Note: Descriptions are shown in the official language in which they were submitted.
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FAST D1SINTEGRAT1NG ORAL DOSAGE FORM
The present invention relates to the field of pharmaceutical orally ingested
solid dosage
forms, which are designed to dissolve rapidly within the mouth. Currently two
main
technologies are used to obtain such type of dosage forms: (1 ) The active
ingredient is
mixed with water-soluble diluents and compressed on a tableting machine at low
to medium
compression force. This is the more conventional approach. (2) A suspension is
prepared
with the active ingredient and appropriate excipients. The suspension is
dispensed into
blister packs and freeze-dried.
Many people are unwilling and/or unable to swallow tablets, capsules or
traditional solid
dosage forms. One approach suitable for these persons is the use of
effervescent tablets or
granules. However, the use of effervescent tablets requires preparatory steps
before
administration of the drug and the presence of water and a suitable mixing
container. In
addition, the manufacture and stability of effervescent tablets is often
problematic. Another
possibility is the use of a chewing gum or chewing tablet containing a
medicament capable
of absorption through the buccal cavity. Substantial disadvantages inherent in
such a
delivery system are that many medicaments are not suited for buccal absorption
and that
many persons are not able to chew gums or tablets because of braces, dental
work etc.
Furthermore, gums are often difficult to prepare.
A more recent approach is the OraSolv~ technology of the company Cima.
Orasolv~ is an
oral dosage form, which involves incorporating microencapsuiated drug
ingredients into a
tablet that dissolves in the mouth without the need for chewing or water. The
Orasolv~
tablets are obtained by compression and packed into special peel-off blister
packs because
their mechanical resistance is insufficient in normal blister packs. The
OraSolv° tablets
normally need 15 to 60 seconds to dissolve in the mouth, which is longer than
ideally
aspired to in modern fast melting oral dosage forms. The same disadvantage of
dissolving
not rapidly enough in the mouth is common with many other approaches to fast
melting oral
dosage forms.
A fast dissolving (normally in 3 to 5 seconds) oral drug delivery system named
ZydisO is
known from the company R.P. Scherer. The principle of this technology consists
in
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preparing an aqueous suspension of the active ingredient and the excipients,
which is
dispensed into blister packs and the water removed by a freeze drying process.
The final
product is obtained by sealing the dried product in special peel-off blister
packs - like
Orasolv~ due to lacking mechanical resistance in normal blister packs. A major
disadvantage of this technology is the time-consuming and costly freeze-drying
process.
Furthermore, the effectiveness of a freeze-drying process always depends on
the physico-
chemical parameters of the active substances used. For certain active
substances,
especially such having a high solubility in water, it is therefore difficult
or impossible to apply
a freeze-drying process and consequently this technology. Finally, the
development of units
with high doses {up to 500 mg or even 1000 mg) of active ingredients and/or
combinations
of active ingredients is difficult or impossible, respectively with this
technology.
The present invention addresses the needs mentioned above and the problems
encountered with currently available technologies. The expensive freeze-drying
process is
avoided. The manufacture of the dosage form of the invention is simple and
suitable for a
broad range of active ingredients with different physico-chemical parameters,
for high dose
unit forms (up to e.g. 1000 mg, in particular 500 mg, of active substance) and
also for
combinations of active ingredients.
The present invention provides a solid pharmaceutical dosage form adapted for
direct oral
administration, i.e. for direct insertion into the mouth of a patient. This is
particularly useful
in administration of medicaments to individuals who cannot or will not chew,
such as
debilitated patients, patients who have difficulty swallowing solids and the
elderly.
Therefore, the present invention relates to a solid pharmaceutical dosage form
for oral
administration, consisting essentially of
{a) at least one active substance,
(b) at least one filler,
(c) at least one binding agent, and
(d) optionally usual auxiliaries,
which dosage form disintegrates when taken into the mouth within 15 seconds,
preferably
within 10 seconds, and especially within 5 seconds.
