Note: Descriptions are shown in the official language in which they were submitted.
~1~~~~'~ -
1
PHARMACEUTICAL TABLETS RELEASING THE ACTIVE SUBSTANCE AFTER A
DEFINITE PERIOD OF TIME
PRIOR ART
Studies and researches for the preparation of systems and/or
prototypes suitable to release an active substance in a controlled
way have had a ~;reat impulse in recent years.
Said researches, which in the field of the pharmaceutical technology
and in the biomcsdical field are generally indicated as "targeting",
have the purpose' of obtaining prototypes and/or therapeutic systems
which release the active substance in a predeterminable way, for
example the pharmaceutical form releases the active substance
following changes of pH (in oral administrations of gastroresistant
pharmaceutical forms) or following changes of temperature (for
example as described in J. Controlled Release 4, 213, 1986 on
thermoreversible hydrogels) or by effect of specific enzymes (for
example as described in the documents of 12th Symposium on
Controlled Release of Bioactive Materials - Geneve 1985 page 45) or
by application of external means of activation such as the
application of magnetic fields to open magnetized microcapsules or
nanocapsules and/or the application of electric fields as in the
recent applications of iontophoresis (as reported by Kari B.,
Diabetes 35, 217, 1986).
All said embodiments result somewhat complex and the preparation of
prototypes and of systems having reproducible releasing
z~~~~z~ -
2
characteristics is very difficult and, particularly in the case of
the application of external activation, qualified operators and
complex devices suitable to activate the system and to allow the
active substance release, are necessary.
Regarding the treatment of chronical diseases which necessitate high
drug doses, for example during the night time, pharmaceutical forms
having a modified releasing (retard forms) and/or therapeutical
systems having a high content of the active substance (from 2 to 5
times with respect to the content of the conventional pharmaceutical
forms) suitable to release the active substance in a gradual way
have been designed and commercialized.
Hydrophilic matrices possibly coated by permeable and/or
semipermeable films are examples of such an embodiment.
In addition more complex pharmaceutical forms defined as
therapeutical systems suitable to release the active substance at a
constant rate have been produced. A typical example of said systems
is the OROS system (described in "Formes Pharmaceutiques nouvelles"
';'EC-DOC Ed. - Paris 1985); such a system is commercially produced
and largely used in the drug administration.
:~11 said systems. are designed to release the active substance in a
regular and slow way obtaining plasmatic levels of the active
substance for long times and for whole releasing time.
'.his fact leads to risks of collateral effects because the drug
administration persists also when does not exist a therapeutical
__
3
necessity in that the rise of the acute disease is due to very
precise chronobiological rhythms as pointed out in the following.
The administration of high doses of drug for prolonged periods of
time causes considerable collateral effects which, in the case of
non-steroid antiinflammatory drugs, leads to the risk of serious
gastric ulcerations and perforations.
In the case of ()ROS system based on indomethacin also letal effects
have been found (Remington's Pharmaceutical Sciences 18th ed. 1990
Mack Publishing Company, Easton, USA).
However all said embodiments, due to high content of the active
substance, besides the risks of toxic effecs involve also the risk
of the burst ef:Fect that is of releasing of the whole drug content
of the pharmaceutical form in a short time and in addition they do
not solve the F~roblem of the necessity of a release temporally
related to exacerbation of the pain or of the symptomatology to be
cured.
However in the pharmaceutical-clinical practice there are several
cases of diseases characterized in that the request of a
therapeutically active substance is not constant for the time but
obeys to circadian rhythms.
Therefore a release of the active substance in different times in a
pulsatory way, for example some hours after administration, should
be desirable.
Typical examples of such posology dosage schemes are well known for
example in therapy of rheumatic diseases and/or of rheumatoid
21 2442
4
arthritis in which the patient shows an exacerbation of the painful
symptomatology during the night and in the first hours in the
morning when the effect of the administration of a traditional
pharmaceutical form is already finished.
The necessity of a release of a drug after a definite period of time
from the administration occurs in several pathological forms. For
example in the arterial hypertension a pressure increase occurs in
the first hours in the morning (when the patient is still sleeping);
similarly in the asthmatic disease a symptomatology exacerbation
during the night occurs. Particularly related to circadian rhythms
are the angina. pains (angina pectoris) which occur, with a
repeatable regu:Larity, at the end of the night period; a similar
behaviour occurs in epileptic patients showing an exacerbated
morbidity during the first hours in the morning.
A further disadvantage of the prior art consists in the effect of
dose dumping particularly in the case of drugs largely soluble in
aqueous liquids, that is in the releasing of a drug excess in a very
short time which causes collateral effects not always easily
supportable by the patient.
In view of overcoming said inconvenient several improvements have
been carried out with the purpose to limit the release from
hydrophilic matrices such as the whole coating by a semipermeable
film suitable to limit the exit of the active substance from the
pharmaceutical form.
