U.S. patent application number 15/201908 was filed with the patent office on 2016-10-27 for orodispersible tablets.
The applicant listed for this patent is LABORATORIOS LESVI, S.L.. Invention is credited to Carmen BEDA PEREZ, Ignacio D EZ MART N, Pablo PABLO ALBA.
Application Number | 20160310470 15/201908 |
Document ID | / |
Family ID | 38962587 |
Filed Date | 2016-10-27 |
United States Patent
Application |
20160310470 |
Kind Code |
A1 |
BEDA PEREZ; Carmen ; et
al. |
October 27, 2016 |
ORODISPERSIBLE TABLETS
Abstract
This invention relates to a an orally disintegrating tablet
obtainable by direct compression of a dry powdered mixture, said
mixture comprising up to 15% by weight of calcium silicate, at
least 50% of a diluent, a disintegrant agent and an active
ingredient. It also relates to a process for preparing the tablets
by homogeneous blending the specific excipients in powder form and
subsequent direct compression of the mixture. Said tablets
disintegrate quickly in the cavity of the mouth, in particular in
less than 15 seconds.
Inventors: |
BEDA PEREZ; Carmen;
(Cabrils-Barcelona, ES) ; D EZ MART N; Ignacio;
(Sant Feliu De Llobregat-Barcelona, ES) ; PABLO ALBA;
Pablo; (Cornella De Llobregat-Barcelona, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
LABORATORIOS LESVI, S.L. |
Sant Joan Despi - Barcelona |
|
ES |
|
|
Family ID: |
38962587 |
Appl. No.: |
15/201908 |
Filed: |
July 5, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12680296 |
Aug 10, 2010 |
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PCT/EP2008/063068 |
Sep 30, 2008 |
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15201908 |
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60977166 |
Oct 3, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5513 20130101;
A61K 9/2095 20130101; A61K 9/2027 20130101; A61K 31/519 20130101;
A61P 25/06 20180101; A61P 9/00 20180101; A61P 15/00 20180101; A61P
29/00 20180101; A61P 15/10 20180101; A61P 7/02 20180101; A61P 11/06
20180101; A61K 9/0056 20130101; A61K 31/422 20130101; A61K 31/4178
20130101; A61P 25/18 20180101; A61K 9/2072 20130101; A61K 9/2009
20130101; A61P 9/12 20180101; A61K 31/4196 20130101; A61P 31/12
20180101; A61K 9/2054 20130101; A61K 9/0007 20130101; A61P 25/24
20180101; A61K 9/2013 20130101; A61P 25/20 20180101; A61P 1/00
20180101; A61P 25/00 20180101; A61K 31/551 20130101; A61P 25/22
20180101; A61K 9/2018 20130101; A61P 3/06 20180101; A61P 3/10
20180101 |
International
Class: |
A61K 31/4196 20060101
A61K031/4196; A61K 9/20 20060101 A61K009/20; A61K 31/519 20060101
A61K031/519; A61K 31/4178 20060101 A61K031/4178; A61K 31/422
20060101 A61K031/422; A61K 31/5513 20060101 A61K031/5513; A61K 9/00
20060101 A61K009/00; A61K 9/46 20060101 A61K009/46 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 1, 2007 |
EP |
07380265.4 |
Claims
1. An orally disintegrating tablet obtained by direct compression
of a dry powdered mixture, said mixture comprising: up to 15% by
weight of calcium silicate; at least 50% by weight of a diluent,
wherein said diluent is selected from the group consisting of
anhydrous lactose, lactose monohydrate, agglomerated lactose,
atomised forms of lactose, microcrystalline cellulose, and mixtures
thereof; at least a disintegrant; and rizatriptan as an active
ingredient, wherein said orally disintegrating tablet presents a
friability no greater than 1% and a disintegration time of less
than 20 seconds, and wherein the dry powder mixture has not been
subjected to any granulation process, dissolution, or dispersion in
a liquid medium.
2. The tablet according to claim 1, wherein the tablet's thickness
is less than 30% of the tablet's major diameter.
3. (canceled)
4. The tablet according to claim 1, wherein the calcium silicate is
crystalline.
5. The tablet according to claim 1, wherein the calcium silicate is
ortho-, meta- or alpha triclinic-calcium silicate.
6. The tablet according to claim 1, wherein said calcium silicate
is amorphous.
7. (canceled)
8. (canceled)
9. The tablet according to claim 1, wherein the disintegrant is
selected from the group consisting of crospovidone, sodium
croscarmellose, sodium starch glycolate, low-substituted
hydroxypropyl cellulose and pregelatinized starch.
10. The tablet according to claim 10, wherein the disintegrant is
crospovidone or sodium croscarmellose.
11. (canceled)
12. (canceled)
13. (canceled)
14. The tablet according to claim 1, wherein the powdered mixture
further comprises an effervescent component.
15. A process for the preparation of a tablet as defined in claim
1, which comprises: a) mixing the dry powdered ingredients in the
required amount, and b) applying direct compression to the mixture
obtained in step a), wherein the mixture obtained in step a) has
not been subjected to any granulation process, dissolution, or
dispersion in a liquid medium.
16. The tablet according to claim 1, wherein the dry powder
comprises from 1 to 20% by weight of active ingredient.
