U.S. patent application number 13/120598 was filed with the patent office on 2011-07-21 for use of polyether-based and vinyl monomer-based copolymers as binders for dosing forms comprising solid active ingredients.
Invention is credited to Rainer Dobrawa, Karl Kolter, Angelika Maschke, Kathrin Meyer-Bohm.
Application Number | 20110178183 13/120598 |
Document ID | / |
Family ID | 41343383 |
Filed Date | 2011-07-21 |
United States Patent
Application |
20110178183 |
Kind Code |
A1 |
Meyer-Bohm; Kathrin ; et
al. |
July 21, 2011 |
Use Of Polyether-Based And Vinyl Monomer-Based Copolymers As
Binders For Dosing Forms Comprising Solid Active Ingredients
Abstract
The use of water-soluble or water-dispersible copolymers which
are obtained by free radical-initiated polymerization of a mixture
of i) 30 to 80% by weight N-vinyllactam, ii) 10 to 50% by weight
vinylacetate and iii) 10 to 50% by weight of a polyether, with the
proviso that the total of i), ii) and iii) is equal to 100% by
weight, as binders for producing solid active ingredient-containing
dosage forms.
Inventors: |
Meyer-Bohm; Kathrin;
(Feucht, DE) ; Dobrawa; Rainer; (Stuttgart,
DE) ; Maschke; Angelika; (Mannheim, DE) ;
Kolter; Karl; (Limburgerhof, DE) |
Family ID: |
41343383 |
Appl. No.: |
13/120598 |
Filed: |
September 21, 2009 |
PCT Filed: |
September 21, 2009 |
PCT NO: |
PCT/EP2009/062199 |
371 Date: |
March 23, 2011 |
Current U.S.
Class: |
514/772.5 ;
264/128 |
Current CPC
Class: |
A61K 9/2095 20130101;
A61P 3/00 20180101; A61P 9/00 20180101; A61K 9/1641 20130101; A61P
1/08 20180101; A61K 9/2031 20130101; A61K 47/34 20130101; A61P
31/00 20180101 |
Class at
Publication: |
514/772.5 ;
264/128 |
International
Class: |
A61K 47/32 20060101
A61K047/32; A61P 3/00 20060101 A61P003/00; A61P 9/00 20060101
A61P009/00; A61P 31/00 20060101 A61P031/00; A61P 1/08 20060101
A61P001/08; D04H 1/64 20060101 D04H001/64 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 25, 2008 |
EP |
08165113.5 |
Claims
1. A solid active ingredient-containing dosage form comprising
binders that include water-soluble or water-dispersible copolymers
which are obtained by free radical-initiated polymerization of a
mixture of i) 30 to 80% by weight of N-vinyllactam, ii) 10 to 50%
by weight of vinyl acetate and iii) 10 to 50% by weight of a
polyether, with the proviso that the total of i), ii) and iii) is
equal to 100% by weight.
2. The solid active ingredient-containing dosage form according to
claim 1, wherein the copolymers are obtained from i) 30 to 70% by
weight of N-vinyllactam ii) 15 to 35% by weight of vinyl acetate,
and iii) 10 to 35% by weight of a polyether, is employed.
3. The solid active ingredient-containing dosage form according to
claim 2, wherein the copolymers are obtained from i) 40 to 60% by
weight of N-vinyllactam ii) 15 to 35% by weight of vinyl acetate
iii) 10 to 30% by weight of a polyether.
4. The solid active ingredient-containing dosage form according to
claim 1, in the form of a tablets.
5. The solid active ingredient-containing dosage form according to
claim 1, comprising the binders in an amount of from 1 to 20% by
weight based on the total weight of the dosage form.
6. The solid active ingredient-containing dosage form according to
claim 5, comprising the binders in an amount of from 1 to 10% by
weight in the dosage forms.
7. The solid active ingredient-containing dosage form according to
claim 1, wherein the binders are employed as dry binders.
