Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR THE PREPARATION OF PHARMACEUTICAL
MICROCAPSULES WITH ENHANCED TASTE-MASKING AND HIGH
DISSOLUTION RATE
Field of the invention
s The present invention relates to the field of microencapsulation of active
principles.
A new process is described allowing to obtain pharmaceutical microcapsules
with
enhanced taste masking and an optimal dissolution profile.
State of the art
Achieving an effective encapsulation of active principles is important for the
io preparation of a variety of compositions; when microparticles of an active
principle
must be singly provided with an external coating, microencapsulation
techniques
are employed.
The microencapsulation process consists in coating small drug cores
(microparticles) with a layer of polymer. The polymer layering may be achieved
by
Is different techniques; in particular the microencapsulation by phase
separation (or
coacervation), proved very reliable in obtaining coated microparticles
(M.Calanchi,
"Taste Masking of oral formulations", Pharmaceutical Manufacturing
International,
pp.139-141, 1996; L. Dobetti, S. De Luigi, "Developments in
Microencapsulation",
Pharmaceutical Manufacturing and Packaging Sourcer, p. 39-40, Dec.1988).
2o The production of microcapsules differs from normal drug coating techniques
in
that singly coated, discrete microparticles must be obtained, e.g. in the
order of
500 ~,m or less: to achieve this goal, the aggregation of the formed
microcapsules
must be avoided.
In the pharmaceutical field, microencapsulation of active principles is
applied in
2s particular to prepare pharmaceutical multiparticulate compositions such as
syrups,
permanent or temporary suspensions, chewable or fast melting tablets, etc..
The
microencapsulation is used in particular to mask the taste of those drugs
characterised' by bitterness, throat-burning, saltiness and localised numbing
of the
tongue, etc.
3o Microencapsulation is also used to modulate the drug release profile after
administration. In principle, both taste masking and release-controlling
properties
are obtained by increasing the thickness of the microcapsule wall. As a
CONFIRMATI~N C~P'Y
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consequence, it is easy to prepare taste-masked, slow-release microcapsules,
whereas it is more difficult to obtain taste-masked quick-release ones: the
latter
form is nevertheless very desired, in particular for those drugs with
unpleasant
taste which, for pharmacokinetic and pharmacodynamic reasons, must be
s delivered quickly in the stomach: one typical example is that of antibiotic
drugs (for
example Penicillins, Cephalosporins, Carbapenem, Penems, Penams,
Aminoglycosides, Macrolides, Ketolides, Tetracyclines, Quinolones, etc.) which
are often endowed with an unacceptable taste: they require a strong taste-
masking, but at the same time they must be delivered and absorbed quickly in
the
to stomach, so to ensure a quick onset of action and avoid disturbing the
intestinal
bacterial flora.
A second example is that of antinflammatory drugs or drugs for pain relief.
Often
this kind of drugs needs to be taste masked to avoid bitterness or throat
burning,
but at the same time a fast absorption is mandatory to assure a fast pain
relief.
is Third example is that of drugs characterised by a narrow absorption window.
These drugs require a fast release in the first part of the gastrointestinal
tract to
guarantee the proper bioavailability.
For the purpose of obtaining a good taste masking, the preferred and most
widely
used sealing polymer is ethylcellulose. This polymer is characterised by an
2o efficient sealing capacity and is easily layered onto the drug
microparticles; in
addition it is an absolutely safe excipient, free from toxicity problems.
However
ethyleeNulose-coated microparticles are not capable to associate, to the good
taste
masking, an elevated dissolution rate in the stomach. In order to overcome
this
problem, attempts have been made to reduce the thickness of the microcapsule
2s wall (i.e. using less encapsulating polymer); however this is not a good
solution
because the taste-masking is no longer ensured by the thinner coating. The use
of
coating polymers alternative to ethylcellulose, having e.g. higher solubility
in the
stomach is equally unsatisfactory : in fact, these polymers require much a
thicker
coating to achieve the same level of taste masking of ethylcellulose; as a
result
3o microcapsules with very low potency are obtained: they require bulky dosage
forms such as large tablets or capsules, thus quite problematic from the point
of
view of patient acceptability. In addition, with respect to ethylcellulose,
polymers
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with higher solubility present problems of particle aggregation during the
coating
process, with the result that small-size singly coated microparticles are yet
more
difficult to obtain.
