Note: Descriptions are shown in the official language in which they were submitted.
~3S65~L
--2--
The present invention relates to a delivery device forzero-order release, i.e. at constant release rate, of an
active principle in a fluid phase wherein the active prin-
ciple is either inherently soluble or can be solubilized.
This constant release rate regimen is described mathema-
tically by the equation
dQ
- = constant
dt
wherein _ is the release rate, and Q is the amount of
dt
substance released at time t; or alternativel~, in inte-
grated fo~m, as
Q = constant O t
which shows that the amount of released substance is a
linear function of time.
The term "active principle" is used herein and is intended
to be construed in its broadest sense as encompassinq any
chemical substance or composition which will produce a bio-
active or pharmacological response either at the site of
application or at a site remote therefrom. Insecticides,
fertilizers, pharmaceuticals and nutrients are, therefore,
included, although not as limiting examples, within the in-
tended meaning of "active principle".
:~Z3S65~
The need of providing means suitable for releasing an active
principle according to a programmed release scheme into an
environment wherein the substance is intended to be active
has long been felt in several technological sectors such as,
e.g. the insecticide, fertilizer~ pharmaceutical and health
food industries.
The purpose of a programmed release is to achieve selectivi-
ty and accuracy in delivering the optimum dose of bioactive
substance to the desired target, while negligibly affecting
non-target sites, at preselected times and for as long as it
may be desirable in order to maximize effectiveness.
In the agricultural field, one goal, for instance, is that
of providing an intense and prolonged insecticidal activity,
while minimizing pollution to soil and water. In the pharma-
cological field, a goal is to maintain the plasma level of adrug constantly within the therapeutically effective range
for a long time, etc.
Among the controlled release systems and devices, those with
constant release rate (zero-order release rate) have raised
particular interest.
Although the applicability of the device of the present inven-
-~'
`" 123S6~
tion is by no means confined to the pharmaceutical field,
reference will be hereinbelow made for simplicity sake to
the administration of therapeutically effective substances
in which the need for providing zero-order release dosage
forms is particularly important.
For application in the pharmaceutical field, the device of
the present invention may take one of the usual dosage forms
of administration, such as tablets, capsules, lozenges, dis-
coids, rectal and vaginal suppositories, globuli and the like.
Several so-called "sustained release" or "slow-release" dosage
forms are available in the markèt. However, the pharmacokinet-
ic analysis of blood samples drawn from patients who have been
administered such forms shows the presence of a peak of plasma
concentration (which frequently causes untoward side-effects)
followed by a sudden drop of concentration, well below the
threshold of therpeutical effectiveness. At best a certain
prolongation of the therpaeutical activity may be attained
but the drawbacks of conventional immediate release adminis-
tration forms are not eliminated.
Recently, an orally administrable indomethacin-containing
- ~235654
pharmeutical composition has been marketed, which releases
the active principle at constatn release rate. This novel ad-
ministration form (OROS) comprises a core tablet containing
durgs and excipients, at least one of them having osmotic ac-
S tivity, which is coated with a semipermeable polymer memberane.The membrane is permeable only to water and is provided with
a small orifice. After ingestion, the osmotic agent in the
core causes an influx of water which effects dissolution of
the drug. The osmotic pressure differential brings about
outflow of a saturated drug solution from the orifice. As
long as undissolved drug and/or osmotic agent remains, the
pressure gradient is const.ant and the drug delivery rate
through the orifice remains zero order.
Because of continued decrease of drug content in the system
with time, however, the drug solution becomes less than sat-
urated and the osmotic pressure gradient and the drug deliv-
ery rate decline exponentially toward zero. The system ceases
to function when iso-osmotic conditions set in~
Although about 70~ of the drug content is actually released
in zero-order fashion, this system presents the serlous draw-
back to channel the whole drug solution through the orifice
in the membrane.
.~
~Z35654
This extremely specific localization of the release of active
principle and its high concentration (saturated drug solutlon
outflow taking place only from a pract~cally puncitform area
of the OROS tablet) can bring about, particularly when the
active principle is as aggressive as indomethacin, damage to
the gastric mucosa areas which are exposed to or are located
in the close proximity to the release drug.
The main object of the present invention is to provide a de-
livery device for zero-order release of an active prinicple
which does not present the drawbacks of the known devices and
systems.
:~;
-- 7 --
A~o~di~ t~ the present inven~ion~ the d~livery d~vice
for 2~ro-order release of~an active principle intv a
d~solution fluid there~o~ comprises ~ ~oli~ m~trix-
type reservoir ~ormed o~ a polymer material ~hich is in-
soluble ~nd unswellable in the dissolution fluid~ Thereservoir i~ po~ous, at least a portion o~ t~e active
principle bein~ dispersed in ~he pores of the reservoir.
