U.S. patent application number 12/753571 was filed with the patent office on 2010-10-14 for granulate for the formulation of orodispersible tablets.
This patent application is currently assigned to E-PHARMA TRENTO S.p.A.. Invention is credited to Paolo Andreatta, Silvia Boschetti, Riccardo Catalano, Massimiliano ROSSI.
Application Number | 20100260854 12/753571 |
Document ID | / |
Family ID | 40909993 |
Filed Date | 2010-10-14 |
United States Patent
Application |
20100260854 |
Kind Code |
A1 |
ROSSI; Massimiliano ; et
al. |
October 14, 2010 |
GRANULATE FOR THE FORMULATION OF ORODISPERSIBLE TABLETS
Abstract
This invention relates to a granulate comprising mannitol and
sorbitol in a weight ratio of between 70:30 and 97:3. This
invention also relates to the use of the said granulate in the
preparation of orodispersible tablets, to the orodispersible
tablets obtained with the said granulate and to a process of
production for obtaining the said granulate.
Inventors: |
ROSSI; Massimiliano;
(Villamontagna, IT) ; Catalano; Riccardo; (Molina
di Fiemme, IT) ; Boschetti; Silvia; (Aldeno, IT)
; Andreatta; Paolo; (Villazzano, IT) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND MAIER & NEUSTADT, L.L.P.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
E-PHARMA TRENTO S.p.A.
Frazione Ravina
IT
|
Family ID: |
40909993 |
Appl. No.: |
12/753571 |
Filed: |
April 2, 2010 |
Current U.S.
Class: |
424/489 ;
514/772 |
Current CPC
Class: |
A61K 9/1623 20130101;
A61K 47/26 20130101; A61P 1/08 20180101; A61K 9/2018 20130101; A61P
37/08 20180101; A61P 29/00 20180101; B01J 2/16 20130101; A61P 25/22
20180101; A61K 9/0056 20130101 |
Class at
Publication: |
424/489 ;
514/772 |
International
Class: |
A61K 9/16 20060101
A61K009/16; A61K 47/10 20060101 A61K047/10; A61P 1/08 20060101
A61P001/08; A61P 29/00 20060101 A61P029/00; A61P 37/08 20060101
A61P037/08; A61P 25/22 20060101 A61P025/22 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 2009 |
EP |
09425135.2 |
Claims
1. A granulate comprising a mixture of mannitol and sorbitol in a
ratio by weight of between approximately 70:30 and approximately
97:3.
2. The granulate according to claim 1, comprising a mixture of
mannitol and sorbitol in a ratio by weight of between approximately
80:20 and approximately 95:5.
3. The granulate according to claim 2, comprising a mixture of
mannitol and sorbitol in a ratio by weight of approximately
90:10.
4. The granulate according to any one of claims 1 to 3, in which
the said mixture is formed of granules having an average size of
between 50 .mu.m and 500 .mu.m.
5. The granulate according to claims 4, in which the said mixture
is formed of granules having an average size of between 150 .mu.m
and 350 .mu.m.
6. The granulate according to any one of claims 1 to 5,
characterised in that it has a residual moisture content of less
than 0.20% by weight relative to the weight of the same
granulate.
7. The granulate according to claim 6, characterised by a residual
moisture content equal to or lower than 0.10% by weight.
8. The granulate according to any one of claims 1 to 7,
characterised by a compressibility index of more than 4.5.
9. An orodispersible tablet comprising at least one active
ingredient dispersed in a granulate comprising a mixture of
mannitol and sorbitol in a ratio by weight of between approximately
70:30 and approximately 97:3.
10. The tablet according to claim 9, in which the quantity of the
said granulate is equal to or greater than 50% by weight relative
to the weight of the said tablet.
11. The tablet according to either of claim 9 or 10, in which the
said active ingredient is selected from the group comprising
non-steroidal anti-inflammatory drugs (NSAIDs), anxiolytics,
antiemetics, antihistaminics and proton pump inhibitors.
12. The tablet according to any one of claims 9 to 11, comprising a
further excipient selected from the group consisting of diluents,
sweeteners and flavourings.
13. A process for the production of a granulate comprising mannitol
and sorbitol, the said process comprising the following steps: (i)
providing mannitol and sorbitol in the form of powder, (ii)
providing a mixture of the said mannitol and the said sorbitol in a
ratio by weight of between approximately 70:30 and approximately
97:3, (iii) introducing the said mixture into a fluidised bed
granulator, (iv) granulating the said mixture under the following
conditions: (a) spraying a quantity of water of between 5% and 35%
by weight with respect to the weight of the said mixture, and (b)
introducing air at a temperature below 80.degree. C. with a
moisture content of less than 5000 ppm.