17. The tablet according to claim 1, wherein said calcium silicate,
lactose diluent, at least one disintegrant, and rizatriptan have
been previously and independently passed through a sieve with mesh
size lower than 650 .mu.m.
18. The process of claim 15, wherein said calcium silicate, lactose
diluent, at least one disintegrant, and rizatriptan have been
previously and independently passed through a sieve with mesh size
lower than 650 .mu.m.
19. The tablet according to claim 1, wherein the mixture comprises
up to 10 weight % of calcium silicate.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to solid pharmaceutical
formulations, in particular it relates to a tablet for oral
administration which disintegrates rapidly by the action of saliva
in the oral cavity, having also good palatability, friability,
mechanical strength properties and employing a conventional
manufacturing method to obtain them.
BACKGROUND OF THE INVENTION
[0002] The development of solid formulations that disintegrate
quickly in the mouth without requiring water are very interesting
due to the advantages that these pharmaceutical formulations
provide for patients who have difficulty in swallowing, such as old
people, infants, patients with mental problems and non-cooperative
patients, as well as the population in general; since it makes it
possible for the drug to be administered without the need for
water. Moreover, since the formulation disintegrates inside the
mouth, the drug may be absorbed in the oral, pharyngeal and
gastrointestinal regions. The pre-gastric drug absorption avoids
hepatic first-pass metabolism.
[0003] In the European Pharmacopoeia (Ph.Eur.) 5th edition,
Supplement 5.2, published in June 2004, orodispersible tablets are
defined as non-coated tablets for placing in the mouth which
disintegrate quickly before they are swallowed. It also establishes
3 minutes as the time under which they must disintegrate in the
disintegration test for tablets and capsules, according to the Ph.
Eur. 2.9.1. method.
[0004] Several technologies are available to produce commercial
oral fast-dissolving systems. The technologies are usually grouped
according to the method employed in the preparation: freeze drying
(Zydis.RTM., Quicksoly.RTM. and Lyoc.RTM.), molding
(FlashDose.RTM.) and compaction technologies.
[0005] Freeze drying (lyophilization) is a process in which a
solvent is removed from a drug solution or a drug suspension
containing structure-forming excipients. The tablets are
characterized by a highly porous network; they quickly absorb water
and dissolve, releasing the incorporated drug. The freeze drying
process occurs at a low temperature, which eliminates the adverse
thermal reactions that may affect drug stability. However, the
freeze-drying process is very expensive and problematic when
scaling up. In addition, the resulting dosage form is characterised
by high friability, low stability at high temperatures and humidity
levels, and by showing poor mechanical properties. Moreover,
sometimes, special packaging is required.
[0006] The molding technology can be based in two different
processes: the solvent method and the heat method. The solvent
molding process involves preparation of a drug solution or
suspension that contains a drug and the excipients and evaporating
the solvent at ambient pressure and drying. In the heat molding
method, the tablets are formed using a candy floss or shearform
matrix, which is composed of saccharides or polysaccarides
processed into amorphous floss by the simultaneous action of flash
melting and centrifugal forces. The molding technology allows
preparing high drug dose tablets and the resulting tablets present
a rapid dissolution. However, because of their low mechanical
strength, molded tablets are subject to erosion and breakage during
the handling and opening of the blister pockets. Moreover, taste
masking is an additional requirement with this technology.
[0007] The conventional process used to prepare fast-dissolving
tablets has some advantages, such as being a well established
technology, having low manufacturing cost and allowing easy
technology transfer (e.g. easy to transfer to different producers).
Many strategies for developing tablets with high porosity and
suitable mechanical strength have been attempted, including:
granulation (wet granulation, dry granulation and mold granulation)
followed by compression; and direct compression.
[0008] In the granulation process, fast dissolving tablets are
prepared by mixing the granules with a superdisintegrant and other
appropriate excipients and compacting to obtain tablets capable of
quickly disintegrating in the mouth with a limited amount of
saliva. Formulation based on this technology is FlashTab.RTM. to
Prographarm which is described in European patent EP 0 548 356.
[0009] On a related matter, EP1681048 describes an orally
disintegrating tablet of olanzapine prepared with granulation as
intermediate step and subsequent compression of the granules. A
similar method is also disclosed in DE102005009241 and IP. Com.
Journal, 2006, but they incorporate other active ingredients.
EP1488811 refers to orally disintegrating tablets of pravastatin
which are obtained by compression moulding of prepared granules.
EP1674083 discloses fast disintegrating tablets prepared by first
granulating a dispersion containing the ingredients in a
spray-drying device, mixing the obtained granules with the active
ingredient and magnesium stearate and finally, subjecting the
mixture to a tabletting process.
[0010] Although tablets obtained through the granulation
methodology demonstrate rapid dissolution, its rate is correlated
to the hardness of the tablet and can be slower than freeze-dried
tablets. Moreover, possible problems can be related to drug
stability after granulation.
[0011] Direct compression represents the simplest and most
cost-effective tablet-manufacturing technique from a technological
point of view. Fast-dissolving tablets can be prepared by using
suitable excipients with improved properties. Two known
formulations based on this technology are Ziplets.RTM. to Eurand
which are described in international patent application WO 99/44580
and DuraSolv.RTM. by Cima described in U.S. Pat. No. 6,024,981.