At present no microencapsulation process is available, capable to produce
small
microcapsules, ensuring at the same time a good taste masking, a fast onset of
action, and a high potency.
Summary of the invention
The present application discloses a microencapsulation process characterised
by
coating drug cores with a first layer of ethylcellulose and further coating
the
io obtained microcapsules with a layer of an acrylic polymer. The obtained
microcapsules show a high potency, an optimal taste masking, and ensure a
quick release in the stomach. The invention allows thus to produce superior
pharmaceutical formulations, especially useful in the case of drugs with
unpleasant taste in particular drugs, which require an immediate delivery in
the
is stomach, even if the administration in form of reconstitutable suspensions
is
required.
Description of the figures
Figure 1: Caffeine, microscope image of lot. B1, described in the experimental
part, showing an evident aggregation phenomena.
2o Figure 2: Teophylline, particle size distribution of microcapsules of
invention (lot.
C2)
Figure 3: Fluoxetine, microscope image of lot. C3s representing the
microcapsules
of the invention.
Figure 4: Caffeine, microscope image of lot. C1, representing the
microcapsules of
25 the invention.
Detailed description of the invention
A first objective of the present invention is a process for the production of
microcapsules containing a drug, characterised by the following steps:
a. - coating drug microparticles with a layer of ethylcellulose
3o b. - further coating the product of a. with a layer of an acrylic polymer
The present process is particularly suitable for those drugs which have an
unpleasant taste and require quick delivery into the stomach; however, any
drug
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available in microparticular form can be subjected to the present process; for
the
purpose of the invention, the term "drug" includes also mixtures of two or
more of
them.
The step a. obtains singly coated microcapsules. The coating step a. can be
s performed by microencapsulation techniques which, as such, are well-known in
the art. Among them, microencapsulation by phase separation (also known as
microencapsulation by coacervation ) is preferred.
The known process of phase separation can be summarised in the following, non
limitative, step sequence: (i) dispersion: the creation of a two phase system
in
io which a liquid phase (e.g. ethylcellulose solution in cyclohexane) and a
solid
phase (drug particles) are present simultaneously; (ii) phase separation;
thanks to
the action of the coacervation-inducing agent (e.g. an ethylene polymer like
epolene) a third phase is formed. This phase called coacervate is a highly
concentrated polymer solution in solvent which spreads onto the surface of the
is suspended drug cores. As a result, fluid droplets of coacervate coalesce
and
enwrap the drug cores with a continuous layer of membrane (gel phase). The
deposition of the polymeric membrane is promoted by a reduction of the total
free
interfacial energy brought about by the decrease of the coating material
surface
area during the coalescence of the liquid droplets; (iii) hardening: the fluid
2o polymeric film is hardened by cooling down the suspension to room
temperature;
(iv) separation: microcapsules are separated from the liquid medium by
settling.
The supernatant is then removed and the microcapsules can be washed with fresh
solvent to remove the residues of phase separation agent. Finally the
microcapsules are filtered, dried and sifted.
2s Another known technique applicable to perform step a, is the fluidized bed
coating. In this case the ethylcellulose coating can be ensured by spraying
onto
pharmaceutical cores either an organic solution or an aqueous dispersion of
the
polymer. The choice is strictly dependent on the chemical and physical
characteristics of the cores to be coated.
3o If the next step b. is also performed by fluidized bed coating, the overall
process is
particularly advantageous in that it can be performed in the same reactor by
simply
changing the coating solution when passing from step a. to b.