The reservoir comprises a ~ablet $ormed of a homogeneous
mixture of the polymer materia~, the a~ive prin~iple,
~0 and ~n addi~ive which is ~oluble into the dissolution
~luid wi~h neg~tive heat of solution.
A coating uni~ormly su~rou~ds the reservoir, This coating
comprises t~o membrane~.
The first, release rate-con~ollin~l ~embrane is homoge-
15 neous ~nd continuously w~aps the reser~oir and is ~ormedof a ~ilm-formin~ polymer material insoluble in the dis-
solution ~uid ~nd pe~me~ble to the subs~n~e. The thick-
ness o~ the ~irst membrane is de~ermined by ~he equation
~S ~S
thickness = h =
wherein: D is the constant of diffusion across the mem-
br~ne;
fi is the sur~ace area through which diffusion
Dc~llrs;
3 5 6
CS i~ the saturation concentr~tion of ~he s~-
stance in the dissolution fluid; and
R is the substance r~le~3e r~
The second, protective, mem~rane is homoyeneous a~d continu-
ously wraps the rel~ase ra~e-con~rollin~ me~brane, ~he pro-
tective membrane being formed of a fil~-forming poly~er
~terial soluble in th~ dissolu~ion fluid.
Partic~ ly relevant for the purposes o~ the p~esent inven-
tion is the thicknessi h, of the re~ea~e rate-controlling
membrane. Thi~kness, h, i~ dedu~ed ~rom ~ick~s la~. Fick's
law establishe~ that once ~te~dy-state conditions are
a~t~ined, ~he ~elease rate remains cons~an~ and independent
o~ time if a solute is con~ined within a "reservoir"
surrounder by a continuous polymer membrane and ~he thermo-
dynamical a~tivi~y of the solute is kept const~n~ withinthe reservoir. When the energy of the syste~ is the so~ute
diffusion energy ~oss the m~mbrane, Fi~k's l~w i~ repre-
sented ~y
d~ D S Cs
dt = R = -h
Since D, ~ and h are assumed to re~ai~ ~onstant, th~
amount of solute which dif~uses across the mem~rane per time
unit is constant, i.e. di~usion occurs according to zero-
order kinetics~
i23565~
The operation of the device of the present inventior. may
be described as follows.
The dissolution fluid, for example body fluids, first dis-
solves the protective membrane and hydrates the release
rate-controlling membrane. The dissolution fluid then pene-
trates inside the solid reservoir and dissolution of the ac-
tive principle thus begins, either because it is inherently
soluble or because its dissolution is promoted by the "in
situ" presence of suitable buffer agents, as it will be i]lus-
trated in greater detail below. Thereafter, the concentra-
tion of the inner solution will reach the saturation value,
Cs. From this moment on so long as the active principle
concentration remains equal to Cs, the amount released from
the surface of the delivery rate-controlling membrane will
be directly proportional to the time; i.e. the release will
be according to zero-order release kinetics. In contrast,
the solid reservoir if uncoated would release the active
principle proportionall~ to the square root of time
(Higuchi's law).
`~;
~35654
--10--
It is apparent that in order to maintain as long as possible
the conditions determining the zero-order kinetics, it is es-
sential that the active principle concentration remain subs-
tantially equal to Cs, and that the pH inside the system, the
diffusion coefficient, the surface area and thickness of the
delivery rate-controlling membr~ne remain substantially con-
stant during the device life-span.
These objects are attained by the present invention through
both the suitable selection of polymer. materials for the sol-
lQ id reservoir and the delivery rate-controlling membrane, and
the selection of appropriate additives, particularly the addi-
tives which promote the formation of the channel network ~:.
throughout the solid reservoir, buffer the active principle
solution, inhibt the solid reservoir swelling, and plasti-
cize the delivery rate-controlling membrane. Specifically, the
qualitative and quantitative composltion of the soli.d reser-
voir is mainly governed by the active principle solubility, as
it will be apparent by the following detailed description of
the various:embodiments of the inention and the respective
roles of their components.
123S654
Solid ma~rix-t~pe re~erVoir
The solid matrix-type reservoir pre~erably comprises from
3 to 20% by weigh~ of polymer material, ~o~ 30 to ~G% by
weight of ac~ive principle; ~nd ~rom 5 tO 50% ~y ~eight o~
a~ additi~e soluble into the dissolution ~luid with neg~tive
~o~ution hea~.
The p~lymer mater~al should be ungwella~le and insolub~e in
the active principle's dissolution fluid in order.~o a~oid
alterations of the ~elease rate-controlling membrane as ~y
~racking and, ~or pharmaceutic~l dosaye forms~ also biocom
p~tible. Typical materials include cellulose ~ceta~e, high
viscosity hydroxypropylmethyl cellulose, ~ellulose acetate
propionate, ethyl cellulose and polymethacrylates.