CA 02250115 2004-09-14
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2a
According to one aspect of the present invention,
there is provided a solid pharmaceutical dosage form for
oral administration, consisting substantially of a mixture
of (a) at least one active substance; (b) at least one
filler selected from the group consisting of mannitol,
lactose, calcium phosphates, calcium sulphates, sucrose,
glucose, fructose, sorbitol and xylitol, in an amount of at
least 50 weight $; (c) at least one binding agent selected
from the group consisting of polyethylene glycols, acacia,
tragacanth, starch, cellulose materials,
polyvinylpyrrolidones, alginic acid or a salt or an ester
thereof, carrageenan gum, xanthan gum, gellan gum and
gelatin, in an amount of from 0.1 to 10 weight o; and (d)
optionally one or more pharmaceutically acceptable
auxiliaries, which dosage form does not contain agar; which
dosage form has a density of 300-900 mg/ml; which dosage
form is manufactured without applying any compression force
to the mixture of the components (a), (b), (c) and (d); and
which dosage form disintegrates within 15 seconds when taken
into the mouth.
According to another aspect of the present
invention, there is provided a process for preparing a solid
pharmaceutical dosage form for oral administration, the
process comprising: (A) preparing a suspension of solution,
said suspension or solution comprising (1) at least one
active substance; (2) at least ane filler selected from the
group consisting of mannitol, lactose, calcium phosphates,
calcium sulphates, sucrose, glucose, fructose, sorbitol and
xylitol, in an amount of at least 50 weight o; (3) at least
one binding agent selected from the group consisting of
polyethylene glycols, acacia, tragacanth, starch, cellulose
materials, polyvinylpyrrolidones, alginic acid or a salt or
an ester thereof, carrageenan gum, xanthan gum, gellan gum
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2b
and gelatin, in an amount of from 0.1 to 10 weight ~; (4)
optionally one or more pharmaceutically acepptable
excipients; and (5) a solvent, said suspension or solution
not comprising agar; (B) dispensing the suspension or
solution into molds, corresponding in size and shape to that
of the pharmaceutical dosage form; (C) removing the solvent
without applying a freeze-drying process, thereby producing
dried units of the solid pharmaceutical dosage form having a
density of 300-900 mg/ml; and (D) either removing the dried
units for storage from the molds for storage in suitable
containers, or, sealing the dried units directly into the
molds.
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More precisely, the solid pharmaceutical dosage form consists essentially of a
mixture,
especially a homogeneous mixture, of the components (a), (b), (c) and (d)
mentione above.
Active substances are especially pharmaceuticals but may be also, for example,
vitamins,
minerals or dietary supplements. Pharmaceuticals may include, without
limitation, antacids,
analgesics, anti-inflammatories, antibiotics, laxatives, anorexics,
antiasthmatics,
antidiuretics, antiflatulents, antimigraine agents, antispasmodics, sedatives,
antihyperactives, tranquilizers, antihistamines, decongestants, betablockers,
hormones and
combinations thereof. Preferred active substances are analgesics and non-
steroidal anti-
TM
inflammatory drugs, such as diclofenac, ketoprofen, ibuprofen, aspirin or
paracetamol or a
pharmaceutically acceptable salt thereof, and hormones, e.g. melatonin.
Especially
preferred is diclofenac which may be present either as free acid or as a
pharmaceutically
acceptable salt thereof, e.g. the potassium or sodium salt.
The filler can be chosen from those known in the art including mannitol,
lactose, calcium
hosphates, calcium sulphates, sucrose, glucose, fructose, sorbitol and
xylitol. It has been
found that a particularly advantageous filler is mannitol, because it is
particularly useful in
forming the low density matrix of the dosage form that disintegrates rapidly
within the
mouth. Furthermore, mannitol permits an easy drying process of the formulation
after filling
the suspensioNsolution into the blisters because of its non-hygroscopic
character. The filler
is usually present in an amount of at least 50 weight-%, preferably at least
60 weight-%,
and especially at least 70 weight-% of the total dosage form.
The binding agent (or binder) is primarily used to give sufficient consistency
to the
formulation to avoid breaking of the article when removed from the blisters
and during
handling. Binding agents that can be used include polyethylene glycols,
acacia, tragacanth,
starch, cellulose materials, polyvinylpyrrolidones, alginic acid or a salt or
an ester thereof,
carrageenan gum, xanthan gum, gellan gum and the like. Also gelatin comes into
consideration as a binder.