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The product of step a. is an ethylcellulose microcapsule containing the drug.
Preferably the obtained microcapsule has a drug / ethylcellulose weight ratio
comprised between 1:1 and 30:1, more preferably between 3:1 and 15:1. The drug
/ ethylcellulose weight ratio is herein referred as PR (phase ratio).
s To apply the additional coating of acrylic polymer (step b.), it is
preferable to use a
spray-coating technique: according to this embodiment, the microcapsules
obtained in step a. are suspended in a fluidised bed and sprayed with a
solution or
suspension of the acrylic polymer. Preferably, the solvent used to form this
solution or suspension is an acidic aqueous solvent, a hydroalcoholic solvent,
an
to organic solvent, or mixtures thereof. When a hydroalcoholic solution is
used, it
preferably comprises the following weight percentages of components,
calculated
with respect to the total weight of the solution:
acrylic polymer: 4-20%, preferably 7-20°I°
alcohol (e.g. ethanol): 30-94%, preferably 40-75
is water: 0-40%, preferably 10-35%
micronised inorganic material (e.g. talc): 2-20°I°, preferably 5-
9%.
The acrylic polymer can be layered indifferently during one or more layering
steps:
in the latter case a multilayered acrylic coating is obtained.
Advantageously, the product of step b. has an acrylic polymer content
comprised
2o between 5% and 40% by weight ; an optimal range of this polymer is 10-25%
The acrylic polymer used in step b. is chosen among acrylic polymers for
pharmaceutical use: they are well-known in pharmaceutical technology, and can
be indifferently linear, branched and/or cross-linked polymers of acrylic
and/or
methacrylic acid.; the chosen polymer must be soluble at acidic pH, (e.g. 1 g
?s dissolves in 1 N HCI); Representative, but not limitative examples of these
polymers are the products of the class comprising Eudragit E (cationic
copolymer
based on dimethylaminoethyl methacrylate and neutral methacrylic esters).
A further object of the present invention are the microcapsules obtained by
the
process above described. The process according to the present invention allows
.o to obtain small taste-masked microcapsules (i.e. having a weight median
diameter
comprised between 20 - 800 p.m, preferably 100 - 400 p.m, with potency (i.e.
mg
drug/g of the end product of step b.) comprised between 400 and 950 mg/g, and
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capable to release at least 80% of the drug contained therein within 30
minutes,
preferably in 10 minutes in a simulated gastric fluid test or in acidic media.
The
high level of potency is a pharmaceutically advantageous feature which allows
to
obtain, at constancy of drug content, smaller tablets or capsules, (i.e.
containing
s lesser amounts of coating polymers) which are being more acceptable by the
patient. The reduction in the amounts of coating polymers involves the further
advantage that the present compositions can dissolve in water without forming
thickened viscous solutions around the drug cores: this further eases the drug
diffusion and the establishing of a fast onset of action. The obtained
microcapsules
io further show the advantage of an improved suspendability in water, i.e.
they do not
form aggregates, do not float on the surface of a suspending medium, nor they
adhere to side walls of a glass: therefore they do not require a separated
wetting
treatment with surfactants, such as instead required in case of ethylcellulose
microcapsules.
is Moreover the obtained microcapsules show the capability of maintaining the
taste
masking properties when suspended in neutral or basic aqueous media. The use
of resuspended dosage form is often required for easiness and effectiveness of
administration (e.g. dosage form as monodose sachet and dry powders for
extemporaneous suspension).
2o The above described microcapsules, simultaneously ensuring elevated taste
masking l elevated potency / elevated dissolution rate, are new and represent
a
further object of the present invention. These microcapsules can be further
processed, optionally in presence of suitable pharmaceutical excipients, into
suitable pharmaceutical formulations, e.g. dry powders for extemporaneous
2s suspensions, tablets, minitablets, microcapsule-containing capsules,
monodose
sachets, fast disintegrating tablets, syrups, etc.