5
~1 244 2 5
A further improvement in the preparation of hydrophilic matrices is
described in the US Patent 4.839.177 issued on 13.06.1989 and in
European Patent F,pplication No. 0432607 filed on 03.12.90 where a process
is described having the purpose of limiting the releasing surface by
partially coating the matrix surface by an impermeable film and/or
by a polymeric material barrier which hinders the drug diffusion
limiting its re:Lease to the free surface in contact with the
dissolution medium.
Also in these embodiments the active substance release, although
slowed down and without rising of burst effect, begins with a rate
dependent on the formulation factors immediately after the immersion
of the pharmaceutical form into the dissolution medium and/or
immediately after the administration to the patient.
SUMMARY
B
We have now found, and constitutes an object of the present
application for industrial invention, a new pharmaceutical tablet
for oral adminisl:ration suitable to release the active substance
after a definite period of time from the administration.
Said pharmaceutical tablet consists of:
2o - a core contair.,ing the active substance or substances to be
released in the gastric or intestinal tract, polymeric substances
which swell and/or gel and/or erode on contact with water or aqueous
liquids and adjuv;3nt and excipient substances normally used in the
pharmaceutical technique;
- a layer applied externally to said core, preferably by
21 24425
compression, suitable to allow the release of the active substance
or substances contained in the core after a definite period of time,
and consisting of natural and/or synthetic polymeric materials of
the class of hydrophilic polymers which erode and/or gel and/or
dissolve in an <iqueous medium and adjuvant and excipient substances
normally used ire the pharmaceutical technique. Such a layer does not
contain active substance but acts only as a releasing modulator
allowing the release of the active substance contained in the core
after a definite period of time which can be controlled by proper in
vitro tests;
- a possible ga.stroresistant and enterosoluble coating applied on
said external layer.
A new pharmaceutical form is obtained which does not release the
active substance contained in the core for a definite period of
time. In fact the release of the active substance after
administration of the pharmaceutical form occurs only when the
characteristics of said external layer are modified by the contact
with the gastro-intestinal liquids in such a way to allow the active
substance dissolution. The finished pharmaceutical tablet (core +
external layer) can be coated with a film of gastroresistant
polymeric material in such a way to allow the system activation only
when the tablet attains the duodenal tract.
DETAILED DESCRIPTION OF THE INVENTION
The characteristics and advantages of the pharmaceutical tablets
7
with release of the active substance after a definite period of time
according to the present invention, will be pointed out to a greater
extent during th.e course of the following detailed description.
Said tablets consist of:
- a core containing the active substance and polymeric substances
swelling and/or gellable and/or erodible on contact with water or
aqueous liquids and adjuvant substances;
- a layer externally applied to said core, able to prevent the
immediate release of the active substance contained in the core and
to allow the re7_ease of the said active substance after a definite
period of time, consisting of natural and/or synthetic polymeric
substances belonging to the class of the erodible and/or gellable
and/or soluble in an aqueous medium hydropilic polymers and adjuvant
substances;
- a possible gastroresistant and enterosoluble coating.
Said tablet has the form shown in Figure 1, in which the core is
indicated by (1), the layer externally applied to the core is
indicated by (2) and the possible coating is indicated by (3).
The core (1) is prepared by compression of the relative mixture
possibly pregra:nulated, the layer (2) is preferably applied by
compression of the relative mixture possibly pregranulated and the
coating (3) is preferably applied by film-coating.
One of the chara~~teristics of the tablet according to the invention
consists in that in the preparation of the core, in addition to the
active substance, also polymeric substances able to modulate (to
21 24425
slow and/or to speed up) the release of the active substance, are
used.
:fin active substance very soluble in water and/or aqueous liquids
independently from the pH value of the dissolution medium and/or of
the gastrointestinal tract may be used or an active substance poorly
soluble in the same conditions, may be used. In this case particular
adjuvants may be used to facilitate the quick dissolution as, for
example, described in the volume "Techniques of Solubilization of
Drugs" by S.H. Jalkowsky Ed. - M.Dekker New York 1985 and
l0 lliropean Patent A~~plication No. 0468392 filed on July 22, 1991.
ton steroid (NSAID) or steroid antiinflammatory drugs as sodium
diclofenac, indomethacin, ibuprofen, ketoprofen, diflunisal,
piroxicam, naproxen, flurbiprofen, sodiun tolmetin, or sleep
inductors and tranquillizers as diazepam, nitrazepam, flurazepam,
oxazepam, chlordiazepoxide, medazepam, lorazepam or active
substances for the anginous and the hypertensive attacks prevention
as diltiazem, trapidil, urapidil, benziodarone, dipyridamole,
lidoflazine, naphthydrofuryl oxalate, perhexiline maleate,
oxyfedrine hydrocloride, or drugs of peptidic nature as insulin,
calcitonin and soa~atostatin, may be used as active substances.