Direct compression based technologies uses suitable excipients with
improved properties, most notably superdisintegrants which
accelerate the rate of disintegration and hence dissolution. Water
soluble excipients and, sometimes, effervescent agents assist in
the disintegration process. Addition of insoluble compounds which
increase the efficiency of the superdisintegrant: the
disintegration time decreases as the amount of hydrophilic
insoluble compound increases.
[0012] Ziplets.RTM. technology is used to obtain taste masking and
fast release of water-soluble or water insoluble drugs from
microcapsules and granules. The resulting fast-dissolving tablets
are obtained by direct compression of mixtures that contain at
least one inorganic excipient that is insoluble in water, for
example, calcium phosphate, one or more disintegrants, for example,
crospovidone and optionally, water soluble excipients. However, the
resulting compositions contain a high percentage of insoluble
excipients which leave a high amount of residue in the mouth and
jeopardise their palatability.
[0013] The DuraSolv.RTM. technology is designed to provide stronger
tablets without packaging precautions. This technology is based on
employment of conventional non-direct compression fillers (such as
dextrose, mannitol, sorbitol, lactose and sucrose) in the form of
fine particles that quickly dissolve without producing a gritty or
sandy sensation in the mouth.
[0014] However, all the above processes for obtaining
orodispersible tablets involve, to a greater or lesser extent, the
following disadvantages: [0015] A high content of insoluble
excipients or microencapsulated active ingredients that give the
formula a gritty feel after they have been disintegrated in the
oral cavity and, consequently, problems with palatability. [0016]
Excessively long disintegration times in comparison with oral
lyophilisates or wafers, which, in general, dissolve in less than
10 seconds. [0017] Insufficient mechanical resistance to resist
conventional packaging and transport operations.
[0018] U.S. Pat. No. 6,610,266 describes the preparation of calcium
metasilicates with low aspect ratio, and its use to prepare
fast-disintegrating tablets by direct compression. However, large
amounts of this excipient, about 40% by weight, are required for
preparing the tablets, thus negatively affecting the size as well
as the palatability of the tablet.
[0019] International application WO03/030868 also discloses the use
of calcium silicate to prepare flashmelt oral dosage formulations.
In this case, in addition to use even higher proportions of said
excipient, the manufacturing process is more complex since it
comprises a previous granulation of the ingredients.
[0020] Therefore, it is an object of this invention to provide
orodispersible tablets which can be dissolved quickly in the oral
cavity, which presents good palatability properties and that can be
obtained by conventional processes, such as direct compression.
BRIEF SUMMARY OF THE INVENTION
[0021] The authors of the present invention have surprisingly found
that a formulation based on a dry powdered mixture comprising up to
15% by weight, at least 50% by weight of a diluent and a
disintegrant, allows preparing orodispersible tablets by direct
compression, with disintegration times very similar to those
obtained using more complex techniques. In fact, the orodispersible
tablets can be disintegrated in the mouth cavity in less than 15
seconds, having also a high mechanical resistance, a low friability
and higroscopicity, which involve important advantages with respect
to other technologies which require preparing tablets with low
resistance and high porosity in order to get short disintegration
times.
[0022] Direct compression provides important advantages over other
complex techniques since the active ingredient is not subjected to
humidity conditions (water or other solvents) or to high
temperatures, conditions which are known to diminish the stability
of the oral formulation. In addition, due to its simplicity, it
only requires simple machinery leading to a reduction in economic
and energetic manufacturing costs.
[0023] Unlike other typical formulations used in direct
compression, which are not only rather expensive but also very
coarse and granular in nature resulting in a coarse dispersion in
the mouth, the formulation used in the invention to prepare the
orodispersable tablets provides an improved palatability. This
technical feature is mainly derived from the incorporation of
calcium silicate as excipient which avoids the remaining excipients
to agglutinate forming agglomerates which render difficult the
dispersion of the tablet in the mouth leading to an unpleasant
taste and therefore to a diminished patient compliance.
[0024] Furthermore, one of the main advantages conferred by this
formulation is the possibility of providing tablets with a
thickness less than 30% of its major diameter, thus favouring the
disintegration in the mouth and also improving the palatability.
These features make even easier the administration of active
ingredients to patients who have difficulty in swallowing. In
addition, since the amount of calcium silicate is very low, it is
also possible to elaborate tablets with a high content of active
ingredient, without affecting the final size of the tablet.
[0025] Therefore, in a first aspect, the present invention relates
to an orally disintegrating tablet obtainable by direct compression
of a dry powdered mixture, said mixture comprising: [0026] up to
15% by weight of calcium silicate; [0027] at least 50% by weight of
a diluent, [0028] at least a disintegrant; and [0029] at least an
active ingredient.
[0030] Moreover, the inventors have found that by incorporating an
effervescent component in the formulation, an even higher
improvement in the palatability of the tablets is achieved.
Consequently, the formulation of the invention can further comprise
an effervescent component.
[0031] A second aspect of the present invention relates to a
process for the preparation of a tablet as defined above, which
comprises: [0032] a) mixing the dry powdered ingredients in the
required amount, and [0033] b) applying direct compression to the
mixture obtained in step a).
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention is directed to an orally
disintegrating tablet obtainable by direct compression of a dry
powdered mixture, said mixture comprising up to 15% by weight of
calcium silicate, at least 50% by weight of a diluent, at least a
disintegrant, and at least an active ingredient. This solid
formulation rapidly disintegrates in the mouth of a patient, also
providing a positive organoleptic sensation since non-water soluble
components are considerably minimized.