The additive soluhle in the dissolu~ion fluid With negative
heat o~ solu~ion ~enerally is a polyol, including su~ars,
such as mannitol~ dextros~, sorbitol, xylitol and the like.
Both th~ role played by this additive and amount thereo~ are
strictly dependent on active principle 1 5 solubility. ~cwever,
also an acid, e.~. citric acid, can be used.
~hen the ~ctive principle is soluble in the dis~olution Pluid,
the additive acts mainly as a plasticizer towards the ~elease
ra~e-controlling ~embrane.
~35654
- 12 -
The negative he~t 0~ ~olu~ion.is an essen~ial property ofthe additive in order that it ~an act a plasticizer,avoid-
ing a reservoir volume increase and ~esul~ant release rate-
con~rolling me~brane ~o~i~ic~tion.
When the ~C~i~e prin~iple is sparingly soluble, th~ ~dditive
~lso plays the role of promotiny the forma~ion of a c~el
network in the solid reser~oir, thus gradually increasing
its porosity. Consequen~ly, both the dissolution process of
the active princlple and its ea~e of rea~hi~g ~he inner sur
~ace of the me~brane ~hrough the channels filled with disso
lution fluid are maxi~ized. This con~ribu~es ~o ~aintai~ing
the active principle concentra~ion in the solu~ion inside
the system equal to the saturation value, Cs.
When the a~ditive acts solely ~s plasticizer, it is suffi-
~ient that the solid reservoir ~ontains f~om about 5 ~o
about 15% by weigh~ o~ additive whereas, when it also acts
as channeller, ~he solid r.eservoir will.c~ntain from about
15.to 50X by.wei~ht of ~dditive.
When the ac~i~e pri~ciple ~s solu~le, i~ itself ac~s as chan
neller. When.the activ.e pri~ciple i~ sp~rin~ly solubl~ ~is-
solution then i~ ~avoured by the presence of khe additive
~.~35654
addi~ive channeller. In either c~se, ~he poro~i~y oP the sol
id reservoir increases as more ~nd more of the active prinl-
ciple di~solves without, howeve~, the outer dimensi~ns o~ the
solid reser~oir being ~here~y affec~ed.
If the active principle~s solubili~y is influenced by the
pH of the dissolution liquid, ~he solid reservoir will
conveniently include one or more suitable buff~r agents
~hich will be selected, according ~o criteria well-known
in this art, depending on the chemico-physical character-
istics of the bioac~i~e ~ubs~nce to be sol~iliz~d. The
system inner pH c~nsequently will remain substantially
~o~s~a~t, ~gain Pavourin~ the uniform dissolu~ion of ~he
ac~ive principle. In ~uch instan~es ~he solit ma~rix-~ype
reservoi~ co~veniently will contain up to 30% ~y wei~h~,
preferably from 5 to 20~ by weight, of the buffering agent~
Release rate-~ontrollin~Lme~br~ne
The polymer ma~e~ial o~ the Pirst, release rate-controlling,
membrane mu~ be a Pil~orming polymer which is permeabl~
~ the a~ e principle bu~ insoluble in the dissolution
fluid. These are essentia~ prerequisi~es so that ~he mem-
~rane fea~ure8, p~rticularly i~s ~hic~nes8 and surfa~e area,
~i~35659~
are not su~ject to al~erations which would in tu~n a~e~k
the release kinetics ~P the a~ e principle. The polymer
also must be bioco~patible ~or ph~rm~eutic~l do~ge ~orms.
Sui~able polymer material o~ the release rate-~o~trolling
membrane include vinyl polymers and copolymers,celluloses
cellulose a~e~a~e, hydroxy-propylmethylcellulose, cellulose
acetate propionate, ethylcellulose, ac~ylic polymers and
copolymers and the like.
In order that the charact~rizing features of the release
ra~e-~ontrolling membrane do no~ ~ary with ti~e, the plas-
ticizing a~io~ exer~ed on this memb~ne by the additive
with a negative heat o~ solution cvntained in the solid res
ervoir is essential. The releas~ rate-controlling mem~r~ne
i~self may ~on~ain a further plasti~izer, e.g. d~hylpoly-
siloxane or cas~or oil.
~he thickness of ~he rel~as~ rate-controlling membrane is
determined by ~he previously mentioned equation. Generally,
the thickness wlll ~e between 0.04 and 0~01 mm. In pra~ e,
the ~hickness conveniently c~n be ex,pressed as milli~rams of
coatingfcm of surface area oP solid ~eservoir, a sui~a~le
coatin~ correspo~din~ to 4-8 m~cm .
Protective ~embra~e
. . .
.
