Note: Descriptions are shown in the official language in which they were submitted.
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SOLID DOSAGE FORM COMPRISING DESMOPRESSIN AND METHOD FOR
MANUFACTURING THEREOF
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a novel pharmaceu-
tical composition as a solid dosage form comprising
desmopressin as a therapeutically active ingredient, and
to a method for manufacturing thereof.
Description of the Related Art
Desmopressin, also known as dDAVP, is the therapeu-
tically active ingredient (as its acetate salt) in the
pharmaceutical product Minirin°, which is marketed inter
alia as a nasal spray and a tablet formulation.
Desmopressin is primarily used in the treatment of
primary nocturnal enuresis, i.e. bedwetting, in children,
but it is approved also for the treatment of nocturia and
diabetes insipidus. The first market introduction of the
tablet formulation was in Sweden in 1987.
In short, a solid dosage form such as a tablet
formulation is typically manufactured by compression of a
suitable granulate to the desired solid dosage form,
where the granulate is composed of the required
constituents as a mixture of solid particles. Typical
such particles are the therapeutically active ingredient,
various excipients (fillers), disintegrating agents,
lubricants and binders, optionally together e.g. with
flavoring agent, preservative and/or colorant. The
commercially available Minirin° tablet is prepared
according to this general protocol, and the tablet was
first disclosed as set forth in the patent US 5 047 398.
For a comprehensive overview of pharmaceutical tablet
manufacturing, see "Tableting" (by N.A. Armstrong) in
"Pharmaceutics - The science of dosage form design", pp
647-668; Ed. M.E. Aulton, Churchill Livingstone,
Edinburgh, London, Melbourne and New York, 1988.
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The Minirin° tablet that is currently marketed, and
thus produced in industrial scale, consists of the thera-
peutically active ingredient desmopressin together with
potato starch and lactose as excipients, and a suitable
amount of binder and lubricant, respectively.
In any tablet compression of a granulate composed of
a mixture of solid particles there is a general need to
perform the compressing operation at the highest possible
speed while at the same time minimising machine wear and
obtaining tablets of a quality that meets the regulatory
demands of all relevant territories.
SUMMARY OF THE INVENTION
It has now been discovered that a certain dimension
of the excipient particles unexpectedly provides a
substantial improvement on the speed of the manufacturing
process, while both machine wear and tablet quality
remain substantially unaltered compared to the industrial
manufacturing process hitherto used. In essence, the
dimension in question seems to affect the flowability of
particles and granulate in such a manner that it provides
an improved overall capacity, and hence speed, in the
manufacturing process for the desmopressin tablet
formulation.
More specifically, the present invention relates to
a pharmaceutical composition as a solid dosage form
comprising desmopressin, or a pharmaceutically acceptable
salt thereof, as a therapeutically active ingredient
together with a pharmaceutically acceptable excipient,
diluent or carrier, or mixture thereof, wherein at least
one of said excipient, diluent and carrier is a
disaccharide, wherein the said disaccharide has an
average particle size in the range of from 70 to 500 Vim.
DETAILED DESCRIPTION OF EMBODIMENTS
In many cases the terms excipient, diluent and
carrier can be used interchangeably, and they may even
refer to one and the same substance, or to a mixture of
similar such substances. The proper use and understanding
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of these terms is self-explanatory and lies well within
the ability of a person skilled in the art of
pharmaceutical formulation.
The pharmaceutical composition according to the
present invention may optionally comprise at least one
additive selected from a disintegrating agent, lubricant,
binder, flavoring agent, preservative, colorant and a
mixture thereof. Where considered suitable also other
additives may be included. Representative examples of
disintegrating agents, lubricants (e. g. magnesium
stearate); binders (e. g. Kollidon~ 25, BASF), flavoring
agents, preservatives and colorants, and suitable
mixtures thereof, as well as any other conventional
additive that may be considered by a person skilled in
the art practising the present invention, can be found in
"Handbook of Pharmaceutical Excipients"; Ed. A.H. Kibbe,
3rd Ed., American Pharmaceutical Association, USA and
Pharmaceutical Press UK, 2000. As an example, also
applicable in the practising of the present invention, it
can be mentioned that typical amounts of lubricants and
binders are in the order of less than 6 percent by weight
of the pharmaceutical composition.
In the marketed tablet resulting from the hitherto
used manufacturing process, the lactose particles
(PharmatoseT'" 150M provided by DMV, the Netherlands) have
an average size of about 50 Vim, as determined by an air
jet sieve (provided by Alpine GmbH, DE). That particle
size does not provide a granulate that allows a
compressing speed exceeding about 170 000 tablets per
hour (h). In contrast thereto, the process according to
the present invention allows a compressing speed of up to
about 250 000 tablets/h with the desired tablet quality
and retained low level of wear on the tabletting
machinery.