[0035] The orodispersible tablet is advantageously used in cases
where administration without water is necessary, cases of
administration to patients who have difficulty in swallowing
tablets, or cases of administration to the elderly or to children
where there is a fear of blocking the throat if it is unusual
tablet form. The orodispersible tablets can be safely administered
orally to humans.
Calcium Silicate
[0036] In the context of the present invention, by the term
"calcium silicate" it is understood a material, natural or
synthetic, of formula CaSiO.sub.3 characterized by having a ratio
of moles of calcium to moles of silicon, of about 1.0. In a
particular embodiment, the calcium silicate used in the present
invention is a naturally-occurring mineral, also known as
wollastonite, having a CaO/SiO.sub.2 molar ratio ranging from about
0.8 to 1.3. There exist different crystalline types of wollastonite
mineral such as, type 1A (wollastonite), 2M (parawollastonite) and
7M (pseudowollastonite), being type 1A the most prevalent naturally
form. These naturally-occurring calcium silicates have a
crystalline form and high aspect ratios (above 3:1 and even above
20:1), that provide rigidity and strength.
[0037] Particularly preferred is the use of calcium silicate in
crystalline form, more preferably ortho-, meta- and alpha-triclinic
forms of calcium silicate. Examples of crystalline alpha triclinic
calcium silicate are those commercially available from Aldrich
Chemical, which meets the following specifications: 1.3 m.sup.2/g
surface area, 0.63 g/cc bulk density, 2.90 g/cc true density and
<1% w/w volatiles, and those from J.M. Huber Inc., Tomita
Pharmaceutical Co., and Aldrich Chemical which meets the following
specifications: 1.0 to 15 m.sup.2/g surface area, 0.50 to 0.63 g/cc
bulk density, 2.40 to 2.90 g/cc true density and <1% w/w
volatiles. Examples of ortho- and meta-calcium silicate forms are
available from Alfa-Aesar and cover the following range of
specifications for calcium silicate: 0.98 to 2.5 m.sup.2/g surface
area, 0.49 to 0.90 g/cc bulk density, 2.90 to 3.30 g/cc true
density and <1% w/w volatiles.
[0038] In another preferred embodiment, the calcium silicate used
in the formulation is amorphous and it is generally produced
synthetically. The silica source can be selected from naturally
occurring pure forms of crystalline silicon dioxide or from
synthetic amorphous silicon dioxide. The preferred form of silica
is amorphous silicon dioxide, such as precipitated silica, silica
gel, fumed silica or colloidal silica. The calcium source may be
selected from the group including, silicates, oxides, carbonates,
sulfates, hydroxides and salts or mixtures thereof.
[0039] Examples of amorphous calcium silicate are those
commercially available from Celite Corp (micro-cel C) and J.M.
Huber (Hubersorb 250NF and Hubersorb 600NF), which covers the
following specifications: 190 to 210 m.sup.2/g surface area, 0.07
to 0.13 g/cc bulk density, 1.70 to 2.5 g/cc true density and 1% to
14% w/w volatiles.
[0040] In addition to the naturally-occurring or synthetic calcium
silicates discussed above, it is also possible to use in the
formulation synthetic calcium metasilicates as those disclosed in
patent application U.S. Pat. No. 6,610,266. Said calcium
metasilicates are characterized by having a low aspect ratio and
forming structured aggregates of uniform particles yielding high
water absorption characteristics. Specifically, this low aspect
ratio (average major axial diameter/average minor axial diameter)
of the calcium metasilicate is between about 1:1 to about 2.5:1,
preferably from about 1:1 to about 1.5:1, and an water absorption
of from about 20 ml/100 g to about 220 ml/100 g, preferably from
about 20 ml/100 g to about 100 ml/100 g. The major axis is
perpendicular, although not necessarily coplanar, with the minor
axis. The calcium metasilicate can be dehydrated (or
"calcined").
[0041] In the context of the present invention, the term calcium
silicate also includes mixtures of the different grades of the
calcium silicates mentioned above.
Diluent
[0042] The formulation according to the present invention also
comprises at least 50% by weight of a diluent. Examples of diluents
which can be used in the invention include, without limitation,
saccharides such as monosaccharides, oligosaccharides or
polysaccharides, and/or their oxidised and/or reduced forms;
ribose, lactose in its various forms, anhydrous, monohydrate,
agglomerated forms or atomised forms; sugar alcohols such as
mannitol, maltol, sorbitol, maltitol, xylitol, isomalt and
erythritol, cellulose powder, microcrystalline cellulose, silified
microcrystalline cellulose or derivatives of cellulose modified
chemically, such as hydroxypropyl cellulose, hydroxypropyl methyl
cellulose; isomalt, starch, sucrose, pharmaceutically acceptable
inorganic compounds such as dibasic calcium phosphate, carbonates
of calcium or of magnesium, magnesium oxide, sugar alcohols
selected from mannitol, sorbitol, maltitol, maltol, isomalt,
xylitol, erythritol, or mixtures thereof. In a preferred
embodiment, the diluent is an oligosacharide or a sugar alcohol of
medium or low solubility selected from maltol, and mannitol and
mixtures thereof. More preferably, the diluent is selected from
lactose, lactose monohydrate and mannitol.
