U.S. patent application number 10/501899 was filed with the patent office on 2005-04-21 for new process 1.
This patent application is currently assigned to Galenica AB. Invention is credited to Alander, Jari, Hansson, Henri, Hovgaard, Lars, Norberg, Staffan, Svard, Marianne.
Application Number | 20050084526 10/501899 |
Document ID | / |
Family ID | 20286712 |
Filed Date | 2005-04-21 |
United States Patent
Application |
20050084526 |
Kind Code |
A1 |
Alander, Jari ; et
al. |
April 21, 2005 |
New process 1
Abstract
The invention refers to a process for the preparation of a
self-dispersing or self-emulsifying tablet comprising the steps
mixing a granulation medium containing an active lipophilic
substance with one or more fillers and auxiliary components,
granulation of said mixture into granules, drying of said granules,
sieving of the granules into a homogeneous size, mixing of the
granules with tabletting aids, and compressing said mixture into
tablets, which is characterised in that the granulation medium
comprises an oil, a surfactant and a polar liquid. The invention
also refers to a process for the preparation of tablets from a
granulation medium comprising oil and surfactant, as well as to
tablets prepared by said processes.
Inventors: |
Alander, Jari; (Karlshamn,
SE) ; Norberg, Staffan; (Karlshamn, SE) ;
Hansson, Henri; (Helsingborg, SE) ; Svard,
Marianne; (Veberod, SE) ; Hovgaard, Lars;
(Farum, DK) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
Galenica AB
Medeon P A Hanssons vag 41
Malmo
SE
S-205 12
|
Family ID: |
20286712 |
Appl. No.: |
10/501899 |
Filed: |
September 14, 2004 |
PCT Filed: |
January 21, 2003 |
PCT NO: |
PCT/SE03/00092 |
Current U.S.
Class: |
424/464 ;
264/109 |
Current CPC
Class: |
A61K 9/1694 20130101;
A61K 9/2027 20130101; A61K 9/1075 20130101; A61K 9/1274 20130101;
A61K 9/2013 20130101; A61K 9/2018 20130101; A61K 9/1617
20130101 |
Class at
Publication: |
424/464 ;
264/109 |
International
Class: |
A61K 009/20; D04H
001/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 21, 2002 |
SE |
0200154-3 |
Claims
1. A process for the preparation of a self-dispersing or
self-emulsifying immediate release tablet comprising the following
steps, mixing a granulation medium containing an active lipophilic
substance with one or more non-swellable fillers and optional
binders, granulation of said mixture into granules, drying of said
granules, sieving of the granules into a size below 1 mm, mixing of
the granules with tabletting aids, and compressing said mixture
into tablets, characterised in that the granulation medium
comprises an oil, a surfactant selected from the group consisting
of fatty acid esters of glycerol, and fatty acid esters of
polyethylene glycol, and a polar liquid.
2. A process according to claim 1, characterised in that the
granulation medium is a microemulsion.
3. A process according to claim 1, characterised in that the
granulation medium is an emulsion.
4. A process according to claim 1, characterised in that the
granulation medium is a liquid crystalline phase.
5. A tablet, characterised in being prepared by a process according
to any of claims 1-4.
Description
[0001] The present invention refers to a process for preparing
self-dispersing or self-emulsifying tablets containing a lipophilic
substance, as well as to tablets and granules obtained by said
process.
BACKGROUND
[0002] Poorly soluble active drug substances most often present
problems in the making of drug formulations. The water solubility
is crucial for absorption and hence bioavailability in the case of
the most important route of absorption, passive diffusion. In order
to overcome a solubility problem, the formulator is compelled to
either increase the solubility on the molecular level by creating a
pro-drug or by adding solubility enhancing additives or excipients.
The second alternative often includes excipients of lipophilic
character like oils. In addition surface-active agents, or
detergents are added in order to create an emulsion. The created
emulsion could be thermodynamically stable, i.e. a microemulsion.
