U.S. patent application number 11/486214 was filed with the patent office on 2006-11-09 for pharmaceutical composition as solid dosage form and method for manufacturing thereof.
This patent application is currently assigned to Ferring B. V.. Invention is credited to Hakan Lomryd, Helena Nicklasson, Lars-Erik Olsson.
Application Number | 20060252696 11/486214 |
Document ID | / |
Family ID | 33309778 |
Filed Date | 2006-11-09 |
United States Patent
Application |
20060252696 |
Kind Code |
A1 |
Lomryd; Hakan ; et
al. |
November 9, 2006 |
Pharmaceutical composition as solid dosage form and method for
manufacturing thereof
Abstract
The present invention relates to a novel pharmaceutical
composition as a solid dosage form comprising desmopressin as a
therapeutically active ingredient, and to a method for
manufacturing thereof. The 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 substance selected
from a monosaccharide, disaccharide, oligosaccharide and a
polysaccharide, wherein the said substance has an average particle
size in the range of from 60 to 1,000 .mu.m. A method according to
the present invention provides an improved production of solid
dosage forms of desmopressin.
Inventors: |
Lomryd; Hakan; (Malmo,
SE) ; Nicklasson; Helena; (Malmo, SE) ;
Olsson; Lars-Erik; (Malmo, SE) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Ferring B. V.
|
Family ID: |
33309778 |
Appl. No.: |
11/486214 |
Filed: |
July 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10425993 |
Apr 30, 2003 |
7094545 |
|
|
11486214 |
Jul 14, 2006 |
|
|
|
Current U.S.
Class: |
514/53 ;
514/10.9 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61K 9/2027 20130101; A61K 38/095 20190101; A61K 9/2059 20130101;
A61K 31/4025 20130101 |
Class at
Publication: |
514/012 ;
514/053 |
International
Class: |
A61K 38/22 20060101
A61K038/22; A61K 31/7012 20060101 A61K031/7012 |
Claims
1. 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 .mu.m, and wherein said solid
dosage form is a tablet.
2. The pharmaceutical composition according to claim 1, wherein
said average particle size is in the range of from 75 to 350
.mu.m.
3. The pharmaceutical composition according to claim 3, wherein
said average particle size is in the range of from 100 to 200
.mu.m.
4. The pharmaceutical composition according to claim 4, wherein
said average particle size is in the range of from 120 to 180
.mu.m.
5. The pharmaceutical composition according to claim 1, wherein
said disaccharide is lactose.
6. The pharmaceutical composition according to claim 1, wherein the
total combined amount of said excipient, diluent and carrier is
from 5 to 99 percent by weight of the pharmaceutical
composition.
7. The pharmaceutical composition according to claim 1, which
comprises desmopressin acetate in an amount of from 20 to 600 .mu.g
per unit of solid dosage form.
8. The pharmaceutical composition according to claim 5, wherein
said lactose is lactose-a-monohydrate.
9. The pharmaceutical composition according to claim 6, wherein the
total combined amount of said excipient, diluent and carrier is
from 50 to 99 percent by weight of the pharmaceutical
composition.
10. The pharmaceutical composition according to claim 1, wherein
said tablet is adapted for administration by a route selected from
the group consisting of oromucosal, buccal and sublingual
administration.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/425,993, filed Apr. 30, 2003, the contents
of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel pharmaceutical
composition as a solid dosage form comprising desmopressin as a
therapeutically active ingredient, and to a method for
manufacturing thereof.
TECHNICAL BACKGROUND
[0003] Desmopressin, also known as dDAVP, is the therapeutically
active ingredient (as its acetate salt) in the pharmaceutical
product Minirin.RTM., 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.
[0004] 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.RTM. tablet is prepared according to this general protocol,
and the tablet was first disclosed as set forth in the patent U.S.
Pat. No. 5,047,398, the teachings of which are incorporated herein
by reference. 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, the entire teachings of which are incorporated
herein by reference.
[0005] The Minirin.RTM. tablet that is currently marketed, and thus
produced in industrial scale, consists of the therapeutically
active ingredient desmopressin together with potato starch and
lactose as excipients, and a suitable amount of binder and
lubricant, respectively.
[0006] 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.
DISCLOSURE OF THE INVENTION
[0007] 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.
[0008] 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
substance selected from a monosaccharide, disaccharide,
oligosaccharide and a polysaccharide, wherein the said substance
has an average particle size in the range of from 60 to 1000
.mu.m.
[0009] In those embodiments where there is a mixture of at least
two of the aforementioned types of saccharides, at least one of
them must accordingly be within the specified particle size range
of the present invention.
[0010] 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 of these terms is self-explanatory and
lies well within the ability of a person skilled in the art of
pharmaceutical formulation.
[0011] 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.RTM. 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,
3.sup.rd Ed., American Pharmaceutical Association, USA and
Pharmaceutical Press UK, 2000, the teachings of which are
incorporated herein by reference. 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.
[0012] As used herein, the expression oligosaccharide relates to a
chain, with any degree of branching, of from three to ten
monosaccharide units linked via glycoside bonds. Accordingly, as
used herein, the expression polysaccharide relates to a chain, with
any degree of branching, of at least eleven monosaccharide units
linked via glycoside bonds. Synthetically modified derivatives and
analogues of naturally occurring saccharides are also possible to
use in the practising of the present invention.
[0013] In the marketed tablet resulting from the hitherto used
manufacturing process, the lactose particles (Pharmatose 150M
provided by DMV, the Netherlands) have an average size of about 50
.mu.m, 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.
[0014] As further examples of an upper limit for said average
particle size mention can be made of 900, 800, 700 and 600 .mu.m.
