Note: Descriptions are shown in the official language in which they were submitted.
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Dispersible tablet
The present invention relates to a pharmaceutical composition comprising
Nimorazole, which
disintegrates in water. In particular, the invention concerns a pharmaceutical
composition such as
a tablet comprising Nimorazole or a pharmaceutically acceptable salt thereof,
for dispersion in
water and administration via a tube to a patient with swallowing difficulties.
Technical Background
The patent US 4371540 describes the use of radiosensitizers for hypoxic cells.
Administration is
performed via an intravenous route or suggested to be done orally using a
prodrug, wherein the
prodrug is the acetate ester of the compound.
The patent US 4462992 suggests administration parenterally, subcutaneously,
intravenously,
intramuscularly or intraperitoneally, or alternatively oral administration.
The patent application US 2010/322939 describes oral administration of
Nimorazole 90 minutes
prior to radiotherapy treatment.
According to Bowman, Corinne ("Administration of drugs to patients with
swallowing difficulties",
Journal of the Malta College of Pharmacy Practice, Issue 12 Winter 2007, pp.
42-45) patients who
are unable to swallow due to a debilitating condition become dependent on an
enteral feeding
tube both for nutritional needs and for administration of medicines.
Information regarding this
mode of administration is very scarce and also associated with increased risk
of tube obstruction,
increased toxicity and reduced efficacy due to an inadequate administration
method. Bowmann
notes that "Unfortunately, crushing tablets is mistakenly taken for granted by
some healthcare
professionals without considering that the properties of the medication may be
affected", and
finally "Crushed tablets are the most frequent cause of obstruction of feeding
tubes which results
in increased morbidity and trauma to the patient besides the cost of replacing
the tube. This may
require surgical intervention".
Summary of the invention
Nimorazole is inter alio used to improve the efficacy of irradiation treatment
for cancer patients.
Patients such as cancer patients may suffer from swallowing difficulties. In
particular cancer
patients undergoing irradiation treatment in the head and neck region and
concurrent
Nimorazole treatment may have difficulties swallowing Nimorazole tablets, and
thus have a need
for having Nimorazole administered via an alternative route. The amount of
Nimorazole necessary
for an effective treatment, such as about 2 g for each treatment, aggravates
this problem, as it
implies the use of large tablets or a high number of tablets.
Nimorazole is slightly soluble in water (The Merck Index, 14th Edition).
Experiments indicate that
the solubility in water is about 5 mg/ml. Further, in order to achieve a
reasonable dissolution rate,
it is usually necessary to apply excessive amounts of liquid in order to
obtain sink conditions.
Preparing a bulky solution of Nimorazole for further distribution creates
additional problems in
terms of storage stability and difficulties distributing a large container
comprising liquid.
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There is a need for providing a liquid medium comprising an amount of
Nimorazole exceeding the
solubility limit of Nimorazole in water, in order to be able to administer
effective amounts of
Nimorazole via a feeding tube while avoiding the intake of excessive amounts
of liquid medium.
There is a need for being able to provide a liquid medium comprising
Nimorazole within a short
time frame. In addition, there is a need to provide a liquid medium comprising
Nimorazole which
is able to pass via a feeding tube without causing obstruction.
Attempts were made to provide a granulate comprising Nimorazole, which was
formulated with
the intent to be dispersed in water, administered via a feeding tube, and
quickly dissolve in the
stomach at low pH. However, the granulate suffered from the drawback that the
granulate was
not sufficiently dispersed in water at neutral pH, and thus created
obstructions in a feeding tube.
The development of the granulate comprising Nimorazole was subsequently
stopped.
Attempts were made to provide a powder comprising Nimorazole, which was
formulated to be
quickly dispensed in water at neutral pH. Up to five sachets of powder had to
be opened and
carefully emptied into water, making sure that all the powder of each sachet
was emptied
completely. While this powder did not obstruct the feeding tube, it was seen
as a quite tedious
procedure that could impact patient compliance to the treatment. The
development of the
powder comprising Nimorazole was subsequently stopped. Further, the powder was
less suitable
for oral administration unless it was dispersed in water.
According to aspects and embodiments of the invention, the abovementioned
problems are
addressed by the present invention.
Surprisingly, it has been possible to provide a liquid medium comprising an
amount of Nimorazole
exceeding the solubility limit of Nimorazole in water, making it possible to
administer effective
amounts of Nimorazole via a feeding tube while avoiding the intake of
excessive amounts of liquid
medium. Further, it has been possible to provide a liquid medium comprising
Nimorazole within a
short time frame. In addition, it has been possible to provide a liquid medium
comprising
Nimorazole which is able to pass via a feeding tube without causing
obstruction.
According to an aspect, the invention concerns a pharmaceutical composition
comprising
Nimorazole or a pharmaceutically acceptable salt thereof, for disintegration
in water or an
aqueous medium and administration via a tube.
A feeding tube may suitably be used. In particular, the invention concerns a
pharmaceutical
composition which allows administration using a feeding tube to a patient with
swallowing
difficulties.
The pharmaceutical formulation or tablet according to the invention preferably
disintegrates
upon contact with water, forming a dispersion. The forming of the dispersion
may be aided by
stirring in the water, or shaking a container comprising the tablet and water.
According to another aspect, the invention concerns a solid pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, and
further comprising: a
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disintegrant; optionally one or more additional excipients; and a coating;
said pharmaceutical
composition allowing administration via at least two different routes:
i) oral administration, or
ii) disintegration in water or an aqueous medium to provide a dispersion,
and
subsequent administration of said dispersion via a tube.
Surprisingly, it has been possible to device a pharmaceutical formulation or
tablet, which may be
used directly for oral administration, and which alternatively may be
dispersed in water in a short
time frame for administration via a feeding tube. The pharmaceutical
formulation or tablet may
be dispersed in a small volume of water. The dispersed particles are
sufficiently small to provide a
slow sedimentation rate, allowing administration of the particles in dispersed
state from e.g. a
bottle via a feeding tube.
A pharmaceutical formulation in the form of a tablet is easy to handle and
dosage may easily be
measured and subsequently checked. Using a powder from individual sachets
makes a dosing of
several sachets cumbersome. Further, the use of a powder makes a dosage check
after
measurement of the intended dosage cumbersome, while a small number of tablets
are easily
counted for verification of dosage. Finally, a tablet provides a smaller
surface area than a powder,
thus potentially increasing the storage stability of the product.
According to an aspect, the invention concerns a kit of parts comprising a
pharmaceutical
composition according to the invention, and instructions for preparing a
dispersion of said
pharmaceutical composition for administration via a tube.
According to an aspect, the invention concerns a method for manufacturing a
pharmaceutical
formulation or tablet according to the invention, comprising wet granulation
of Nimorazole.
Further information concerning wet granulation may be found in references such
as: International
Journal of Pharmaceutical Frontier Research, April-June 2011; 1(1):65-83,
"Pharmaceutical
Processing ¨ A Review on Wet Granulation Technology", Rajesh Agrawal and Yadav
Naveen; "Wet
Granulation: End-Point Determination and Scale-Up", Michael Levin, Ph. D.