The process and microcapsules of the invention can be used to taste-mask a
wide
variety of active ingredients that have a bitter or non-bitter taste and that
are
desired to be released rapidly. Active ingredients useful with this invention
include
3o antibiotic and antibacterial agents such as ketolides; antiviral agents,
analgesics,
anesthetics, anorexics, antiarthritics, antiasthmatic agents, anticonvulsants,
antidepressants, antidiabetic agents, antidiarrheals, antihistamines, anti-
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inflammatory agents, antiemetics, antineoplastics, antiparkinsonism drugs,
antipruritics, antipsychotics, antipyretics, antispasmodics, H2 antagonists,
cardiovascular drugs, antiarrhythmics, antihypertensives, ACE inhibitors,
diuretics,
vasodilators, hormones, hypnotics, immunosuppressives, muscle relaxants,
s parasympatholytics, parasympathomimetics, psychostimulants, sedatives,
antimigrane agents antituberculosis agents and tranquilizers. Generally, the
actives used in conjunction with the present methodology are those which are
bitter or otherwise unpleasant-tasting and thus in need of taste masking.
The present invention is now illustrated by reference to the following
experimental
to examples which have no limiting function.
EXPERIMENTAL PART
Eguipment
~ 5 L microencapsulation reactor
~ pneumatic stirrer/ propeller
is ~ break-water
~ thermostat
~ Tray dryer
~ Fluid bed
Materials
20 ~ Caffeine
~ Teophyilline
~ Fluoxetine
~ Ethylcellulose
~ Polyethylene
2s ~ Cyclohexane
~ Eudragit E
~ Micronised talc
~ Ethanol
~ Purified water
3o Process description
Phase separation
3000 g of cyclohexane were poured into a 5L jacketed stainless steel reactor.
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Then, under a gentle stirring ensured by a helix, a fixed amount of drug,
ethylcellulose and polyethylene were added.
The stirring rate was then increased to 500 rpm. The system was then heated to
30°C to cause the ethylcellulose solubilisation in cyclohexane.
s The final microcapsules were dried in an oven overnight at 40°C and
sifted by 500
pm screen.
Fluid bed coating
A fixed amount microcapsules obtained as described in the previous paragraph
were loaded in a Glatt GPCG 1 fluid-bed equipped with 4" Wurster insert, plate
to type B, spraying nozzle 1.0 mm, and sprayed with a coating suspension
having
the following qualitative composition:
Eudragit~ E100
Micronised talc
Ethanol
is Purified water
The second layer of coating suspension were subsequently applied. The final
product was sifted by 500 pm screen. The coating level obtained was calculated
as microcapsules theoretical weight gain.
Residual cyclohexane, residual ethanol and residual polyethylene were well
within
2o the acceptance limits for pharmaceuticals.
Analytical methods
Dissolution Rate Method (i):
USP Paddle, 900 mL or 500 mL, HCI 0.1 N or pH 1.2 buffer, 50 or 100 rpm, 37
°C
Samples were collected at fixed times, during, at least, 30 minutes time
period.
as Data at 10 minutes and 30 minutes are reported.
Taste Masking evaluation (TM)
Obtained by sensorial judgement.
A fixed amount of microcapsules was evaluated as is or after suspension in a
appropriate aqueous media.
3o Particle Size Distribution (PSD)
Performed by sieve analysis using the automatic siever mod. Octagon Digital,
equipped with sieves (Endecotts types).
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D. Optical Microscopy (PSD)
Performed by a Ortolux microscope and a Zeiss Axioscopic 2 microscope.
EXPERIMENTAL RATIONALE
Three experimental sets were performed.
s In the first set only the coating (i.e. ethylcellulose) was applied.
In the second set only the layer of the acrylic polymer was applied.