The polymer materi~l of the second, pro~ctive, ~rane mRst be a
35i~;54
- 15 -
~ilm-forming poly~e~, easîly soluble or dispersable in the
dissolution liquid. Again for ph~rmaceu~ical dos~e ~orms,
this polym~r should be ~iocompati~le.
Preferably. ~he poly~er material of the protective ~embrane
is a soluble cellulo~e deri~a~i~e, mos~ pre~erably. low
~iscosity hydroxypropylmethylcellulo~e.
po~ion o~ the ~ctive principle may be ineorporated i~to
the polymer material of ~he protective membran~ so as to
allow the active principle to beco~e immedia~ely a~ailable
'~O
(e.g. in order to rapidly reach the therapeutic~lly e~Pec-
tive pl~sm~ level~, thereby compensating ~or the time la~
in the a~tive prlnciple release. This time la~ is obviously
rela~ed ~o the time which is necess~y for the ~ele~se rate-
controlling membrane ~o become hydrated and the proper work-
ing equilibrium ~onditions in t~e device to be attained. For
this purpose fro~ 5 to 20% by wei~ht o~ the a~ti~e principle
can be incorporated into the protective membra~e.
As pre~iously stated, biocompatible polymer materials willbe
used for the manu~a~ture o~ pharma~utical dosage forms. ~he
exhausted ~elivery de~ice will, there~ore, be easily removed
It also is possible to utilize biodegradable polymqrs,
565
-- 16 --
provided ~hat durin~ the ~ e~ o~ t~e de~i~e ( e.g. Por
laast 10 ~o 12 hours follow~n~ oral administrat~on ) no
noteworthy degradatlon phenom~na o~cur.
il 111
`iER~`i. TELEi_ClP!ER ~35;;~ 7--æ5; ~:3S~ 515553~iæ5~,# 4
-- ~56~
Aecording to an embodiment which is p~rticularly preferred
in the case of an orally administ~able pharm~ceutical dos-
age form~ the device of this inven~ion ~akes on ~he shape
of a bicon~ex discoid. ~igures 1 and 2 show the longitudi-
~al ~ross-sectional views of two such embodiments.
Preferably, the solid matrix-type reservoir of ~he biconvex
discoid has dia~e~er co~prised between ~ and 16 mm; the
bendin~ r~di~s of the ~pheric~l se~men~s of the biconvex
dis~oid is from 10 to 1~ mm and the diameter:~hickness
10 r~tio o~ the bicon~ex ~iscoid is from 2 to 5.
In the case the amount o~ ~ctive principle con~ained in
the dosage unit is below about 200 mg, the edges of the
opposed spherical seg~ents are subs~nti~lly in mating
~elationship to each other and the dis~oid assumes the fla~,
15 lenticular shape shown in Fi~. 1.
When the amount of active principle exceeds 200 mg/dosage
unit, the discoid takes on the customary shape illustrat~d
in Fig. 2, the dis~oid co~prisin~ ~ ~ylindri~al body with
the spherical segments above and below the cylindrical body.
20 ~he present in~entio~ ~lso ~omprises a p~o~ess for manu~a~-
turing the prev~o~sly illustr~te de~ice. T~e process is char-
acterized in that it comprises the following steps;
?~ERn~ TELE~CI~IEF~ 4~5,-5- 7-85; '~ 5~ lS5f~3~1~6S;# 5
3 5
- 18 -
(1) Mixi~g the ~ctive principle and the addi~ive soluble in
the dissolution fluid with ne~ati~e he~t of solution with
~ solution of the polymer material of the solid matrix-
type reservoir in an organic solvent, ~ranulating, dry-
ing and a~ding a lubricant to the drîed granulate;
(2~ compres~ing the mixture o~ step ~1) in a t~let press ac-
cording ~o known technique~ a~ a press ~ o~ 2500-4300Kg~cm ,
thus ob~ainin~ the solid m~trix-type reservoir;
(3) Applying the release rate-~ontrolling membrane onto
the reservoir by contacting the reservoir o~ step (2~
with a phase containing the first $ilm-~ormin~ polymer;
and
~4) Applying the p~ote~tive ~embrane onto ~he reservoir
coated with the release rate-control~ e~br~ne, by
con~acting the product of step t3) with a phase contain-
ing the second film-forming polymer.
Steps (3) and (4) ~an be carried ou~ in a pan according
~o known pro~edures. In such cases, ~he first and second
film-forming polyme~ m~y be applied as solu~ions in organic
solvents. Alternatively, steps (3) and ~4) c~n ~e ~rried
out accordin~ to well-known fl.uid bed techniques.
x~RO~ TELE~ ER ~C~5; ~5~ 35; ~ 135~5~16~; # f~
3~;S4
- lg -
The device of ~he present inventio~ p~esents sever~l ~dvan-
t~ge~ over the prior art devices.