Metropolitan
Computing Corporation, East Hanover, New Jersey, USA; and Parikh D. "Handbook
of
Pharmaceutical Granulation Technology", Marcel Dekker, Inc. New York, 1997.
According to an aspect, the invention concerns a method of treatment of
cancer, wherein
irradiation treatment is combined with the administration of at least one
pharmaceutical
formulation or tablet according to the invention, wherein said at least one
pharmaceutical
formulation or tablet is allowed to disintegrate in water or an aqueous medium
and administered
via a tube. This is particularly relevant when the patient has or acquires
problems with swallowing,
such as for cancer in the head and neck region.
This method is particularly preferred for patients with swallowing
difficulties undergoing
treatment with Nimorazole.
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According to an aspect, the invention concerns a method of radiosensitizing
hypoxic tumor cells
comprising administering Nimorazole, wherein the administration comprises:
providing a solid
pharmaceutical composition comprising Nimorazole or a pharmaceutically
acceptable salt
thereof; dispersing said solid pharmaceutical composition in water or an
aqueous medium to
obtain a dispersion; and administering said dispersion via a tube.
According to an aspect, the invention concerns a use of a tablet according to
the invention,
wherein said tablet is dispersed in water and administered via a tube.
According to an aspect, the invention concerns an aqueous pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, wherein
at least part of said
Nimorazole or pharmaceutically acceptable salt thereof is dispersed in an
aqueous medium in
form of solid particles.
Detailed Disclosure
According to an embodiment, the invention concerns a pharmaceutical
composition comprising
Nimorazole or a pharmaceutically acceptable salt thereof, for disintegration
in water or an
aqueous medium and administration via a tube. A feeding tube may suitably be
used.
The expression "water or an aqueous medium" covers the possibility of using
water or water
comprising one or more salts, such as a saline solution, and/or any (other)
components for the
patient, such as at least one active ingredient. It also covers the
possibility of water comprising
one or more nutrients, optionally with one or more active ingredients.
The pharmaceutical composition or tablet according to the invention preferably
disintegrates
upon contact with water, forming a dispersion. The forming of the dispersion
may be aided by
stirring in the water, or shaking a container comprising at least one tablet
and water.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for administration to a patient with swallowing difficulties. According to a
preferred embodiment,
the invention concerns a pharmaceutical composition or tablet for
administration to a patient
with little, insufficient or no saliva, such as a patient with non-normal
salivary function.
According to an embodiment, the invention concerns a solid pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, and
further comprising: a
disintegrant; optionally one or more additional excipients, such as a binder;
and a coating; said
pharmaceutical composition allowing administration via at least two different
routes: oral
administration, or disintegration in water or an aqueous medium to provide a
dispersion, and
subsequent administration of said dispersion via a tube.
The solid pharmaceutical composition is preferably a tablet.
The pharmaceutical composition is preferably provided in a solid form which is
stable over time.
Preferably, the pharmaceutical composition is stable for 6 months, preferably
12 months, more
preferred 18 months, preferably 24 months, more preferred 30 months,
preferably 36 months, or
even longer. Preferably, the pharmaceutical composition retains its
dispersibility upon storage, i.e.
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during storage for 6 months, preferably 12 months, more preferred 18 months,
preferably 24
months, more preferred 30 months, preferably 36 months, or even longer.
The disintegrant makes it possible to provide a dispersion in a short time
interval. Preferably, the
solid pharmaceutical composition allows the provision of a dispersion
comprising an amount of
Nimorazole or a pharmaceutically acceptable salt thereof, wherein the amount
of Nimorazole or a
pharmaceutically acceptable salt thereof exceeds the solubility limit of
Nimorazole in the water or
the aqueous medium. Preferably, the solid pharmaceutical composition allows
the provision of a
dispersion comprising an amount of Nimorazole or a pharmaceutically acceptable
salt thereof,
wherein the amount of Nimorazole or a pharmaceutically acceptable salt thereof
exceeds the 5
mg / ml of water or the aqueous medium.
The coating may serve as taste-masking, as Nimorazole has an unpleasant taste.
An unpleasant
taste may lower patient compliance. Additionally, a coating may improve
storage stability of the
pharmaceutical formulation.
Having a pharmaceutical composition which allows two different routes of
administration carries
a number of advantages. Firstly, patient compliance is improved, as the
patient is already used to
the pharmaceutical composition if or when the patient needs to change route of
administration.
Secondly, the costs associated with production and obtaining marketing
approval are lowered, as
only one product needs to be produced and approved.
Preferably the dispersion of the solid pharmaceutical composition may be done
by the patient. It
is further preferred that administration of the dispersion may be performed by
the patient. This
allows out-patient or ambulatory use.
An excipient is generally a pharmacologically inactive substance. Examples
include, but are not
limited to, diluents, disintegrants, binders, glidants, lubricants, and
coatings. Other examples of
suitable excipients may be found in Handbook of Pharmaceutical Excipients, 7th
Ed. by Rowe,
Raymond C. et al., Pharmaceutical Press, London.
Diluents are inactive ingredients that are added to tablets and capsules in
addition to the active
drug. Some very common diluents in tablets include starch, cellulose
derivatives, and magnesium
stearate (also a lubricant). Diluents fill out the size of a tablet or
capsule, making it practical to
produce and convenient for the consumer to use. By increasing the bulk volume,
diluents make it
possible for the final product to have the proper volume for patient handling.
A good diluent must
be inert, compatible with the other components of the formulation, non-
hygroscopic, relatively
cheap, compactible, and preferably tasteless or pleasant tasting. Plant
cellulose (pure plant
Diluent) is a popular diluent in tablets or hard gelatin capsules. Dibasic
calcium phosphate is
another popular tablet diluent. A range of vegetable fats and oils can be used
in soft gelatin
capsules. Other examples of diluents include: lactose, sucrose, glucose,
mannitol, sorbitol, calcium
carbonate, and magnesium stearate.
Disintegrants expand and dissolve when wet causing the tablet to break apart.
They ensure that
when the tablet is in contact with water, it rapidly breaks down into smaller
fragments, facilitating
dissolution or dispersion. Examples of disintegrants include, but are not
limited to: crosslinked
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polymers, such as crosslinked polyvinylpyrrolidone (crospovidone), and
crosslinked sodium
carboxymethyl cellulose (croscarmellose sodium); and the modified starch
sodium starch
glycolate. Specific examples further include Indion 414, L-HPC, and
pregelatinised starch.