8. The solid active ingredient-containing dosage form according to
claim 7, wherein the binders are employed as dry binders for direct
tableting.
9. The solid active ingredient-containing dosage form according to
claim 1, wherein the binders are employed in the form of wet
granules or fluidized-bed granules.
10. The solid active ingredient-containing dosage form according to
claim 1, wherein the binders are in the form of sintered
granules.
11. The solid active ingredient-containing dosage form according to
claim 10, where the sintered granules are obtained at temperatures
of 50 to 100.degree. C.
12. The solid active ingredient-containing dosage form according to
claim 11, where the sintered granules are obtained at temperatures
of 70 to 100.degree. C.
13. The solid active ingredient-containing dosage form according to
claim 1, where the binders are granulated in the presence of
further pharmaceutical excipients.
14. The solid active ingredient-containing dosage form according to
claim 1, where the binders are granulated in the presence of active
pharmaceutical ingredients.
15. A process for producing a solid pharmaceutical dosage form,
which comprises mixing, as binders, water-soluble or
water-dispersible copolymers which are obtained by free
radical-initiated polymerization of a mixture of i) 30 to 80% by
weight of N-vinyllactam, ii) 10 to 50% by weight of vinyl acetate
and iii) 10 to 50% by weight of a polyether, with the proviso that
the sum of i), ii) and iii) is equal to 100% by weight, with active
pharmaceutical ingredients and optionally further pharmaceutical
excipients, and subsequently converting the mixture into the solid
pharmaceutical dosage form.
16. The process according to claim 15, wherein the binders are
mixed dry with the active pharmaceutical ingredients and optionally
the further pharmaceutical excipients to form a dry mixture, and
the dry mixture is converted into the solid pharmaceutical dosage
forms.
17. The process according to claim 16, wherein the binders are
incorporated in the form of granules into the solid pharmaceutical
dosage form.
18. The process according to claim 17, wherein the granules are
obtained by wet granulation, fluidized-bed granulation or sinter
granulation.
19. The process according to claim 17, wherein further
pharmaceutical excipients are incorporated into the granules.
20. The process according to claim 17, wherein the active
pharmaceutical ingredients are incorporated into the granules.
21. The process according to claim 15, wherein the mixture of the
binders, the active pharmaceutical ingredients and the optionally
further pharmaceutical excipients is converted by compression into
the solid dosage form.
Description
[0001] The present invention relates to the use of copolymers which
are obtained by polymerizing vinyl acetate and N-vinyllactams in
the presence of a polyether as binders, especially as dry binders,
for solid active ingredient-containing dosage forms, especially
tablets.
[0002] Binders improve the compressibility of active
ingredient-containing formulations to solid dosage forms by
improving the particle adhesion.
[0003] Criteria for the standard of quality when testing compressed
dosage forms such as tablets are according to the European
Pharmacopoeia the uniformity of mass (weight uniformity),
resistance to crushing, friability and disintegration.
[0004] Cellulose powders, for example microcrystalline or microfine
celluloses, result in very hard tablets, but adversely affect the
flowability of the mixture for tableting.
[0005] Further binders such as hydroxypropylmethylcelluloses or
polyvinylpyrrolidones are very effective wet binders.
[0006] Dry binders suitable for granulation without addition of
solvents or direct compression are hydroxypropylcelluloses or
copovidone (copolymer of N-vinylpyrrolidone and vinyl acetate in
the ratio 60:40 by weight).
[0007] The previously disclosed binders, especially those suitable
as dry binders, are frequently able to satisfy the various criteria
for the standards of quality only in part. Thus, tablet strength
and disintegration time often show antipodal behavior. The
friability, that is the attrition, may also be unsatisfactorily
high both for soft tablets through edge attrition and for very hard
tablets through capping tendencies.
[0008] The object therefore was to provide novel and improved
binders, especially dry binders, for pharmaceutical, cosmetic, food
product, agrotechnical or other industrial applications which show
improved properties in terms of the resistance to crushing and
friability of the dosage forms.