Disintegrant
[0043] By the term "disintegrant" it is understood a compound which
facilitates the break-up of a tablet when it is placed in aqueous
environment. Disintegrants once in contact with water, swell,
hydrate, change in volume or form to produce a disruptive force
that opposes the efficiency of the binder/s causing the compressed
table to break apart. They belong to different morphological
classes and posses different functionality properties. Suitable for
use in the formulation of the invention include natural starches,
such as maize starch and potato starch; directly compressible
starches such as starch 1500; modified or pregelatinized starches
such as carboxymethylstarches and sodium starch glycolate; natural
or chemically-modified cellulose, especially crosslinked sodium
carboxymethyl cellulose (croscarmellose sodium) or low substituted
hydroxypropyl cellulose; microcrystalline cellulose; gum,
especially agar gum, and guar gum; alginic acid or salts thereof;
acetates and citrates; sugars (especially lactose, mannitol and
sorbitol); aluminum oxide; synthetic polymers such as cross-linked
polyvinylpyrrolidones, specially crospovidone.
[0044] In a preferred embodiment of the invention, the disintegrant
agent is crospovidone and croscarmellose sodium.
Active Ingredient
[0045] The active ingredient can include pharmaceutical
ingredients, vitamins, minerals and dietary supplements. In a
particular embodiment, the active ingredient is a pharmaceutical
ingredient. Pharmaceutical ingredients that may be used include,
but are not limited to, gastrointestinal function conditioning
agents, anti-inflammatory agents, analgesics, agents for erectile
dysfunction therapy, anti-depressants, sedatives, hypnotics,
neuroleptics, anti-migraines, antihistaminic agents, for example
loratadine, desloratadine, pseudoephedrine, cetirizine and mixture
thereof, anti-bacterial agents, antiviral agents, cardiovascular
agents, diuretics, anti-hypertensive agents anti-hypolipidemic
agents, anti-ulcer agents, antiemetics, anti-asthmatic agents,
anti-depressants, anti-thrombotic agents, chemotherapeutic agents,
hormones, anti-helmintic agents, anti-diabetic agents,
corticosteroids, peptides, proteins, recombinant drugs and mixtures
thereof.
[0046] In a preferred embodiment, the pharmaceutical ingredient is
selected from the group consisting of loratadine, desloratadine,
aripiprazole, olanzapine, risperidone, ondansetron, zolmitriptan,
rizatriptan, frovatriptan, eletriptan, almotriptan and salts
thereof.
[0047] In another particular embodiment of the invention, the
active ingredient is selected from a vitamin, a mineral, a dietary
supplement and mixtures thereof.
[0048] As used in this disclosure, the term "vitamin" refers to
trace organic substances that are required in the diet. Examples of
vitamins include, without limitation, thiamine, riboflavin,
nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid,
vitamin B.sub.12, lipoic acid, ascorbic acid, vitamin A, vitamin D,
vitamin E and vitamin K. The term vitamin also includes choline,
carnitine, and alpha, beta and gamma carotenes.
[0049] The term "mineral" refers to inorganic substances, metals,
and the like required in the human diet. Examples of minerals
include, without limitation, calcium, iron, zinc, selenium, copper,
iodine, magnesium, phosphorous, chromium and the like, and mixtures
thereof.
[0050] The term "dietary supplement" as used herein means a
substance which has an appreciable nutritional effect when
administered in small amounts. Dietary supplements include, without
limitation, ingredients such as pollen, bran, wheat germ, kelp, cod
liver oil, ginseng, fish oils, amino acids, proteins and mixtures
thereof. As will be appreciate, dietary supplements may incorporate
vitamins and minerals.
[0051] In general, the amount of active ingredient incorporated in
the formulation may be selected according to known principles of
pharmacy. An effective amount of pharmaceutical ingredient is
specifically contemplated. By the term "effective amount" it is
understood that the amount or quantity of a drug or
pharmaceutically active substance which is sufficient to elicit the
required therapeutic response. As used with reference to a vitamin
or mineral, the term "effective amount" means an amount at least
about 10% of the recommended daily dose.
[0052] The amount of the active ingredient used can vary greatly.
Those of ordinary skill in the art will appreciate that the
physical characteristics of the active ingredient, the size of the
tablet and the requirements of other ingredients will directly
influence its limiting content in the formulation. However,
generally, the active ingredient does not exceed 30% by weight,
preferably from 1 to about 20% by weight, most preferably from 1 to
about 15% by weight based on the total weight of the formulation.
In addition, the authors of the present invention have found that
by incorporating an effervescent component in the formulation of
the invention an improvement of the palatability of the tablets is
obtained, thus providing a pleasant organoleptic sensation.
Therefore, the formulation of the present invention can further
comprise an effervescent component. Suitable effervescent
components that can be used in the formulation of the invention are
a mixture comprising a CO.sub.2 donor and an organic acid. Typical
CO.sub.2 donors include carbonates and bicarbonates such as sodium
bicarbonate, potassium bicarbonate, sodium carbonate and potassium
carbonate. Examples of organic acids include, without limitation,
citric, malic, tartaric, adipic and fumaric acid.
[0053] The pharmaceutical composition of the present invention can
also include other conventional excipients like surfactants,
flavouring agents, lubricants, sweeteners, glidants, antiadherants
and mixtures thereof, which affect the elegancy and performancy of
the orodispersible pharmaceutical compositions. The additional
excipients used in said formulation are present in small amounts,
e.g. generally less than 10%, preferably 5% of the total mass of
the tablet.