Binders hold the ingredients in a tablet together. Binders ensure that tablets
and granules can be
formed with required mechanical strength, and give volume to tablets. Examples
of binders
include: saccharides and their derivatives: disaccharides, sucrose, lactose;
polysaccharides and
their derivatives, such as starches, cellulose or modified cellulose, such as
microcrystalline
cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); sugar
alcohols such as xylitol,
sorbitol or maltitol; further Protein: gelatin; and Synthetic polymers:
polyvinylpyrrolidone (PVP),
polyethylene glycol (PEG). Examples include gelatin, cellulose, cellulose
derivatives,
polyvinylpyrrolidone, starch, sucrose and polyethylene glycol. Other examples
include cellulose,
methyl cellulose, polyvinylpyrrolidone and polyethylene glycol.
Glidants are used to promote powder flow by reducing interparticle friction
and cohesion. These
are used in combination with lubricants as they have no ability to reduce die
wall friction.
Examples include fumed silica, talc, and magnesium carbonate.
Lubricants are agents added to tablet and capsule formulations to improve
certain processing
characteristics. Lubricants inter alia prevent ingredients from clumping
together and from sticking
to the tablet punches or capsule filling machine. Lubricants also ensure that
tablet formation and
ejection can occur with low friction between the solid and die wall. Common
minerals like talc or
silica, and fats, e.g. vegetable stearin, magnesium stearate or stearic acid
are examples of
lubricants used in tablets or hard gelatin capsules.
Coatings protect ingredients from deterioration by moisture in the air and
make large or
unpleasant-tasting tablets easier to swallow. For most coated tablets, a
cellulose ether
hydroxypropyl methylcellulose (HPMC) film coating is used which is free of
sugar and potential
allergens. Occasionally, other coating materials are used, for example
synthetic polymers, shellac,
corn protein zein or other polysaccharides. A specific example is Opadry.
Capsules are coated
with gelatin.
According to an embodiment, the invention concerns a solid pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, and
further comprising:
diluent; disintegrant; binder; glidant; lubricant; and optionally one or more
additional excipients;
and a coating.
According to an embodiment, the invention concerns a solid pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, and
further comprising:
diluent, 1 - 50 %; disintegrant, 0.5 - 15%; binder, 0.5 - 15 %; glidant, 0.5 -
3 %; lubricant, 0.5 - 3 %;
and optionally one or more additional excipients; and a coating, 0.5 - 5 %.
According to an embodiment, the invention concerns a solid pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, and
further comprising:
diluent, 2 - 25 %, preferably 4¨ 15%, more preferred 6 ¨ 10%, preferably 7-9%;
disintegrant, 1 -
12 %, preferably 3 ¨ 10%, more preferred 5 ¨ 9%, preferably 7-8%; binder, 1 -
10 %, preferably 2 ¨
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8%, more preferred 3 ¨ 6%, preferably 4 - 5%; glidant, 0.6 ¨ 2.5 %, preferably
0.8 ¨ 2%, more
preferred 0.9 ¨ 1.8%, preferably 1 ¨ 1.5%; lubricant, 0.6 ¨ 2.5 %, preferably
0.8 ¨ 2%, more
preferred 0.9 ¨ 1.8%, preferably 1 ¨ 1.5%; and optionally one or more
additional excipients; and a
coating, 0.7 - 4 %, preferably 1 ¨ 3%, more preferred 1.5 ¨ 2.5%, preferably 2-
2.2%.
According to an embodiment, the invention concerns a solid pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, and
further comprising:
a) An intragranular part, comprising: diluent; disintegrant; and binder;
and
b) An extragranular part, comprising: diluent; disintegrant; glidant; and
lubricant; and
c) A coating.
According to an embodiment, the invention concerns a solid pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, and
further comprising:
a) An intragranular part, comprising: diluent, 1 - 50 %; disintegrant, 0.5 -
15%; and binder,
0.5 - 15 %; and
b) An extragranular part, comprising: diluent, 0.5 - 50%; disintegrant, 0.5 -
15%; glidant, 0.5 -
3 %; and lubricant, 0.5 - 3 %; and
c) A coating, 0.5 - 5 %.
According to an embodiment, the invention concerns a solid pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, and
further comprising:
a) An intragranular part, comprising: diluent, 2 - 25 %, preferably 4¨ 15%,
more preferred 6
¨ 10%, preferably 7 - 8%; disintegrant, 0.7 - 10 %, preferably 1 ¨ 8%, more
preferred 1.5 ¨
5%, preferably 2-3%; and binder, 1 - 10 %, preferably 2 ¨ 8%, more preferred 3
¨ 6%,
preferably 4-5%; and
b) An extragranular part, comprising: diluent, 0.7 - 25 %, preferably 0.8 ¨
10%, more
preferred 0.9 ¨ 5%, preferably 1 - 2%; disintegrant, 1 - 10 %, preferably 2 ¨
8%, more
preferred 4¨ 7%, preferably 5-6%; glidant, 0.6 ¨ 2.5 %, preferably 0.8 ¨ 2%,
more
preferred 0.9 ¨ 1.8%, preferably 1 ¨ 1.5%; and lubricant, 0.6 ¨ 2.5 %,
preferably 0.8 ¨ 2%,
more preferred 0.9 ¨ 1.8%, preferably 1 ¨ 1.5%; and
c) A coating, 0.7 - 4 %, preferably 1 ¨ 3%, more preferred 1.5 ¨ 2.5%,
preferably 2 - 2.2%.
According to an embodiment, the invention concerns a pharmaceutical
composition which is an
immediate release tablet. An immediate release tablet disintegrates in water
within 30 minutes.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for disintegration in water within 15 minutes, preferably 10 minutes, more
preferred 5 minutes,
preferably within 3 minutes to produce a dispersion for administration to a
patient via a tube.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet,
wherein said dispersion passes through a sieve screen with a nominal mesh
aperture of 710 m.
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According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet,
which disintegrates within 10 min., preferably within 5 min., using water at
25 C, preferably 20 C,
more preferred at 15 C.
According to an embodiment, the invention concerns a pharmaceutical
composition which is a
dispersible tablet. The expression "dispersible tablet" refers to a tablet,
which may be dispersed in
water before administration, providing a homogeneous dispersion. Dispersible
tablets
disintegrate within 3 minutes using water at 15 ¨ 25 C. The fineness of
dispersion should comply
with a test comprising placing 2 tablets in 100 ml water and stirring until
completely dispersed. A
smooth dispersion is produced, which passes through a sieve screen with a
nominal mesh
aperture of 710 m.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet,
which allows complete dispersion of one or more pharmaceutical compositions or
tablets
comprising a total of at least 1000 mg Nimorazole in 100 ml water at 25 C upon
stirring, thereby
providing a dispersion; said dispersion passing through a sieve screen with a
nominal mesh
aperture of 710 m. According to embodiments, the term "complete dispersion"
covers the case
wherein at least 90%, more preferred at least 95%, preferably at least 98%,
more preferred 99%,
preferably 100% Nimorazole is dispersed or dissolved.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for administration via a feeding tube.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for administration via a feeding tube selected among the group consisting of a
percutaneous
endoscopic gastrostomy tube, a nasogastric feeding tube, a nasojejunal feeding
tube, a gastric
feeding tube, and a jejunostomy feeding tube.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for administration via a percutaneous endoscopic gastrostomy ("PEG") tube or a
nasogastric
("NG") feeding tube.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of bedridden or geriatric patients. These patient groups often
suffer from
difficulties swallowing tablets.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of patients undergoing irradiation treatment, particularly
irradiation treatment of
the head and/or neck region.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of intubated patients, such as patients having inserted a tube
into the
gastrointestinal tract. Individual differences may influence if and at what
point during a treatment
regime patients are intubated.