14. The process according to claim 13, in which the said mannitol
has an average particle size of less than 100 .mu.m and the said
sorbitol has an average particle size of between 200 .mu.m and 250
.mu.m.
15. The process according to claim 13 or 14, in which the said
mixture has an average particle size of less than 200 .mu.m,
preferably between 100 .mu.m and 150 .mu.m.
16. The process according to any one of claims 13 to 15, in which
the said mixture has a ratio by weight between the said mannitol
and the said sorbitol between approximately 80:20 and approximately
95:5.
17. The process according to any one of claims 13 to 16, in which
the quantity of water is between 15% and 25% by weight with respect
to the weight of the mixture.
18. The process according to any one of claims 13 to 17, in which
the said air has a temperature between 65.degree. C. and 75.degree.
C.
19. The process according to any one of claims 13 to 18, in which
the said air has a moisture content equal to or lower than 1000
ppm.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a granulate for the formulation of
orodispersible tablets, in particular the formulation of
orodispersible tablets comprising pharmaceutical or nutritional
active ingredients.
[0002] In particular this invention relates to a granulate
comprising mannitol and sorbitol in a weight ratio between 70:30
and 97:3. This invention also relates to the use of the said
granulate in the preparation of orodispersible tablets, to
orodispersible tablets obtained using the said granulate and to a
production process for obtaining the said granulate.
[0003] The orodispersible tablets obtained using the granulate
according to this invention have high porosity and may comprise a
high content of the active ingredient in comparison with the
orodispersible tablets known in the art.
STATE OF THE ART
[0004] Orodispersible (OD) tablets are tablets taken orally which
rapidly disintegrate in the mouth through the effect of the solvent
action of saliva and the mechanical action of the tongue. OD tablet
formulations have better acceptability than traditional swallowable
tablets, both in patients having difficulty with swallowing such
conventional tablets (for example young children and the elderly),
and patients with gastro-intestinal syndromes, who have greater
problems in absorbing the active ingredients from solid
pharmaceutical forms taken orally, which may be disturbed by the
presence of the still undissolved solid tablet within the
gastro-intestinal tract.
[0005] The disintegration of an OD tablet does not take place
through a single mechanism, but involves various phenomena such as
swelling of the disintegrant in contact with saliva, the formation
of small channels promoted by the presence of pores in the tablet,
the presence of effervescent substances, the mechanical action of
the tongue, and so on.
[0006] In any event, the penetration of water (saliva) within an OD
tablet is the first and fundamental step to disintegration, and for
this it is necessary to find a compromise between the physical
characteristics of the tablet and the chemical properties of the
excipients used in the formulation.
[0007] U.S. Pat. No. 6,149,938 relates to a process for obtaining a
useful granulate for the production of a solid form for oral use
which rapidly disintegrates in the buccal cavity. This granulate is
prepared by the fluidised bed granulation of an aqueous solution
comprising a water-soluble or water-dispersible polymer and a
polyalcohol, which may optionally be mixed with other solid
components, and subsequent drying in a fluidised bed dryer. The
polyalcohol preferably used is sorbitol, but others such as
mannitol, xylitol, maltitol and so on may also be used; the
quantity of polyalcohol varies between 50% and 90% by weight with
respect to the total weight of the tablet obtained by compression
of the granulate. The tablets described in the examples include
lubricants, have a weight of between 1 and 2 grams, and a
disintegration time of between 30 and 140 seconds.
[0008] Despite the fact that the Official Pharmacopoeia has used
the term OD tablets to define tablets which disperse in the mouth
within 3 minutes before swallowing, the US FDA has defined OD
tablets as a solid form containing an active ingredient which
disintegrates rapidly, normally in a matter of seconds, when placed
on the tongue. Generally the disintegration of an OD tablet occurs
between a few seconds and approximately one minute (Bandari et al.,
"Orodispersible tablet: An overview", Asian Journal of
Pharmaceuticals, January 2008). Taking a time of 20-30 seconds as a
commercially acceptable value for the definition of fast
disintegration, no tablets having a mass of more than 600 mg are
found on the market because increased mass makes it difficult for
saliva to penetrate the tablet and therefore inhibits the function
of the disintegrants, with consequent slowing of
disintegration.