Said formulations are mostly intended for use as wet systems as
mixtures or soft gelatine capsules.
[0003] It is well known that lipophilic substances with a very low
solubility in water will have a higher bioavailability when
administered in a microemulsion, see for instance "Lipid
microemulsions for improving drug dissolution and oral absorption:
physical and biopharmaceutical aspects." Constantinides, P. P.
(1995) Pharmaceutical Research, 12, (11) 1561-1572; and "Enhanced
intestinal absorption of an RGD peptide from water-in-oil
microemulsions of different composition and particle size.",
Constantinides, P. P. et al., (1995) Journal of controlled release
34, 109-116; and "Lipid-based vehicles for the oral delivery of
poorly water soluble drugs", Humberstone, A. J. and Charman, W. N.;
(1997) Advanced Drug Delivery Reviews, 25, 103-128.
[0004] Tablets are in general the preferred dosage form, being
comparatively less expensive to manufacture, easy to store and
administer. There is, however, no general way to formulate poorly
soluble lipophilic drug substances as tablets with fast and high
bioavailability.
PRIOR ART
[0005] A number of references are known referring to inclusion of a
microemulsion in a solid dose form in order to replace costly and
inconvenient capsule forms for administration of drugs with
improved bioavailability.
[0006] Self-emulsifying tablets are disclosed by Schwarz, J., et
al. in no. 6209 from the 27.sup.th Proceed. Int'l Symp. Control.
Rel. Bioact. Mater. (2000) Controlled Release Society, Inc. A
self-emulsifying controlled release tablet for oral delivery of
hydrophobic drugs is described. The drug is contained within the
oil droplets of the formed emulsion creating a significant
improvement of in bioavailability. In a later article, no. 6107
from the 28.sup.th Proceed. Int'l Symp. Control. Rei. Bioact.
Mater. (2001), Controlled Release Society, Inc., Schwartz, J., et
al. describes a controlled release formulation that utilises the
formation of a gel-forming matrix for creating a diffusion
controlled release tablet.
[0007] WO 00/41676, Merck Sharpe and Dohme Ltd, discloses a
self-emulsifying system for providing solid dosage forms of
hydrophobic active agents, comprising a mixture of microcrystalline
cellulose with an oily substance, surfactant and water, which is
extruded and spheronised into pellets. The pellets are said to be
filled into capsules or to be compressed into tablets. There are,
however, no examples of tablets nor any mentioning of tabletting
aids, and the described size distribution of the pellets does not
seem to be suitable for tabletting.
[0008] WO 00/09093, CIMA Labs Inc., discloses drug containing
microemulsions adsorbed onto solid particles forming a free
flowing, compressible powder. Said powder can be converted into
tablets, granules, pellets or other solid dosage forms.
[0009] WO 99/44589, Gattefoss S. A., discloses an oral pellet for
immediate release of an active substance, comprising at least said
active substance, a binding agent and a diluting agent.
[0010] There is, however, still a need of a process for production
of self-dispersing or self-emulsifying immediate release tablets,
wherein the total lipophilic content constitutes a substantial
amount, in order to increase the solubility of a lipophilic active
substance.
BRIED DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 shows the dissolution in phosphate buffer, pH 7.4, of
tablets according to the invention containing different amounts of
curcumin compared to a curcumin tablet formulation without lipid
and surfactant.
[0012] FIG. 2 shows the dissolution in phosphate buffer, pH 7.4, of
a tablet according to the invention containing cyclosporine-A in
comparison to a Sandimmun Neoral.RTM. capsule.
DESCRIPTION OF THE INVENTION
[0013] It has now been found that a self-dispersing, immediate
release tablet containing a lipophilic substance with low
solubility in water can be prepared by a conventional tabletting
method, by using a granulation medium in the form of an emulsion,
microemulsion or dispersed liquid crystalline phase. When the
tablet is dissolved in water, or gastric juice or gastrointestinal
fluids, a dispersion of the lipophilic substance is spontaneously
formed.