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According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of patients having received at least a number selected among 1,
2, 3, 4, 5, 6, 7, 8, 9
or 10 irradiation treatments for cancer of the head and/or neck region.
While Nimorazole is usually administered from the first irradiation treatment,
using a tube
becomes particularly relevant when the patient begins to experience problems
swallowing,
usually from the 5th or 6th irradiation treatment.
Thus, the need for administration of Nimorazole via a feeding tube does
usually not occur before
after the 4th or 5th irradiation treatment, as the swallowing difficulties is
usually not present early.
During the first about four fractions of irradiation treatment direct oral
administration is
preferred, i.e. in the form of a tablet taken orally, while the need for
administration via a feeding
tube usually occurs later, i.e. from the 5th or 6th irradiation treatment.
Hence, for a Nimorazole tablet to be used with concurrent radiotherapy, it is
convenient to have a
tablet which may both be administered directly orally, and which may be used
for making a
dispersion or solution for administration via a feeding tube. However, due to
the unpleasant taste
of Nimorazole, it is preferable that the tablet comprises a coating, masking
the taste.
Conventional coatings suffers from the drawback that they make it difficult to
make a dispersion,
and parts of the coating may get stuck in a feeding tube.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for swallowing or for disintegration in water or an aqueous medium and
administration via a tube.
This tablet is specifically adapted to allow swallowing or allow
disintegration in water or an
aqueous medium at the discretion of a person administering the tablet.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
further comprising a coating facilitating swallowing and masking the taste of
Nimorazole.
The taste of Nimorazole is unpleasant to most patients. Thus, without a
coating, many patients
will feel the swallowing of Nimorazole tablets objectionable. However, a
coating tends to impede
the disintegration of the tablet in water. Surprisingly, it has been possible
to device a coating,
which facilitates swallowing, and masks the taste of Nimorazole, and still
allows producing a
dispersion in water quickly.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for curative treatment or reirradiation of cancer.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for 1st line irradiation treatment of cancer with curative intent or 2nd line
reirradiation treatment
of cancer with curative and/or palliation intent.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for curative or palliative treatment of cancer in patients undergoing
radiotherapy, particularly for
patients with cancer in the head and/or neck region.
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According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of patients with hypoxic cancer. Methods for testing whether
cancers are hypoxic
are known in the art.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of an indication selected among breast cancer, head/neck cancer,
esophagus cancer,
lymphoma, cervical cancer, colorectal cancer, brain cancer, lung cancer,
bladder cancer, and
prostate cancer. The invention is particularly relevant for patients with a
swallowing problem,
which may or may not be caused by irradiation treatment. The cancer treatment
may be with or
without concurrent chemotherapy.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of head/neck cancer.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of cervical cancer or inoperable lung cancer.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment of non-smokers. Nimorazole may appear to have reduced or little
influence on the
efficacy of irradiation treatment of cancer among patients who have not
stopped smoking during
treatment. According to an embodiment, cessation of smoking during therapy is
warranted.
According to an embodiment, the invention concerns a pharmaceutical
composition, comprising
at least 250 mg Nimorazole or a pharmaceutically acceptable salt thereof.
According to an embodiment, the invention concerns a pharmaceutical
composition, comprising
10 - 2500 mg, more preferred 100 - 2000 mg, preferably 300 - 1500 mg, more
preferred 400 ¨
1000 mg, preferably 500 mg Nimorazole or a pharmaceutically acceptable salt
thereof.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet,
subject to the proviso that 3 - 5 of said pharmaceutical compositions or
tablets may be dispersed
in 2 dl water at 25 C, preferably 20 C, more preferred 15 C within 15,
preferably 10, more
preferred 5, preferably within 3 minutes.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
allowing dispersion of 1500 - 2500 mg, preferably 2000 mg, Nimorazole in 2 dl
water at 25 C,
preferably 20 C, more preferred 15 C within 15, preferably 10, more preferred
5, preferably
within 3 minutes.
According to an embodiment, the invention concerns a pharmaceutical
composition or a tablet
for treatment alone or combined with chemotherapy. According to an embodiment,
the invention
concerns a tablet for treatment alone or combined with chemotherapy for
patients undergoing
irradiation of a total of 40 Grey during a course of treatment.
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According to an embodiment, the invention concerns a kit of parts comprising a
pharmaceutical
composition according to the invention, and instructions for preparing a
dispersion of said
pharmaceutical composition for administration via a tube.
According to an embodiment, the invention concerns a method for manufacturing
a
pharmaceutical composition, comprising wet granulation of Nimorazole.
According to an embodiment, the invention concerns a method for manufacturing
a
pharmaceutical composition, comprising a wet granulation step performed using
a Rapid Mixer
Granulator, or alternatively using a device selected among the group
consisting of a Super Mixer
Granulator, Oscillating Granulator, Inline homegenizer, Caleva Mini Mixer, and
High Shear Mixers.
According to an embodiment, the invention concerns a method for manufacturing
a
pharmaceutical composition, comprising a wet granulation step preceded by dry
mixing in a
granulator or alternatively, said dry mixing may be performed using a device
selected among the
group consisting of a Conta blender, Octagonal blender, Double cone blender,
Conical blender,
and a Multi Mill.
According to an embodiment, the invention concerns a method for manufacturing
a
pharmaceutical composition, comprising drying the wet granular mass resulting
from a wet
granulation until a pre-determined loss on drying (%L0D) is obtained.
According to an embodiment, the invention concerns a method for manufacturing
a
pharmaceutical composition, comprising drying the wet granular mass resulting
from a wet
granulation until said %LOD is in the range of 0 to 10%, preferably 0.5 to
5.0%, more preferred
within 1.5 to 3.0%.
According to an embodiment, the invention concerns a method for manufacturing
a
pharmaceutical composition, comprising sifting all granules through a no. 20
(20#) sieve or finer
prior to compression.
According to an embodiment, the invention concerns a method for manufacturing
a
pharmaceutical composition, comprising sifting all extragranular ingredients
through a 20#,
preferably 25#, more preferred 30# sieve or finer prior to compression.
According to an embodiment, the invention concerns a method of treatment of
cancer, wherein
irradiation treatment is combined with the administration of at least one
tablet according to the
invention, wherein said at least one tablet is allowed to disintegrate in
water or an aqueous
medium and administered via a tube. This method is particularly preferred for
patients with
swallowing difficulties undergoing treatment with Nimorazole.