However, in a preferred embodiment of said pharmaceutical
composition, said average particle size is in the range of from 70
to 500 .mu.m. In another preferred embodiment, said average
particle size is in the range of from 75 to 350 .mu.m. In yet
another preferred embodiment, said average particle size is in the
range of from 1100 to 200 .mu.m. In a further preferred embodiment,
said average particle size is in the range of from 120 to 180
.mu.m. In the most preferred embodiment of the present invention,
said average particle size is 140 .mu.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.
Pharmatose 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 .mu.m, respectively.
[0015] According to the commercial provider the particle size
distribution of Pharmatose DCL 15 is that essentially all particles
have a size below 500 .mu.m, whereas approximately 72% of the
particles have a size of from 75 to 350 .mu.m.
[0016] 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", 5.sup.th 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.
[0017] Accordingly, it is preferred that said substance is a
disaccharide, preferably lactose, and more preferably
lactose-.alpha.-monohydrate.
[0018] As said polysaccharide, starch is preferred, and of the many
available starches, potato starch is the most preferred. As
examples of potato starches mention can be made of Pharma M20,
Pharma M14 (provided by KMC, DK) and AmylSolVat (provided by
Lyckeby Starkelse AB, SE).
[0019] In a preferred embodiment, both said disaccharide and
polysaccharide are present in the pharmaceutical composition. In
that particular embodiment, the weight ratio between said
disaccharide and polysaccharide is typically from 100:1 to 1:100,
preferably from 10:1 to 1:10, and more preferably from 2:1 to
1:2.
[0020] 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
with the aforementioned additives, where the latter is preferably
lubricant and binder.
[0021] The pharmaceutical composition as a solid dosage form
according to the present invention is typically a perorally
available tablet. As an alternative non-limiting embodiment, the
said tablet may be adapted for oral, including buccal and/or
sublingual, administration.
[0022] The composition typically comprises desmopressin acetate in
an amount of from 20 to 600 .mu.g per unit of solid dosage form. As
an example, a typical tablet containing 100 .mu.g of desmopressin
acetate is white, convex and oval (6.7.times.9.5 mm) with a
thickness of 3-4 mm and a weight of 200 mg. As another example, a
tablet containing 200 .mu.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.
[0023] 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:
[0024] 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
substance selected from a monosaccharide, disaccharide,
oligosaccharide and a polysaccharide, wherein said substance has an
average particle size in the range of from 60 to 1000 .mu.m; [0025]
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; [0026] iii) optionally
performing said mixing and/or formation of a granulate in the
presence of at least one additive selected from a disintegrating
agent, lubricant, binder, flavoring agent, preservative, colorant
and a mixture thereof; [0027] iv) optionally drying said granulate;
[0028] v) compressing said granulate into said solid dosage
form.
[0029] 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 .mu.m. Discrete granules with a size above 2 mm are
usually not transferred to the subsequent compressing step.
[0030] 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 (UltimaPro.TM.
series), Huttlin GmbH, DE (HDG series), Diosna Dierks & Soehne
GmbH, DE (VAC series), Fluid Air Inc., US (Magnaflo.RTM. 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 O. 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.RTM. series), Diosna as above (CCS and VAC
series), Romaco Zanchetta SpA, IT (Rote E, Roto D and Roto P
series) and L. B. Bohle Maschinen und Verfahren GmbH, DE
(Granumator GMA and Vagumator VMA series); The aforementioned
equipment in general also provides drying of the prepared
granules.
[0031] As indicated above, further examples of an upper limit for
said average particle size are 900, 800, 700 and 600 .mu.m. In a
preferred embodiment of the method of the present invention, said
average particle size is in the range of from 70 to 500 .mu.m. In
another preferred embodiment, said average particle size is in the
range of from 75 to 350 .mu.m. In yet another preferred embodiment,
said average particle size is in the range of from 100 to 200
.mu.m. In a further preferred embodiment, said average particle
size is in the range of from 120 to 180 .mu.m. In the most
preferred embodiment of the present invention, said average
particle size is 140 .mu.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).
[0032] It is accordingly preferred that said substance is a
disaccharide, preferably lactose, and more preferably
lactose-a-monohydrate. Said monosaccharide may also be D-mannitol,
D-sorbitol or xylitol or a mixture thereof.
[0033] Said polysaccharide is preferably a starch, and more
preferably potato starch. Preferred particular potato starches are
the same as those mentioned above.
[0034] 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, RI
90FT, R290FT, R292F and R233 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).
[0035] 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.
[0036] 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.
[0037] 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 .mu.m, preferably in the range of
from 100 .mu.m to 2 mm.
[0038] In a preferred embodiment of the method, both said
disaccharide and polysaccharide are present in the mixing step. The
weight ratio between said disaccharide and polysaccharide is then
typically from 100:1 to 1:100, preferably from 10:1 to 1:10, and
more preferably from 2:1 to 1:2.
[0039] The method is preferably 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.
[0040] 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 20 to 600 .mu.g of
desmopressin acetate per unit of solid dosage form (see above and
the experimental part for examples of a tablet).
[0041] In a further aspect, the present invention also relates to a
pharmaceutical composition as a solid dosage form that is
obtainable by the novel method as defined above, both in general
and as outlined in the specific embodiments.
[0042] 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
Example 1
Preparation of Solid Dosage Form of dDAVP
[0043] Desmopressin acetate (100 or 200 g; provided by PolyPeptide
Laboratories AB, SE), polyvinyl pyrrolidone (PVP) as binder (1.84
kg; Kollidon.RTM. 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 .mu.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 (150.degree. C.), all with
continued mixing. The dried granulate is 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).
[0044] The process is typically adapted to provide a tablet
containing 100 or 200 .mu.g of desmopressin acetate with the
aforementioned appearance, dimension and weight.
* * * * *