Crosslinked polyvi.nylpyrrolidone, hydroxypropylmethylcellu-
lose, crosslinked sodium carboxymethylcellulose,
carboxymethylstarch, potassium methacrylatedivinylbenzene,
copolymer,polyvinylalcohols, starchs, starchs derivatives,
B
_.. _
9
betacyclodextrir.~ and dextrins derivatives in general may be used,
for example, as polymeric substances in the preparation of the said
core. Said polymeric substances constitute from 1.0 to 90x of the
core weight.
As far as the hydroxypropylmethylcellulose is concerned various
types with different molecular weight (between 1.000 and 4.000.000)
and with different substitution degree may be used.
Said types of hydroxypropylmethylcellulose present differentiated
characteristics being mostly erodible or mostly gellable depending
on the substitution degree (S. D.) shown in the polymer chain.
In addition adjuvant substances as natural and/or synthetic
polymeric materials belonging to the class of the so called gellable
hydrophilic polymers, able to slow the release of the active
substance from t:!~e core, may be used.
Finally, excipients normally used in the pharmaceutical technique as
mannitol, lactose, magnesium stearate, colloidal silica and others
as glyceryl monostearate, hydrogenated castor oil, waxes, mono-bi-
and trisubstituted glycerides, may be used.
When the penetration of the water and/or aqueous fluids in the core
2 O is to be helped, hydrophilic diluents as mannitol, lactose, starchs
of different origin, sorbitol and xylitol are introduced.
When the penetration of water and/or aqueous fluids in the core is
to be slowed down, hydrophobic diluents as glyceryl monostearate,
hydrogenated casi:or oil, waxes and mono-bi-trisubstituded glycerides
are introduced. It is to remark that generally in the case of
10
hydrophylic matrices, like those generally constituting the said
core, particularly in the case of very soluble in aqueous liquids
drugs, the "dose dumping" effect may occur, that is the release of
an excessive amount of drug in a very short period of time, this
fact causing thE~ appearance of collateral effects not always easily
tolerable by the patient.
The pharmaceutical tablets of the invention have the advantage of
releasing the active substance contained in the core after a
definite period of time and, containing a reduced amount of drug
compared to the traditional retard forms, of avoiding the dose
dumping effect.
Such result is reached by completely coating said core with an
external layer, preferably but not necessarily, obtained by
compression.
Said layer consists of natural and/or synthetic polymeric materials
belonging to the class of the gellable hydrophilic polymers and/or
to the class of the erodible hydrophilic polymers and/or gellable
and soluble in water and/or in the dissolution medium at a rate
which can be rigorously predetermined and controlled with proper
tests in vitro, the rate of erosion and/or of dissolution being
determined by a~_1 the substances constituting the formulation. In
addition to said polymeric materials, excipients as hydrophilic
agents, so called canalizing agents, may be used in the formulation
used for said layer when the erosion or gelling or dissolution
_.
11
process is to he accelerated, or hydrophobic and water repellent
agents when saiaL process have to be slowed down.
Other technological adjuvants able to give to the material or to the
mixture the suitable characteristics of industrial workability are
moreover used.
The polymeric substances used in the preparation of the external
layer, can show characteristics of gastroresistance and
enterosolubility allowing the activation of the system only after
the tablet has reached the enteric tract and in particular
formulations of said polymeric substances able to obtain tablets
expressly designed to the release of the active substance at the
colon level, are possible.
The polymeric substances used for the external layer preparation are
selected in the class comprising hydroxypropylmethylcellulose with a
molecular weight between 1.000 and 4.000.000, hydroxypropylcellulose
with a molecula~~ weight between 2.000 and 2.000.000, carboxyvinyl
polymers, polyvinylalcohols, glucansn scleroglucans, mannans,
xanthans, carbo~s:ymethylcellulose and derivatives, ethylcellulose,
methylcellulose and, in general, cellulosic derivatives.
As far as the hydroxypropylmethylcellulose is concerned the remarks
expressed on this substance in the use for the core preparation, are
confirmed.
Said polymeric substances may be present in a percentage between 5
and 90 per cent of the total weight of said layer but preferably
between 50 and 8!j per cent.
z~z~~z~
12
Said polymeric substances, used one by one or mixed together, are
able to determinate a "retard" in the release of the active
substance contained in the core in a period of time between 15
minutes and more' than $ hours, also modifying the drug release rate
from the core.
Said polymeric substances may be contained in the core too, when a
slowed release of the active substance is to be obtained.
Said external layer has a thickness between 0.2 and 4.5 mm if it is
by compression applied and between 0.1 and 4.5 mm if it is by film
coating applied.
In the case said external layer is applied by compression diluents
as those traditionally used in the solid forms preparation or fatty,
waxy, natural arid synthetic or semisynthetic substances as glyceryl
monostearate and semisynthetic triglycerydes derivatives,
semisynthetic glycerides, hydrogenated castor oil.
glycerylpalmitostea-
rate, glyceryl behenate and other adjuvants such as binders as
polyvinylpyrrolidone, gelatin, ethylcellulose, methylcellulose,
sodium carboxymethylcellulose and other natural or synthetic
substances well known to the skilled in the field, may be used.