In a preferred embodiment, said average particle
size is in the range of from 75 to 350 ~.m. In yet another
preferred embodiment, said average particle size is in
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the range of from 100 to 200 Vim. In a further preferred
embodiment, said average particle size is in the range of
from 120 to 180 Vim. In the most preferred embodiment of
the present invention, said average particle size is 140
~m (as measured by an air jet sieve). The lactose
particles sold as Pharmatose~ DCL 15, marketed by DMV in
the Netherlands, are of this most preferred average
particle size. Other particular embodiments may involve
use of e.g. Pharmatosen DCL,11, Pharmatose~ DCL 21 and
Pharmatose~ DCL 40, all provided by the aforementioned
DMV, which have an average particle size of 110, 150 and
165 Vim, respectively.
According to the commercial provider the particle
size distribution of Pharmatose~ DCL 15 is that
essentially all particles have a size below 500 Vim,
whereas approximately 72% of the particles have a size of
from 75 to 350 Vim.
In an air jet sieve measurement of particle size,
air is drawn upwards, through a sieve, from a rotating
slit so that material on the sieve is fluidised. At the
same time a negative pressure is applied to the bottom of
the sieve which removes fine particles to a collecting
device. Size analyses and determination of average
particle size are performed by removal of particles from
the fine end of the size distribution by using single
sieves consecutively. See also "Particle Size
Measurement", 5th Ed., p 178, vol. 1; T. Allen, Chapman &
Hall, London, UK, 1997, for more details on this. For a
person skilled in the art, the size measurement as such
is thus of conventional character.
Accordingly, it is preferred that said disaccharide
is lactose, more preferably lactose-a-monohydrate.
The total combined amount of said excipient, diluent
and carrier is usually from 5 to 99, preferably from 50
to 99, percent by weight of the pharmaceutical
composition, the balance up to 100% being the
therapeutically active ingredient optionally together
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with the aforementioned additives, where the latter is
preferably lubricant and binder.
The pharmaceutical composition as a solid dosage
form according to the present invention is typically a
5 perorally available tablet. As an alternative non-
limiting embodiment, the said tablet may be adapted for
oral, including buccal and/or sublingual, administration.
The composition typically comprises desmopressin
acetate in an amount of from 20 to 600 ~g per unit of
solid dosage form. As an example, a typical tablet
containing 100 ~g of desmopressin acetate is white,
convex and oval (6.7 x 9.5 mm) with a thickness of 3-4 mm
and a weight of 200 mg. As another example, a tablet
containing 200 ~g of desmopressin acetate is white, round
(8 mm diameter) and convex with a thickness of 3-4 mm and
a weight of 200 mg.
Accordingly, a further aspect of the present
.invention relates to a method for the manufacturing of a
pharmaceutical composition as a solid dosage form
comprising desmopressin, or a pharmaceutically acceptable
salt thereof, as a therapeutically active ingredient,
wherein said method comprises the steps of:
i) mixing desmopressin and an excipient, diluent or
carrier, or mixture thereof, optionally in the
presence of a wetting agent, wherein at least one
of said excipient, diluent and carrier is a
disaccharide, wherein said disaccharide has an
average particle size in the range of from 70 to
500 Vim;
ii) subjecting the resulting mixture to formation of
a granulate, optionally in the presence of a
wetting agent, suitable for compression into said
solid dosage form;
iii) optionally performing said mixing and/or forma
tion of a granulate in the presence of at least
one additive selected from a disintegrating
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' agent, lubricant, binder, flavoring agent, pre-
servative, colorant and a mixture thereof;
iv) optionally drying said granulate;
v) compressing said granulate into said solid dosage
form.
The method according to the present invention can as
such, once the specific components are identified and
included, be practised by using conventional equipment
for the manufacturing of pharmaceutical formulations. A
granulate suitable for compression into tablets typically
has an average granulate size of at least about 100 ~tm.
Discrete granules with a size above 2 mm are usually not
transferred to the subsequent compressing step.
As non-limiting examples mention can be made of the
following equipment for granulation: directly heated
fluidised solid beds e.g. provided by GEA/Collette NV, BE
(UltimaProTM series), Huttlin GmbH, DE (HDG series),
Diosna Dierks & Soehne GmbH, DE (VAC series), Fluid Air
Inc., US (Magnaflo~ series) and Vector Corp., US (GMX
series); indirect conduction moving solids bed, including
paddle systems, rotary systems and agitation systems,
which are e.g. provided by Jaygo Inc., US (JRB and
Novamix series), Paul 0. Abbe Inc., US (Rota-Cone, Rota-
U, Rota Blade, Cylindrical Ribbon/Paddle, Plow and Sigma-
blade series), Forberg A/S, NO (Forberg II series), Gemco
Inc., US (D/3 Double Cone, V-Shape and Slant-Cone
series), LittlefordDay Inc., US (Double Arm, Day Nauta
and Daymax series), Patterson-Kelly, Harsco Corp., US (P-
K Solids Processor~ series), Diosna as above (CCS and VAC
series), Romaco Zanchetta SpA, IT (Roto E, Roto D and
Roto P series) and L.B. Bohle Maschinen and Verfahren
GmbH, DE (Granumator GMA and Vagumator VMA series);
The aforementioned equipment in general also provides
drying of the prepared granules.