[0009] Conventional OD tablets (as for example described in WO
03/009830 and in WO 00/27357) always include at least one
disintegrant which swells as a result of water absorption and/or
water channelling. However, the presence of a disintegrant, which
is necessary for the disintegration of conventional OD tablets, has
two disadvantages--on the one hand it increases the mass of the
tablet restricting the possibility of adding the active ingredient
in larger doses, and on the other it absorbs saliva, leaving a dry
feeling in the oral cavity.
[0010] EP 1 800 669 relates to a solid pharmaceutical composition
comprising a central core containing the active ingredient and
excipients for an orodispersible formulation and an orodispersible
coating, for the oral, oral mucosal or sublingual administration of
agomelatin. In more detail, the orodispersible coating is obtained
with a specific diluent for orodispersible preparations, or using a
conventional diluent with one or more added disintegrants. The
orodispersible diluent may comprise granules obtained by the
co-atomization of lactose and starch (Strarlac.RTM.), or a atomized
polyalcohol, for example sorbitol or mannitol, or a atomized
mixture based on polyalcohols, for example excipients commercially
marketed such as Partek.RTM. and Pharmaburst.RTM.. In OD tablets
prepared using this method and described in the examples the
polyalcohol used is mannitol for direct compression or
Starlac.RTM.. The tablets obtained using this method have a maximum
weight of 350 mg and in vitro tests describe a disintegration time
of less than 3 minutes.
[0011] The methods of preparation described above for the
production of OD tablets (for example in WO2007/104771 and U.S.
Pat. No. 5,866,163) include both methods used for the production of
conventional tablets and alternative methods, such as fusion or
lyophilisation processes in moulds, which are already known to
those skilled in the art. The production of OD tablets requires
suitably designed manufacturing units because of the poor
mechanical properties of the tablets. Lubricants have to be added
to increase the compressibility and flowability of the powders, but
there is the disadvantage that these excipients reduce the
wettability of the tablet and therefore the rate of
disintegration.
SUMMARY OF THE INVENTION
[0012] The object of this invention is to provide a granulate for
the formulation of orodispersible tablets which overcomes the
problems described.
[0013] In the course of extensive experimentation the Applicant has
had to make a selection of components considering various
parameters such as, for example, speed and safety of manufacture,
compressibility, palatability, stability, food intolerances,
solubility, purchase cost and availability on the market.
[0014] The Applicant has found that a granulate comprising mannitol
and sorbitol in a specific weight ratio makes it possible to
manufacture OD tablets which disintegrate rapidly, in times less
than 30 seconds, in contact with saliva in the oral cavity, with
good palatability.
[0015] Surprisingly the Applicant has found that the granulate
according to this invention obtained from the combination of
mannitol and sorbitol, two readily available and inexpensive
polyalcohols, has made it possible to obtain an OD tablet which at
the same time disintegrates and/or dissolves in the oral cavity
without the need to add a disintegrant.
[0016] The absence of disintegrants and the presence of
polyalcohols ensures that the tablets are more palatable. In fact
in conventional OD tablets the quantity of disintegrant is such
that it completely absorbs the saliva present in the oral cavity,
because the water absorbtion capacity of these excipients varies
between 3 and 10 times their weight, leaving the patient treated
with a feeling of dryness in the mouth (plaster effect).
[0017] Mannitol and sorbitol are highly hygroscopic and soluble in
water, which is essential for oral administration where the
quantity of liquid (saliva) available for disintegration is
fractions of a millilitre.
[0018] The Applicant has surprisingly found that OD tablets
obtained with the granulate according to this invention may have a
very much greater mass, up to 2000 mg and even more, in comparison
with conventional OD tablets comprising a disintegrant, whilst
keeping disintegration times below 30 seconds.
[0019] The Applicant has therefore observed that the possibility of
obtaining tablets having a mass of more than 2 g also includes the
possibility of adding a greater quantity of the active ingredient
to the formulation in comparison with conventional tablets.
[0020] In addition to this, the increase in tablet size makes it
possible to apply less pressure per unit surface area during the
compression step, and as a consequence to obtain greater
porosity.
[0021] The Applicant has found that the granulate according to this
invention has good mechanical properties, with high compressibility
and flowability, which means that it can be used without the
addition of lubricating agents.
[0022] Thus, in a first aspect, this invention relates to a
granulate of a mixture of mannitol and sorbitol in a ratio by
weight of between approximately 70:30 and approximately 97:3.
[0023] The Applicant has found that use of the granulate according
to this invention makes it possible to obtain tablets with a high
compressibility index. The compressibility index is given by the
ratio between the hardness of the tablet and the compression force.