[0014] Tablets are conventionally prepared by compressing a powder
or granules or a mixture thereof. The most important properties of
the powder and granules for manufacturing of tablets are
flowability, compactability and homogeneity in order to produce
tablets having a sufficient hardness, good weight control and good
dose uniformity. Granulation is the process in which powder
particles are made to adhere to form larger particles i.e.
granules. The granulation of powder together with optional binding
material can be performed in several ways, such as wet, dry or
melting processes. The distinct difference between wet and melt
granulation is that wet granulation is followed by a drying step
where the granulation medium, that is water or some other polar
liquid, is dried off. Melt granulation on the other hand includes a
cooling step where at least one of the melted materials
solidifies.
[0015] The invention refers to a process for preparing a
self-dispersing or self-emulsifying immediate release tablet, which
is characterised by the following steps,
[0016] mixing a granulation medium containing an active lipophilic
substance with one or more non-swellable fillers and optional
binders,
[0017] granulation of said mixture into granules, drying of said
granules,
[0018] sieving of the granules into a size below 1 mm,
[0019] mixing of the granules with tabletting aids, and
[0020] compressing said mixture into tablets, characterised in that
the granulation medium comprises an oil, a surfactant and a polar
liquid.
[0021] The composition of the granulation medium is dependent on
the process to be used, which in turn is dependent on the active
substance to be dissolved or dispersed. Oil, surfactant and polar
liquid can be mixed in different proportions and in different ways
giving a microemulsion, an emulsion or micellar phase or a
dispersed liquid crystalline phase.
[0022] The granulation medium can be an emulsion. An emulsion is a
dispersion of one phase in another, such as oil in water, and the
surfactants act as stabilisers of the emulsion. An emulsion is not
thermodynamically stable and the formation thereof requires an
energy input. A kinetically stable, finely dispersed emulsion can
be obtained by agitation of the system and the emulsion may remain
finely dispersed for a relatively long time depending on the
composition.
[0023] According to a preferred aspect the granulation medium is a
microemulsion. Microemulsions are thermodynamically stable
isotropically clear solutions consisting of water, oil and
surfactants. They can be characterised as o/w (oil-in-water), w/o
(water-in-oil) or as bicontinuous phases. According to another
terminology they are described as a micellar or a reversed micellar
solution. The formation of a microemulsion requires no energy
input.
[0024] If water is replaced by another polar liquid, a non-aqueous
microemulsion can be obtained.
[0025] According to still another aspect of the invention the
granulation medium is a dispersed liquid crystalline phase. When
oil, water and surfactants are mixed liquid crystalline phases can
also be obtained, such as lamellar, hexagonal, reversed hexagonal
and cubic liquid crystal phases. Just as with emulsions the liquid
crystalline phases require a homogenisation before use.
[0026] Different phases of the three components oil, surfactant and
polar liquids are described in for instance Jonsson et al.
"Surfactants and Polymers in Aqueous Solutions", Wiley (1999).
Evans and Wennerstrom "The Colloidal Domain, where physics,
chemistry and biology meet", Wiley (1999).
[0027] The type of oil to be used in the process of the invention
is determined by the solubility properties of the active substance.
The use of oil/fat in tablet compositions imposes a binding
reducing property that is dependent on the melting temperature,
concentration of oil/fat and choice of other excipients. An oily
component tends to break the interparticulate bondings and reduce
the tablet strength and also increase capping and laminating
tendencies of the compact. In order to reduce these problems and
still enable a high concentration of oil/fat in the tablet
formulation the choice of the melting point of the mixture of
lipophilic active substance, oil and surfactant is important, as
well as the choice of binder, filler and tabletting aids.
[0028] The surfactant is preferably selected from the group
consisting of fatty acid esters of glycerol, and fatty acid esters
of polyethylene glycol.
[0029] The polar liquid can in addition to water be an alcohol,
such as ethanol or propylene glycol.