In a preferred embodiment, said average particle
size is in the range of from 75 to 350 Vim. In yet another
preferred embodiment, said average particle size is in
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the range of from 100 to 200 Vim. In a further preferred
embodiment, said average particle size is in the range of
from 120 to 180 ~.m. In the most preferred embodiment of
the present invention, said average particle size is 140
~.m. The lactose particles sold as Pharmatose'" DCL 15,
marketed by DMV in the Netherlands, are of this most
preferred average particle size. Other possible
embodiments of the present method may involve the
aforementioned variants of Pharmatose~" DCL (vide supra).
It is accordingly preferred that said disaccharide
is lactose, more preferably lactose-a-monohydrate.
In the method according to the present invention,
the manufactured solid dosage form is typically a
perorally available tablet. Where desired, it may also be
in a form and/or composition adapted for oromucosal
administration. Preferred examples of the latter are
buccal and/or sublingual administration. Examples of
tablet compressing equipment suitable for the practising
of the present invention are rotary presses provided by
Elizabeth-Hata International, US (HT series), Courtoy NV,
BE (R090F, R100M, R190FT, R290FT, R292F and 8233 series),
Vector Corp., US (2000, 200 and Magna series), Fette
GmbH, DE (Hightech, Medium, Special and WIP series),
Manesty, UK (Xpress, Diamond and Value series) and Kilian
& Co. GmbH, DE (S, T, E, RX and KTS series).
In a preferred embodiment of the present inventive
method said steps of mixing and formation of granulate
are performed in a single integrated machinery that is
adapted for such a "one-pot", i.e. combined, process. An
example of such integrated machinery, alternatively
denoted one-pot (single pot) equipment, is the FT series,
provided by Forberg A/S, Norway.
It is preferred that where used, said wetting agent
is selected from water and a mixture of water and an
alcohol, preferably ethanol. A water/ethanol 1:3 mixture
is typically used, albeit many other combinations are
also possible.
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' As indicated above, it is preferred that said
resulting mixture is subjected to formation of a
granulate with an average granulate size of a least 100
Vim, preferably in the range of from 100 ~m to 2 mm.
The method is performed in such a manner that the
total combined amount of said excipient, diluent and
carrier is from 5 to 99, preferably from 50 to 99,
percent by weight of the pharmaceutical composition.
In the most preferred embodiment, desmopressin
acetate is used and mixed with said excipient, diluent
and/or carrier in an amount that eventually provides from
to 600 ~g of desmopressin acetate per unit of solid
dosage form (see above and the experimental part for
examples of a tablet).
15 In order to substantiate and illustrate the present
invention in more detail, the following example is
provided. It shall not be construed as a limitation of
how the invention may be practised.
Example
20 Example 1: Preparation of solid dosage form of dDAVP
Desmopressin acetate (100 or 200 g; provided by
PolyPeptide Laboratories AB, SE), polyvinyl pyrrolidone
(PVP) as binder (1,84 kg; Kollidon~ 25 provided by BASF
GmbH, DE) and granulation liquid (water/ethanol 1:3
mixture) are combined in a vessel and mixed at room
temperature until a clear solution is achieved. The
potato starch (77 kg, average particle size about 40-50
~m according to laser diffraction measurements;
AmylSolVat provided by Lyckeby Starkelse AB, SE), is
weighed and sieved through a 2 mm sieve. Lactose (120 kg,
DCL 15 provided by DMV NV, NL; see above for the details
of this product) is weighed and loaded together with the
starch into a single pot mixer (FT-350; provided by
Forberg A/S, NO) and mixed therein. The granulation
liquid solution is then sprayed onto the powder mixture,
after which the moist granulate is dried with warm air
(50°C), all with continued mixing. The dried granulate is
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then sieved (2 mm) and transferred to a double cone
mixer. Magnesium stearate (max 1.0 kg; provided by Peter
Greven NV, NL) is then weighed in, sieved (1 mm) and
transferred to the double cone mixer for final mixing.
Tablets are then compressed from the resulting mixture by
using a conventional rotary tablet compression machine
(Kilian S-250), whereby a compressing speed of about
250 000 tablets/h is attainable with adequate tablet
quality and low machine wear. A tablet of adequate
quality has a smooth surface without scratches or chipped
edges, and it shows no tendencies to lamination (so-
called capping).
The process is typically adapted to provide a tablet
containing 100 or 200 ~g of desmopressin acetate with the
aforementioned appearance, dimension and weight.