For the same compression force the tablets obtained using the
granulate according to this invention have greater hardness and
lower density. Greater hardness imparts the necessary strength upon
the tablet to withstand mechanical stresses during the processes of
production and packaging without breaking up. Lower density imparts
greater porosity on the tablet and therefore a greater rate of
disintegration because water penetrates within the OD tablet more
quickly.
[0024] Thus, in a second aspect, this invention relates to an OD
tablet comprising a granulate of a mixture of mannitol and sorbitol
in a ratio by weight of between approximately 70:30 and
approximately 97:3.
[0025] The Applicant has also observed that the characteristics of
the granulate according to this invention are advantageously
obtained through a fluidised bed granulation process by controlling
the dimensions of the mannitol and sorbitol particles, the quantity
of water, and the temperature and humidity of the air used in the
granulation process.
[0026] Thus, in a third aspect, this invention relates to a process
for producing a granulate comprising mannitol and sorbitol, the
said process comprising the following steps: [0027] (i) providing
mannitol and sorbitol in the form of powder, preferably having an
average particle size of less than 100 .mu.m and between 200 .mu.m
and 250 .mu.m respectively, [0028] (ii) providing a mixture of the
said mannitol and the said sorbitol in a ratio by weight of between
approximately 70:30 and approximately 97:3, [0029] (iii)
introducing the said mixture into a fluidised bed granulator,
[0030] (iv) granulating the said mixture under the following
conditions: [0031] (a) spraying a quantity of water of between 5%
and 35% by weight with respect to the weight of the said mixture,
and [0032] (b) introducing air at a temperature below 80.degree. C.
with a moisture content of less than 5000 ppm, preferable equal to
or lower than 1000 ppm.
BRIEF DESCRIPTION OF THE FIGURES
[0033] FIG. 1 shows the in vitro and in vivo disintegration times
of tablets 10 according to the invention as a function of hardness,
and comparison tablets 11 described in Example 5 below.
DETAILED DESCRIPTION OF THE INVENTION
[0034] In at least one of the aforesaid aspects this invention may
show one or more of the preferred characteristics described
below.
[0035] Preferably the granulate according to this invention
comprises mannitol and sorbitol in a ratio by weight of between
80:20 and approximately 95:5, and even more preferably
approximately 90:10.
[0036] Advantageously the granulate according to this invention has
an average particle size of between 50 .mu.m and 500 .mu.m,
preferably between 150 .mu.m and 350 .mu.m. For values below 50
.mu.m the granulate tends to become compacted because of prevalence
of weak forces (of the Van der Waals, dipole-dipole and hydrogen
bond type) over the weight force of the particle and low
flowability problems occur. At values over 500 .mu.m the granulate
shows an increase in the inter-particle empty spaces, which
increases the apparent volume. Apparent volume is defined as the
space occupied by a particular quantity of granulate when poured
and caused to fall into a container of cubic or rhomboidal shape.
As the apparent volume increases, there is an increase in flow
time, the time which reflects the ease of which the granulate
becomes distributed in the container. As the apparent volume and
flow time increase, the variability in the time required by the
granulate to fill the rhomboidal container and the cubic container
increases.
[0037] According to a preferred aspect the granulate according to
this invention has a density of less than 1 g/cm.sup.3, and more
preferably less than 0.75 g/cm.sup.3.
[0038] The low density of the granulate is an indication of its
high porosity, and makes it possible to obtain OD tablets with
reduced disintegration times, increased hardness (imparting the
ability to withstand mechanical stresses) and good
compressibility.
[0039] Advantageously the granulate according to this invention has
a very low residual moisture content, less than 0.20% by weight
relative to the weight of the granulate. More preferably the
granulate according to this invention has a residual moisture
content equal to or lower than 0.10% by weight relative to the
weight of the granulate.
[0040] The Applicant has observed that for residual moisture values
slightly above that specified (up to 0.50%) there are increases in
the hardness of the tablets over time which have an adverse effect
on the rate of disintegration in the mouth, while at residual
moisture values well beyond those specified (up to 1.00% and more)
the stability of the final tablet is compromised.
[0041] The granulate according to this invention is prepared using
a fluidised bed granulation technique. Under specific conditions
this type of granulation makes it possible to obtain the product
with the desired characteristics.