[0009] WO 2007/051743 discloses the use of copolymers obtained by
polymerizing N-vinyllactam, vinyl acetate and polyethers as
solubilizers for active ingredients which are slightly soluble in
water.
[0010] The object has been achieved according to the invention by
the use of water-soluble or water-dispersible copolymers which are
obtained by free radical-initiated polymerization of a mixture of)
[0011] 30 to 80% by weight of N-vinyllactam, [0012] ii) 10 to 50%
by weight of vinyl acetate and [0013] iii) 10 to 50% by weight of a
polyether, with the proviso that the total of i), ii) and iii) is
equal to 100% by weight, es binders for producing solid active
ingredient-containing dosage forms.
[0014] Preferred polymers are obtained from: [0015] i) 30 to 70% by
weight of N-vinyllactam [0016] ii) 15 to 35% by weight of vinyl
acetate, and [0017] iii) 10 to 35% by weight of a polyether.
[0018] Particularly preferred polymers are obtained from: [0019] i)
40 to 60% by weight of N-vinyllactam [0020] ii) 15 to 35% by weight
of vinyl acetate [0021] iii) 10 to 30% by weight of a
polyether.
[0022] The proviso that the total of components i), ii), and iii)
equals 100% by weight also applies to the preferred and
particularly preferred compositions.
[0023] Suitable as N-vinyllactam are N-vinylcaprolactam or
N-vinylpyrrolidone or mixtures thereof. N-Vinylcaprolactam is
preferably used.
[0024] Suitable polyethers are preferably polyalkylene glycols. The
polyalkylene glycols may have molecular weights of from 1000 to 100
000 D [daltons], preferably 1500 to 35 000 D, particularly
preferably 1500 to 10 000 D. The molecular weights are determined
on the basis of the OH value measured as specified in DIN
53240.
[0025] Suitable polyalkylene glycols which are particularly
preferred are polyethylene glycols. Also suitable are polypropylene
glycols, polytetrahydrofurans or polybutylene glycols, which are
obtained from 2-ethyloxirane or 2,3-dimethyloxirane.
[0026] Suitable polyethers are also random or block copolymers of
polyalkylene glycols obtained from ethylene oxide, propylene oxide
and butylene oxides, such as, for example, polyethylene
glycol-polypropylene glycol block copolymers. The block copolymers
may be of the AB or ABA type.
[0027] The preferred polyalkylene glycols also include those
alkylated on one or both terminal OH groups. Suitable alkyl
radicals are branched or unbranched C.sub.1- to C.sub.22-alkyl
radicals, preferably C.sub.1-C.sub.18-alkyl radicals, for example
methyl, ethyl, n-butyl, isobutyl, pentyl, hexyl, octyl, nonyl,
decyl, dodecyl, tridecyl or octadecyl radicals.
[0028] General processes for preparing the copolymers of the
invention are known per se. The preparation takes place by free
radical-Initiated polymerization, preferably solution
polymerization, in nonaqueous, organic solvents or in mixed
nonaqueous/aqueous solvents. The preparation of the copolymers and
their conversion into the powder form is described in detail in WO
2007/051743, the disclosure of which concerning the preparation of
the copolymers is hereby incorporated by reference.
[0029] The polymers have Fikentscher K values in the range from 10
to 60, preferably 15 to 40, measured in a 1% by weight ethanolic
solution.
[0030] The polymers are suitable according to the invention as
binders for producing solid dosage forms, especially as binders for
producing tablets.
[0031] The polymers have glass transition temperatures in the range
from 30 to 120.degree. C., preferably from 50 to 80.degree. C.
[0032] The use as dry binders for powder mixtures for direct
tableting is preferred.
[0033] The polymers are, however, also suitable for use in wet
granulation, fluidized-bed granulation or dry granulation.
[0034] In the case of wet granulation, the binder may be employed
in the form of an aqueous or else organic solution comprising
preferably 1 to 30% by weight of binder. The polymer solution may
be granulated with the other ingredients in, for example, a mixer
or kneading device.