[0054] The lubricant is used herein as an additional excipient that
can affect the performance of an orodispersible pharmaceutical
composition. Suitable examples of lubricants include but are not
limited to talc, sodium benzoate, sodium stearyl fumarate (Pruv),
calcium stearate, magnesium stearate, zinc stearate, glyceryl
behenate, stearic acid and glyceryl monostearate. Preferred
lubricant for the composition of the present invention is sodium
stearyl fumarate or magnesium stearate or combination thereof.
Preferably the lubricant(s) of the present invention are used in an
amount of about 0.25 to 5% by weight.
[0055] Suitable flavouring agents used in the composition of the
present invention include but are not limited to strawberry,
cherry, orange, peppermint, black currant, banana, raspberry, red
fruits, wild berries and caramel flavour. Preferably the flavouring
agents of the present invention are used in an amount of less than
2% by weight.
[0056] The sweetener may be selected from the group especially
comprising aspartame, potassium acesulfame, sodium saccharinate,
neohesperidine dihydrochalcone, sucralose, sucrose, fructose,
monoammonium glycyrrhizinate, and mixtures thereof. Preferably the
sweetener of the present invention is used in an amount of about 1
to 2% by weight.
[0057] The orally disintegrating tablet of the invention can be
rapidly disintegrated in the mouth, having also a high mechanical
resistance and low friability. The term friability refers to an
index which provides a measure of the ability of a tablet to
withstand both shock and abrasion without crumbling the handling of
manufacturing, packaging, shipping and consumer use. The
orodispersible tablet of the present invention presents a
friability no greater than 1%, preferably no greater than 0.8%.
[0058] The formulation used in the invention allows preparing
orodispersible tablets with a very low thickness, thus increasing
the tablet surface and consequently the speed of disintegration. In
a particular embodiment of the invention, the orodispersible tablet
has a thickness less than 30% of its major diameter. This small
thickness facilitates the disintegration of the tablet as well as
its palatability. Thus, in a particular embodiment, the
orodispersible tablet of the invention disintegrates in less than
20 seconds, more preferably in less than 15 seconds, even more
preferably in less than 10 seconds.
[0059] The orally disintegrating tablet of the present invention is
prepared by direct compression of a dry powdered mixture. The term
"direct compression" is used in the context of the invention to
define a process by which tablets are compressed directly from
powder blends of the active ingredient and the excipients
(including diluents, fillers, disintegrants and lubricants), which
flow uniformly into a die cavity and form a firm compact. No
pretreatment of the powder blend by wet or dry granulation
procedures is applied. When potent drugs are incorporated in the
formulation, these can be sprayed out of solution onto one of the
excipients.
[0060] By the term "dry powdered mixture" it is understood a
mixture of ingredients in powder form, wherein said ingredients
have been previously and independently passed through a sieve with
mesh size lower than 650 .mu.m, that guarantees a mean particle
size lower than that size, without having been subjected to any
granulation process, dissolution or dispersion in a liquid
medium.
[0061] In a particular embodiment, the calcium silicate, the
diluent, the disintegrant agent and the active ingredient are
homogeneously mixed together in powder form to provide a
homogeneous mixture. The mixture is then subjected to direct
compression to provide a solid preparation in the form of a tablet.
For example, the powder mixture is fed to the die of a tablet press
and sufficient pressure is applied to form the solid tablet. Such
pressure can vary, and typically ranges about 1.000-20.000 N, being
particularly preferable 3.000-15.000 N. Direct compression is the
easiest way of manufacturing tablets and has the great advantage of
having a low manufacturing cost. Moreover, it uses conventional
equipment, commonly available excipients and a limited number of
process steps.
[0062] The resulting compressed solid preparation possesses a
suitable strength and hardness and does not disintegrate during
distribution and storage.
[0063] The following non-limiting examples will further illustrate
specific embodiments of the invention. They are, however, not
intended to be limiting the scope of the present invention in any
way.
EXAMPLES
Example 1
[0064] Orodispersible tablets were made according to the method
defined below using the formulation having the ingredients shown in
table I:
TABLE-US-00001 TABLE I mg % (w/w) 1. Olanzapine 10.00 mg 12.50% 2.
Lactose monohydrate 54.61 mg 68.26% 3. Hydroxypropylcellulose 3.20
mg 4.00% low-substituted 4. Crospovidone 2.40 mg 3.00% 5. Calcium
silicate 7.20 mg 9.00% 6. Aspartame 1.07 mg 1.33% 7. Banana Flavor
0.16 mg 0.20% 8. Orange Flavor 0.16 mg 0.20% 9. Colloidal anhydrous
silica 0.40 mg 0.50% 10. Magnesium stearate 0.80 mg 1.00% Total 80
mg 100%
Manufacturing Method
[0065] The orodispersible tablet was obtained according to the
following procedure: [0066] a) the components of the formulation
were weighted; [0067] b) components 4 and 5 were sieved through a
screen with a mesh size of 0.5-0.6 mm; [0068] c) the materials of
stage "b" were mixed in a suitable container until a homogeneous
mixture was obtained; [0069] d) components 1, 2, 3, 6, 7, 8 and 9
were sieved through a screen with a mesh size of 0.5-0.6 mm; [0070]
e) the materials of stage "d" were mixed with the blend obtained in
stage "c" in a suitable container until a homogeneous mixture was
obtained; [0071] f) the component 10 was sieved through a screen
with a mesh size of 0.3-0.4 mm, it was incorporated into the
homogeneous mixture obtained in section "e", and the whole was
mixed in a suitable container for approximately 5 minutes [0072] g)
the mixture powder obtained in stage "f" was compressed in a
tabletting machine equipped with suitable punches.