[0042] The process of producing the granulate according to this
invention comprises the following steps: [0043] (i) providing
mannitol and sorbitol in the form of powder, preferably having an
average particle size of less than 100 .mu.m and between 200 .mu.m
and 250 .mu.m respectively, [0044] (ii) providing a mixture of the
said mannitol and the said sorbitol in a ratio by weight of between
approximately 70:30 and approximately 97:3, [0045] (iii)
introducing the said mixture into a fluidised bed granulator,
[0046] (iv) granulating the said mixture under the following
conditions: [0047] (a) spraying a quantity of water of between 5%
and 35% by weight with respect to the weight of the said mixture,
and [0048] (b) introducing air at a temperature below 80.degree. C.
with a moisture content of less than 5000 ppm, preferable equal to
or lower than 1000 ppm.
[0049] The Applicant has observed that the use of a mixture of
mannitol and sorbitol having an average mixture particle size of
less than 200 .mu.m, preferably between 100 .mu.m and 150 .mu.m,
makes it possible to obtain a final granulate having a greater
compressibility index. Because mannitol is always the main
component in the mixture (in a quantity of between 70% and 97% by
weight) with respect to sorbitol, which is always the secondary
component (in a quantity between 30% and 3% by weight), the latter
may also be used in the form of a powder having an average particle
size of more than 200 .mu.m. In particular the Applicant has found
that better results are obtained with a mixture comprising mannitol
having an average size of less than 100 .mu.m and sorbitol having
an average size between 200 .mu.m and 250 .mu.m.
[0050] In addition to this, the Applicant has observed that the use
of water as a solvent makes it possible a better granulation and
workability of the two polyalcohols, in addition to being non-toxic
and non-hazardous.
[0051] Advantageously the preferred quantity of water is between
10% and 30% by weight, more preferably between 15% and 25% by
weight with respect to the weight of the mixture of mannitol and
sorbitol in the said mixture.
[0052] Preferably the temperature of the air introduced into the
fluidised bed granulator is higher than 60.degree. C., more
preferably between 65.degree. C. and 75.degree. C., and even more
preferably around 70.degree. C. The relative moisture content of
the air introduced into the fluidised bed granulator is less than
5000 ppm, preferably equal to or lower than 1000 ppm.
[0053] The Applicant has observed that temperatures equal to or
higher than 80.degree. C. may cause chemical and physical changes
in the granulate, with the occurrence of fusion and yellowing. On
the other hand the Applicant has observed that temperatures below
60.degree. C. would require long drying times, which, although in
principle practicable, are not convenient from the industrial point
of view. In particular the Applicant has observed that optimum
drying times from the industrial point of view are less than 30
minutes, preferably equal to or lower than 20 minutes. The choice
of relative humidity values for the air introduced into the
fluidised bed granulator also depends on drying temperature and
times, and the desired residual moisture content.
[0054] The granulate obtained through the process according to this
invention has perfect flowability and has a regular particle size
which permits precise dosing.
[0055] The granulate obtained through the process according to this
invention also has high compressibility.
[0056] Compressibility is measured as the ratio between the
hardness of the tablet and the compression force applied in order
to obtain that hardness. This ratio is defined as the
"Compressibility Index" (CI).
[0057] The Applicant has found that the granulate according to this
invention has a compressibility index of more than 4.5, a value
which is not found with other known excipients for the production
of orodispersible tablets.
[0058] A high CI value means that greater hardness can be obtained
with less compression force. This avoids the addition of a
lubricant among the excipients, which, as known to those skilled in
the art, is used to prevent the granulate to stick to the punches
and walls of the mould during the compression step and ensures that
the particles comprising the granulate can flow.
[0059] Applying less compression forces also means obtaining a
lower density and as a consequence greater porosity in the tablet
so obtained. This means a greater rate of water penetration and a
shorter disintegration time.
[0060] Other factors being the same, the possibility of obtaining
greater hardness imparts better mechanical properties on the
tablets, which ensures less problems during the steps of production
and packaging of the final pharmaceutical form.
[0061] This invention also relates to an OD tablet comprising the
granulate according to this invention.
[0062] Advantageously the tablet according to this invention
comprises at least 50% by weight of granulate, preferably between
50% and 99% by weight. The presence of a quantity of granulate of
more than 50% by weight ensures a good compression yield regardless
of the mechanical characteristics of the active ingredient used,
and makes it possible to achieve good compression yields even with
difficultly compressible active ingredients. Below this percentage
the compression yield may decrease appreciably because of the lack
of contact between the particles of the granulate according to this
invention.
[0063] The Applicant has also observed a further advantage of the
tablets according to this invention which is correlated with the
absence of disintegrants.