[0030] The granulation can be performed in different ways using
mixing or agitation equipment such as a planetary mixer, a high
shear mixer or a fluid bed. Fluid bed has the advantage compared to
the other techniques that the drying process can be performed in
the same vessel as is used for the granulation. The other
techniques normally require a discharging step between the
granulation and drying if not a single processing equipment is used
such as a vacuum/microwave high shear mixer. Granulation can also
be performed by means of extrusion/spheronisation and spray drying,
which, however, are more complex operations producing powder
aggregates, which normally are not used for tablet production. To
be suitable for tabletting the granules should preferably have an
average diameter below 1 mm, especially within the range of 125-710
um.
[0031] The choice of granulation medium and granulation process
depends on the material to be granulated as well as the properties
wanted for the granules. In some cases, specific properties of the
active substance have to be considered when choosing granulation
medium, method of granulation and tablet processing. The
compression of the granules is typically done with low compressive
force and with the addition of small amounts of plastic deformable
binder.
[0032] A filler is by definition a component used for diluting the
formulation in order to achieve a reasonable unit dose weight. In
order to provide an immediate release tablet the filler must not
form a gel, but should rather be of a non-swellable type. As
examples of non-swellable fillers can be mentioned microcrystalline
cellulose and dicalcium phosphate, which are not soluble, and
lactose, which is soluble in water.
[0033] To achieve acceptable tabletting properties when a high
ratio of oil/fat is used, that is about >20% of the tablet
formulation, a binder typically has to be used. The binder is added
to the granulation medium and hardens on drying to form solid
bridges binding the particles together. As examples can be
mentioned PVP (Povidone), cellulose derivatives, pre-gelatinised
starch. The binder can be used dissolved in the granulation medium
or as a dry powder in the final mix.
[0034] Tabletting aids are for example lubricants, such as
magnesium stearate, and disintegrants, such as croscarmellose
sodium and sodium starch glycolate, and glidants, such as colloidal
silicon dioxide (Aerosil 200). In addition flavouring, colouring,
and coating agents can be added.
[0035] An active substance, preferably a pharmaceutically active
substance, which preferably can be administered in a tablet
according to the invention in order to improve the bioavailability,
is for instance a hydrophobic or lipophilic substance with a low
solubility in water. Substances having a log P value
(octanol:water) of above 2 are candidates for the process of the
invention.
[0036] The invention also refers to tablets prepared by the
process.
[0037] Tablets can be manufactured as immediate release tablets but
also with an enteric coating if the active substance is to be
released in the intestines or if the active substance is
susceptible to acidic degradation. Coatings can also be applied for
taste-masking or to provide a special colour.
[0038] If large amounts of an active substance are to be
administered it might be preferred to use another type of tablet,
such as a loozenge, a chewable tablet or effervescent tablets.
[0039] When the tablet is brought into contact with water or
gastric juice the molecularly dissolved active substance is
spontaneously dispersed and a microemulsion, colloidal emulsion or
drops of emulsion are obtained, which will improve the distribution
of the active substance. Disintegration of a lipid/surfactant
containing tablet can result in for instance a microemulsion, an
emulsion or fine colloidal emulsions, which all improve or
facilitate the distribution of a lipophilic drug in the
gastrointestinal tract.
[0040] According to another aspect the invention refers to a
process for the preparation of a self-dispersing tablet comprising
the following steps,
[0041] mixing a heated granulation medium containing an active
lipophilic substance with one or more non-swellable fillers and
optional binders,
[0042] granulation of said mixture into granules which are allowed
to cool,
[0043] sieving of the granules into a size below 1 mm,
[0044] mixing of the granules with tabletting aids, and
[0045] compressing said mixture into tablets, characterised in that
the granulation medium comprises an oil and a surfactant.
[0046] In said process the granulation medium consists of an
oil/fat in combination with one or more surfactants, which are
mixed with the lipophilic drug substance.