According to an embodiment, the invention concerns a method of
radiosensitizing hypoxic tumor
cells comprising administering Nimorazole, wherein the administration
comprises: Providing a
solid pharmaceutical composition comprising Nimorazole or a pharmaceutically
acceptable salt
thereof; Dispersing said solid pharmaceutical composition in water or an
aqueous medium to
obtain a dispersion; and Administering said dispersion via a tube.
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Patients receiving Nimorazole in form of tablets may have difficulties
swallowing. A new route or
way of administration of Nimorazole particularly suitable for these patients
is suggested. There is
a need for a pharmaceutical composition, which may be administered via a tube
without the need
of crushing tablets. The dispersion to be administered may easily be prepared
by the patient, in
particular without the need to crush tablets. Thus, this is particularly
suitable for out-patient
administration, i.e. patients receiving Nimorazole as part of ambulatory
treatment, e.g. patients
who are requested to take the treatment in the home or on the way to the
hospital before
irradiation treatment at a treatment facility such as a hospital. Further,
there is a need of taste-
masking pharmaceutical compositions or tablets comprising Nimorazole.
According to an embodiment, the invention concerns a use of a tablet according
to the invention,
wherein said tablet is dispersed in water and administered via a tube.
According to an embodiment, the invention concerns an aqueous pharmaceutical
composition
comprising Nimorazole or a pharmaceutically acceptable salt thereof, wherein
at least part of said
Nimorazole or pharmaceutically acceptable salt thereof is dispersed in water
or an aqueous
medium in form of solid particles.
According to an embodiment, the invention concerns an aqueous pharmaceutical
composition
obtainable by dispersing a pharmaceutical composition in water or an aqueous
medium.
According to an embodiment, the invention concerns an aqueous pharmaceutical
composition,
wherein said Nimorazole or pharmaceutically acceptable salt is present in a
concentration
exceeding 5 mg / ml water or an aqueous medium.
The term "concentration" refers to the abundance of a constituent divided by
the total volume of
a mixture. The term can be applied to any kind of mixture, and is not confined
to solutes and
solvents in solutions.
According to an embodiment, the invention concerns a solid pharmaceutical
composition
comprising:
i) Nimorazole or a pharmaceutically acceptable salt thereof;
ii) a disintegrant;
iii) optionally one or more additional excipients; and
iv) a coating;
said pharmaceutical composition allowing oral administration, preferably as a
tablet, and further
allowing, as an alternative, administration via a feeding tube, wherein prior
to administration via a
feeding tube the pharmaceutical composition is disintegrated in water or an
aqueous medium to
provide a dispersion which is administered via the feeding tube.
According to an embodiment, the invention concerns the pharmaceutical
composition wherein
the additional excipients comprise a diluent, a binder, a glidant, and a
lubricant.
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According to an embodiment, the invention concerns the pharmaceutical
composition
comprising:
diluent, 1 -50 wt%;
disintegrant, 0.5 ¨ 15 wt%;
binder, 0.5 - 15 wt%;
glidant, 0.5 - 3 wt%;
lubricant, 0.5 - 3 wt%;
optionally one or more additional excipients; and
a coating, 0.5 - 5 wt%.
According to an embodiment, the invention concerns the pharmaceutical
composition
comprising:
diluent, 7 - 9 wt%;
disintegrant, 7 ¨ 8 wt%;
binder, 4 - 5 wt%;
glidant, 1¨ 1.5 wt%;
lubricant, 1¨ 1.5 wt%;
optionally one or more additional excipients; and
a coating, 2 ¨ 2.2 wt%.
According to an embodiment, the invention concerns the pharmaceutical
composition
comprising:
an intragranular part, comprising a diluent, a disintegrant, and a binder;
an extragranular part, comprising a diluent, a disintegrant, a glidant, and a
lubricant; and
a coating.
According to an embodiment, the invention concerns the pharmaceutical
composition that is
formulated as a tablet, an immediate release tablet or a dispersible tablet.
According to an embodiment, the invention concerns the pharmaceutical
composition that
disintegrates in water at 20 C within 5 minutes.
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According to an embodiment, the invention concerns the pharmaceutical
composition that after
disintegration in water or an aqueous medium passes through a sieve screen
with a nominal mesh
aperture of 710 p.m.
According to an embodiment, the invention concerns the pharmaceutical that can
be dispersed to
provide at least 1000 mg Nimorazole in 100 ml water at 25 C within 5 minutes
upon stirring,
wherein said dispersion passes through a sieve screen with a nominal mesh
aperture of 710 p.m.
According to an embodiment, the invention concerns the pharmaceutical
composition, wherein
the feeding tube is selected from the group consisting of a percutaneous
endoscopic gastrostomy
tube, a nasogastric feeding tube, a nasojejunal feeding tube, a gastric
feeding tube, and a
jejunostomy feeding tube.
According to an embodiment, the invention concerns the pharmaceutical
composition, wherein
the coating facilitates swallowing and masks the taste of Nimorazole.
According to an embodiment, the invention concerns the pharmaceutical
composition, wherein
the composition comprises at least 250 mg Nimorazole or a pharmaceutically
acceptable salt
thereof per dosing unit.
According to an embodiment, the invention concerns the pharmaceutical
composition that can be
dispersed to provide at least 2000 mg of Nimorazole or a pharmaceutically
acceptable salt thereof
in 2 dl of water at 25 C within 3 minutes.
According to an embodiment, the invention concerns a kit of parts comprising
the pharmaceutical
composition and instructions for preparing a dispersion of the pharmaceutical
composition for
administration to a patient via a feeding tube.
According to an embodiment, the invention concerns a kit of parts comprising:
a) a solid pharmaceutical composition comprising:
i) Nimorazole or a pharmaceutically acceptable salt thereof;
ii) a disintegrant;
iii) optionally one or more additional excipients; and
iv) a coating;
said pharmaceutical composition allowing administration to a patient via a
feeding tube by
disintegrating the solid pharmaceutical composition in water or an aqueous
medium to provide a
dispersion which is administered via the feeding tube; and
b) instructions for disintegrating the solid pharmaceutical composition in
water or an aqueous
medium to form a dispersion and administering the dispersion via a feeding
tube.
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According to an embodiment, the invention concerns the pharmaceutical
composition, made by a
method comprising performing wet granulation of a composition comprising
Nimorazole or a
pharmaceutically acceptable salt thereof.
According to an embodiment, the invention concerns a method for manufacturing
a
pharmaceutical composition, the method comprising performing wet granulation
of Nimorazole
or a pharmaceutically acceptable salt thereof.
According to an embodiment, the invention concerns a method of treating cancer
by
radiosensitizing hypoxic tumor cells, the method comprising performing
radiation treatment
combined with the administration of at least one solid pharmaceutical
composition comprising:
i) Nimorazole or a pharmaceutically acceptable salt thereof;
ii) a disintegrant;
iii) optionally one or more additional excipients; and
iv) a coating;
wherein said at least one solid pharmaceutical composition is allowed to
disintegrate or is
dispersed in water or an aqueous medium and administered to a patient via a
feeding tube.