For example magnesium stearate, stearic acid, sodium stearate, talc,
sodium benzoate,. boric acid, polyoxyethylenglycols and colloidal
silica, are used.
Moreover diluent., lubricant, antiadherent and glidant substances,
~124~~5
13
hydrophilic and canalizing agents and other substances able to give
to said layer i:he requested characteristics can be used, as the
following examples will better specify.
Said external layer may be obtained also by film-coating and/or
lacquering process according to methods well known to the skilled in
the field.
In such case besides the basic polymeric material as before
described plasticizing substances as butylphthalate,
propylphthalate, dietylphthalate, zein, polyoxyethyl-
englycols with different molecular weight and opacity agents as
titanium dioxide and other adjuvants well known to the skilled in
the field, may be used.
On said layer, independently from the ways of application, a film of
gastroresistant ;and enterosoluble polymeric material can be further
applied, to allow the system activation only after the tablet has
reached the duodE~num-intestinal tract.
Pharmaceutical systems of the last type may be used for the
preparation of giblets specifically designed and adressed to release
the active subst:3nce in the last part of the intestinal tract, that
is at the colon 7_evel.
As polymeric materials to obtain the gastroresistance, cellulose,
acetophthalate, cellulose acetopropionate, cellulose trimellitate,
acrylic and methacrylic polymers and copolymers with different
molecular weight and solubility dependent on different pH values may
be used.
14 ~~ 244 2 5
Said materials may be applied on the finished pharmaceutical form
(core + external layer) by the classic film-coating process using
solutions in organic solvents or aqueous dispersions and operating
by nebulization i.n basin or in fluidized bed.
Said gastroresist.ant and enterosoluble materials may also be used in
association with retarding polymers.
The following examples refer to the preparation of prototypes of the
realization before described and they are reported only for
explanatory and not limitative purpose of the present invention.
EXAMPLE 1 - PREPARATION OF TRAPIDIL BASE TABLETS
1 - a - Preparation of the core granulate
N' 10.000 cores each having the following unit composition, are
prepared:
Trapidil*(Inverni della Beffa, Milan, I) 150.0 mg
Hydroxypropylmeth;ylcellulose (Methocel*K4,
colorcon, Orpingt~~n, U.K.) 30.0 mg
Mannitol (USP grade, C. Erba, Milan, I) 98.3 mg
Polyvinylpyrrolidone (PlasdoneR K29-32,
Gaf Corp., Wayne, NY, U.S.A.) 3.'7 mg
Magnesium stearate (USP grade, C. Erba Milan, I) 2.0 mg
Colloidal silica (Syloid*244, Grace GmbH, Worms, D) 1.0 mg
The hydrophilic core manufacture process consists in the preparation
of a granulate by mixing, in a sigma Erweka K5 type mod. (Frankfurt
~~ trade-marks
t~
15
a.M. -D) mixE~r, the proper amounts of active substance,
hydroxypropylmethylcellulose and mannitol; the homogeneous powder
mixture is wE~tted with a 20x w/v alcoholic solution of
polyvinylpyrroLidone and the mass is forced on a 25 mesh grid
obtaining a regular granulate which is dried in a 40-45 'C air
circulation stove.
The granulate, dried to a constant weight, is placed in a Turbula
T2A mod. (Bachofen - Basel - CH) powder mixer and added with
magnesium stearate and colloidal silica and mixed for 20'.
The granulate, lubricated and analyzed for the active substance
content, is submitted to the compression stage as forward described.
1 - b - Preparat:ion of the granulate forming the external la er
The necessary amount of granulate for obtaining N' 10.000 external
layers of 300 m~; each having the following composition, is prepared.
Hydroxypropylmet:hylcellulose (Methocel E 5
Premium, Colorcon, Orpington, U.K.) 240.0 mg
Hydrogenated ca~.tor oil
(Cutina HR, Henls:el, Dussendorf, D) 52.7 mg
Polyvinylpyrrolidone (PlasdoneR K29-32,
Gaf Corp., Wayne, NY, U.S.A.) 2.5 mg
Blue lacquer (Eigenmann - Veronelli, Milan, I) 0.3 mg
Magnesium steara.te (USP grade, C. Erba, Milan, I) 3.0 mg
Colloidal silica. (Syloid 244, Grace GmbH, Worms, D) 1.5 mg
The manufacture process consists in the preparation of a granulate
16
by mixing in a sigma Erweka K5 type mod. (Frankfurt a.M. -D) mixer
the proper amounts of hydroxypropylmethylcellulose, hydrogenated
castor oil and
blue lacquer; tine homogeneous powder mixture is wetted with a 20 y
w/v alcoholic solution of polyvinylpyrrolidone and the mass is
forced on a 25 mesh grid obtaining a regular granulate, of blue
color, which is dried in a 40 - 45 ~C air circulation stove. The
granulate, dried to a constant weight, is placed in a powder mixer
(Turbula T2A mod.) and added with magnesium stearate and colloidal
silica and mixed for 20'.