At least 70% by weight of ~he ~ctive p~inciple is released
with zero-order kinetics, in most cases in 4-~ ho~rs. This
can be de~on~t~ated quantitatively in in vitro models.
Moreover, ~he rele~se o~ active principle takes place over
~he whole sur~ace o~ the device, not from a limi~ed zone
~hereo~. Consequently, the flux of the active principle
solution at the outer surface of the device is slower than
the flux presented by prior art de~ices and the danger of
an excessive level of active prin~iple bein~ released in
a limited environment is thus mini~ized. Unintentional
~upture of the releas~ rate-~on~rollin~ membr~ne is extremely
unlikely because of the dimensional st~bility of the solid
reservoir and me~brane and the plasticized condition of this
lat~er. However, even i$ the membrane did rup~u~e, this event
would not bring about a sudden ~elease ("dose dumping") of
active principle ~hole content into the environment~
The solid reservoir ~e~ely would release the active prin~iple
at a rate p~Oportional to ~he sq~are root of time, behaving
as cont~olling modulator of the rele~se.
-
-` ~23S6S~L
- 20 -
The active prînciple solubili~y ~180 i~ widely independent
o~ the dissoluti~n fl~id pH and possibL~ variatlons the~eo~,
the pH o~ the saturated ~lution of ~C~ive principle ~ithin
the device remaining pra~tically unchan~ed.
Finally remarkable stability and stren~h d~ring handling
~nd storage o$ ~he device is acheived t in part be~ause of
the prote~tive ~embrane.
~;~3~65~L
- 21
The following non-limiting examples illustrate typi~al
~elivery devices a~cording ~o ~he ~nv~n~ion wherein the
ac~ive principle is an orally administrable dru~. ~n these
specific examples the device takes on ~he typic~l shape o~ a
biconvex di~coid ~ablet.
~.
Pre~aration o~ tablets o~ the lyslne salt of _ndomethacin
( a ) Preparation of the solid matrix-~ype reservolrs
In order to prepare 1,000 solid matrix-type reservoirs,
the following amounts o~ produc~s were used:
Lysine salt of indomethacin
t~tive principle) 9
Cellulose acetate propionate
~average ~ole~ular weigh~- 7S,000) 10 g
Eastman Kodak, 482-20 type
Disodium phosphate 80 g
Mannitol 70 9
Talc
Magnesium steara~e
The active principle, sodium phosphate, mannitol and
talc were fed into a powder mixer and thorou~hly ~ixed
~;~35659l
therein until a completely homogenous mixture was
obtained.
A solution of the polymer material in 55 ml of 1:1 ace-
tone:isopropanol was prepared. The previously obtained
powder mixture then was wetted with this solution. The
resulting material was granulated through a 800~ sieve,
dried and then granulated again through a 42C~ sieve.
The grnaulate thus obtained was mixed with magnesium
stearate and subjected to compression by means of re~
cessed punches having diameter of 12 mm, at the pres-
sure of 3,000 Kg/cm2, thereby producing biconvex, lenti-
cular solid matrix-type reservoirs (see Fig. 1).
The geometrical features of such reservoirs were the
following:
15 diameter 12 mm
bending radius of the spherica~
segments forming the bicon~ex
reservoir ` 14 mm
diameter: thickness ration 4
20 exposed surface area
area of one spherical segment 1.15 cm2
area of the pair of spherical segments 2.30 cm2
area of the lateral surface 0.30 cm2
overall surface area 2.60 cm2
1~3S6S~
-23~
(b) Application of the release rate-con-tro:lZiny mémbrane
In order to apply the drug release rate-controlling mem-
brane, the following products were used:
low permeability acrylic Eolymer 4.5 g
(EUDRAGIT RS, Rohm Pharma)
high permeability acrylic polymer 18.2 g
(EUDRAGIT RL, Rohm Pharma)
castor oil 0.6 g
acetone 110 ml
10 isopropanol 110 ml
The release rate-controlling membrane was applied in
a pan by spraying the polymer solution in short bursts
followed by drying intervals with cold air.
The thickness of the release rate-controlling membrane
15 was 0.06 mm, corresponding to 5.4 mg of coating/cm2 of
surface area of biconvex solid matrix-type reservoir.
.
(c) Application of the protective membrane
In order to apply the protective memberane, the following
products were used:
hydroxypropyl methyl cellulose 3.0 g
(Pharmacoat 606*, Shin Etsu Chemical)
* trade mark
` ERU"~ ~ELE~ FlER ~ '5- 7-æ~; g:4J~ i3~57~3;3,~
,
3; Z3S6S~
- 24 -
tita~ium dioxide 1~0
magnesium carbonate 2.5 ~
indomethacin lysinate 5-0 g
colvent mixture 8~ ml
S ~acetone:isopropanol 1:1~
The polymer sol~tion for applying the p~ote~tive membra-
ne was applied in a p~n onto the solid matrix-type ~es-
ervoirs coated with the release ra~e-controlling me~b~ane
~rom the previous step.