According to an embodiment, the invention concerns a method of treating cancer
by
radiosensitizing hypoxic tumor cells, the method comprising performing
radiation treatment
combined with the administration of at least one solid pharmaceutical
composition, wherein said
at least one solid pharmaceutical composition is allowed to disintegrate or is
dispersed in water or
an aqueous medium and administered to a patient via a tube.
According to an embodiment, the invention concerns the method, wherein the
radiation
treatment comprises:
providing said solid pharmaceutical composition comprising Nimorazole or a
pharmaceutically
acceptable salt thereof;
dispersing the solid pharmaceutical composition in water or an aqueous medium
to obtain a
dispersion;
administering the dispersion to a patient via a feeding tube; and
administering radiation to the patient.
According to an embodiment, the invention concerns the method, wherein the
dispersion
contains said Nimorazole or pharmaceutically acceptable salt thereof at a
concentration
exceeding 5 mg / ml of water or the aqueous medium.
According to an embodiment, the invention concerns the method, further
comprising
administering chemotherapy to the patient.
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According to an embodiment, the invention concerns the method, wherein the
cancer is selected
from the group consisting of breast cancer, head/neck cancer, esophagus
cancer, lymphoma,
cervical cancer, colorectal cancer, brain cancer, lung cancer, bladder cancer,
and prostate cancer.
According to an embodiment, the invention concerns a dispersion containing
dispersed
particulate Nimorazole or a pharmaceutically acceptable salt thereof in water
or an aqueous
medium, wherein the concentration of Nimorazole or its pharmaceutically
acceptable salt
exceeds the solubility limit in water or the aqueous medium, and wherein the
dispersion is
formulated for administration to a patient via a feeding tube.
According to an embodiment, the invention concerns the aqueous dispersion,
wherein the
particulate Nimorazole or its pharmaceutically acceptable salt has an average
diameter of less
than 710 p.m.
All cited references are incorporated by reference.
The accompanying Figures and Examples are provided to explain rather than
limit the present
invention. It will be clear to the person skilled in the art that aspects,
embodiments and claims of
the present invention may be combined.
Unless otherwise mentioned, all percentages are in w/w.
Examples
Examples Al, A2, A3, and A4
Tablet ingredients and manufacture
Tablet Al Tablet A2 Tablet A3 Tablet A4
Name of ingredient Specification mg/tablet mg/tablet
mg/tablet mg/tablet
Intragranular
Nimorazole INH. 500 500 500
500
Cellulose Ph. Eur. 50 50 50
34
microcrystalline (Avicel
PH 101)
Sodium Starch 14
Glycolate
Crospovidone (Kollidon Ph. Eur. 14 14
19.5
CL)
Povidone K30 [Binder] Ph. Eur. 28 28 28
28
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Purified water BP Q.S. Q.S. Q.S.
Q.S.
Extragranular
Cellulose Ph. Eur. 9 9 9
9
microcrystalline (Avicel
102)
Crospovidone (Kollidon Ph. Eur. 35 35 35
45.5
CL)
Silica Colloidal Ph. Eur. 7 7 7
7
anhydrous
(Cab-o-sil)
Magnesium Stearate Ph. Eur. 7 7 7
7
(VG)
Total weight of core tablet 650 650 650
650
Film Coating
Opadry 03657695 Grey INH. 6.5 6.5 13
16.25
Purified water BP 58.5 58.5 117
Q.S.
Total weight of coated tablet 656.5 656.5 663
666.25
Purified water evaporates during process and does not appear in finished
product.
Unless otherwise mentioned, the environmental conditions are about 22 C.
Crospovidone was
replaced with Sodium Starch Glycolate for Tablet Al. Tablets were manufactured
using the
following steps.
i. Sifting with vibratory sifter: Crospovidone was mixed with cellulose
microcrystalline
PH 101 and finally mixed with Nimorazole. The material was sifted through a
30#
sieve using vibratory sifter.
ii. Binder preparation and binder addition: Povidone K30 was
dispersed into weighed
quantity of purified water to prepare a 20% w/w dispersion under stirring.
iii. Dry mixing in rapid mixer granulator: The sifted material from step i.
was loaded into
Rapid Mixer Granulator, and the material dry mixed for 10 min at slow speed of
impeller, keeping Chopper off.
iv. Wet mixing: The binder of step ii. was added into step iii. within 2
minutes with slow
speed of impeller, keeping Chopper off. If required, additional sufficient
quantity of
purified water was added within one min.
v. The wet mass of step iv. was mixed up to 1 minute with slow speed of
impeller and
slow speed chopper to get uniform consistency of the wet mass. The wet mass
was
discharged from Rapid Mixer Granulator with impeller at slow speed.
vi. Wet milling in co-mill: The wet mass of step v. was passed through a
8.00 mm screen
using co-mill at 700 RPM.
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vii. Drying in fluidized bed processor! dryer of the wet granular mass was
performed
with an inlet temperature of 60 10 C, ensuring uniform drying, until loss on
drying
(%L0D) was obtained. The percent loss on drying (%L0D) of the granules was
determined at 105 C in auto mode in moisture analyzer, and drying was
continued
until %LOD reached within the limit, in the range of 1.5 to 3.0%.
viii. Sizing: The dried granules obtained in step vii. were sifted through
a 20# sieve using
Vibratory sifter to get uniform sized granules.
ix. 20# retained granules of step viii. were sifted through 14#. 14#
retained and 14#
passed granules were collected separately.
x. The 14# retained granules obtained in step ix. were milled through 2.0mm
SS screen
using co-mill at 700 RPM. The milled granules were passed through 20# sieve
using
vibro sifter.
xi. Both the oversized granules obtained in step x. and 14# passed 20#
retained fraction
of step ix. were milled through 1.0mm SS screen using co-mill at 700 RPM. The
milled
granules were passed through 20# sieve using vibro sifter.
xii. All the granules were finally sifted through 20# SS sieve using
vibratory sifter.
xiii. Blending & Lubrication in pillar type bin blender: Extragranular
cellulose
microcrystalline and crospovidone was sifted through 40# sieve using vibratory
sifter.
Subsequently, this was blended with the sifted granules for 10 minutes.
Separately,
silica colloidal anhydrous and magnesium stearate was sifted through 30# sieve
using
vibratory sifter. The mixture was added, and lubrication performed for 3
minutes.
xiv. Compression in rotary press tablet compression machine. Tablets with
average weight
of 650 mg were produced, having a disintegration time of not more than 15
minutes.
xv. Coating dispersion preparation in stirrer: Opadry 03657695 Grey was
dispersed in to
weighed quantity of purified water to prepare a 10% w/w dispersion under
stirring.
xvi. Coating in autocoater: The compressed core tablets were sprayed with
the film
coating dispersion. The curing was at 45 C inlet temperature.
xvii. Packaging in blister packing machine.
Tablets Al, A2, A3 and A4 are all suitable for oral administration as well as
dispersion in water
before being administered via a feeding tube. The tablets differed in terms of
time necessary for
dispersion and storage stability. Preliminary experiments indicate the amount
of coating provides
a trade-off between storage stability and dispersion time. More coating tend
to provide improved
storage time but also increased time for disintegration or dispersion.