Preferred as binding agents are polyethylene glycols, carrageenan gum, xanthan
gum,
gellan gum, starch, cellulose materials, polyvinyl pyrrolidones, alginic acid
or a salt or an
ester thereof, and also gelatin.
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Especially preferred are polyethylene glycols and polyvinylpyrrolidones. In
particular,
polyethylene glycol, e.g. polyethylene glycol 6000, is used. The binding agent
is usually
present in an amount of from 0.1 up to 10 weight-% and especially of from 0.2
up to 3
weight-% of the total dosage form.
Covered by the term "usual auxiliaries" are, for example, lubricants. They are
primarily used
to avoid sticking of the dried product to the surface of the mould. Examples
of lubricants
which can be used are talc, magnesium stearate or calcium stearate, stearic
acid,
polyethyleneglycols, sodium stearyl fumarate, hydrogenated vegetable oil, a
behenic acid
derivative and the like. It has been found that talc, hydrogenated vegetable
oil and a
behenic acid derivative - in particular talc - are especially useful
lubricants in the dosage
forms of the present invention. A behenic acid derivative is e.g. glyceryl
behenate (also
called "tribehenin") which corresponds to a mixture of glycerides (mainly
triglycerides) of
fatty acids (mainly behenic acid). Corresponding products on the market
include the
Compritol~ series of the company Gattefosse (France). If used, the lubricant
is usually
present in an amount of up to 15 weight-%, e.g. in an amount of from 1 up to
15 weight %,
and especially in an amount of up to 10 weight-% of the total dosage form.
The dosage forms of the present invention may include further auxiliaries
(adjuvants) known
in the art including flavors, aromas, sweeteners, colorants, buffering agents,
acidifying
agents, diluents, preservatives and the like.
The present invention further relates to a process for preparing the solid
pharmaceutical
dosage form for oral administration of the invention, which process comprises
(A) preparing a suspension or solution which contains all the components (a),
(b), (c) and
(d) of the dosage form,
(B) dispensing the suspension or solution into moulds, corresponding in size
and shape to
that of the pharmaceutical dosage form,
(C) removing the solvent without applying a freeze-drying process, and
{D) removing the dried units for storage in suitable containers or sealing
them directly in the
moulds.
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Thus, the manufacture of the dosage form according to the present invention
includes
preparing a suspension (or solution), where the active ingredient is dispersed
or dissolved in
a solvent together with all the other components of the composition, such as
fillers, binders
and the usual auxiliaries present. The solvent is e.g. water, or a mixture of
water with a co-
solvent, e.g. ethanol, or even a pure non-aqueous solvent, e.g. ethanol. The
active
ingredient is nom~ally used as the pure substance in different crystalline
forms but it can
also be e.g. microencapsulated. After preparation of the suspension (or
solution), the latter
is dispensed into moulds, e.g. blisters. This may be done either manually,
semi-
automatically or automatically.
Surprisingly, it is possible to dry the moulds, e.g. blisters, - that is to
remove the solvents) -
without applying a freeze-drying process, as known e.g. from the Zydis~
technology of the
prior art. This can be done, for example, by simple storage at room
temperature or at
elevated temperatures, or by storage at room temperature or at elevated
temperatures
under reduced pressure, or by applying microwave radiation, or by applying
microwave
radiation under reduced pressure. The evaporation normally is done at a
temperature of
from 10 up to 80°C, e.g. at room temperature between 15 and
25°C, or by heating up to
80°C, especially up to 50°C. "Under reduced pressure" preferably
means pressures of from
0.1 mbar up to 200 mbar, but also high vacuum, e.g. 0.001 to 0.1 mbar, is
possible. When
microwave radiation is applied, this is preferably done in a system that is
able to work on-
line (continuously) during the manufacturing process. The process is simple
and suitable for
a broad range of active ingredients with different physico-chemical
parameters, for high
dose unit-#orms (up to 1000 mg, in particular 500 mg of active substance) and
also for
combinations of active ingredients.
From the, above-said it has become clear that the dosage form of the present
invention is
manufactured without applying any compression force to the mixture of the
components (a),
(b), (c) and (d). As a result of the particular process of manufacture used,
the dosage form
of the invention normally has a density of 200-1000 mg/ml, preferably 300-900
mg/ml, more
preferably 600-900 mg/ml, or 400-800 mg/ml. This is a density that is much
lower than that
of compressed dosage forms like normal tablets etc. (having densities of above
1000
mg/ml). As a result of its unusually low density, the dosage form of the
invention
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disintegrates more rapidly than would be the case, if the mixture of its
components (a), (b),
(c) and (d) are subjected to compression force.