EXAMPLES
[0047] The following Examples 1-10 all refer to the preparation of
granulation media. In Example 1 a microemulsion is obtained, in
Examples 2-3 non-aqueous microemulsions, in Examples 4 an emulsion,
and in Examples 5-6 dispersed liquid crystalline phases. In Example
7 the lipophilic substance curcumine is used as model of an active
substance, and in Examples 8-10 the granulation media contains the
lipophilic active substances naproxene, indomethacin and
cyclosporine-A, respectively.
[0048] Examples 11-14 refer to wet granulation, Examples 15-18 to
tabletting using the granulation media described in Examples 1, 2,
7 and 10.
[0049] In the examples below the following substances are used as
surfactants:
[0050] AKOLIP LM, Karlshamns AB, Sweden, a mixture of
glycerolesters of C.sub.8-C.sub.18 fatty acids and macrogolesters
of C.sub.8-C.sub.18 fatty acids (melting point 44.degree. C.,
HLB-value 14);
[0051] AKOLINE HH, Karlshamns AB, glycerol esters of medium chain
fatty acids (melting point 25.degree. C., HLB-value 5-6); AKOLINE
MCM, Karlshamns AB, caprylic/capric glycerides (melting point
25.degree. C., HLB-value 5-6);
[0052] Myrj 52s, Uniqema, Gouda, The Netherlands, PEG-40-stearate
(HLB Value 16.9);
[0053] Rylo MG12, Danisco A/S, Copenhagen, Denmark;
[0054] Tween 80, Uniqema.
[0055] As example of an oil has been used:
[0056] AKOSOL 403, Karlshamns AB, hydrogenated palm kernel oil
(melting point 34.degree. C.)
[0057] As polar liquids in addition to water has been used:
[0058] Ethanol 99.5%;
[0059] PEG 600, polyethylene glycol (melting point 25.degree.
C.);
[0060] PEG 3000, polyethylene glycol (melting point 48-54.degree.
C.).
[0061] As examples of fillers have been used:
[0062] Avicel PH-102, FMC International, Ireland, microcrystalline
cellulose;
[0063] Pharmatose DCL 11, DMV International, Holland, lactose;
and
[0064] Isomalt DC-100, Palatinit, Germany, a mixture of
disaccharides.
[0065] As an example of a binder has been used
[0066] Povidone K25, IFP, USA, polyvinyl pyrrolidone.
Example 1
Microemulsion
[0067]
1 Akolip LM 9.0% Akosol 403 1.0% Water 90.0%
[0068] Akolip LM and Akosol 403 are melted at 60.degree. C. and
added to water at room temperature using gentle stirring. Oil
soluble active compounds can be dissolved in the surfactant/oil
mixture before mixing with water or added to the microemulsion
solution.
Example 2
Non-Aqueous Microemulsion
[0069]
2 Akolip LM 72.0% Akoline MCM 13.5% Akosol 403 4.5% Ethanol 99.5%
10.0%
[0070] All components are added to ethanol, heated to about
40.degree. C. and stirred until a clear to slightly opalescent
solution is obtained.
Example 3
Non-Aqueous Microemulsion
[0071]
3 Akolip LM 7.0% Akoline HH 2.0% Akosol 403 1.0% Ethanol 90.0%
[0072] Akolip LM, Akoline HH and Akosol 403 are melted at
60.degree. C. and added to ethanol at room temperature using gentle
stirring. Oil soluble active compounds can be dissolved in the
surfactant/oil mixture before mixing with ethanol or added to the
microemulsion solution.
Example 4
[0073] Emulsion
4 Akolip LM 31.0% Akoline MCM 5.8% Akosol 403 2.0% PEG 3000 2.5%
Ethanol 99.5% 20.0% Water 38.7%
[0074] The surfactants, Akolip LM and Akoline MCM, are melted to
60.degree. C. The fat, Akosol 403, is separately melted to
60.degree. C. and added to the surfactants with gentle stirring.
The PEG 3000 is added and allowed to melt in the mixture. Half of
the water is added at 60.degree. C. and the resulting microemulsion
is cooled to 30.degree. C. where the ethanol and the rest of the
water is added forming an oil-in-water emulsion, which can be used
as a granulation medium.