TABLE-US-00002 [0072] Disintegration time 10 sec. Weight 80 mg
Resistance to crushing 33N Friability <0.1% Thickness 1.77
mm
Disintegration Time
[0073] The disintegration time has been measured according to the
following procedure. A filter paper was placed on the bottom of
Petri dish and then purified water was poured to achieve a
homogeneous humectation. The tablet prepared as defined above was
placed on the humectated paper and the complete disintegrating time
of the tablet was measured. The test was done six times and the
results were averaged.
Tablet Weight
[0074] 20 tablets were weighted in an automatic balance and the
average mass was calculated.
Resistance to Crushing
[0075] The resistance to crushing of 10 tablets is determined
according to the equipment and method described in the Ph. Eur.
2.9.8.
Friability
[0076] The friability of the tablets is performed according to the
equipment and method described in the Ph. Eur. 2.9.7.
Thickness
[0077] The thickness of a tablet is the distance between the middle
point of the two surfaces of the tablet and it is measured with a
micrometer.
Example 2
[0078] The tablet was prepared according to the procedure described
below using the formulation having the ingredients shown in table
II:
TABLE-US-00003 TABLE II mg % (w/w) 1. Olanzapine 10.00 mg 13.33% 2.
Lactose monohydrate 40.98 mg 54.63% 3. Hydroxypropylcellulose 3.00
mg 4.00% low-substituted 4. Crospovidone 3.00 mg 4.00% 5. Calcium
silicate 9.00 mg 12.00% 6. Aspartame 1.00 mg 1.33% 7. Calcium
carbonate 3.00 mg 4.00% 8. Tartaric acid 3.75 mg 5.00% 9. Banana
Flavor 0.15 mg 0.20% 10. Colloidal anhydrous silica 0.38 mg 0.50%
11. Magnesium stearate 0.75 mg 1.00% Total 75 mg 100%
Manufacturing Method
[0079] The orodispersible table was obtained according to the
following procedure: [0080] a) components of the formulation were
weighted; [0081] b) components 4 and 5 were sieved through a screen
with a mesh size of 0.5-0.6 mm; [0082] c) the materials of stage
"b" were mixed in a suitable container until a homogeneous mixture
has been obtained; [0083] d) components 1, 2, 3, 6, 7, 8, 9 and 10
were sieved through a screen with a mesh size of 0.5-0.6 mm; [0084]
e) the materials of stage "d" were mixed with the blend obtained in
stage "c" in a suitable container until a homogeneous mixture was
obtained; [0085] f) the component 11 was sieved through a screen
with a mesh size of 0.3-0.4 mm, it was incorporated into the
homogeneous mixture obtained in section "e", and the whole was
mixed in a suitable container for approximately 5 minutes; [0086]
g) the mixture powder obtained in stage "f" was compressed in a
tabletting machine equipped with suitable punches.
TABLE-US-00004 [0086] Disintegration time 11 sec. Weight 75 mg
Resistance to crushing 36N Friability 0.17% Thickness 1.65 mm
Example 3
[0087] The tablet was prepared according to the procedure described
below using the formulation having the ingredients shown in table
III:
TABLE-US-00005 TABLE III PR-42 mg % (w/w) 1. Zolmitriptan 2.5 2.77
2. Mannitol granular 73.45 81.61 3. Crospovidone 4.5 5 4. Calcium
silicate 6.3 7 5. Aspartame 0.9 1 6. Orange Flavour 0.9 1 7.
Strawberry Flavour 0.1 0.11 8. Magnesium Stearate 1.35 1.5 Total 90
100
Manufacturing Method
[0088] The orodispersible table was obtained according to the
following procedure: [0089] a) the components of the formulation
were weighted; [0090] b) component 1, enough amount of 2 to achieve
a homogeneous mixture, 3 and 4 were sieved through a screen with a
mesh size of 0.5-0.6 mm; [0091] c) the materials of stage "b" were
then mixed together in a suitable container until a homogeneous
mixture was obtained; [0092] d) the rest of component 2, and
components 5, 6, and 7 were sieved through a screen with a mesh
size of 0.5-0.6 mm; [0093] e) the materials of stage "d" were mixed
together in a suitable container until a homogeneous mixture was
obtained; [0094] f) component 8 was sieved through a screen with a
mesh size of 0.5-0.6 mm, it was incorporated into the homogeneous
mixture obtained in section "e", and the whole was mixed in a
suitable container for approximately 2 minutes; [0095] g) the
mixture powder obtained in stage "f" was compress in a tabletting
machine equipped with suitable punches.
TABLE-US-00006 [0095] Disintegration time 9 sec. Mean tablet weight
90 mg Tablet crushing strength 17N Tablet friability 0.45% Tablet
thickness 2.1 mm
Example 4
[0096] The tablet was prepared according to the procedure described
below using the formulation having the ingredients shown in table
IV:
TABLE-US-00007 TABLE IV mg % (w/w) 1. Ondansetron base 4.00 mg
5.30% 2. Spry dried mannitol 42.38 mg 56.50% 3. Microcrystalline
cellulose 11.25 mg 15.00% 4. Sodium croscarmellose 2.25 mg 3.00% 5.