The granulate, 7_ubricated, is submitted to the compression stage as
forward described.
1 - c - Preparat.ion of the finished tablets
For the preparation of the tablets as shown in Fig. 1 a Dry-Cota
(Mannesty - Liverpool U.K.) rotating press machine is used; this
machine, as it is known to the skilled in the field, consists of two
coupled rotating presses of which the first for the core ( 1 )
manufacture and the second for the application of the external layer
(2) by compression. A suitable system of transfer allows the correct
location and centering of the core.
The machine is equipped with circular convex punchs (diameter=10.0
mm; R=10.0 mm) for the manufacture of the cores and of circular
convex punchs (diameter=12.0; R=10.0 mm) for the application of the
external layer.
In the present a:nd in the following examples R indicates the bending
1~ 212425
radius of the punch.
The loading ho~~per of the first press is filled up with the
granulate described at the point la while the two loading hoppers of
the second press; are filled up with the granulate described at the
point lb.
The first press is adjusted for producing 285 mg cores (equivalent
to 150 mg of active substance) while the second one is adjusted for
delivering an amount of granulate equivalent to 300 mg, for the
external layer. With this amount an external layer of about 1.0 mm
thickness is obtained.
Both said cores and the finished tablets are submitted to the
dissolution test as below specified.
1 - d - Dissolut:ion test
To estimate the releasing characteristics of the cores and of the
finished (dry-coated) tablets, the equipment 1 described in USP XXII
is used operating at 100 r.p.m. and using deionized water at 3'7 'C
as dissolution fluid. The release of the active substance is
controlled by U.V. spectrophotometric determination at 299 nm using
a sampling and reading automatic system (Spectracomp 602 by Advanced
Products - Milanl.
The results of the tests are reported in the table 1.
21 2425
TABLE 1
Time(h) Drug % released from Drug x released
the core without from the
external layer finished tablet
1 32.4 0.0
2 52.0 2.13
3 67.4 15.8
4 80.6 35.9
6 98.7 74.2
8 100.5 98.2
99.8
It is possible to point out that the application of the external
layer by the described technique causes a delay of about two hours
in the appearance of the active substance in the dissolution medium
and such behaviour quite corresponds to the aims of the present
5 invention.
1 - a - Preparat:ion of finished tablets with different thickness of
the external layer
The cores descrubed at the point 1 - c) are used but the press
machine for the <~pplication of the external layer to said cores uses
10 circular convex punchs of diameter=13.0 mm and R=10.0 mm; the
machine is adjusted for producing an external layer of about 1.5 mm
thickness, delivering a granulate amount of 400 mg.
19 ~ 2~.244~25
Also in this case the finished 685 mg average weight tablets, are
submitted to they dissolution test according to the point ld.
The obtained results, ever in comparison with the cores, are
reported in the table II.
TABLE II
Time(h) Drug x released from Drug y released
the core without from the
external layer finished tablet
1 32.4 0.0
2 52.0 0.4
3 67.4 5.8
4 80.6 21.4
6 98.7 65.4
8 100.5 98.2
to
99.4
Also in this case it is clear that the active substance release from
the finished tahlet begins only after a period of about two hours
compared to the core without external layer.
This behaviour ~~onfirms the validity of the embodiment and points
out how an even considerable change of the external layer, leads to
a change in the "time-lag" of about 30 - 60 minutes confirming the
security of the preparation because also important changes in weight
and thickness of said
layer allow to obtain comparable results.
z~2~~~~
EXAMPLE 2 - PREPARATION OF SODIUM DICLOFENAC BASE TABLET
2 - a - Preparation of the core granulate
N' 10.000 cores,, according to the following detailed way, each
having the following unit composition, are prepared:
5 Sodium diclofenac (Jago Pharma AG, Muttenz,CH) 150.0 mg
Hydroxypropylmethylcellulose (Methocel K15 M,
Colorcon, Orpington, U.K.} 60.0 mg
Mannitol (USP grade, C. Erba, Milan, I) 50.0 m
g
Polyvinylpyrrolidone (PlasdoneR K29-32,
Gaf Corp., Wayne, NY, U.S.A.) 20.0 mg
Magnesium stearate (USP grade, C. Erba, Milan, I) 3.0 mg
10 Colloidal silica (Syloid 244, Grace GmbH, Worms, D) 2.0 mg
The core manufacture process consists in the preparation of a
granulate by mixing, in a sigma Erweka K5 type mod. (Frankfurt a.M.
-D) mixer, the proper amounts of sodium diclofenac,
hydroxypropylmetlzylcellulose and mannitol; the powder homogeneous
15 mixture, is wetted with a 20~ w/v alcoholic solution of
polyvinylpyrrolidone and the mass is forced on a 25 mesh grid
obtaining a reg~slar granulate which is dried in a 40-45 ~C air
circulation stove=.
The granulate, dried to a constant weight, is placed in a Turbula
20 T2A mod. (Bachofen - Basel - CH) powder mixer and added with
magnesium stearal~e and colloidal silica and mixed for 20'.