The dried units may e.g. be sealed or removed from the moulds for storage in
suitable
containers. According to a preferred embodiment of the invention, the dried
blisters are
finally sealed to obtain the finished product, either in special peel-off
blister packs or,
preferably, in normal blister packs.
The dosage form is presented e.g. as a tablet of a size and shape adapted for
direct oral
administration to a patient. The tablet is pleasant to take and, once placed
into the mouth,
will disintegrate substantially and instantly without any voluntary action by
the patient, e.g.
chewing. Upon disintegration of the tablet, the active ingredient is released
and can be
swallowed as a suspension or absorbed from the buccal cavity. Buccal
absorption can be
particularly advantageous for substances submitted to a high first hepatic
metabolism.
The dosage form according to the present invention is convenient to use for
the consumer
without the need of water or additional devices. Moreover, the instant
disintegration andlor
dissolution gives a sensation of a rapid and powerful action of the
pharmaceutical dosage
form and makes it unique and motivating for the patient to take.
An oral dosage form according to the present invention may also be, for
example, a shaped
article. The mass of each such an article is generally less than about 2.0 g.
Preferably, the
articles are circular, disk-like with a diameter between 5 and 20 mm.
The following examples illustrate the invention.
Examgle-1: Fast melting oral dosage form containing 12.5 mg of Diclofenac
potassium
(overall weight: 200 mg)
Composition m unit
Diclofenac potassium 12.5
Mannitol 152.3
Polyethylene glycol 6000 1.6
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Citric acid 10.0
Talc i 6.0
Aspartam 6.0
Lemon aroma 1.6
Purified water 150.0
Diclofenac potassium, mannitol, talc, aspartam and the aroma are mixed for 5
min, sifted
through a 0.5 mm mesh screen and then mixed again for 15 min. Citric acid and
polyethylene glycol are dissolved in purified water. The former dry mixture
containing
diclofenac potassium etc. is suspended in the latter aqueous solution under
stirring. While
stirring, adequate aliquots of the suspension are dispensed manually with a
pipette in
blisters, and the blisters are dried at room temperature for 10 h. The dried
units may now be
removed from the blisters and stored in glass containers. Alternatively, the
dried blisters
may be sealed to obtain the finished product.
In an analogous manner as described in example 1, also the fast melting oral
dosage forms
of examples 2 to 5 are manufactured.
Exam I~: Fast melting oral dosage form containing 12.5 m~ of Diclofenac
potassium
(overall weight: 200,4 mg)
Coma~osition m unit
Diclofenac potassium 12.5
Mannitol 152.3
Polyvinylpyrrolidone 2.0
Citric acid 10.0
Talc 16.0
Aspartam 6.0
Lemon aroma 1.6
Purified water 150.0
x m I 3: Fist melting oral dosage form containing 12.5 ma of Ketoprofen
(overall weight: 190 mg)
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_g_
Composition m-g/unit
Ketoprofen 12.5
Mannitol 152.3
Polyethylene glycol 1.6
Talc 16.0
Aspartam 6.0
Mint aroma 1.6
Purified water 150.0
Example 4: Fast melting oral dosage form containin-g 3.0 mg of Melatonin
(overall weight: 190 mg)
Composition m_a/unit
Melatonin 3.0
Mannitol 161.8
Polyethylene glycol 1.6
Talc 16.0
Aspartam 6.0
Mint aroma 1.6
Purified water 150.0
Examl Ip a 5: Fast meltino oral dosage form containing 12.5 mg diclofenac
potassium
(overall weight : 400 mg)
Com osition (mg/unit)
Diclofenac potassium 12.5
Mannitol 353.5
Gellan gum 2
Polyethylene glycol 8
Talc 16
Aspartam 6
Mint aroma 2
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_g_
Purified water 37.5
ethanol 75
In this example - contrary to example 1 - the drying of the blisters is done
at 50°C under
reduced pressure (0.1 mbar). Finally, the dried blisters are sealed to obtain
the finished
product.