Calcium silicate 6.75 mg 9.00% 6. Aspartame 1.00 mg 1.30% 7.
Calcium carbonate 3.39 mg 4.52% 8. Tartaric acid 2.24 mg 2.98% 9.
Peppermint flavour 1.00 mg 1.30% 10. Magnesium stearate 0.75 mg
1.0% Total 75 mg 100.00%
Manufacturing Method
[0097] The orodispersible table was obtained according to the
following procedure: [0098] a) the components of the formulation
were weighted; [0099] b) components 4 and 5 were sieved through a
screen with a mesh size of 0.5-0.6 mm; [0100] c) the materials of
stage "b" were mixed in a suitable container until a homogeneous
mixture was obtained; [0101] d) components 1, 2, 3, 6, 7, 8, 9 and
10 were sieved through a screen with a mesh size of 0.5-0.6 mm;
[0102] e) the materials of stage "d" were mixed with the blend
obtained in stage "c" in a suitable container until a homogeneous
mixture was obtained; [0103] f) the component 10 was sieve through
a screen with a mesh size of 0.3-0.4 mm, it was incorporated into
the homogeneous mixture obtained in section "e", and the whole was
mixed in a suitable container for approximately 5 minutes; [0104]
g) the mixture powder obtained in stage "f" was compressed in a
tabletting machine equipped with suitable punches.
TABLE-US-00008 [0104] Disintegration time 9 sec. Weight 75 mg
Resistance to crushing 34N Friability 0.20% Thickness 1.65 mm
Example 5
[0105] The tablet was prepared according to the procedure described
below using the formulation having the ingredients shown in table
V:
TABLE-US-00009 TABLE V mg % (w/w) 1. Ondansetron base 4.00 mg
10.00% 2. Lactose monohydrate 27.95 mg 69.88% 3.
Hydroxypropylcellulose 1.60 mg 4.00% low-substituted 4.
Crospovidone 1.20 mg 3.00% 5. Calcium silicate 3.60 mg 9.00% 6.
Aspartame 0.53 mg 1.33% 7. Peppermint flavour 0.52 mg 1.30% 8.
Colloidal anhydrous silica 0.20 mg 0.50% 9. Magnesium stearate 0.40
mg 1.00% Total 40 mg 100%
Manufacturing Method
[0106] The orodispersible table was obtained according to the
following procedure: [0107] a) the components of the formulation
were weighted; [0108] b) components 4 and 5 were sieved through a
screen with a mesh size of 0.5-0.6 mm; [0109] c) the materials of
stage "b" were mixed in a suitable container until a homogeneous
mixture was obtained; [0110] d) components 1, 2, 3, 6, 7 and 8 were
sieved through a screen with a mesh size of 0.5-0.6 mm; [0111] e)
the materials of stage "d" were mixed with the blend obtained in
stage "c" in a suitable container until a homogeneous mixture was
obtained; [0112] f) the component 9 was sieved through a screen
with a mesh size of 0.3-0.4 mm, it was incorporated into the
homogeneous mixture obtained in section "e", and the whole was
mixed in a suitable container for approximately 5 minutes; [0113]
g) the mixture powder obtained in stage "f" was compressed in a
tabletting machine equipped with suitable punches.
TABLE-US-00010 [0113] Disintegration time 6 sec. Weight 40 mg
Resistance to crushing 21N Friability 0.34% Thickness 1.02 mm
Example 6
[0114] The tablet was prepared according to the procedure described
below using the formulation having the ingredients shown in table
VI:
TABLE-US-00011 TABLE VI mg % (w/w) 1. Risperidone 2.00 mg 2.50% 2.
Lactose monohydrate 64.3 mg 80.40% 3. Crospovidone 2.50 mg 3.10% 4.
Calcium silicate 7.50 mg 9.40% 5. Sodium Cyclamate 2.00 mg 2.50% 6.
Cherry Flavor 0.40 mg 0.50% 7. Colloidal anhydrous silica 0.40 mg
0.50% 8. Magnesium stearate 0.90 mg 1.10% Total 80 mg 100%
Manufacturing Method
[0115] a) the components of the formulation were weighted; [0116]
b) components 3 and 4 were sieved through a screen with a mesh size
of 0.5-0.6 mm; [0117] c) the materials of stage "b" were mixed in a
suitable container until a homogeneous mixture was obtained; [0118]
d) components 1, 2, 5, 6 and 7 were sieved through a screen with a
mesh size of 0.5-0.6 mm; [0119] e) the materials of stage "d" were
mixed with the blend obtained in stage "c" in a suitable container
until a homogeneous mixture was obtained; [0120] f) the component 8
was sieved through a screen with a mesh size of 0.3-0.4 mm, it was
incorporated into the homogeneous mixture obtained in section "e",
and the whole was mixed in a suitable container for approximately 5
minutes [0121] g) the mixture powder obtained in stage "f" was
compressed in a tabletting machine equipped with suitable
punches.
TABLE-US-00012 [0121] Disintegration time 12 sec. Weight 80 mg
Resistance to crushing 37N Friability <0.1% Thickness 1.80
mm
* * * * *