[0035] In the case of fluidized-bed granulation, the binder in the
form of a solution, preferably an aqueous solution, may be sprayed
onto a fluid bed of components in powder form, and agglomeration
takes place. Located within the fluid bed there may be the active
pharmaceutical ingredients and/or further pharmaceutical
excipients.
[0036] According to one other preferred embodiment, the polymers
are also suitable for processing by sinter granulation. In this
case the polymers are softened by the energy input from the mixing
operation, and/or as a result of elevated temperature, and as a
result of this softening there is agglomeration of the components
employed. As a result of the softening and subsequent
solidification by cooling, solid-material bridges are formed. The
operation may be conducted such that there is surface softening or
partial softening of the polymer particles. It is also possible to
operate the sinter granulation in such a way that there is complete
softening of the polymers. Complete softening may be advisable if
particularly strong binder bridges are desired.
[0037] Sinter granulation may take place in a heatable mixer,
kneading device or screw extruder.
[0038] In the case of processing in a screw extruder, the extruder
is used without a die plate, in other words in open mode. The
process takes place without pressure being applied. Through a
suitable choice of screw configuration it is possible to set the
particle size of the granules with a narrow particle size
distribution. The screw configuration to be selected for this
purpose, as a function of the mixture used, can be determined by
the skilled person, by means of a few suitable tests.
[0039] Sinter granulation may take place at temperatures of 50 to
120.degree. C., preferably 70 to 100.degree. C. The temperature
particularly suitable is dependent on the composition of the
mixture. Where plasticizing substances are included in the
processing operation, lower temperatures may optionally be
selected.
[0040] Irrespective of the granulating method used, it is possible
to incorporate, for example, the active pharmaceutical ingredients
and also other pharmaceutical excipients, such as surface-active
compounds, further binders, fillers, acidifiers, buffers, flavors
and fragrances, stabilizers or colorants into the granules.
[0041] To produce the solid dosage forms, the active pharmaceutical
ingredient may be processed intragranularly or extragranularly.
Thus it is possible to produce granules which comprise further
pharmaceutical excipients but no active ingredient, and then to mix
these granules with the active ingredients. It is also possible to
incorporate an active ingredient both intragranularly and
extragranularly. Combinations of the different active ingredients
may also be used. In the case of active ingredients which are
incompatible with one another, one may be processed intragranularly
and the other extragranularly.
[0042] The granule particles may have average particle sizes of 100
to 1000 .mu.m, preferably 200 to 600 .mu.m. In the granule
particles the fraction of binder according to the invention may be
1 to 60%, preferably 5 to 30% by weight.
[0043] The binder of the invention can be employed in amounts of
from 1 to 20% by weight, preferably 1 to 10% by weight, based on
the total weight of the dosage form.
[0044] Pharmaceutical preparations for producing solid dosage forms
may, besides the binders of the invention, also comprise
conventional pharmaceutical excipients such as fillers,
disintegrants, coloring agents, flavorings, film-forming
water-insoluble polymers, thickeners or surface-active agents, and
further conventional binders in the amounts conventional for his
purpose.
[0045] Examples of suitable fillers are sugars, sugar alcohols or
mixtures thereof. Suitable sugars or sugar alcohols are trehalose,
mannitol, erythritol, isomalt, maltitol, lactitol, xylitol,
sorbitol. Furthermore, inorganic substances may also be used as
fillers. Suitable in this case are dicalcium and tricalcium
phosphates.
[0046] As disintegrants can be employed in amounts of from 1 to 25%
by weight, preferably 2 to 15% by weight, particularly preferably 3
to 10% by weight. Such disintegrants are water-insoluble but not
film-forming. Examples of suitable disintegrants are crospovidone,
a crosslinked polymer of N-vinylpyrrolidone. Also suitable is
croscarme/lose, a crosslinked carboxymethylceliulose, where
croscarmellose also means according to the invention the sodium and
calcium salts thereof. Also suitable is sodium carboxymethyl
starch. L-Hydroxypropylcellulose, preferably with 5 to 16%
hydroxypropyl groups, is likewise suitable.