10 In the poly~er solution for ~pplying the pro~ective membra-
ne, 10% by weight of the total active principle was ~dded.
The ki~eti~ feature~ of the indomethacin lysi~ate re-
lease were determined both in "in vitro~ models ~nd "in vivo".
"In vitro" model
15 "In_~itro" experiments were carried out both on (i) the un-
coated solid matrix-type reservoirs, and (ii) ~he finished
devi~es; î.e., on the reservoirs coated both with the re-
lease rate-~ontrolling membrane a~d with ~he protective
membrane loaded ~ith ~ portion of the active principle
20 which is desired to be immediately available.
To carry out such experirnents, a USP XXI l'paddle" appa-
rat~s was ~sed with distilled w~ter a~ 37C as ~he dis-
solution medium,
The res~lt$ were ~s ~ollows:
:~235~S4
-25-
A - Indomethacin lysinate release from the solid matrix-
-type reservoir
Time (min.) Total drug released (mg) Rate (mg/hr)
.
gO
54 54
43
120 75 37-5
B - Indomethacin lysinate release from the solid matrix-
-type reservoir coated with both the release rate-
-controlling membrane and protective membrane loaded
with a portion of the drug
Time (hours) Total drug released (m~) Rate (mg/hr)
1 14 14
2 25 12.5
lS 3 40 13.3
4 57 14.25
77 15.4
6 93 15.5
The foregoing results demonstrate that the drug
is wholly released from ~he solid matrix-type reservoir
in about 5 hours. After the release rate-controlling
membrane is applied, the release rate "ln vitro" remains
substantially constant through the sixth hour.
'~
"ERD"` TELE~ RlER ~aS;C5~ S; q:~5~r1 ; ~ f~l'51~3~i6~ 5
_ . ., _ _ . . ... .
23S~S~
-- 2~; -
"In_vlvo" expei~iments
A healthy volun teer was admi~istered ~he s~me ~device..The following plas~a levels of ac~ive prin~iple were
detected .
Time ( hours ) mcg~ml
1 . ~;
2 2.5
3.z
1 .5
012 1.1
24 0.13
`~E~ ELE~-CI~-ER ~5; 25-- 7--~5~ 17'~3~;6~; # 6
Z35~5
-- 27 --
ample 2
Preparation of t~blets of me~hisoprinol
(a) Preparation of the~ 3~ 9 reservoirs
In order ~o prepare 1,000 solid matrix-type reservoirs,
the fo~lowing amounts o~ products were used;
~e~hisoprino~ 500 9
~active principle)
cellulose aceta~e propionate25~0 g
(as in Example 1)
mannitol 10 Y
magnesi~m stearate 8.0 g
Compounding, ~ranulation and compression procedu~es
as in Example 1.
The geometrical ~eatures of the solid matrix-type res-
ervoirs thus obtained (see Fig 2) were identical to
those o~ the embodiment in Example 1, excep~ that ~he
area of the side wall was 1.32 cm , total area was
3.62 cm and the dia~eter: thickness ratio was 2.
(b) Applic~tion o~ the ~elease rate-~ontro_ling memb~ane
Solution of polymer material and application procedures
as in Example ~. The membrane thickness was 0.07 ~,
correspondin~ to 6 mg of ~o~tin~/cm2 surface area o~
solid reservoir.
~c) Application o$ the protective_membrane
~5 The s~me proçedures ~s those o~ Example 1 were followed,
?~ERCI~ TELE~ PlER 4qS: ~5- 7-~;5, '~ 61'S~S~i3~;# 7
;` ~23565~
except that no active principle was loaded i~ the
protective membrane.
Procedures and apparatus as in ~x~mple 1.
A - Methisoprinol release ~rom the solid matrix-type reservoir
Time (min.) Total drug reseased (mg ?
~25
~0 31~
~0 3~5
120 405
B - Methisoprinol release from the solid ma~ix-type reser-
voir coated with both the release rate-controlling
membrane and the protective membrane.
15Time ~hours) Total drug released ~mg~
___
1 53
115
3 173
4 223
S 273
315
7 357
.`~ERO" TELE~ 5, ~5- 7-~35, ~ 135~ ; # ;3
3S~5~
- 29 -
~ e 3
Pre~ration_o~_ta~lets o~ acetyl L-carnitine ~hlorld~
(a) Prepar~tion of the ~olid matrix-ty~_reservoirs
., _ _ . _, .,
In or~er to prepare 1,000 solid matrix~type reservoirs,
the $ollowing amounts of prod~s were used:
acetyl L-carnitine 500
(active prin~iple)
cellulose acetate propionate40 g
(as in Example 1)
mannitol 50
talc 15
magnesium stearate . 10 g
Compounding, granulation and compression procedures ~
in Example 1, except that a pressure of 4000 k~m was
1~ used.