Example B
Nimorazole Coated Tablets Comprising Crospovidone ¨ General Recipe
Dry mix containing Nimorazole, cellulose microcrystalline, crospovidone,
granulated using
granulating fluid, dried and sized. Granules further blended and lubricated
with extragranular
material and compressed in to tablets. Core tablets further film coated.
Tablets deliver 500 mg of
Nimorazole.
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Qty. Per Qty. Per
Sr. No. Name of Ingredient Category Tablet Tablet (mg)
[range] [Actual]
Intragranular
Active 500.000 mg
01. Nimorazole 500.000
ingredient
02. Cellulose microcrystalline
Diluent 1 - 50 % 50.000
(Avicel PH 101) (7.69%)
Disintegrant 0.5 - 15% 14.000
03. Crospovidone (Kollidon CL)
(2.154%)
04 Povidone K30 Binder 0.5 - 15 % 28.00 (4.30
%)
05 Purified Water Q.S. Q.S.
Extragranular
06. Cellulose microcrystalline
Diluent 0.5 - 50% 9.000
(Avicel 102) (1.385%)
07. Disintegrant 0.5 - 15% 35.000
Crospovidone (Kollidon CL)
(5.385 %)
08 Silica Colloidal anhydrous Glidant 0.5 - 3 %
7.000 (1.07 A)
( Cab- o -Sil)
09 Magnesium Stearate (VG) Lubricant 0.5 - 3 % 7.000
(1.07%)
Coating
10. Opadry 03657695 Grey Coating 0.5 - 5 % 13.00 (2.0%)
Example C
Nimorazole Tablets Comprising Sodium Starch Glycolate ¨ General Recipe
Dry mix containing Nimorazole, cellulose microcrystalline, Sodium starch
glycolate, granulated
using granulating fluid, dried and sized. Granules further blended and
lubricated with
extragranular material and compressed in to tablets. Tablets deliver 500 mg of
Nimorazole.
These tablets have no coating. The absence of a coating means that in general
patients dislike
swallowing the tablets due to the unpleasant taste of the active ingredient.
Qty. Per Tablet Qty. Per Tablet
Sr. No. Name of Ingredient
[range] (mg)
[Actual]
Intragranular
01.
Nimorazole 500.000 mg 500.000
Cellulose microcrystalline
02. 1 - 50 % 50.000 (7.69%)
(Avicel PH 101)
03.
Sodium starch glycolate 0.5 - 15% 14.000 (2.154%)
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04 Povidone K30 0.5 - 15 % 28.00 (4.30%)
05 Purified Water Q.S. Q.S.
Extragranular
06. Cellulose microcrystalline
0.5 - 50% 9.000 (1.385%)
(Avicel 102)
07. Sodium starch
glycolate 0.5 - 15% 35.000 (5.385 %)
08 Silica Colloidal anhydrous
0.5 - 3 % 7.000 (1.07%)
( Cab- o -Sil)
09 0.5 - 3 % 7.000 (1.07%)
Magnesium Stearate (VG)
Example D
Nimorazole Oral Powder
Dry mix of Nimorazole, Citric acid Anhydrous, Aspartame, Mannitol and Sucrose
granulated using
granulating fluid to prepare granules. Granules dried and sized and blended
with flavor. Blend
packed in single unit dosage form i.e. sachet. When one sachet is dispersed in
250 ml water yields
a dispersion which delivers 500 mg of Nimorazole.
This oral powder is less suited for direct oral administration without being
dispersed in water.
Qty.
Per
Qty. Per Sachet
Sr. No. Name of Ingredient Sachet(mg)
( range)
(Actual)
Intragranular
01. Nimorazole
500.00 mg 500.00
02. Citric acid
Anhydrous 0.5 - 15 % 40.00 (3.13%)
03. Aspartame 0.5-
25 % 250.00 (19.6 %)
04 Mannitol 0.5- 50% 185.00(14.51%)
05 Sucrose 0.5 - 50 % 100.00 (7.84%)
06. Purified Water
Q.S. Q.S.
Extragranular
07. Flavor 0.5 -
50% 40 (3.17%)
08 NAT FL Modulator (Sweet) FMT TM P 0.5 - 50% 160 (12.5%)
Example E
Nimorazole oral granules
Nimorazole, Cellulose Microcrystalline, Silica Colloidal Anhydrous, Maize
Starch,
Hydroxypropylcellulose, Povidone granulated by spraying granulating fluid by
using Top spray
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assembly. Granules further coated with basic butylated methacrylate copolymer
hydro-alcoholic
solution. Quantity equivalent to unit dose packed in sachet dispersed in 250
ml of water delivers
500 mg.
These granules have a tendency to clog a feeding tube, when the granules are
allowed to
disintegrate or disperse in water.
Qty. Per Dose Qty. Per Dose
Sr. No. Name of Ingredient
( range) (mg) (Actual)
Core granules
01. Nimorazole 500
mg 500 mg
Cellulose Microcrystalline 0.5 - 50%
02. 140* (19.8%)
(Avicel 101)
03. Silica Colloidal
Anhydrous 0.5 - 3% 5.00* (0.7%)
04 Maize Starch 0.5 - 15% 22.00*(3.11)
05 Hydroxypropylcellulose (HPC-L) 0.5 - 15% 7.50*(1.06%)
06. Povidone (Dry
Mixing) 0.5 - 15% 5.00*(0.7%)
07. Povidone
(Binding) 0.5 - 15% 20.00*(2.82%)
08. Purified Water
q.s. q.s.
Extragranular
09. Talc 0.25 - 3%
5.25 (0.74%)
10. Silica Colloidal
Anhydrous 0.15 - 3% 1.75 (0.25%)
Coated Granules
Coating Dispersion Ingredient
11. Basic Butylated Methacrylate Copolymer 0.5 - 10% 26.25*(3.71%)
12. Macrogol 6000
2 - 30% 2.625 @(10.0%)
13. Talc 5 - 50%
13.125 (50%)
14. Silica Colloidal
Anhydrous 0.5 - 3% 0.058 (0.22%)
15. Isopropyl Alcohol
q.s q.s
16. Purified Water q.s q.s
Total weight
Lubrication of coated Granules
17. Talc 0.05 - 3%
0.800
18. Silica Colloidal
Anhydrous 0.02 - 3% 0.354
* Quantity expressed as % w/w of core granules
@ Quantity expressed as % w/w of Polymer weight
Disintegration and Solubility
Experiments indicate the solubility of Nimorazole in water is 4.91 mg/ml.
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Tablet Al
Tablets Al had a thickness of 5.61 to 5.65 mm. The disintegration time was
measured to 2 ¨ 3 min.
Tablet A2
Tablets A2 had a thickness of 5.65 to 5.68 mm. The disintegration time was
measured to 18
seconds.
