CA1235654A - Delivery device for zero-order release of an active principle in a fluid phase - Google Patents

Abstract

ABSTRACT
A delivery device for zero-order release of an active principle into a dissolution fluid includes a reservoir consisting of a solid matrix of a homogeneous mixture of a polymer material, at least a portion of the active prin-ciple and an additive soluble in the dissolution fluid with negative heat of solution, a coating on the solid matrix-type reservoir of a first, release rate-controlling insoluble membrane which modulates the active principle release according to the desired kinetics; and a second, protective membrane on the release rate-con-trolling membrane of a soluble polymer material.

Description

~3S65~L

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".

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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.

:~;

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;

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).

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~35654 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.

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 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 ~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, 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 (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.

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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.

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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~

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 A - Indomethacin lysinate release from the solid matrix--type reservoir Time (min.) Total drug released (mg) Rate (mg/hr) .
gO

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)

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 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 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~
___

4 223 .`~ERO" TELE~ 5, ~5- 7-~35, ~ 135~ ; # ;3 3S~5~

~ 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) ~4~
~o 335 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~

3 ~10 4 2~0 ~48 ~ 411 ~EF~ TELE~ i ER ~la5, -5~ S a: ~8~ 1 'S~3~i~6~

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~) bO g1 ~ERCI` TELE'~P ~ ER ~5, ~ ,5. ~ M , ~ 61 35~3~i~6~

:~35~i5 ~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) 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~

~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 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 Time ( hl~urs ) Tota~ d ~L_eleased ( mg ) 1 ~

~o \~ER~ ELE~`OP!E~ 4~5; ~5~ ,5; ~: 5i~M ; ~ ~135~ ; #14 ~235654 ~ 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 (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 - 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 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

~'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

Claims (16)

WHAT IS CLAIMED IS:

1. A delivery device which in the presence of a dissolution fluid releases a biologically active principle at a substantially constant rate for an extended period of time, the device comprising (a) a reservoir comprising (i) a solid porous matrix of homogenous polymeric material which material is insoluble and unswellable in the dissolution fluid;
(ii) an additive which is soluble in the dissolution fluid and which has a negative heat of dissolution with respect to said fluid; and (iii) the biologically active ingredient, said additive and biologically active ingredient being disposed in the pores of said matrix;
(b) a first homogenous and continuous coating of a film-forming polymer on said reservoir, said polymer being insoluble in said dissolution fluid with said coating being permeable to both said fluid and to a solution of said active ingredient in said fluid, the thickness of said first coating being such as to comply substantially with the relationship:

in which D is the diffusion constant across said first cotaing;
S is the surface area of said first coating;
Cs is the saturation constant of the active principle in the dissolution fluid; and R is the release rate; and (c) a second homogenous and continuous coating of a a film-forming polymer material which is soluble in the dissolution fluid disposed over said first coating.

2. A device according to claim 1 wherein said reservoir includes a buffer.

3. A device according to claim 2 wherein said buffer constitutes up to about 30% by weight of said matrix.

4. A device according to claim 1 wherein said biologically active principle is present in an amount from about 30 to about 90% of the weight of said reservoir.

5. A device according to claim 1 wherein said additive which is soluble in the dissolution fluid with a negative heat of solution is present in an amount of from about 5 to about 50% of the weight of said reservoir.

6. A device according to claim 5 wherein said additive is a polyol or an acid.

7. A device according to claim 6 wherein said additive is mannitol, dextrose, sorbitol, or xylitol.

8. A device according to claim 1 wherein said matrix constitutes from about 3 to about 20% of said reservoir.

9. A device according to claim 8 wherein the polymeric material of said matrix is cellulose acetate, high viscosity hydroxypropylmethyl cellulose, cellulose acetate propionate, ethyl cellulose, or polymethacrylate.

10. A device according to claim 1 wherein said first homogenous and continuous coating is a vinyl polymer or co-polymer, cellulose, cellulose acetate, hydroxypropylmethyl cellulose, cellulose acetate propionate, ethyl cellulose, an acrylic polymer, or an acrylic co-polmer.

11. A device according to claim 1 wherein said second coating is low viscosity hydroxypropylmethyl cellulose.

12. A device according to claim 1 wherein additional active principle is present in said second polymeric coating.

13. A device according to claim 1 wherein a plasticizer is present is said first coating.

14. A device according to claim 1 wherein said biological-ly active principle is an orally adminsterable drug.

15. A device according to claim 14 wherein the outer sur-face of said reservoir is a biconvex discoid defined by the circular intersection of two opposed spherical segments, the discoid having diameter from 6 to 16 mm, the bending radius of the spherical segments of the bi-convex discoid being comprised between 10 and 18 mm, the diameter:thickness ratio of the biconvex discoid being comrpised between 2 and 5.

16. A device according to claim 14 wherein said reservoir de-fines an intermediate cylindrical wall segment and two opposed spherical end segments intersecting said cylin-drical wall segment.