaluation
In order to demonstrate the utility of the invention, a group of healthy
s volunteers was selected and requested to fast overnight. On the study day,
they were given radiolabelled, coated capsules (as described in Example 1)
together with a meal containing a second radiolabel in the form of
technetium-99m. The meal comprised scrambled eggs in which was
incorporated technetium sulphur colloid, labelled with technetium-99m
according to the procedure described by Knight et al. (1981), J. Nucl.
Med. 23, 21. Using this dual label approach, it was possible to
distinguish between the position {and integrity) of the coated capsule and
the position (and spreading) of the meal. This was achieved by placing
the subject in front of a gamma camera, for example a General Electric
is Maxi camera, field of view 40 cm. 'the break up of the capsules can be
visualised on the camera and representative pictures obtained using a data
capture method such as magnetic tape;. By this method it was possible to
ascertain when the capsules broke up and whether they broke up in the
stomach or in the small intestines. At: the time-point at which the capsules
2o broke up, it was also possible to ascE;rtain the location of the food
within
the gastrointestinal tract.
The results for nine subjects are shown in Table 1. It can be seen that in
all but one case the capsules were retained in the stomach where they
2s broke up, releasing their contents. In contrast, the technetium-labelled
food was found to be in the distal small intestine or in the colonic region.
Interestingly, in the one subject where the capsule was not retained in the
stomach, it broke up in the upper rel;ions of the small intestines (probably
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WO 99/37290 PCT/GB99/00193
close to the preferred absorption site for drugs exploiting the di- and tri-
pedtide pathway) while the food had reached the colon or was located
largely at the ileocecal junction. Thus, in all cases, it was demonstrated
that effective separation of the drug delivery system from the co-
s administered food was achieved.
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WO 99/37290 PCT/GB99100193
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