[0064] In general it is observed that for constant compression and
hardness tablets show a decrease in density corresponding to an
increase in weight, and therefore an increase in their volume and
porosity. Technically, if the values of density (Y) and weight (X)
of a tablet obtained at constant pressure are plotted on a system
of coordinates it will be observed that the resulting straight line
has a negative angular coefficient. Lines which are all parallel to
each other are obtained for different pressure values.
[0065] In conventional tablets which contain disintegrants the
increase in mass has nevertheless a limit associated with both the
length of the route which the water (saliva) has to travel in order
to penetrate within the tablet and promote the disintegrant's
swelling mechanism, and the quantity of water (saliva) available
within the oral cavity.
[0066] On the contrary the phenomenon of increased porosity with
increased volume results in an advantage for tablets according to
this invention.
[0067] The Applicant has in fact observed that using the granulate
according to this invention the mass of the tablets is greater, and
the rate of disintegration is also greater. This happens because
disintegration of the tablet according to the invention depends
only on contact between the granulate and water (saliva). Because
the latter can penetrate the tablets with greater porosity more
quickly, the volume and as a consequence the mass of the tablets
can be increased without a corresponding increase in disintegration
times.
[0068] The tablets according to this invention may comprise any
active ingredient which is suitable for oral administration.
Examples of the active ingredients which may be advantageously used
in preparing tablets according to this invention are non-steroidal
anti-inflammatory drugs (NSAIDs), anxiolytics, antiemetics,
antihistaminics, proton pump inhibitors, and so on.
[0069] The active ingredients formulated in OD tablets may
advantageously be coated with one or more layers of a polymer,
either to mask the unpleasant taste of the active ingredient or to
obtain gastric protection or prolonged/delayed release over time.
Examples of polymers which are advantageously used to coat the
active ingredients used in preparation of the tablets according to
this invention are for example Eudragit (Evonik), Methocel (Dow),
Kollicoat (BASF), Klucel (Signet), Aqualon, Aquacoat, Lustreclear
(FMC), Opadry (Colorcon), Spectracel, Spectrablend (Sen-sient).
[0070] These polymeric coatings are fragile in the compression
step. The compression materials and methods conventionally used
requires high compression forces which can compromise the integrity
and as a consequence the function of the coating. As a result of
its high compressibility the granulate according to this invention
makes it possible to reduce the risk of breakdown of the polymer
coating because no high compression force is required. In
particular the Applicant has observed that the granulate according
to this invention has an ultimate strength which is five times less
than the ultimate strength for the coating polymer.
[0071] In addition to this the use of a high percentage of
granulate according to this invention, equal to at least 50% of the
weight of the tablet, reduces adhesion phenomena by limiting
contact between the granules of coated active ingredient and as a
consequence the coating function is not compromised.
[0072] The tablet according to this invention may also comprise
other ingredients typically used in the preparation of
orodispersible tablets such as for example diluents, sweeteners,
flavourings and the like.
[0073] Examples of suitable diluents comprise lactose, starch,
dextrose, xylitol, and so on.
[0074] Examples of suitable sweeteners comprise aspartame,
saccharin, acesulphame, and so on.
[0075] Examples of suitable flavourings comprise grapefruit
flavour, raspberry flavour, lemon flavour, orange flavour, caramel
flavour, vanilla flavour, cream flavour, and the like.
[0076] The following examples are intended to illustrate preferred
aspects of the invention, without nevertheless having the object of
restricting it. Those skilled in the art will be able to find
various modifications which fall within the spirit of the invention
and the scope of the claims.
Example 1
[0077] A mixture of powdered mannitol (average size less than 100
.mu.m) and powdered sorbitol (average size between 200 .mu.m and
250 .mu.m) in a weight ratio of 9:1 was used to prepare the
granulate using different granulation methods.
[0078] Using the dry granulation technique, the mixture was first
compacted by a tablet press into slugs having a diameter of
approximately 20-30 mm. Using different compression forces, slugs
T.sub.A, T.sub.B, T.sub.C having respective hardness of 20N, 50N
and 120N were obtained. The slugs were then broken up using an
oscillating granulator and sieved through a 1000 .mu.m sieve.
Granulates A, B and C obtained from slugs T.sub.A, T.sub.B, T.sub.C
respectively had the average sizes and densities indicated in Table
1.
[0079] Using the wet granulation technique, the mixture was wet
granulated with purified water in an Erweka AR400 granulator. The
paste was dried on a fluidised bed and sieved through a 1000 .mu.m
mesh. Granulate D had an average size and density as indicated in
Table 1 below.