[0047] Further excipients which can be employed are water-insoluble
polymers which are insoluble in the pH range from 1 to 14, that is
have a pH-independent insolubility in water at every pH. However,
also suitable are polymers which are insoluble in water at every pH
in the pH range from 6 to 14, but are soluble in an acidic medium.
The polymers may be film-forming polymers. Film-forming means in
this connection that the polymers have a minimum film-forming
temperature of from -20 to +150.degree. C., preferably 0 to
100.degree. C., in aqueous dispersion. Suitable polymers are
polyvinyl acetate, ethylcellulose, methyl methacrylate-ethyl
acrylate copolymers, ethyl acrylate-methyl
methacrylate-trimethylammoniumethyl methacrylate terpolymers, butyl
methacrylate-methyl methacrylate-dimethylaminoethyl methacrylate
terpolymers. The acrylate-methacrylate copolymers are described in
detail in the European Pharmacopoeia as polyacrylate dispersion
30%, in the USP as ammonio methacrylate copolymer and in JPE as
aminoalkyl-methacrylate copolymer E. Polyvinyl acetate can be
employed as aqueous dispersion with solids contents of from 10 to
45% by weight. Additionally preferred is polyvinyl acetate with a
molecular weight of between 100 000 and 1 000 000 daltons,
particularly preferably between 200 000 and 800 000 daltons,
[0048] The formulations may further comprise as components
additional water-soluble polymers in amounts of from 0 to 15% by
weight. Suitable water-soluble polymers are for example
polyvinylpyrrolidones, vinylpyrrolidone-vinyl acetate copolymers,
polyvinyl alcohols, polyvinyl alcohol-polyethylene glycol graft
copolymers, polyethylene glycols or ethylene glycol-propylene
glycol block copolymers.
[0049] It is further possible to employ thickeners such as
methylcellulose, hydroxypropyl-methylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, carrageenans,
pectins, xanthans or alginates. It is possible by adding thickeners
such as, for example, high molecular weight polysaccharides for the
mouthfeel to be additionally improved by increasing the softness
and the sensation of volume.
[0050] It is possible if desired to employ further pharmaceutically
customary excipients in amounts of from 0 to 15% by weight, for
example such as acidifiers, buffer substances, sweeteners,
flavorings, flavor enhancers and colorants. The following
substances are particularly suitable in this connection: citric
acid, tartaric acid, ascorbic acid, sodium dihydrogenphosphate,
cyclamate, saccharin Na, aspartame, menthol, peppermint flavor,
fruit flavors, vanilla flavor, glutamate, riboflavin, beta
carotene, water-soluble colorants, finely divided color lakes.
[0051] In addition, surface-active compounds can also be added, for
example sodium lauryl sulfate, dioctyl sulfosuccinate, alkoxylated
sorbitan esters such as polysorbate 80, polyalkoxylated derivatives
of castor oil or hydrogenated castor oil, for example
Cremophor.RTM. RH 40, alkoxylated fatty acids, alkoxylated hydroxy
fatty acids, alkoxylated fatty alcohols, alkali metal salts of
fatty acids and lecithins.
[0052] It is further possible to add pigments such as iron oxides,
titanium dioxide, colloidal or precipitated silica, calcium
carbonates or calcium phosphates.
[0053] The finished tablets can also be provided with conventional
coatings.
EXAMPLES
[0054] The angle of repose and the flow rate were determined in
accordance with DIN ISO 4324. The bulk density was determined in
accordance with Pharm. Eur. 5. Apparatus used: tablet tester
(Kramer), tablet disintegration tester ZT 74 (ERWEKA), friability
tester TAR 20 (ERWEKA)
Example 1
Dry Binder
[0055] The binding power was assessed on a polymer A, obtained from
13% by weight polyethylene glycol PEG 6000, 57% by weight
N-vinylcaprolactam and 30% by weight vinyl acetate with a K value
of 35.