In the third set the drug microparticles were first coated with a layer of
ethylcellulose and further with a layer of an acrylic polymer, according to
what
described in the present invention.
io RESULTS
First Set
Drug Coating TM DRT DRT PSD Potency Batch
10 min 30 min % W/W
Caffeine 10 -- > 80 > 80 ++ 90 A1
% %
Caffeine 30 ++ 30 % 54 % ++ 70 A2
Theophylline10 - > 80 > 80 ++ 90 A3
% %
Theophylline15 -- 57 % > 80 ++ 85 A4
%
Theophylline35 ++ 19 % 44 % ++ 65 A5
Fluoxetine 15 -- > 80 > 80 ++ 85 A6
% %
Fluoxetine 20 -- > 80 > 80 ++ 80 A7
% %
Fluoxetine 30 +- 37 % 65 % ++ 70 A8
Legends:
PSD (Particle Size Distribution)
is ++ : No significant aggregation
- : Significant aggregation
+- : Improved but not acceptable
TM (Taste Masleing)
++ : Satisfactory
20 - : Not satisfactory
+- : Improved but not acceptable
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From the evaluation of the aforementioned results, it's evident that:
~ at low level of coating the dissolution rate is quite fast, but the taste
masking is
not acceptable
~ at higher level of coating the taste masking properties significantly
improve, but
s the release profile is too slow and therefore not acceptable. Moreover the
potency decreases dramatically
~ in some cases, even using higher levels of coating (with a significant
decrease
of the dissolution rate), the taste masking is not acceptable. This is
probably
related to a higher surface area of the drug used.
to ~ the application of ethylcellulose, even at high percentage, leads to
acceptable
particle size distribution
Second Set
Drug CoatingTM DRT DRT PSD Potency Batch
w/w 10 30 min % W/w
min
Caffeine 10 -- n.a. n.a. -- 90 B1
Theophylline25 -- > 80% > 80% +- 75 B2
Theophylline40 -- > 80% > 80% +- 60 B3
Fluoxetine 30 -- > 80% > 80% -- 70 B4
Fluoxetine 40 -- > 80% > 80% -- 60 B5
n.a.: not available. DRT was not performed due to dramatic agglomeration
phenomena
Legends:
PSD (Particle Size Distribution)
++ : No significant aggregation
- : Significant aggregation
+- : Improved but not acceptable
TM (Taste Masking)
++ : Satisfactory
-- : Not satisfactory
+- : Improved but not acceptable
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From the evaluation of the aforementioned results, it's evident that:
~ the application of the acrylic polymer, even at high percentage, doesn't
affect
significantly the release in simulated gastric fluid, but is not able to
assure the
required taste masking
s ~ even applying a low level of acrylic polymer, the particle size
distribution
resulted not acceptable due to agglomeration phenomena.
In order to overcome this drawback, the coating of batches B2 and B3 was
performed using a very low spraying rate, leading to a time consuming process,
not economically compatible with an industrial application of this technology.
to Despite using this condition, the particle size distribution was not
considered
completely satisfactory due to a residual aggregation. Anyway the taste
masking properties were not satisfactory.
Third Set
Drug I CoatingII CoatingTM DRT DRT PSD Potency Batch
W/W % W/W 10 min 30 min % W/W
Caffeine 7.5 25 ++ >80 >80 ++ 67.5 C1
% %
Theophylline11.3 25 ++ 54 % >80 ++ 63.7 C2
%
Fluoxetine 24.2 15 ++ 76 % >80 ++ 60.8 C3
%
is
Legends:
PSD (Particle Size Distribution)
++ : No significant aggregation
- : Significant aggregation
20 +- : Improved but not acceptable
TM (Taste Masking)
++ : Satisfactory
- : Not satisfactory
+- : Improved but not acceptable
2s From the evaluation of the aforementioned results, it's evident that:
~ The application of the two layers leads to microcapsules able to properly
mask
the taste, even when suspended in a liquid media, and also ensuring a fast
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release and avoiding significant microcapsule aggregation.
~ Moreover the overall coating amount is relatively low, so ensuring the
possibility
to obtain suitable potency.