21
The granulate, lubricated and analyzed for the active substance
content, is submitted to the compression stage as forward described.
2 - b - Preparat:ion of the granulate forming the external layer
A granulate having the same composition as reported in the former
example 1 - b), is used.
2 - c - Preparation of the finished tablets
For the preparal~ion of the tablets a Dry-Cota (Manesty - Liverpool
U.K.) rotating F~ress machine formerly described, is used.
The machine is equipped with circular convex punchs (diameter=10.0
mm; R=10.0 mm) for the manufacture of the cores and with circular
convex punchs (diameter=12.0; R=10.0 mm) for the application of the
external layer.
The first press is adjusted for producing 285 mg cores (equivalent
to 150 mg of active substance) while the second one is adjusted for
delivering an amount of granulate equivalent to 300 mg, for the
external layer. With this amount an external layer of about 1.0 mm
thickness is obtained.
Both said core.. and the finished tablets are submitted to the
dissolution test as below specified.
2 - d - Dissolution test
To estimate the releasing characteristics of the cores and of the
finished tablets, the equipment 1 (described in USP XXII) is used
operating at 1C0 r.p.m. and using deionized water at 37 'C as
dissolution fluid. The release of the active substance is controlled
by U.V. spectrophotometric determination at 276 nm using a sampling
22
and reading automatic system (Spectracomp 602 by Advanced Products -
Milan).
The results of the tests are reported in the table III.
TABLE III
Time(h) Drug y released from Drug x released
the core without from the
external layer finished tablet
1 18.6 0.0
2 32.1 0.9
3 44.3 7.7
4 55.7 18.9
6 76.9 43.6
8 98.0 66.3
100.3 90.1
i2 99.6
It is possible to point out that the application of the external
5 layer causes a delay of about two/three hours in the appearance of
the active substance in the dissolution medium and such behaviour
quite correspond: to the aims of the present invention.
2 - a - Preparation of finished tablets with different thickness of
the external layf~r
10 The cores described at the point 2 - c ) are used but the pressing
machine for the application,by pressing, of the external layer to
23
said cores uses. circular convex punchs of diameter=13.0 mm and
R=10.0 mm; the machine is adjusted for producing an external layer
of about 1.5 mm thickness, delivering a granulate amount of 400 mg.
Also in this case the finished 685 mg average weight tablets, are
submitted to the dissolution test according to the point 2d.
The obtained results, ever in comparison with the cores, are
reported in the table IV.
TABLE IV
Time(h)Drug % released from Drug x released
the core without from the
external layer finished tablet
1 18.6 0.0
2 32.1 p.3
3 44.3 3.2
4 55.7 13.3
6 76.9 35.8
8 98.0 60.1
l0 100.3 81.6
12 98.7
Also in this case it is clear that the sodium diclofenac release
from the finished tablets begins only after a period of about
two/three hours ~~ompared to the core without external layer.
______.. ___~,.. ~.._. _..____.~ . _..~~_ _._..__.._ _..._ _.
2~2442~
24
EXAMPLE 3 - PREPARATION OF KETOPROFEN BASE TABLETS
3 - a - Preparat;ion of the core granulate
N' 10.000 cores, according to the following detailed ways, each
having the following unit composition, are prepared:
Ketoprofen (soc.Med.Scandicci,Firenze,I) 150.0 mg
Maize starch (U~~P grade, C.Erba, Milan,I) 120.0 mg
Polyvinylpyrroli.done (PlasdoneR K29-32,
Gaf Corp., Wayne~, NY, U.S.A.) 2.0 mg
Crosslinked polyvinylpyrrolidone (Polylasdone XLR
Gaf Corp., Wayne~, NY, U.S.A.) 30.0 mg
Carboxymethylsta.rch (ExplotabR,Edward Mendell
Co. Inc. Carmel, NY, U.S.A) 28.0 mg
Magnesium steara.te (USP grade, C. Erba Milan, I) 1.5 mg
Colloidal silica. (Syloid 244, Grace GmbH, Worms, D) 0.5 mg
The core manufacture process consists in the preparation of a
granulate by miring, in a sigma Erweka K5 type mod. (Frankfurt a.M.
-D) mixer, the proper amounts of ketoprofen and maize starch;
the omogeneous powder mixture is wetted with a 20y w/v alcoholic
solution of pol;yvinylpyrrolidone and the mass is forced on a 25
mesh grid obtaining a regular granulate which is dried in a 40-45 ~C
air circulation stove.
The granulate, dried to a constant weight, is placed in a Turbula
T2A mod. (Bachofen - Basel - CH) powder mixer and crosslinked
~~ 24~2~
polyvinylpyrrol.idone and carboxymethylstarch are added to the
granulate and mixed for 20', magnesium stearate and colloidal silica
are subsequently added and the granulate is mixed for further 20'.
The granulate, lubricated and analyzed for the active substance
5 content, is submitted to the compression stage as forward described.