Geometrical features of solid reservoirs (see Fi~ s
in Ex~mple 2.
(b~ Appliçati.on of the release rate-controllin~ membrane
Solution o~ polymer material and appliçatien proçedures
~0 as in Example 1. The memb~ane thi~kness w~ 0.08 m~,
corre~ponding to ~.~ mg of coa~ing/cm surf~ce area of
solid reser~oi~.
(c) Application of the _rotective membrane
The same procedures ~s those of Example 1 were followed,
~ERCI~ ~ TELE~ F l Ei~ 15, '5- 7-~;5, 9 ~ l 35~ 3~
.. . . ~
``. 123S~5
~ 30 --
except that no active principle was l~ded in the
protective membrane.
"I~ vitro" model
Procedures and apparatus as in Example 1.
A - Acetyl L-carnitine release $rom the solid matrix-type
reservoir
Time (min.) Total drug released (mg)
158
~4~
~o 335
120
B - Acetyl L-carnitine release from the solid ~at~x-type
~ese~voi~ coated with both the release rate-controlling
membrane and the protective membrane.
15Time ~hours) Total_drug released ~m~
1 60
2 135
3 ~10
4 2~0
~48
~ 411
~EF~ TELE~ i ER ~la5, -5~ S a: ~8~ 1 'S~3~i~6~
3S654
- 31 -
Example 4
Pre_aration o~ ta~lets o~ clome~a~in lysinate
(a) Prepar~tion of the solid ~trix-type reservoirs
____ ___ .
In order ~o prepare 1,000 ~olid ma~rix-type ~eservoirs,
the foll~wing amounts of products wPre used:
clo~etacin lysinate, correspondin~
to clometacin (active pri~iple) 150
disodium phosph~te 40 g
cellulose aceta~e propiona~e 10
(as in Example 1)
mannitol 20 g
t~ 9
~agne~u~ steara~e 5 g
Compounding, granula~ion and ~ompression proce~ures as
in Example 1~
Gaometrical features of solid reservoirs (see Fig 1) as
in Example 1.
(b) and (c) As in Example 1.
I'In vitro"_model
20 Procedures and appar~tus as i~ Example 1.
A - Clometacin lysinate release from the solid m~trix-type
reservoir
T me (min.) Total dru~ relea5ed ~m~)
63
bO g1
~ERCI` TELE'~P ~ ER ~5, ~ ,5. ~ M , ~ 61 35~3~i~6~
:~35~i5
-- 32 --
~0 105
120 1~
B - Clometacin lysinate from the solid m~t~ix-type ressrvoir
coated ~ith both the release rate-controlli~g ~embrane
and protective membrane loaded with a portion of the dru~
Time (hours) Total drug releas~d (mg)
1 15
2 40
61
4 78
6 11
Example 5
Preparation o$ tablets of ~rimeb~ine
-
15 (~) Prep~ration of the solid ~a~rix-~ype reservo~rs
In o~der to prepare 1,000 solid matrix-type reservoirs,
the ~ollowin~ amounts o~ products were used:
trimebutine, base 140 g
(ac~ive p~inciple)
2~ cellulose acet~te propionate 1 o 9
~as in Examp~e 1)
~nhydro~s citri~ ~cid 100
manni tol 45
talc 35 ~
25 magnesium stear~te 3 g
`iEROi; ~ELE~ IER 4q---,;25-- ,--æ~;q:5~ ; ~ 61'563~i~;6~;~1Z
S~S~
-- 33 --
~ompounding, ~ranulation and compr~s~ion p~ocedu~es as
in Example 1.
Geomet~ie~l ~ea~ures of solid reservoirs (see Fig 1) as
in example 1.
(b~ ~pplication o$ the re~ease rate~controllin~ membrane
Solution of polymer material and applicatiOn procedures
as in Example 1. ~he ~embr~ne thickness was V.05 mm,
corresponding to 5 m~ of eoa~ing/cm2 surface area of
solid reservoir.
10 ~c) Applicatlon o~__he protect've membr~ne
The same procedures as those of Example 1 were followed.
''In vi~o" model
Procedures and apparatus as in Example 1.
A - Trimebutine release from the solid m~trix-~ype reservoir.
15Time (min.) Tot~l d~ug ~eleasgd (mg)
~4
~0
120 105
20 B - Trimebutine release ~rom the solid matrix-type res~rvoir
coated with bo~h the release rate-con~rollin~ mem~rane
and protective mem~rane loaded with a portion of the
drug.