[0080] Using the fluidised bed technique, the mixture was
introduced into a Glatt WCG-CD200 fluidised bed granulator together
with dry hot air at 70.degree. C. (residual moisture content less
than 1,000 ppm) and purified water was sprayed in a quantity of
approximately 20% by weight with respect to the weight of the
mixture. Granulate E had an average size and density as indicated
in Table 1 below.
TABLE-US-00001 TABLE 1 Granulate Density Average size A 0.606 259 B
0.645 234 C 0.714 231 D 0.921 221 E 0.513 242
[0081] The five granulates A-E so obtained were used to prepare
respectively five tablets 1-5 in a dose of 2.6 g in a tablet press
equipped with punches having a diameter of 25 mm exerting a
compression force of 65 KN. The hardness and thickness values for
the tablets so obtained are shown in Table 2 below.
TABLE-US-00002 TABLE 2 Tablet Hardness (N) Thickness (mm) 1 90 4.6
2 90 4.6 3 100 4.5 4 160 4.3 5 300 4.6
[0082] The data in Table 2 clearly show that granulate E according
to this invention makes it possible to obtain tablets with a
greater hardness for the same compression force.
Example 2
[0083] Granulate E according to this invention was compared with a
series of commercial excipients ready for compression. The
comparison was made by comparing a series of tablets as described
in Example 1 and measuring the resulting hardness of each tablet
obtained. The results are summarised in Table 3 below.
TABLE-US-00003 TABLE 3 Excipient Hardness (N) CI Granulate E 300
4.62 Xylitab 200 (Danisco) 285 4.38 Sorbitol (Roquette) 245 3.77
Maltodextrin 215 3.31 Isomalt (Diamalt) 214 3.29 Emdex (Mendell)
212 3.26 Ercawax 4000 (Erca) 196 3.02 Pearlitol (Roquette) 163 2.51
Lactose DC 105 1.62 Microtal (T&L) 92 1.42 Saccharose 75 1.15
Fructose 50 0.77 Citric acid 45 0.69
[0084] The data in Table 3 showed that granulate E has the best
compressibility index (CI) in comparison with the excipients known
in the art.
Example 3
[0085] Granulate E according to this invention was prepared
following the procedure described in Example 1, varying the process
conditions (temperature and humidity) of the air. The results are
summarised in Table 4 below.
TABLE-US-00004 TABLE 4 Temperature (.degree. C.) Relative humidity
(%) Result 80 0.1 Non-conforming product - product melted and
turned to yellow 70 0.1 Optimum product - moisture content 0.1%
after 20 minutes drying 50 0.1 Non-conforming product - product
moisture content 0.25% after 50 minutes drying (long) 70 1
Conforming product - product moisture content 0.20% after 60
minutes drying (long) 70 10 Conforming product - product moisture
content 0.20% after 70 minutes drying (long) 70 25 Non-conforming
product - product moisture content 0.25% after 70 minutes drying
(long)
Example 4
[0086] Three test granulates F-H were prepared using the procedure
described in Example 1, but varying drying times so as to obtain a
different residual moisture content, as shown in Table 5.
TABLE-US-00005 TABLE 5 Residual moisture Granulate Time (minutes)
content (%) F 20 0.11 G 10 0.26 H 0 0.78
[0087] The three granulates F-H so obtained were used to prepare
three lots of tablets 6-8 respectively with a dosage of 2.6 g in a
tabletting machine having punches of diameter of 25 mm exerting a
compression force of 65 KN. The hardness values of the tablets so
obtained were measured immediately after preparation (T0), after
one month (T1), and after three months (T3). Table 6 below
summarises the values obtained.
TABLE-US-00006 TABLE 6 Hardness (N) Tablet T0 T1 T3 6 291.6 300.4
288.7 7 290.0 331.2 >350 8 294.1 * * * The tablet in lot 8 was
already degraded at one month
[0088] The data in Table 6 clearly showed that the residual
moisture content of the granulate has an appreciable effect on the
hardness of the tablets over time. The tablets in comparison lots 7
and 8 proved unusable one month and/or three months after
preparation. The increased hardness of the tablets in lot 7 had an
adverse effect on the disintegration rate in the mouth while the
tablets in lot 8 were already degraded after one month. The tablets
in lot 6 obtained from granulate according to this invention showed
constant values for hardness over time and no degradation.
Example 5
[0089] Granulate E according to this invention was used to prepare
tablets of different hardness in the presence or absence of
disintegrants as shown in Table 7.