3 - b - Preparation of the granulate forming the external layer
A granulate haying the same composition as reported in the former
example 1- b), is used.
3 - c - Preparation of the finished tablets
10 For the preparation of the ketoprofen base tablets the Dry-Cota
(Mannesty - Liverpool U.K.) rotating press machine before described,
is used.
The machine is equipped with circular convex punchs (diameter=10.0
mm; R=10.0 mm) for the manufacture of the cores and of circular
15 convex punchs (diameter=12.0; R=10.0 mm) for the application of the
external layer.
The machine is adjusted for producing 332 mg cores (equivalent to
150 mg of active substance) while it is adjusted for delivering an
amount of granulate forming the external layer equivalent to 300 mg.
20 Said amount allows to obtain an external layer of about 1.0 mm
thickness .
Both said cores and the finished tablets are submitted to the
dissolution test as below specified.
3 - d - Dissolut:ion test
25 To estimate the releasing characteristics of both the cores and of
_..
26
the finished tablets, the equipment 1 (described in USP XXII) is
used operating at 100 r.p.m. and using simulated intestinal fluid as
dissolution fluid, pH=7.5 (according to USP XXII) without enzymes at
37 ~C. The release of the active substance is controlled by U.V.
spectrophotometr:ic determination at 262 nm using a sampling and
reading automatic system (Spectracomp 602 by Advanced Products -
Milan).
The results of the tests are reported in the table V.
TABLE V
Time Drug ~ released from Drug x released
(min) thE~ core without from the
exi~ernal layer finished tablet
3 100.2 0.0
60 0.0
120 0.0
150 94.5
180
99.8
It is possible to point out that the cores release the active
substance in three minutes while, with the application of the
external layer, the active substance is released only after a delay
of about 120 minutes. Said behaviour quite corresponds to the aims
of the present invention.
_._._ ___.__ ~~._y__ ____.~~._
__
27
3 - a - Preparal:ion of finished tablets with different thickness of
the external layer
The cores descr=Lbed at the point 3 - c ) are used but the pressing
machine for the application of the external layer to said cores uses
circular convet: punchs of diameter=13.0 mm and R=10.0 mm; the
machine is adjusted for producing an external support of about 1.5
mm thickness, delivering a granulate amount of 400 mg.
Also in this case the finished 732 mg average weight tablets, are
submitted to the dissolution test according to the point 3 - d.
The obtained rE~sults, ever in comparison with the cores, are
reported in the table VI.
TABLE VI
Time Drug y released from Drugx released
(min) the core without from the
external layer finished tablet
3 100.2 0.0
60 0.0
120 0.0
180 84.2
240 99.7
Also in this case it is clear that the ketoprofen release from the
finished tablet begins only after a period of about two/three hours
compared to the core without external layer.
_v.. ~_ , . _..___.~~_~
2~~~~~~
28
EXAMPLE 4 - PREPARATION OF SODIUM DICLOFENAC BASE TABLETS
4 - a - Preparation of the core granulate
N' 10.000 cores, according to the following detailed ways, each
having the following unit composition, are prepared:
Sodium diclofena<: (Jago Pharma AG,Muttenz,CH) 150.0 mg
Hydroxypropylmethylcellulose (Methocel K15,
Colorcon, Orpingl:on, U.K.) 60.0 mg
Mannitol (USP grade, C. Erba, Milan, I) 50.0 mg
Polyvinylpyrrolidone (PlasdoneR K29-32,
Gaf Corp., Wayne" NY, U.S.A.) 20.0 mg
Magnesium stearai:e (USP grade, C. Erba Milan, I) 3.0 mg
Colloidal silica (Syloid 244, Grace GmbH,Worms, D) 2.0 mg
The core manufacture process consists in the preparation of a
granulate by mixing, in a sigma Erweka K5 type mod. (Frankfurt a.M.
-D) mixer, t:he proper amounts of sodium diclofenac,
hydroxypropylmethylcellulose and mannitol;
the homogeneous powders mixture is wetted with a 20x w/v alcoholic
solution of polyvinylpyrrolidone and the mass is forced on a 25
mesh grid obtaining a regular granulate which is dried in a 40-45 ~C
air circulation ~;tove.
The granulate, dried to a constant weight, is placed in a Turbula
T2A mod. (Bachofen - Basel - CH) powder mixer and added with
magnesium stearate and colloidal silica and mixed for 20'. The
_______._ _.._~~.___ , _ _ __~ _..~.~...r_
_ ~~~~4~a
29
granulate, lubricated and analyzed for the active substance content,
is submitted to the compression stage as forward described.
4 - b - Preparation of the granulate forming the external layer
The necessary amount of granulate for obtaining N' 10.000 external
layers of 300 mg each having the following composition, is prepared.