XER0.~ TELE~ RIER~5;~5- 7-135; ~:50f ~ 6135~3~ 6~;#13
^` ~i235654
-- 34 --
Time ( hl~urs ) Tota~ d ~L_eleased ( mg )
1 ~
2 30
3 50
S 4 67
~o
6 103
\~ER~ ELE~`OP!E~ 4~5; ~5~ ,5; ~: 5i~M ; ~ ~135~ ; #14
~235654
- 35 -
~ x~mpl~ 6
Pre~aration o~ tablets o~ trimebutine
Trimebut.ine tablets according to this invention were also
prepared as follows:
~a) Preparation of the solid matrix-type reservoirs
In order to prepare 1,000 solid matrix-type reservoirs,
the follvwing amounts of products were used.
trimebutine, base 135 g
ethylcell~lose 2~ 9
~nh~drous ~itri~ acid 100 g
ta~c 44 g
magnesium stearate
Trimebu~ine, cit~ic acid, talc and 18.0 g of ethylcell~-
lose we~e ~ho~o~hly ~ixe~ ~or 20 ~inutes.
1`he ~ixture was kneaded with 70 ml of a 10% ethylcellu-
lose solution in ethyl~cetate. The resulting mixture Was
granulated ~hrough a 800 ~ sieve. The gran~les were
dried, mixed wikh ma~nesium stearate a~d pressed by means
of reeessed 12 mm punches at 3,000 kg/cm . ~eometrical
features of ~he solid reser~oirs (~ee Fi~ 1l as in
Example 1~
~EF~` TELE~ '` I E~ C,~
. ... . ~
~3565
-- 36 --
(b) ~plication o~ the rele~se rate-~ontrollin~ mem~rane
This membrane was ~pplied in ~ pan ~y spr~ying a 6-~%
solution of 4:1 Eud~agit RL/Eudragit R5 in 1:1 iso-
propanol~acetone, containing 1~ by weight o~ castor
oil (22 mg o~ poly~er per reservoir were applied)
(c) ~lieation of the protec~ive me~br~ne
A 6% hydroxypropylmethylcellulose solution in isopropa-
nol-CH2C12 (corresponding to 60-70 mg o~ polymer per
reservoi~) ~a~ used. The solu~ion also ~ontained 15 ~g
o~ trimebutine per reservoir.
"In vitro" model
The procedures and the apparatus were the same as those of
Example 1.
A - Trimebutine release from the svlid m~trix-~ype reservoir
15Ti~e (~in.) T al drug release~ (mg)
~0 47
~4,&
77,0
87,8
20100 34,5
180 115
- Trim~butine release ~rom the solid matrix-type re~ervoir
coate~ with both the release rate-controlling membrane
and protecti~e membrane loaded with ~ pO~tion of the drug~
`~EF~CI:`~ TELEC:l P.ER~S5; ~ 135; S: 5~ 17563~6~; ~$16
~LZ~5654
- 37 --
Time ~hours)To~al dru~ relea
0.5 ~2-5
1 45.0
2 82.5
3 105.0
4 1~0.0
127.5
Example_
10 Pre~ara~ion of diltiazem tablets
(a) Preparation of the solid ma_rix-ty~e ~eservoirs
In or~er ~o pr~pare 1,000 solid matrix-type rese~voirs,
the following amounts o~ products ~ere us~d:
diltia~e~ HCl 120 g
(active principle)
~ellulose ace~a~e propionate 14 g
tsee Ex. 1~
mannitol 20
~ 183 g
magnesi~m stear~te 3 g
Compo~ndin~, ~ranul~ion and ~omprçssion proce~ures as
in Example 1. solid reservoirs weigh~ing ~40 mg each
were obtained; thickness 3.2-3.3 mm.
(b) and (c) Applicati~n of relea~e rate~ontrolli~ ~em~r~ne
~5 (~5 m~ o~ polymer per reservoi~) ~n~ prote~tive membrane
(no active principle loaded therein) as in Example G.
~ER~I~ TELE~ iER ~5;25~ 5, g:5S~ 1'565~:6g:#17
~ . , _ . _ . . _ . . .
~3~i659L
- 38 -
~'In vitro" model
A - ~iltiazem release from the solid matrix-type reservoir
ime tmin) Total drug released ~mg)
40.0
S 30 57.6
6g.6
~0.4
85.2
B - Diltiazem release from the solid matrix~type reservoir
10 coated wîth both the release rate-controlling membrane
and protec-tive me~br~ne.
T~e (hours~ Total drug rel~ased (mg)
0~5 14.4
1 2~.5
2 67.6
~ 8~.9
4 102.3