TABLE-US-00007 TABLE 7 Tablet Ingredients (mg) 10a 10b 11a 11b
Granulate E 1000 1000 925 925 Avicel PH200 -- -- 50 50 Kollidon CL
-- -- 25 25 Hardness (N) 25 45 25 45
[0090] The disintegration time for each tablet was measured using
the in vitro method according to the European Pharmacopeia, and the
in vivo method. The results are summarised in Table 8 below.
TABLE-US-00008 TABLE 8 Disintegration time (seconds) Tablet
Hardness In vitro method In vivo method 10a (i) 25 40 15 10b (i) 45
100 25 11a (c) 25 30 20 11b (c) 45 55 50
[0091] The data in Table 8 showed that the in vitro method
according to the European Pharmacopoeia does not predict the in
vivo behaviour of tablets 10 according to this invention.
[0092] In fact, in vitro tablets 10 according to the invention
showed an increase in disintegration time with increased hardness
(from 40 to 100 seconds) and in all cases always longer than the
disintegration time of comparison tablets 11 (30 and 55
respectively). Wholly negative results were also expected from the
in vivo test following these results.
[0093] Vice-versa, in vivo, comparison tablets 11 behaved
consistently with the in vitro results, with similar disintegration
times (20 and 50 respectively), while tablets 10 according to the
invention showed completely different and positive disintegration
times, much shorter than those for tablets 11 (15 and 25
respectively).
[0094] The graph in FIG. 1 shows the different trends shown by
tablets 10 according to the invention and comparison tablets 11, in
vitro and in vivo respectively, with increasing hardness.
Example 6
[0095] Granulate E according to this invention was used to prepare
two series of tablets in the presence or absence of disintegrants
as shown in Table 9. The tablets used in the test were produced in
order to simulate a tablet containing an active ingredient (not
actually present) which would require a coating (for example in
order to mask its unpleasant flavour). Syloid FP, sodium lauryl
sulphate, stearic acid and Eudragit Epo were used to prepare the
polymer coating.
TABLE-US-00009 TABLE 9 Tablet Ingredients (mg) 12 (c) 13 (i) Base
for deposition of the active ingredient Polysorbate 20 1.0 1.0
Simeticone dry 1.0 1.0 Sugar spheres 60 250.0 250.0 Coating film
Syloid FP 30.2 30.2 Sodium lauryl 4.0 4.0 sulphate Stearic acid 6.0
6.0 Eudragit Epo 40.3 40.3 Disintegrants Avicel pH200 75.0 --
Kollidon CL 25.0 -- Other excipients Aspartame 15.0 15.0 Caramel
flavour 20.0 20.0 Granulate E 532.4 632.4 Total weight 1,000.0
1,000.0 (i) invention (c) comparison
[0096] Tablets 12 and 13 were used in a test panel of 25 volunteers
to check the in vivo disintegration rate and to have an objective
evaluation of the palatability of the product. The organolectic
characteristics about which the participants in the test had to
give their opinion were the following: [0097] ease of swallowing
[0098] dry feeling in the mouth [0099] persistent presence of
residue [0100] ease of disintegration [0101] overall
satisfaction
[0102] In order to express their feelings the participants in the
test were instructed to use the scale shown in Table 10 and to take
the tablets without water and without chewing. The tablets were
distributed blind.
TABLE-US-00010 TABLE 10 Score Meaning 0 None 1 Very little 2 Little
3 Some 4 Much 5 Very much
[0103] Table 11 below shows the results obtained.
TABLE-US-00011 TABLE 11 13 (i) 12 (c) Average Standard Average
Standard value deviation value deviation Disintegration time (sec)
11.5 3.3 20.0 4.7 Ease of swallowing 4.8 0.4 4.5 0.7 Dryness of the
mouth 0.5 0.7 1.9 0.9 Presence of residue 0.4 0.7 1.2 0.9 Ease of
disintegration 4.9 0.3 4.5 0.5 Overall satisfaction 4.8 0.5 4.1
0.7
[0104] The results were collected and analysed by statistical
processing using the t test (two tail .alpha.=0.05) through which
the means of the values obtained can be compared. Given a first
value for the mean and its standard deviation, this method can be
used to check whether this first mean value differs from another
mean value obtained. The disintegration time for tablets 13
according to the invention proved to be significantly less than the
disintegration time for comparison tablets 12 containing
disintegrants. In addition to this, tablet 13 according to the
invention proved to be more acceptable overall, with a
disintegration time of almost 50% less than that of comparison
tablet 12.
* * * * *