Hydroxypropylmethylcellulose (Methocel K4M
Colorcon, Orpington, U.K.) 135.0 mg
Mannitol (USP grade, C. Erba, Milan,I) 135.0 mg
Polyvinylpyrrolidone (PlasdoneR K29-32,
Gaf Corp., Wayne, NY, U.S.A.) 24.6 mg
Red eudralack {E127, Biosintex, Milan, I) 0.3 mg
Magnesium stearate (USP grade, C. Erba , Milan, I) 3.0 mg
Colloidal silica (Syloid 244, Grace GmbH, Worms, D) 1.5 mg
The manufacture process consists in the preparation of a granulate
by mixing in a sigma Erweka K5 type mixer the proper amounts of
hydroxypropylmethylcellulose (in this case a high molecular weight
and high viscosity K type hydroxypropylmethylcellulose is used,
which forms a g~~llable instead of erodible barrier), mannitol and
red lacquer; the homogeneous powder mixture is wetted with a 20
w/v alcoholic solution of polyvinylpyrrolidone and the mass is
forced on a 25 mesh grid obtaining a regular granulate, of pink
colour, which is dried in a 40 - 45 ~C air circulation stove. The
granulate, dried to a constant weight, is placed in a powder mixer
(Turbula T2A mod.) and added with magnesium stearate and colloidal
_ ~~24~~~
silica and mixed for 20'.
The granulate, .Lubricated, is submitted to the compression stage as
forward described.
4 - c - Preparat;ion of the finished tablets
5 For the preparation of the tablets as shown in Fig. 1 a Dry-Cota
(Mannesty - Liverpool U.K.) rotating press machine is used; said
machine, as it i.s known to the skilled in the field, consists of two
coupled rotating; presses of which the first is assigned to cores (1)
manufacture and the second to the application, by compression, of
10 the external la~~er (2) . A suitable system of "transfer" allows the
correct location. and centering of the core.
The used machine is equipped with circular convex punchs
(diameter=10.0 u~m; R=10.0 mm) for the manufacture of the cores and
of circular co~avex punchs (diameter=12.0; R=10.0 mm) for the
15 application of the external layer.
The loading ho~~per of the first press is filled up with the
granulate described at the point 4a while the two loading hoppers of
the second pres~o are filled up with the granulate described at the
point 4b.
20 The first press is adjusted for producing 285 mg cores (equivalent
to 150 mg of active substance) while the second one is adjusted for
delivering an amount of granulate equivalent to 300 mg, for the
external layer. With this amount an external layer of about 1.0 mm
thickness is obtained.
_..._...._. __.._~ ....-_,. _..~__..___._~
._ ~124~25-
31
Both said corer and the finished tablets are submitted to the
dissolution test as below specified.
4 - d - Dissolution test
To estimate the releasing characteristics of the cores and of the
finished (dry-coated) tablets, the equipment 1 described in USP XXII
is used operating at 100 r.p.m. and using deionized water at 37 ~C
as dissolution fluid. The release of sodium diclofenac is controlled
by U.V. spectrop~hotometric determination at 276 nm using a sampling
and reading automatic system (Spectracomp 602 by Advanced Products -
Milan).
The results of the tests are reported in the table VII.
__..._. _.._._._ _.._.__~.__..___.T.___~~__ __~~-.
__ z~ ~~~z-~
32
TABLE VII
Time(h) Drug x released from Drug x released
l:he core without from the
external layer finished tablet
1 18.6 O.o
2 32.1 0.6
4 55.7 7.2
6 76.9 17.7
8 98.0 3o.8
l0 100.8 45.3
s2 59.4
14 72.4
16 86.6
18 95.7
20 98.6
It is possible to point out that the application of the external
layer by the de~~cribed technique causes a delay of about three/four
hours in the appearance of the active substance in the dissolution
medium and such behaviour quite corresponds to the aims of the
present invention.
4 - a - Preparai:ion of finished tablets with different thickness of
the external layer
The cores descr=Lbed at the point 4 - c ) are used but the pressing
.__..... . ..... ..... ..__._...___._._.r..~__ _.,.__._~ ~_._....
_ z~z4~z~
33
machine for the application of the external layer to said cores uses
circular convex punchs of diameter=13.0 mm and R=10.0 mm; the
machine is adjusted for producing an external layer of about 1.5 mm
thickness, deliv~aring a granulate amount of 400 mg.
Also in this care the finished 685 mg average weight tablets, are
submitted to the dissolution test according to the point -d.
The obtained results, ever in comparison with the cores, are
reported in the table VIII.
TABLE VIII
Time(h) Drug ~ released from Drug y released
'the core without from the
external layer finished tablet
1 18.6 0.0
2 32.1 0.0
4 55.7 0.1
6 76.9 5.8
8 98.0 14.3
to 100.8 25.4
12 38.7
14 52.9
16 67.4
18 84.8
20 95.6
Also in this case it is clear that the active substance release from
m z~.~~4z~
the finished tablet begins only after a period of about three/four
hours compared t.o the core without external layer.
This behaviour confirms the validity of the embodiment and in this
case points out that a change of the external layer leads to a
change in the "tame-lag" of about one/two hours compared to a lower
thickness.