Example 5
Liquid Crystalline Dispersion
[0075]
5 Akolip LM 45.0% Akosol 403 5.0% Rylo MG12 10.0% Water 40.0%
[0076] The solid components are melted at 60.degree. C. and
carefully mixed by gentle stirring. Water is added using vigorous
stirring to yield a semisolid, translucent, birefringent mass on
cooling to 30.degree. C. The liquid crystal formed in this way may
be dispersed in additional water or in liquid oil or a melted fat
to obtain a suitable granulation medium.
Example 6
Liquid Crystalline Dispersion
[0077]
6 Akolip LM 15.0% Akosol 403 5.0% Rylo MG12 25.0% Water 55.0%
[0078] The solid components are melted at 60.degree. C. and
carefully mixed by gentle stirring. Water is added using vigorous
stirring to yield a semisolid, translucent, birefringent mass on
cooling to 30.degree. C. The liquid crystal formed in this way may
be dispersed in additional water or in liquid oil or a melted fat
to obtain a suitable granulation medium. Oil soluble or sensitive
actives as well as auxiliary ingredients can be added to the
dispersion or even before performing the dispersion.
Example 7
Granulation Medium Containing Curcumin as a Model Drug Compound
[0079]
7 Akolip LM 37.1% Akoline MCM 15.9% Curcumin 14.0% Ethanol, 99.5%
33.0%
[0080] The surfactants, Akolip LM and Akoline MCM, are melted and
mixed at 60.degree. C. The ethanol is added to the heated
surfactant mixture during mixing. After cooling to 40.degree. C.,
curcumin is added and the mixture is gently stirred until it is
dissolved. The resulting liquid can be used as a granulation
medium.
Example 8
Granulation Medium Containing Naproxene
[0081]
8 Akoline MCM 14.0% Tween 80 61.0% Naproxene 10.0% Ethanol 99.5%
15.0%
[0082] The surfactants, Akoline MCM and Tween 80, are melted and
mixed at 60.degree. C. The ethanol is added to the heated
surfactant mixture during mixing. After cooling to 40.degree. C.,
naproxene is added and the mixture is gently stirred until it is
dissolved. The resulting liquid can be used as a granulation
medium.
Example 9
Granulation Medium Containing Indomethacin
[0083]
9 Akoline MCM 21.6% Tween 80 50.4% Indomethacin 8.0% Ethanol 99.5%
20.0%
[0084] The surfactants, Akoline MCM and Tween 80, are melted and
mixed at 60.degree. C. The ethanol is added to the heated
surfactant mixture during mixing. After cooling to 40.degree. C.,
indomethacin is added and the mixture is gently stirred until it is
dissolved. The resulting liquid can be used as a granulation
medium.
Example 10
Granulation Medium Containing Cyclosporine-A
[0085]
10 Akolip LM 35.0% Akoline MCM 15.0% Cyclosporine-A 16.7% Ethanol,
99.5% 33.3%
[0086] The surfactants, Akolip LM and Akoline MCM, are mixed in the
pre-heated ethanol, 40.degree. C. Cyclosporine-A is added and the
mixture is gently stirred until it is dissolved. The resulting
liquid can be used as a granulation medium.
Example 11
Wet Granulation Process Using a Soluble Filler
[0087] The granulation medium is prepared according to any of the
Examples 1-10 and added to lactose or an equivalent filler. The
amount of water in the granulation medium, if used, is optimised,
as is the total amount of granulation fluid. The granulation is
performed in ordinary pharmaceutical equipment, e.g. high shear
mixer etc. The wet mass is dried on trays or in a fluid bed at
temperatures of about 20-60.degree. C. The dry granules are passed
through a sieve from approx. 500 to 1000 .mu.m. The total amount of
granulation medium depends on the composition of the medium. After
drying a second granulation step could be performed.