Dissolution
The % Cumulative Drug Release was measured in 900 ml 0.1 N HCI in a USP type
II apparatus at 50
RPM for 30 minutes, with measurements performed at 5, 10, 20, and 30 minutes.
500 mg % Cumulative Drug Release
Nimorazole
tablets 5 min. 10 min. 20 min. 30 min.
Tablet Al 74 94 96 100
Tablet A2 86 94 96 98
The use of Crospovidone as a disintegrant instead of Sodium Starch Glycolate
decreased the
disintegration time, and provided a significant increase in dissolution rate,
wherein more than
85% of the drug was released within 5 minutes.
Tablet A4
Preliminary experiments indicate Tablet A4 disintegrates in less than 3
minutes. About 85% of the
active ingredient, Nimorazole, dissolves before 10 minutes, and the active
ingredient is almost
completely dissolved before 30 minutes.
Comparison with prior art tablets
Dispersibility
The tablet Al (500 mg) of the present invention was compared with the tablet
F4 (200 mg) of the
prior art (this tablet is described in the article "Formulation and In-Vitro
Characterization of
Nimorazole Mouth Dissolving Tablets", Ratnaparkhi, Mukesh R et al., Research
Journal of
Pharmaceutical, Biological and Chemical Sciences (2012), Vol. 3, Issue 3, pp.
303-308.
Dispersibility tests were performed using water at room temperature. In order
to compare
mixtures comprising the same concentration of the active ingredient
Nimorazole, a tablet Al (500
mg) was dispersed in 50 ml water in a glass beaker, while a tablet F4 (200 mg)
was dispersed in 20
ml water glass beaker. Stirring was continued for 3 min.
After stirring, a homogenous dispersion was formed from the tablet Al without
precipitate (Fig. 1,
right), while a phase separation was apparent in the dispersion formed from
the tablet F4, having
a clear solvent phase above a precipitate clearly visible at the bottom of the
beaker (Fig. 1, left).
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Upon emptying the beakers, the beaker used for the tablet Al was left with
negligible amounts of
residue (Fig. 2, right), while the beaker used for the tablet F4 still
comprised remains from the
precipitate (Fig. 2, left).
It was thus shown that the tablet Al of the present invention upon stirring in
water provided a
dispersion, while the prior art tablet F4 did not provide a dispersion upon
stirring in water.
Sieve Testing
Tablets of the invention, Al (500 mg), were compared with prior art tablets,
F4 (200 mg, Ibid.).
Mixtures of water at room temperature and tablets were prepared as noted in
the tablet below.
Mixture Tablet Number of Total amount of Amount of
water
tablets Nimorazole / mg / ml
I Al 2 1000 100
II F4 5 1000 100
Ill F4 2 400 100
Mixture I provided a stable, homogenous dispersion, having a milky appearance
(Fig. 3, right). The
dispersion of Mixture I showed long term stability. Mixture II (Fig. 3, left)
and Mixture Ill both
provided non-homogenous mixtures, with a clear phase separation between
solvent and
precipitate.
The mixtures were poured through sieve screens #20, #30, and #40, having
apertures of 900 m,
600 m and 400 m, respectively. Mixture I passed through all 3 sieve screens
without leaving
any trace of precipitate in any of the sieve screens (Fig. 4, from left to
right: sieve #20, #30, #40).
Upon pouring Mixture ll and Ill through the 3 sieve screens, in both cases
particles remained in all
3 sieve screens (Fig. 5 and 6, respectively; from left to right: sieve #20,
#30, #40).
It was thus confirmed that Mixture I was a smooth dispersion, while Mixture ll
and Mixture Ill
were not.
Further, it was noted that for Mixture I negligible amounts of material was
left behind in the
bottle used for mixing, while for Mixture ll and Ill clearly visible lumps of
the tablets were left
behind. This indicates that for Mixture ll and Mixture Ill not all of the
active ingredient would be
present in the mixture poured from the bottle. Further, that the use of
Mixture ll and Ill would
increase the risk of blocking a feeding tube, and that the release of active
ingredient from the
Mixtures ll and Ill would be slower than for Mixture I, due to the larger
particle sizes resulting
from making mixtures of the prior art tablet.
In vitro Dissolution
The prior art tablet F4 (Ibid.) exhibits slower dissolution rate expressed in
percentage at all
measured points in time than the tablets Al and A2 (see above) of the present
invention. It is
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additionally surprisingly, since the prior art tablets F4 comprise 200 mg
active ingredient, while
the present tablets, Al and A2, comprise 500 mg active ingredient. This should
favor the %
cumulative drug release of the tablets F4 as the actual concentration of the
active ingredient
Nimorazole is lower in the USP apparatus for the 200 mg tablets.
Thus, it is an advantage of the present tablet that higher dissolution rates
are achieved in vitro,
making it easier to achieve peak serum level of the active ingredient at a
specific time, coinciding
with irradiation treatment, and further increasing the serum peak level of the
active ingredient.
Patient Compliance ¨ Test of taste masking properties of Coating
The tablet Al (500 mg) of the present invention was compared with the tablet
F4 (200 mg) of the
prior art (described in the article "Formulation and In-Vitro Characterization
of Nimorazole Mouth
Dissolving Tablets", Ratnaparkhi, Mukesh R et al., Research Journal of
Pharmaceutical, Biological
and Chemical Sciences (2012), Vol. 3, Issue 3, pp. 303-308.
Two informed test persons (healthy volunteers) were requested to place
individual tablets on the
forefront of the tongue for 30 seconds by pressing the tongue with the tablet
up against the
palate. After 30 seconds, the taste sensation is graduated on a scale from one
to ten in terms of
bitterness / taste sensation.
The following scale was used:
No 1 2 3 4 5 6 7 8 9 10
Taste Neutral Slightly unpleasant Very Extremely
taste taste unpleasant unpleasant
taste taste
In addition, a subjective description is given to whether the taste is deemed
to have an adverse
effect in terms of compliance to treatment considering that the treatment will
involve 3 -4 tablets
a day over an average of 30 days.
The results are provided in the table below.
Reported Results tablet Al Results tablet F4
taste and
sensations
Test Person 1 1: No taste 8-9: Very or extremely unpleasant
taste
Very unpleasant, metallic taste after
spitting the tablet out. This sensation
remained a very long time after spitting
the tablet out.
24
CA 02888856 2015-04-21
WO 2014/075692
PCT/DK2013/050384
Test Person 2 1: No taste during the 30 seconds. 7: Very unpleasant
taste
2: Slight taste upon spitting out the Would not be able to keep this tablet in
tablet. the mouth until dissolved due to
very
unpleasant metallic taste.
It was noted that the mouth dissolving tablet F4 would be unsuitable for
patients having no saliva.
Further, due to the very unpleasant taste, this tablet would not be suitable
for combination with
irradiation treatment, due to the large amounts of active ingredient and thus
tablets required.
The suggested mode of administration of F4 (i.e. mouth dissolving) is hence
not suitable for
treatments of patients.