[0056] For comparison, the binding power of povidone K30
(polyvinylpyrrolidone of K value 30) and of copovidone (copolymer
of N-vinylpyrrolidone and vinyl acetate in a weight ratio of 60:40.
K value 28; Kollidon.RTM. VA 64, BASF), and of mixtures without
binder, was assessed as follows.
TABLE-US-00001 Assessment good moderate poor Resistance to crushing
[N] >75 60-75 <60 Friability [%] <0.5 0.5-1.0 >1.0
Disintegration [min] <4 4-6 >6 Weight uniformity [%] <0.6
0.6-0.8 >0.8
[0057] The following compositions were used:
per 500 mg tablet weight 200.00 mg of ascorbic acid powder
231.25 mg of Ludipress.sup.1)
[0058] 50.00 mg of binder 15.00 mg of crospovidone.sup.2) 1.25 mg
of colloidal silicon dioxide.sup.3) 2.50 mg of magnesium stearate
1) Ludipress.RTM.: formulation of 93% by weight lactose, 3.5% by
weight povidone K30 (Kollidon.RTM. 30, from BASF), 3.5% by weight
crospovidone 2) Crospovidone: Kollidon.RTM. CL, from BASF 3)
Aeosil.RTM. 200, from Evonik
[0059] The mixture of components was passed through a sieve with a
mesh width of 0.8 mm, put in a glass bottle and mixed in a Tabula
mixer for 10 minutes, and compressed to tablets.
Tablet format: 12 mm diameter, beveled Compressive force: 18 kN
Tableting rate: 30 rpm rotary press
[0060] The tablets were subsequently tested for their physical
properties.
TABLE-US-00002 Polymer A according Povidone No to the Binder K30
Copovidone binder invention Resistance to 65 90 49 87 crushing [N]
Friability [%] 0.43 1.14 3.5 (15% 0.44 breakage) Disintegration
[min.sec] 1.19 1.02 0.24 2.30 Weight uniformity [%] 4.12 0.58 1.01
0.34
[0061] The binder used according to the invention therefore results
in tablet resistances to crushing which are comparable to those of
tablets comprising copovidone, but at the same time in particular
results in distinctly lower friability.
Example 2
Wet Binder
TABLE-US-00003 [0062] Initial mass Composition after drying Formula
[g] [% by weight] Calcium 350.00 80.8 hydrogenphosphate Lactose
50.00 11.5 Binder 12.40 2.9 DI water 55.00 -- Kollidon CL 18.56 4.3
Magnesium stearate 2.06 0.5
[0063] Calcium hydrogen phosphate and lactose were weighed out into
a Diosna mixer (Diosna P 1/6 (2 L stirring vessel)) and the mixture
was mixed for 1 minute (200 rpm stirrer/2200 rpm chopper). An
aqueous solution of binder with a strength of 18.4% by weight was
added dropwise over the course of 4 minutes with continual stirring
(at 200 rpm stirrer/2200 rpm dropper). Following addition of the
binder solution to the mixture, mixing was continued for 2 minutes.
The stirrer speed was then raised to 1500 rpm for 30 seconds, while
the chopper continued to run at 2200 rpm. Thereafter the moistened
mass was passed through a sieve with a mesh size of 0.8 mm, and the
wet granules were dried in air on racks for 12 hours. The absolute
loss of the granules on drying was determined using an IR drier to
constant mass of 80.degree. C. Subsequently Kollidon CL and
magnesium stearate were added. The overall mass was passed through
a sieve with a mesh size of 0.8 mm and introduced into a glass
bottle, which was sealed, followed by mixing for 5 minutes in a
Turbula mixer (Turbula mixer T2, Willy A Baclofen AG).
[0064] Tablets were then produced and tested as described in
Example 1.