[0088] The granulation medium from Example 7, at a temperature of
about 40.degree. C., is slowly added to Pharmatose DCL-11 in a high
shear mixer in the following proportions:
11 Granulation medium 43% Lactose, Pharmatose DCL-11 57%
[0089] The resulting granules are dried on trays at 30.degree. C.
and passed through a 710-.mu.m sieve. The dried and sieved granules
are suitable for further tablet processing.
Example 12
Wet Granulation Process Using Soluble Filler and Binder
[0090] The granulation medium is prepared according to any of
Examples 1-10 and added to lactose/Povidone. The Povidone could
also be dissolved in the ethanol and included in the granulation
medium. The amount of Povidone is optimised, from about 0.5 to 15%.
The amount of water in the granulation medium, if used, is
optimised, as is the total amount of granulation fluid. The
granulation is performed in ordinary pharmaceutical equipment, e.g.
high shear mixer etc. The wet mass is dried on trays or in a fluid
bed at temperatures of about 20-60.degree. C. The dry granules are
passed through a sieve from about 500 to 1000 .mu.m. The total
amount of granulation fluid depends on the composition of the
fluid. After drying a second granulation step could be
performed.
[0091] The granulation medium from Example 10, at a temperature of
about 40.degree. C. is slowly added to a dry mix of Povidone and
Isomalt DC-100 in a high shear mixer in the following
proportions:
12 Granulation medium 48.4% Povidone K-25 6.4% Isomalt DC-100
45.2%
[0092] The resulting granules are dried on trays at 30.degree. C.
and passed through a 710-.mu.m sieve. The dried and sieved granules
are suitable for further tablet processing.
Example 13
Wet Granulation Process Using Insoluble Filler
[0093] The granulation medium is prepared according to any of
Examples 1-10 and added to microcrystalline cellulose, Avicel
PH-102 or an equivalent filler. The amount of water (less critical
compared to when a water-soluble filler is used) in the granulation
medium, if used, is optimised, as is the total amount of
granulation fluid. The granulation is performed in ordinary
pharmaceutical equipment, e.g. high shear mixer etc. The wet mass
is dried on trays or in a fluid bed at temperatures of approx.
20-60.degree. C. The dry granules are passed through a sieve from
approx. 500 to 1000 .mu.m. The total amount of granulation fluid
depends on the composition of the fluid. After drying a second
granulation step could be performed.
[0094] The granulation medium from Example 9 is used after cooling
to approx. 40.degree. C. and slowly added to Avicel PH-102 in a
high shear mixer in the following proportions:
13 Granulation medium 45.5% Avicel PH-102 54.5%
[0095] The resulting granules are dried on trays at 30.degree. C.
and passed through a 710-.mu.m sieve. The dried and sieved granules
are suitable for further tablet processing.
Example 14
Wet Granulation Process Using Insoluble Filler and Binder
[0096] The granulation medium is prepared according to any of
Examples 1-10 and added to microcrystalline cellulose, Avicel
PH-102 or an equivalent filler and Povidone. The Povidone could be
dry mixed with the filler or dissolved in the granulation medium.
The amount of Povidone is optimised, from approx. 0.5 to 15%. The
amount of water (less critical compared to when water-soluble
filler is used) in the granulation medium, if used, is optimised,
as is the total amount of granulation fluid. The granulation is
performed in ordinary pharmaceutical equipment, e.g. high shear
mixer etc. The wet mass is dried on trays or in a fluid bed at
temperatures of approx. 20-60.degree. C. The dry granules are
passed through a sieve from approx. 500 to 1000 .mu.m. The total
amount of granulation fluid depends on the composition of the
fluid. After drying a second granulation step could be
performed.
[0097] The granulation medium according to Example 10 is used and
Povidone is dissolved in the medium. The resulting granulation
medium, with a temperature of approx. 40.degree. C. is slowly added
to Avicel PH-102 in a high shear mixer in the following
proportions:
14 Granulation medium 55.0% Povidone K-25 dissolved in above 7.5%
Avicel PH-102 37.5%
[0098] The resulting granules are dried on trays at 30.degree. C.
and passed through a 710-.mu.m sieve. The dried and sieved granules
are suitable for further tablet processing.
Example 15
Tablets Originating from Insoluble Filler
[0099] The granulation medium was prepared according to Example 1
and added to Avicel PH-102 in the following proportions
15 Granulation medium 80 g Avicel PH-102 200 g
[0100] The dried granules were passed through a 1.0 mm sieve and
transferred to a Korsch PH 106 rotary tablet press equipped with
round, diameter 10 mm punches. Tablets with a total weight of 400
mg and a crushing strength of 11-14 kp were produced.
Example 16
Tablets Originating From Soluble Filler
[0101] The granulation medium was prepared according to Example 2
and added to Pharmatose DCL-11 in the following proportions
16 Granulation medium 50 g Pharmatose DCL-11 200 g
[0102] The dried granules were passed through a 1.0 mm sieve and
transferred to a Korsch PH 106 rotary tablet press equipped with
round, diameter 10 mm punches. Tablets with a total weight of 400
mg and a crushing strength of 6-8 kp were produced.
Example 17
Tablets with 5.2% Curcumin, Originating from Soluble Filler and
Binder
[0103] The granulation medium was prepared according to Example 7
with the addition of Povidone, and added to Isomalt DC-100 in the
following proportions
[0104] Granulation Medium
17 Granulation medium Akolip LM 56.0 g Akoline MCM 23.0 g Curcumin
21.0 g Ethanol, 99.5% 49.0 g Binder Povidone K-25 50.0 g Filler
Isomalt DC-100 250.0 g
[0105] The ethanol is evaporated during the process. The dried
granules were passed through a 1.0 mm sieve and transferred to a
Diaf.TM.-20 single stroke tablet press equipped with round,
diameter 12 mm punches. Tablets with a total weight of 565 mg and a
crushing strength of 8.4.+-.0.4 kp (n=10) were produced. The
disintegration time was less than 15 min and the friability below
0.5%. The dissolution showed an increase in the solubility with
increasing amount of model substance, up to 10.8%. To be compared
to the solubility of the tablet with the high concentration of
model substance, 10.8%, formulated without the self-emulsifying
components (FIG. 1). The dissolution was performed using 500 ml
phosphate buffer (pH 7.4) in a Prolabo Dissolutest with a paddle
rate of 50 rpm and the temperature preset to 37.degree. C.
[0106] Samples were withdrawn according to a certain time schedule
and analysed with UV-spectrophotometry.
Example 18
Tablets with Cyclosporine-A Originating from Soluble Filler and
Binder
[0107] The granulation medium was prepared according to Example 10
with the addition of Povidone and added to Isomalt DC-100 in the
following proportions
18 Granulation medium Akolip LM 23.0 g Akoline MCM 10.0 g
Cyclosporine-A 11.0 g Ethanol, 99.5% 22.0 g Binder Povidone K-25
22.0 g Filler Isomalt DC-100 154.0 g
[0108] The ethanol was evaporated during the process. The dried
granules were passed through a 1.0 mm sieve and transferred to a
Diaf.TM.-20 single stroke tablet press equipped with round,
diameter 12 mm punches. Tablets with a total weight of 500 mg
(giving a final concentration of 25 mg Cyclosporine-A per tablet)
and a crushing strength between 6 and 8 kp were produced. The
dissolution from the produced tablets was determined and compared
to a Sandimmun Neoral.RTM. 25 mg capsule (FIG. 2). The dissolution
was found to be slightly faster and cyclosporine-A was solved to
the same extent as the commercial capsule formulation. The
dissolution was performed using phosphate buffer (pH 7.4) in a
Prolabo Dissolutest with a paddle rate of 50 rpm and the
temperature preset to 37.degree. C.
[0109] Samples were withdrawn according to a certain time schedule
and analysed with reversed phase HPLC.
* * * * *