Tablet Analysis:
TABLE-US-00004 [0065] Pressing Resistance to Friability
Disintegration pressure Binder crushing [N] [%] [s] 18 kN
Inventive, polymer A 103 0.13 31 Kollidon VA 64 83 0.37 38 Kollidon
30 95 0.18 35 Kollidon 90 F 109 0.15 117
[0066] The inventive polymer used, in comparison to known binders,
had a higher binding strength in tandem with an improved friability
and more rapid disintegration.
Example 3
Sintered Granules
TABLE-US-00005 [0067] Formula Composition [% by weight] Polymer A
50 Lactose 45 PEG 400 5
[0068] The polymer and the lactose (Granulac.RTM. 230, average
particle size 27 .mu.m) were weighed out into a Stephan mixer (UMC
5). The product container was heated at 95.degree. C. by means of a
double jacket design and connected oil bath. This mixture was mixed
for 5 minutes (with a stirrer speed of 1000 rpm). After a
homogenous mixture had been achieved, polyethylene glycol (PEG 400;
Lutrol.RTM. E 400, BASF SE) was added dropwise to the mixture, and
mixing was continued at the same speed for a further 20 minutes.
The finished granules were subsequently passed through a sieve
(mesh size 1000 .mu.m) to remove oversize.
[0069] The resultant granules were characterized and showed
successful agglomeration of the lactose. The average particle
diameter increased from 27 .mu.m (Granulac 230) to 396 .mu.m
(lactose granules with polymer A).
[0070] Surprisingly, the granules formed had virtually no fine
fraction, which suggests uniform agglomeration behavior. This is
evidenced by the d.sub.10 value of 228 .mu.m, which means that less
than 10% by weight of the particles have a particle size of less
than 228 .mu.m. The bulk density of the granules was 0.63 g/ml as
determined using the bulk/tamp volumeter in accordance with Ph.
Eur. The flow behavior of the granules, determined by means of a
Pfrengle funnel, gave an angle of repose of 26.6.degree. and a flow
time of 7.2 seconds.
[0071] The granules were subsequently compressed to form tablets.
Prior to the tableting of the finished granules, 5% by weight of
disintegrant (crospovidone; Kollidon.RTM. CL) and 0.5% by weight of
lubricant (magnesium stearate) were added. The total mass was
passed again through a sieve with a mesh size of 1.0 mm and
introduced into a glass bottle, which was sealed, and mixing took
place for 5 minutes in a Turbula mixer. The pressing mixture was
compressed on an eccentric press (EK0 eccentric press) at 18 kN to
give tablets with a size of 12 mm.
[0072] The properties of the tablets were as follows:
Resistance to crushing: 80 N
Friability: 0.2%
Disintegration: 50 s
Example 4
Sintered Granules; Percentages [% By Weight]
TABLE-US-00006 [0073] Formulation 1 Formulation 2 Formulation 3
Formulation 4 50% polymer A 50% polymer A 50% polymer A 40% polymer
A 30% lactose 30% lactose 25% lactose 35% lactose 20% fenofibrate
15% itraconazole 20% cinnarizine 20% cinnarizine -- 5% PEG 400 PEG
5% 600 5% PEG 600
[0074] The granules will be produced in a twin-screw extruder with
a screw diameter of 16 mm (L/D ratio=40) from ThermoFisher Polylab,
which is operated without pressurization and with an open head.
Granulation took place at a screw speed of 100 rpm with a barrel
temperature (from the 2.sup.nd barrel onward) of 80.degree. C.
TABLE-US-00007 Formulation Formulation Formulation Formulation 1 2
3 4 Angle of 28.degree. 30.degree. 30.degree. 31.degree. repose
Flow rate 8 sec 7 sec 8.1 sec 7.5 sec Bulk density 0.6 g/ml 0.65
g/ml 0.55 g/ml 0.58 g/ml Average 350 .mu.m 420 .mu.m 342 .mu.m 380
.mu.m particle diameter
* * * * *